The microbiota–gut–brain axis in mental and neurodegenerative disorders: opportunities for prevention and intervention

AD is a progressive loss of memory, cognitive capabilities, speech, executive abilities, and language (). There are also changes in personality and behavior with the disease. AD decreases life span; the median survival rate of a person with AD is 5–9.3 years (;). Many common neuropathological factors are linked with progressive AD. Neurofibrillary tangles are pathological, entangled structures in the cytoplasm of neuron cell bodies, dendrites, and axons (). Neuritic plaques are microscopic lesions in dendrites and terminal portions of axons. Neuritic plaques are also called senile plaques. Granulovacuolar degeneration (GVD) is a state where cells create microscopic vacuoles with granulated protoplasm (). GVD lesions, found in regions such as the neocortex and amygdala, align with areas involved in stress and sleep regulation (). In AD, GVD increases with disease severity, correlating with neurofibrillary lesions and memory decline, similar to β-amyloid plaques and tangles. However, the exact mechanism and the connection to Tau remain unclear (). Reduced dendritic connections hinder neuron impulse transmission. Dopamine and cholinergic neurotransmitter deficiencies are common with all types of AD. Both white and gray matter are lost, best observed in the frontal and temporal lobes of the brain (;). Increased ventricles and sulcal dilatation are a consequence of neuron degeneration within the brain. Reduced cerebral metabolism is a sign of pathological changes at the neuronal level (). When neurofibrillary tangles, neuritic plaques, and other injury occur in neurons within the brain, metabolic function is reduced (). Numerous clinical trials focusing on amyloid-beta (Aβ) and Tau proteins of AD within recent decades have been ineffective (). Existing drugs achieve little cognitive improvement and cannot halt disease progression (). Because of the enigma of AD molecular mechanisms, there is an urgent need for alternative therapies acting on multiple biological pathways (). [Bayles et al., 2018] [Hegde et al., 2022] [Kao et al., 2018] [Metaxas and Kempf, 2016] [Funk et al., 2011] [Thal et al., 2011] [Funk et al., 2011] [Hegde et al., 2022] [Kao et al., 2018] [Wang Z. et al., 2025] [Wang Z. et al., 2025] [Asher and Priefer, 2022] [Bazzari et al., 2019] [Wu et al., 2024]

Amyloid plaques arise from the aggregation of Aβ peptides, particularly Aβ4, which is harmful due to its tendency to form plaques and resist dissolving (). The peptides are generated when the amyloid precursor protein (APP) is cleaved by BACE1 and γ-secretase (). The amyloid cascade hypothesis, which came into being as a result of the work of Hardy and Higgins in 1992, has almost since then been the dominant purview in the field of AD. According to the hypothesis, accumulation of Aβ resulting from APP triggers tau hyperphosphorylation and consequent neurodegeneration (). Tau, which is normally a microtubule-stabilizing protein, becomes pathogenic after being hyperphosphorylated, thereby compromising neuronal transport systems. The hypothesis has expanded to include vascular dysfunction, oxidative stress, microglial activation, and impaired proteolysis (). Nevertheless, one singular hypothesis cannot fully justify the complex etiology or mechanisms underlying AD (). Toxic Aβ oligomers activate microglia and encourage the release of pro-inflammatory cytokines (). Moreover, the deposit of Aβ in the vascular system may lead to the development of cerebral amyloid angiopathy, which is frequently observed in AD and involves cerebrovascular pathology (). 2 [Jarrett et al., 1993] [Ashe, 2020] [Ma et al., 2022] [Roda et al., 2022] [Joe and Ringman, 2019] [De Felice et al., 2022] [Glenner and Wong, 1984]

Insulin, a hormone produced by the pancreas β-cells, regulates glucose metabolism. When the body's tissues become less responsive to insulin, a condition known as insulin resistance, it increases the risk of type 2 diabetes mellitus (T2DM), metabolic syndrome, fatty liver disease, and atherosclerosis (;). Aging often worsens this resistance through chronic high insulin levels. Emerging research links insulin resistance to AD; for instance, diabetic rats induced with streptozotocin show AD-like brain changes, including Aβ and neuroinflammation (). While the exact connection between AD and T2DM remains unclear, insulin resistance contributes to cognitive decline. Enhancing insulin signaling in the hippocampus has shown promise in improving memory and cognition in AD models (). Tau hyperphosphorylation and Aβ accumulation are promoted by microglial and astrocytic actions. Aβ deposits give rise to microglia-mediated neuroinflammation (). While the BBB tries to limit systemic inflammation, it can be compromised by cytokines such as tumor necrosis factor (TNF-α) and IL-1β. Sustained glial activation drives neuroinflammation in a vicious cycle via reactive oxygen species (ROS), cytokines, and chemokines (). Astrocytes, key modulators of neuroinflammation, congregate around Aβ plaques, as described in both human and mouse models. They affect amyloidosis through their role in the synthesis and disposal of Aβ, as well as through interactions with other CNS cells (). In reaction to AD, astrocytes experience a shift in profile, one that is reactive and pro-inflammatory while losing homeostatic roles thus disrupting BBB integrity, ion and neurotransmitter buffering, and energy metabolism (;). Reactive astrocytes also release neurotoxic saturated lipids through the APOJ and the C3 complement component, thus affecting neuronal network activity via C3aR signaling (;). Importantly, as the chief brain source of APOE, astrocytes, especially those expressing the APOE4 allele, promote Aβ aggregation, tau pathologies, BBB breakdown, and cerebrovascular dysfunctions (). [Arnold et al., 2018] [Lee et al., 2022] [Clark et al., 2012] [Biessels and Reagan, 2015] [Thakur et al., 2023] [Thakur et al., 2023] [Frost and Li, 2017] [Liddelow et al., 2017] [Escartin et al., 2021] [Lian et al., 2015] [Liddelow et al., 2017] [Wang M. et al., 2021]

There are still important questions concerning the role of the gut microbiome in astrocyte function in AD that have yet to be studied. Of interest are which species of microbes mediate MGBA-astrocyte signaling; which astrocytic molecular pathways are modulated by the MGBA; how the MGBA-regulated astrocytic pathways contribute to AD pathology; and whether the MGBA-astrocyte could be therapeutically targeted for our benefit. On the immune front, gut microbiota can increase systemic inflammation by releasing lipopolysaccharides (LPS) and proinflammatory cytokines, and they also produce amyloids, which may stimulate neural amyloid production via immune priming. Recognition of bacterial amyloids by toll-like receptor-2 (TLR2) activates immune cells, escalating inflammation (). In the gut, T cells maintain immune balance, differentiating into proinflammatory (Th1, Th17) or anti-inflammatory [Th2, regulatory T cells (Tregs)] subsets (). [Mulak, 2021] [Dressman and Elyaman, 2022]

AD, based on emerging research over the past two decades, may be associated with chronic stress, where prolonged exposure to adverse life events (such as MDD and anxiety) increases the risk of developing the disease (). The HPA axis plays a key role in this connection; it is the central component that regulates the stress response by stimulating the release of glucocorticoids from the adrenal cortex (). Elevated glucocorticoid levels, along with decreased glucocorticoid receptor (GR) function in early AD, are linked to Aβ production and abnormal tau phosphorylation (). Additionally, GR dysregulation impacts dyslipidemia and insulin resistance. Therefore, chronic stress-induced dysregulation of the HPA axis, potentially mediated by imbalances in gut microbiota, might be a crucial link between dysbiosis and the progression of AD (). [Huang et al., 2024] [Mulak, 2021] [Canet et al., 2019] Figure 1

A potential therapeutic approach for AD consists of the BAs, which are produced in the liver (). Although their largest involvement is in nutrient and metabolic regulation, around 10% of them might cross the BBB, as shown in animal studies with mechanistic details (). A comparison of 119 patients suffering from AD with 267 controls found that alterations in serum BAs correlate with cerebrospinal fluid (CSF) Aβ1–42, tau, and p-tau. Higher concentrations of glycochenodeoxycholic acid, glycodeoxycholic acid, hyodeoxycholic acid, and certain bile acid ratios were associated with patient CSF tau and p-tau. Higher hyodeoxycholic acid and certain ratios were associated with lower CSF Aβ1–42. While these associations suggest a link between serum bile acids and AD pathology, a causal relationship has yet to be established (). BAs act in the brain by interacting with key receptors on neurons and glial cells-Farnesoid X receptor (FXR), Takeda G protein receptor 5 (TGR5), GR, and sphingosine-1-phosphate receptor 2 (S1PR2;;). BAs may modulate gut microbiota through antimicrobial properties, with deconjugated BAs produced by bacterial bile salt hydrolases being much less toxic to gut bacteria. In animal models of neurodegenerative disease, activation of TGR5 receptor was neuroprotective, decreasing neuronal death and inflammatory response (). S1PR2, located both in the liver and in the brain, activates the ERK and AKT pathways that regulate cell survival, inflammation, and stress response in the CNS. In the liver, S1PR2 activates pro-insulin signaling through enhancing insulin-degrading enzyme (IDE), thereby potentially alleviating insulin resistance associated with T2DM and AD based on animal mechanistic studies (;). Beyond directly influencing pathological changes in the AD brain, BAs may provide neuroprotective benefits by modulating the microbiota–gut–brain (MGB) axis, which supports memory function. GM also regulates BA synthesis; both antibiotic use and germ-free conditions suppress the expression of CYP7A1 and CYP27A1, key enzymes involved in BA production based on animal mechanistic studies (). Deconjugated BAs, which are less toxic to gut microbes, are reduced in AD, likely due to decreased BSH-secreting bacteria likeand, as observed in human associative studies (). While these findings support the hypothesis that restoring BA–microbiota interactions could influence AD symptoms, causal evidence in humans remains limited and warrants further investigation. Studies consistently show altered MGBA composition in AD patients, suggesting a possible role in disease onset and progression, as shown in. Confounding variables, such as diet and environmental exposures, complicate comparisons. [Grant and DeMorrow, 2020] [Monteiro-Cardoso et al., 2021] [Nabizadeh et al., 2024] [Kiriyama and Nochi, 2019] Figure 2 [Monteiro-Cardoso et al., 2021] [Vettorazzi et al., 2017] [Zangerolamo et al., 2022] [Chiang and Ferrell, 2019] [Mulak, 2021] Table 1 Clostridium Bifidobacterium

PD is the second-most common neurodegenerative disorder after AD. It acts from a lack of equilibrium between two neurotransmitters in the basal ganglia: dopamine (inhibitory) and acetylcholine (excitatory). In typical basal ganglia function, the actions of these neurotransmitters counterbalance each other to refine voluntary movement; however, in PD, the neurons producing dopamine slowly die out, causing an excess of acetylcholine to overstimulate the basal ganglia (). This leads to the major motor symptoms of tremor, bradykinesia, and rigidity, along with postural difficulties, which are classical for PD (). Affected individuals may show other non-motor symptoms, with some being GI-oriented and emerging years before the classical motor features (). Cognitive manifestations include depression, irritability, and anxiety, while GI manifestations encompass constipation, dysphagia, nausea, and prolonged intestinal transit time (;). Most non-motor symptoms go unrecognized when this neurodegenerative disease begins in his prodromal form. Diagnosis and treatment usually begin after the disease shows motor symptoms. It has a complicated pathogenesis associated with environmental modifications, genetic predispositions, deregulated dopamine metabolism, neuroinflammation, oxidative stress, and mitochondrial dysfunction (;). However, the leading theory behind PD pathogenesis is the accumulation of alpha-synuclein aggregates within cells, which trigger neuroinflammation and neuronal apoptosis (). Gut findings of alpha-synuclein abnormalities in early-stage PD are documented in patients having PD. Imaging studies further corroborate that PD may arise from the gut and subsequently spread into the brain (,). Through the spinal cord, the brain communicates with all other body systems, including the endocrine system, which regulates body functions such as stress and mood via hormone secretion, and the immune system, which defends the body from pathogenic infection and promotes healing. These systems share signals through the vagus nerve, which carries information from the body's organs to the brain regions (;;). Some epidemiological studies carried out in Denmark and Sweden have indicated that people who had undergone complete truncal vagotomies decades ago had a lower risk of developing PD later in life (;). This points to the possibility of some disturbances in gut microbial position, thereby predisposing to PD. [Wang Q. et al., 2021] [Obeso et al., 2017] [Cersosimo et al., 2013] [Pfeiffer, 2003] [Li et al., 2023] [Gökçe Çokal et al., 2017] [Wang T. et al., 2020] [Kim et al., 2019] [Horsager et al., 2021] ²⁰²² [Jackson et al., 2019] [Li et al., 2023] Figure 3 [Svensson et al., 2015] [Liu et al., 2017]

The vagus nerve is the tenth cranial nerve. It has been so named from the Latin word meaning "wandering," because it wanders widely through the body. It originates from either side of the medulla oblongata, exits through the jugular foramen, and descends the neck, chest, and abdomen (). Along the way, the vagus nerve sends off branches to innervate and regulate almost all the visceral organs. Functionally, it is vital for the control of immune responses via neural signaling. Containing both motor and sensory fibers, the vagus nerve is also the main afferent pathway from the abdominal organs, lungs, liver, stomach, pancreas, and intestines to the brain. Sensory information from the abdominal organs traverses the vagus nerve to the nucleus of the solitary tract in the brainstem, with projections to several other areas of the CNS, including the cerebral cortex and medulla oblongata (). At present, vagotomy is considered only for those patients who are resistant to pharmacological treatment or who are severely ill with complications, such as perforations or gastric outlet obstruction. In the past, it has also been employed in the treatment of biliary dyskinesia and chronic abdominal pain in neurological conditions (;). [Liu and Forsythe, 2021] [Liu and Forsythe, 2021] [Crile, 1951] [Liu and Forsythe, 2021]

In PD, the spread of the pathological alpha-synuclein from the gut to the brain is mediated along the vagus nerve. There are two major forms of vagotomy: truncal vagotomy, which severs all connections, and selective vagotomy, which maintains intestinal innervation (). Studies have noted that vagotomy can inhibit the misfolding of alpha-synuclein in enteric neurons and reduce the appearance of PD symptoms in animal models (;). [Wang Q. et al., 2021] [Uemura et al., 2018] [Kim et al., 2019]

The total vagotomy can be beneficial in reducing the chances of developing secondary PD, according to a cohort study done in Denmark (). On the other hand, there is a separate study in Sweden that has followed patients after vagotomy and pointed out no relation between vagotomy and PD risk (). However, 5 years of follow-up indicated that within that period, after vagotomy, there is a reduced risk of PD, and very similar results were obtained in the 10-year follow-up. These findings provoke interesting primary questions as to the possible origins of PD-associated alpha-synuclein misfolding from within autonomic nerve fibers of the gut. [Svensson et al., 2015] [Liu et al., 2017]

Selective or highly selective vagotomy may permit α-synuclein pathology from elsewhere in the GI tract to still reach the vagus nerve and, thereafter, the brainstem. Vagotomy in animal studies is said to disrupt the transfer of α-synuclein derived from the gut to the CNS, but human observational evidence is inconsistent, with some studies indicating no change in PD incidence and others suggesting a reduced risk following truncal vagotomy (). Currently, there is too immature an understanding of PD pathophysiology to make vagotomy a potential treatment method, and clarification through research is needed regarding the vagotomy-PD relationship. Therefore, no clinical role for vagotomy exists at present. [Elfil et al., 2020]

The composition of gut microbiota might vary whether PD has an early or late onset. In a study, Pasteurellaceae, Alcaligenaceae, and Fusobacteria were more common in early prodromal PD stages vs.and, which were commonly detected in late-onset PD cases (). Some gut pathogens, such as, and, have been associated with motor complications in PD (). Comamonas Anaerotruncus Aquabacterium, Peptococcus Sphingomonas [Lin et al., 2018] [Qian et al., 2018]

examined the impact of PD medications (levodopa and entacapone) on gut microbiota, finding marked changes in, and. For other drugs such as MAO inhibitors, amantadine, and dopamine agonists, no indication was found for an effect on taxa abundance or microbial functions ().reported lowergroup IV in PD as well as no strongly associated taxa with levodopa (L-DOPA) use, although preliminary data suggestcluster IV may be linked to short-term motor-symptom response to L-DOPA, which deserves a thorough controlled validation. Other studies have shown that the other PD drugs acted independently to shape different microbial profiles, which strengthens the rationale for disentangling drug effects from disease signatures (). [Weis et al. (2019)] [Horsager et al., 2020] [Palacios et al. (2021)] [Hashish and Salama, 2023] Peptoniphilus, Finegoldia, Faecalibacterium, Fusicatenibacter, Anaerococcus, Bifidobacterium, Enterococcus Ruminococcus Clostridium Clostridium

distinguished PD patients who are stable and those with rapid progression, with inconsistent taxa throughout methods and times but uniquely exiting enterotypes, accompanied by a decline infor the rapid-progression cases. Group differences between PD and controls stayed after the removal of confounds such as deep-brain stimulation (DBS), but differed across studies. In general, replications of the PD-microbiome instances are often poorly developed, presumably as a result of confounding by usage of medication, geographical differences, sequencing methods, and analytical pipelines. Nevertheless, some microbial changes were reported consistently: decrease in Prevotellaceae,, and(;;), and increase in/Verrucomicrobiaceae (;;). [Aho et al. (2019)] [Scheperjans et al., 2015] [Unger et al., 2016] [Hopfner et al., 2017] [Keshavarzian et al., 2015] [Heintz-Buschart et al., 2018] [Lin et al., 2018] Prevotella Prevotella P. copri Akkermansia

The most important GI symptom is constipation, which impacts almost 60% of people suffering with PD (). Research indicates that the severity of PD-related constipation helps diagnose the PD stage, with 67% sensitivity and 90% specificity (). References state that the dysbiosis is likely to be responsible for early stage PD GI-related problems, including constipation, with a notable increase in bacterial families that include Lactobacillaceae, Verrucomicrobiaceae, Bradyrhizobiaceae,, and(;). Among these groups, through greater severity of constipation, longer transit times, and harder stool,has been related to constipation (;). Patients suffering from PD and characterized by slowed transit of the intestine may consequently need to receive higher amounts of L-DOPA (;). Such patients lack in terms of absorption of medicines, thus translating into efficacy problems because of the delays in transit. Constipation may also predispose bacteria to reach excessive populations, particularlyspecies that can execute tyrosine decarboxylation, L-DOPA by converting it into dopamine in the gut hence limiting its release into the bloodstream and causing motor fluctuations (). More doses of L-DOPA combined with decarboxylase inhibitors have to be repeated under this scenario, thus denoting a complicated interaction of PD medications with GI tract-related symptoms. [Pavan et al., 2022] [Hashish and Salama, 2023] [Baldini et al., 2020] [Hashish and Salama, 2023] [Lubomski et al., 2022b] [Hashish and Salama, 2023] [Fasano et al., 2013] [Weis et al., 2019] [Menozzi and Schapira, 2024] Bifidobacterium Akkermansia Akkermansia Lactobacillus

Most people who suffer from PD, may have experienced either the condition of small intestinal bacterial overgrowth (SIBO) or colonization by(;;). SIBO could lead to symptoms like bloating, excessive gas, or impaired absorption of nutrients. A relationship between PD and SIBO was first established in 2021 by the symptom of constipation, indicating that aggravation in the severity of constipation might correlate with an increased risk for SIBO (.,). Relief from SIBO not only alleviates the GI discomfort, but it also helps in the amelioration of the motor fluctuations experienced by PD patients (;). Patients with PD and comorbid SIBO—as opposed to those without it—showed more severe dyskinesia which included prolonged rest time, delayed on-time and off-time. Another proof of this was that motor fluctuations in PD patients improved after SIBO eradication, hence providing more support of the association between SIBO and motor fluctuations (). Interestingly, studies show multiple symptoms of PD improve withantibiotic therapy due to increased absorption and bioavailability of L-DOPA (). A trial, double-blind, placebo-controlled study pronounced that motor symptoms do improve from hypokinesia over the year since the eradication ofbut worsen from flexor rigidity (). Although the mechanisms remain unknown, researchers present their theory claiming that the thickening rigidity coexists with SIBO because of overgrowth by certain bacterial strains already present (). The increasing evidence that altered gut microbiota correlate with non-motor features of PD rests on the premise of the need for more evidence to be generated for possible therapeutic strategies to be unveiled. Helicobacter pylori H. pylori H. pylori H. pylori [Gabrielli et al., 2011] [Felice et al., 2016] [Dănău et al] ²⁰²¹ [Gabrielli et al., 2011] [Fasano et al., 2013] [Lubomski et al., 2020] [Pierantozzi et al., 2001] [Dobbs et al., 2010] [Felice et al., 2016]

Evidence consistently points toward the role of gut microbiota in the persistent interaction upon L-DOPA treatment response. It has been seen that the efficacy of L-DOPA in antibiotic therapy was improved as gut microorganism influences drug metabolism and action (;;). As one of the most important dopamine-replacement therapies for PD, L-DOPA is commonly given with carbidopa to improve bioavailability and avoid early conversion into dopamine before penetration into the brain (). Thus, an increasing amount of evidence suggested that the gut microbiome has taken a rather complex interest in influencing the response of the body to L-DOPA treatment. Such studies have shown that antibiotic administration might increase the effectiveness of L-DOPA therapy, indicating that gut microorganisms affect metabolism and the effectiveness of the drug (). Another important fact is that this L-DOPA is co-administered with carbidopa, another important dopamine-replacement therapy for PD, aiming to increase the bioavailability of the substance and prevent early conversion into dopamine prior to entering the brain (). [Hashim et al., 2014] [Hashish and Salama, 2023] [Hey et al., 2023] [Gandhi and Saadabadi, 2025] [Hashim et al., 2014] [Gandhi and Saadabadi, 2025]

The research bylooked at how the administration of levodopa-carbidopa intestinal gel (LCIG) has effects on the gut microbiome in PD. The LCIG treatment involves a continuous infusion of a carboxymethylcellulose aqueous gel directly into the proximal jejunum via a percutaneous gastrojejunostomy tube, with delivery by a portable infusion pump (). When assessing alpha diversity (the diversity and evenness of microbial species within a single sample, representative of microbial richness and community balance), they found no marked changes attributable to LCIG. The LCIG application caused changes in the beta diversity (which assesses the differences in microbial community composition between samples, indicating how similar or dissimilar microbial communities are across individuals or time points). Changes in beta diversity reveal that while overall species richness and evenness among the individuals were stable, LCIG can redistribute the abundance of different taxa, thereby altering cohabitation structure and interrelations among microbial species. This pattern holds biological significance in PD in that it suggests that disease- or treatment-related effects may exert selective pressure on the microbial network in the gut without necessarily lowering the overall number of microbial species present, thereby exerting an influence on GBA signaling and L-DOPA metabolism. The acidic condition of LCIG may alter the chemical situation in the gut, which, finally, leads to hypergrowth of, being acid-tolerant bacteria (). This observation of microbial shift may contribute to the excessive gut inflammation. Research is scarce on the effect of LCIG on the gut microbiota in PD individuals, and more studies are needed to substantiate findings on gut homeostasis. [Lubomski et al. (2022b)] [Olanow et al., 2014] [Lubomski et al., 2022b] Escherichia/shigella

Previously reported changes in the abundance of this family Prevotellaceae in advanced PD seem to have been expanded upon by Bedarf and associates, who have shown a dramatic decrease in the numbers ofin patients with early-stage PD (). Since these species ofproduce SCFAs like butyrate, their decrease may affect intestinal barrier function and immune health and thus be involved in the pathogenesis of PD (). Notably, neither MAO inhibitors nor dopamine agonists appear to affect the composition and function of gut microbiota (). However, emerging data suggest that different PD therapies exert differential effects on gut microbiota, as shown in. Since PD patients are frequently on multiple therapies, it will be important for future studies to determine the independent effect of these therapies on the gut microbiome and their potential roles in the progression and management of the disease. Prevotella copri Prevotella [Bedarf et al., 2017] [Hey et al., 2023] [Bedarf et al., 2017] Table 4

ALS is a serious and progressive disease that damages both the upper and lower motor neurons, which are the nerve cells that control voluntary muscle movement. It usually begins between the ages of 50 and 70 and is slightly more common in men than women, with a male-to-female ratio of about 1.5–1 (). Worldwide, ALS affects about 1–2.6 people out of every 100,000 each year, and at any given time, around 4–8 out of every 100,000 people, especially those of Caucasian descent are living with the disease (;). Roughly 90% of ALS cases happen without a family history (sporadic ALS), while the remaining 10% are inherited (familial ALS). More than 50 genes have been linked to ALS, with the most common being C9ORF72, which causes up to 50% of inherited cases and 5–10% of sporadic ones. Other key genes include SOD1, TARDBP (which codes for TDP-43), and FUS (). Interestingly, ALS and frontotemporal dementia (FTD) are closely related conditions and often share both genetic and disease mechanisms, especially in people with C9ORF72 mutations suggesting they may be part of the same disease spectrum (). In addition to genetics, certain environmental exposures may increase the risk of developing ALS. These include smoking, military service, pesticide exposure, and heavy metals, with smoking raising the risk by about 40% (). [Chiò et al., 2013] [Al-Chalabi and Hardiman, 2013] [Chiò et al., 2013] [Renton et al., 2011] [Parobkova and Matej, 2021] [Al-Chalabi and Hardiman, 2013]

ALS can look very different from person to person in how it begins and how quickly it progresses. In about 70% of people, the first symptoms appear in the limbs usually starting with hand weakness (60%) or leg weakness (40%). Around 30% of patients start with bulbar symptoms, which affect the muscles used for speaking and swallowing, leading to problems like slurred speech (dysarthria), trouble swallowing (dysphagia), and twitching of the tongue muscles (). A small number (less than 5%) have respiratory-onset ALS, where breathing muscles weaken early, and these cases tend to be more severe. [Chiò et al., 2013]

The disease usually begins in one part of the body and spreads gradually, leading to increasing muscle weakness. On average, there's a delay of 10–16 months between the first symptoms and the official diagnosis (). Once diagnosed, median survival is between 2 and 5 years, although patients with bulbar-onset ALS tend to decline more quickly. [van den Bos et al., 2019]

ALS is mostly diagnosed based on clinical signs, using the revised El Escorial criteria, which require signs of both upper motor neuron (e.g., spasticity, brisk reflexes) and lower motor neuron damage (e.g., muscle wasting, twitching) in multiple body regions (). Electromyography (EMG) tests are crucial to show nerve damage and muscle denervation, while nerve conduction studies are used to rule out other diseases. MRI scans are also done to make sure there isn't another condition, such as a structural issue in the brain or spine (). Despite all this, about 10–15% of ALS cases are initially misdiagnosed. Conditions that are often mistaken for ALS include multifocal motor neuropathy, cervical spine disorders, and inclusion body myositis (). [Brotman et al., 2025] [Kwan and Vullaganti, 2022] [Kwan and Vullaganti, 2022]

The development of ALS is driven by several overlapping biological mechanisms that together cause motor neuron degeneration. One key process is glutamate excitotoxicity, where a buildup of glutamate at the synapse due to reduced function of the transporter EAAT2 (also known as GLT-1) leads to overstimulation of N-methyl-D-aspartate (NMDA) receptors. This causes excessive calcium to enter neurons, damaging mitochondria and triggering cell death (). Another central feature is the loss of protein balance, especially involving TDP-43, a protein that is abnormally located in the cytoplasm instead of the nucleus in about 97% of ALS cases. In this mislocated state, TDP-43 forms toxic clumps that interfere with RNA processing and disrupt essential cellular functions (). In patients with mutations in the C9ORF72 gene, the production of harmful dipeptide repeat proteins further disrupts communication between the nucleus and cytoplasm, impairing cell function. Neuroinflammation also plays a major role, with microglial cells releasing inflammatory molecules such as TNF-α, IL-6, and IL-1β, along with ROS, all of which intensify neuronal damage (). In addition, astrocytes, which normally support neurons, become dysfunctional through a process called astrogliosis, which worsens glutamate imbalance and reduces neuronal support (). Other contributors include faulty axonal transport, resulting in buildup of neurofilaments and synaptic breakdown (), and genetic mutations—such as SOD1 (causing harmful protein accumulation), FUS (interfering with RNA handling), and TBK1 or OPTN (which impair the cell's waste disposal system known as autophagy;;). Together, these processes create a toxic environment that progressively destroys motor neurons in ALS. [Arnold et al., 2024] [Prasad et al., 2019] [Liu and Wang, 2017] [Boillée et al., 2006] [Taylor et al., 2016] [Goutman et al., 2022] Figure 4

Recent studies have shown that the gut microbiome, the community of bacteria living in our digestive system may play an important role in the development and progression of ALS. People with ALS often have an imbalance in their gut bacteria, known as dysbiosis, with fewer helpful bacteria likeprausnitzii and Bifidobacterium, and more potentially harmful ones such asand Dorea species (). This imbalance may speed up the disease in several ways. For example, reduced levels of SCFAs (like butyrate, which is normally made by good bacteria) can weaken the BBB, making the brain more vulnerable to harmful substances. At the same time, increased levels of inflammatory molecules, such as LPS from harmful bacteria, can lead to systemic-wide inflammation (). The gut microbiome also affects the immune system, with ALS patients showing increased Th17 immune cells and higher levels of IL-17, an inflammatory cytokine that may worsen the disease (). Together, these findings support a strong connection between gut health and brain health in ALS. Faecalibacterium E. coli [Brenner et al., 2018] [Obrenovich et al., 2020] [Zang et al., 2023]

MS is an autoimmune disease of the CNS, whose hallmark is the demyelination and consequent damage to the demyelinated axons. Demyelination causes a multitude of neurological symptoms, including loss of coordination of movement, ataxia, visual impairments, psychiatric abnormalities such as depression, and cognitive decline (). MS likely results from a combination of genetic and environmental factors (). It is normally diagnosed based on clinical symptomatology complemented by MRI with lesions of various stages, combined with biomarkers of immunologic activity in CSF, namely oligoclonal bands and elevated IgG index (). The experimental autoimmune encephalomyelitis (EAE) animal model of MS has proven the pathogenic function of myelin-reactive T cells in MS pathogenesis (). The triggers of activating self-reactive clones are still to be determined, but may be common infections, molecular mimicry, or inflammation signals from gut microbiota (). Histological evidence has shown that the activated T cells cross the BBB, invade the CNS, and congregate around small venules to trigger localized inflammation (). Over the decades, the EAE model, focused primarily on T cells, has been the model for MS pathogenesis and treatment studies (). Current treatments are largely the primary application of disease-modifying treatments, immunosuppressants, immunomodulators, and immune-reconstitution therapies, in addition to symptomatic treatments such as anticholinergics for urinary incontinence and pain medication for neuropathic pain (). Patient-dependent conditions affecting the effectiveness of treatment or, quite possibly, affecting outcomes through the gut microbiota, however, are still to be established. [Preiningerova et al., 2022] [Preiningerova et al., 2022] [Thompson et al., 2018] [Laaker et al., 2021] [Westall, 2006] [Kuhlmann et al., 2017] [Preiningerova et al., 2022] [Dobson and Giovannoni, 2019]

In patients with MS, it was found that the composition of their microbiota was relatively reduced from that of healthy individuals. Studies are not entirely consistent, but they mostly report an increase in Akkermansiaceae and Methanobacteriaceae, and a decrease in SCFA-producing Bacteroidetes and Clostridia clusters (;;). While EAE models have offered valuable insight into adaptive immune responses, demyelination, and axonal damage in MS, they fall short in replicating the full spectrum of human MS pathology, particularly the disease's onset and heterogeneity (). [Atarashi et al., 2011] [Palm et al., 2015] [Wang et al., 2019] Figure 5

GI symptoms, including anorectal dysfunction such as constipation and fecal incontinence, are commonly reported in MS, affecting approximately 40% of patients (). Additionally,have even reported familial clustering of Inflammatory Bowel Disease (IBD) and MS, suggesting that they have genetic or environmental risk factors in common. In the past few years, several studies have explored the differences in fecal gut microbiota between MS patients and healthy controls, revealing that gut microbial dysbiosis with both depletion and enrichment of certain gut microbiota in MS patients, as shown in. For example,reported increased levels of, and, and reductions in, andin RRMS patients. Whether these changes are a cause or a consequence of the disease remains unclear. Increased levels ofandare increased, whereas those ofdecreased in RRMS patients (). [Nusrat et al., 2012] [Minuk and Lewkonia (1986)] Table 6 [Chen et al. (2016)] [Jangi et al., 2016] Pseudomonas, Mycoplasma, Haemophilus, Blautia Dorea ParaBacteroides, Adlercreutzia Prevotella Methanobrevibacter Akkermansia Butyricimonas

In addition, differences in corresponding changes in expression levels of genes associated with dendritic cell maturation, interferon signaling, and NF-κB signaling pathways in circulating T cells and monocytes have been noted (). The relation between the variation in gut microbiota diversity and relapse risk in children with MS was found with testing by; thus, the depletion ofcorrelated with the relapse risk of pediatric MS. Nevertheless, all those discoveries were performed on gut microbiota obtained from stool samples of MS patients in remission. A recent study has been done on changes in microbiota within small intestinal tissues from MS patients in the active phase. The authors reported an increased Firmicutes/Bacteroidetes ratio andabundance, with a reduction instrains in patients with active MS when compared with healthy controls and patients with MS in remission (). Moreover, the relative presence ofstrains was inversely associated with Th17 cells in the small intestine, while positively related to disease activity (). Although changes in gut microbiota have been reported, it remains uncertain whether these changes are a cause or a consequence of the disease. [Jangi et al., 2016] [Tremlett et al. (2016)] [Cosorich et al., 2017] [Cosorich et al., 2017] Fusobacteria Streptococcus Prevotella Prevotella

MDD is characterized by constant depressed mood, anhedonia, altered sleep and appetite, fatigue, guilt, hopelessness, and suicidal tendencies (). Over the years, a rising trend has been seen in the prevalence of depression since the time of observation (). In 2018, MDD disease burden ranked third in the world according to the WHO, and by 2030, it is supposed to rise to the first (). A psychiatric disorder is formed due to the complex interplay of environmental factors and genetic vulnerability (). The risks of developing several physical comorbidities like cardiovascular diseases, stroke, diabetes, and obesity along with social stigma are quite higher for MDD persons (). Some of these revolve around education, work, and relationships (). In case antidepressants are used in conjunction with psychotherapy, some patients can get better. Unfortunately, not all respond to treatment. As many as 30–50% of depressed patients respond only partially to antidepressants, leaving them with substantial residual symptoms (). Additionally, 10–30% of patients of those who are resistant to the effects of antidepressants and thus non-responders to treatment. Differences in treatment response may be indicative of differences in etiologies and mechanisms, like neuroinflammation, changes in the neuroendocrine system, or alterations in the gut microbiome (). This greatly simplifies a complex process, but a map of the human microbiome may offer new opportunities for tracking therapeutic responses in depression. [Arnaud et al., 2022] [Cui et al., 2024] [Malhi and Mann, 2018] [Souza et al., 2023] [Penninx et al., 2013] [Campbell et al., 2022] [Davis et al., 2021] [Mousten et al., 2022]

Another study showed that both psychosocial as well as physical stressors influence the body's response through the HPA axis (). The HPA axis initiates a response in times of stress, stopping the activity through negative feedback, engaging the hippocampus and the paraventricular nucleus of the hypothalamus. A properly perceived stress situation calls for a rapid and vigorous response, along with a timely cessation of that response (). Dysfunction of the HPA axis is common in individuals with MDD and is capable of activating the axis that would alter gut microbiota and increase gut permeability (). [Godoy et al., 2018] [McEwen and Akil, 2020] [De Punder and Pruimboom, 2015]

MDD is also marked by systemic inflammation with high cytokines IL-6, TNF-α, and IL-1β (). The increased level of inflammatory cytokines is perhaps a result of dysbiosis of the gut microbiota, which may further weaken the integrity of the gut barrier. These stimuli will also stimulate brain microglia and trigger the NLRP3 inflammasome to release IL-1β and IL-18 (). The released mediators would also support neuroinflammation. Inflammation also shifts tryptophan metabolism away from serotonin to neurotoxic kynurenine pathway metabolites, like quinolinic acid, and disturbs neurotransmission and thus plays a role in depressive symptoms (;). Major depression is treated by various pharmacological and non-pharmacological interventions. Exercise and lifestyle modification exert substantial antidepressant effects, especially for mild MDD (). Therefore, modulation of gut microbiota mechanisms might be the key to symptom relief of MDD. [Troubat et al., 2021] [Troubat et al., 2021] [Chen et al., 2021] [Liang et al., 2024] [Marx et al., 2023]

andproduce serotonin, whileandsynthesize GABA (). Microbes likeandalso produce acetate, butyrate, and propionate, which are known to affect the immune, endocrine, and nervous systems (). Gut SCFAs promote serotonin synthesis in the gut and further communicate with the brain via the vagus nerve. Although SCFAs can cross the BBB, serotonin and GABA generally do not, unless barrier integrity is compromised, as seen in stress and depression models (). A translation from gut microbiota research to clinical settings is undermined by the complexity surrounding individual microbial profiles (). Investigative efforts so far concerning enterotypes, such as alpha diversity, the Firmicutes-to-Bacteroidetes ratio, aim at the identification of an MDD-specific fecal signature (). Reduced Firmicutes proportion in MDD patients, as a suggestion for the establishment of an MDD biomarker, was reported by. This, however, was followed by systematic reviews showing inconsistent results and hence raised questions on replicability (). Most studies have shown that the GM of MDD patients differs from that of controls at the phylum, class, order, family, and genus levels, but with a particular emphasis on differences at the phylum, family, and genus levels (). Escherichia Enterococcus Bifidobacterium Lactobacillus Coprococcus Faecalibacterium [Socała et al., 2021] [Valles-Colomer et al., 2019] [Margolis et al., 2021] [Galland, 2014] [Valles-Colomer et al., 2019] [Jiang et al. (2015)] [Barandouzi et al., 2020] Table 7

Higher relative abundance of proinflammatory bacteria likewas found to be increased, and decreased relative abundance ofin the subjects with MDD (). Similarly, patients with MDD also had decreased relative abundance of the generaandcompared to non-depressed individuals in a meta-analysis by. The meta-analytical study shows decreased abundance in the MDD patients when compared to controls in the bacterial families Veillonellaceae, Prevotellaceae, and Sutterellaceae, genera, and shows an increase in abundance in Actinomycetaceae family andgenus (). Interestingly,served as a primary butyrate-producing bacterium in the gut, being crucial for gut homeostasis and possibly alleviating depressive symptoms at least in animal models (). Eggerthella, Atopobium Faecalibacterium Coprococcus Faecalibacterium Coprococcus, Faecalibacterium, Ruminococcus, Bifidobacterium, Escherichia Paraprevotella Faecalibacterium [Knudsen et al., 2021] [Sanada et al. (2020)] [Sanada et al., 2020] [Stilling et al., 2016]

BD is a chronic psychiatric condition characterized by alternating episodes of depression and elevated mood states, which may manifest as mania or hypomania. These episodes often alternate with periods of euthymia but can also occur in rapid succession or with mixed features. The disorder is classified into two main subtypes: bipolar I disorder (BP-I), defined by the presence of at least one full manic episode, and bipolar II disorder (BP-II), characterized by hypomanic episodes without progression to full mania (). Longitudinal studies highlight the persistent and fluctuating nature of BD. Research indicates that individuals with BP-I remain symptomatic for nearly half of their illness course, with depressive symptoms being the most frequent and persistent, significantly outweighing manic/hypomanic and mixed episodes (). Subsyndromal symptoms are more prevalent than full-threshold episodes, while psychotic features occur infrequently and primarily during manic states. The illness trajectory is highly variable, marked by frequent shifts in symptom polarity, underscoring the chronic and recurrent nature of BD (). Epidemiological data further demonstrate that over 90% of individuals with BD experience recurrent episodes, which contribute to progressive neurobiological changes, cognitive decline, and increased medical and psychiatric comorbidities (). Manic episodes are defined by at least 1 week of persistently elevated, expansive, or irritable mood accompanied by increased activity or energy, whereas hypomanic episodes present similar features without marked functional impairment or hospitalization. The presence of psychotic features necessitates classification as mania. The global burden of BD is substantial. The World Mental Health (WMH) survey, using the WHO Composite International Diagnostic Interview (CIDI 3.0), identified BD as one of the most disabling psychiatric conditions, with affected individuals averaging 41.2 days of role impairment per year 36.5 of which were directly attributed to BD (). These findings emphasize the critical need for early intervention, personalized treatment strategies, and ongoing research into the disorder's pathophysiology and long-term management (;). [Grande et al., 2016] [Nierenberg et al., 2023] [Grande et al., 2016] [Nierenberg et al., 2023] [Alonso et al., 2011] [Grande et al., 2016] [Nierenberg et al., 2023]

Biologically, people with BD, especially those who haven't started treatment, show noticeable changes in their gut microbiome. A study byfound that these untreated patients had significantly less diverse gut bacteria (lower α-diversity) compared to healthy individuals. They also had unique bacterial compositions (). These changes were found not only in untreated individuals but also in those who were being treated with the medication quetiapine. The study also looked closely at quetiapine, which was used to treat depressive episodes in BD. It was given on its own (monotherapy) at a dose of 200–300 mg daily for 4 weeks. All participants were confirmed to be experiencing a depressive episode using structured psychiatric interviews and rating scales like the HDRS-17 and MADRS. After treatment, there was a clear improvement in symptoms. Although quetiapine is not directly labeled as an antipsychotic in this study, the effects it had both metabolically and on gut bacteria are consistent with what is known about that class of drugs. Importantly, the study only explored quetiapine's use in bipolar depression and did not extend its findings to other mental health conditions (). [Hu et al. (2019)] [Hu et al., 2019] [Hu et al., 2019]

On the genetic side, research byshowed that BP-II may be genetically different from BP-I and unipolar depression. In their family-based study, relatives of people with BP-II had a higher risk of also having BP-II, suggesting it tends to run specifically in families (). In contrast, less severe mood disorders did not show this familial pattern, supporting the idea that BP-II is a distinct and genetically separate condition. Moreover, the pilot study byobserved that patients with BD had lower gut microbial α-diversity compared to healthy individuals, indicating a less varied gut microbiome. They also found a higher presence ofbacteria in BD patients, with Collinsella specifically enriched in individuals with BD-II compared to those with BD-I, suggesting that different BD subtypes may have distinct microbiome patterns (). However, due to the study's small sample size and lack of consistent grouping based on diagnosis or diet, the results need further investigation. Similarly,reported notable changes in gut microbiota among BD patients. They found that microbial α-diversity decreased as the duration of illness increased, meaning that the variety of gut bacteria reduced over time in individuals with BD (). Compared to healthy controls, BD patients had higher levels of Actinobacteria and, while healthy individuals had moreand, which are generally considered beneficial. Among BD patients with elevated levels of the inflammatory marker IL-6, there were increases inand, suggesting a connection between inflammation and gut microbiota changes. The study also linked specific bacterial groups to metabolic issues in BD. For instance,were more abundant in patients with high cholesterol, andwas associated with markers of oxidative stress. Additionally, more severe depressive symptoms were correlated with an increased presence of, while comparatively healthier BD patients had moreand. These findings support the relevance of MGBA mechanisms in BD pathophysiology, implicating both immune and metabolic pathways as shown in, and are conceptually illustrated through the microbiota–immune–metabolic–brain axis model (;). [Heun and Maier (1993)] [Heun and Maier, 1993] [McIntyre et al. (2021)] [McIntyre et al., 2021] [Painold et al. (2019)] [Painold et al., 2019] Table 8 Figure 6 [Painold et al., 2019] Clostridiaceae Coriobacteria Ruminococcaceae Faecalibacterium Lactobacillales Streptococcaceae Clostridiaceae Eubacterium Enterobacteriaceae Clostridiaceae Roseburia

A cross-sectional study has found that taking atypical antipsychotics (AAPs) led to an increase in a group of gut bacteria calledand a decrease in Akkermansia, which is often linked to gut health (). While there was also an initial drop in Sutterella, this result was no longer significant after adjusting for age, body mass index (BMI), and gender. AAP use was also linked to a general decrease in gut microbial diversity, especially in women. In a related finding, A related study reported that people with BD had lower levels of, a beneficial bacterium known for producing butyrate a short-chain fatty acid important for gut health. Higher levels of this bacterium were associated with better physical wellbeing, mood, sleep quality, and lower anxiety (). Moreover, another study also highlighted the important role ofin producing butyrate (). Independently,tested the effects of small amounts of prebiotic fibers like indigestible dextrin, α-cyclodextrin, and dextran using a lab-based colon model and a small human trial. They found that these supplements increased the production of beneficial SCFAs like acetate and propionate without changing the overall diversity or makeup of gut bacteria. This suggests that low-dose prebiotics can boost gut health without disrupting the balance of the microbiome. Another study found that patients hospitalized for acute mania were 5.5 times more likely to have used systemic antibiotics in the preceding 3 days than controls (). This association suggests that bacterial infections, as evidenced by antibiotic use, may contribute to manic episodes through immune activation, highlighting infection prevention and treatment as potential targets. Complementary findings demonstrated that systemic immune activation via LPS in mice produced sustained reductions in novel object exploration for up to 24 h (). These effects were independent of acute sickness and linked to impaired cognition and motivation, particularly continuous attention and curiosity, through prolonged central amygdala activation. Although not directly tied to BD prevention, the study illustrates how transient inflammation may result in lasting behavioral changes. Lachnospiraceae Faecalibacterium Faecalibacterium [Flowers et al., 2017] [Evans et al., 2017] [Tanca et al., 2017] [Sasaki et al. (2018)] [Yolken et al., 2016] [Haba et al., 2012]

Disruptions to the gut microbiome during early development or the initial phases of psychiatric illness may influence the trajectory of mental disorders () reported that early-life antibiotic exposure is linked to modestly increased risks for several childhood psychiatric disorders, including mood disorders, suggesting sensitive developmental windows for microbiome perturbations (). In first-episode psychosis,identified a distinct microbial signature with elevatedand decreased, correlating with greater symptom severity and poorer 12-month remission. These findings support the use of microbiome-targeted interventions early in life or illness to potentially mitigate progression of severe psychiatric conditions. Changes in the gut microbiome caused by antipsychotic medications particularly risperidone have been linked to weight gain and metabolic effects. In children receiving long-term risperidone, the ratio of Bacteroidetes to Firmicutes (two major bacterial groups in the gut) dropped significantly from 1.24 in psychiatric controls to just 0.20 in those who gained a lot of weight. This shift came with an increase in certain Firmicutes bacteria, especiallyspecies and. On the other hand, children whose weight stayed stable had higher levels of Collinsella aerofaciens (). Supporting this,found that risperidone causes weight gain not only by affecting appetite but also by altering the gut microbiome in ways that reduce the body's ability to burn energy. In mice, risperidone treatment led to gut bacterial changes similar to those seen in obesity more Firmicutes, fewer Bacteroidetes and a 16% drop in resting energy expenditure, especially from anaerobic (non-oxygen-requiring) metabolism. Remarkably, this effect was transferable: when gut microbes or even just viral particles (phages) from risperidone-treated mice were transplanted into healthy mice, the recipients also experienced slower metabolism and weight gain. This suggests that risperidone's metabolic side effects are largely driven by changes in gut microbes, opening up the possibility of targeting the microbiome to prevent or reduce weight gain in patients taking this medication. [Lavebratt et al., 2019] [Lavebratt et al., 2019] [Schwarz et al. (2018)] [Bahr et al., 2015] [Bahr et al. (2015)] Lactobacillus Veillonellaceae Clostridium Erysipelotrichaceae

Anxiety disorders represent a group of persistent neuropsychiatric conditions affecting approximately 4.05% of the global population, with prevalence rising by over 55% since 1990 (). Despite the widespread use of serotonergic medications, benzodiazepines and cognitive behavioral therapy (CBT), therapeutic outcomes remain limited with less than 50% of patients reaching full remission and nearly one-third do not respond to conventional treatments (). Clinically, anxiety disorders encompass disorders such as generalized anxiety disorder (GAD), panic disorder, specific phobias, and social anxiety disorder (SAD), all marked by fear responses, behavioral avoidance, and heightened nervous arousal in perceived threatening situations (). Yet, symptomatology is highly variable across individuals, shaped by underlying neurobiological factors. Evidence suggests a widely distributed neural circuit underpinning anxiety disorders, involving interconnected regions such as the amygdala, hippocampus, bed nucleus of the stria terminalis, insula, hypothalamus, anterior cingulate cortex and prefrontal cortex (). Not all individuals exposed to stress or adversity go on to develop anxiety disorders (). Vulnerability factors include early life trauma, poor social support, co-existing medical conditions, genetic predisposition and sex-based differences (). [Javaid et al., 2023] [De Vries et al., 2016] [Wu et al., 2025] [Drzewiecki and Fox, 2024] [Charney, 2003] [Lai and Xiong, 2025]

Women are nearly twice as likely to develop anxiety disorders, potentially due to enhanced HPA axis activation under stress and modulatory effects of sex hormones on GABAergic and glucocorticoid signaling (). There is a high comorbidity between the anxiety disorders and MDD (). Heritability estimates range between 30 and 50%, although genome-wide study results have been inconclusive (). From a systems perspective, anxiety disorders is characterized by abnormalities in neurotransmitter functions, neurotrophic signaling, the endocannabinoid system and HPA axis function and these alterations are further compounded by chronic inflammation and maladaptive immune responses (). Interestingly, elevated baseline levels of inflammatory markers such as CRP and IL-6 have been linked to both increased risk and severity of anxiety (), while epidemiological data show that individuals with inflammatory autoimmune diseases like psoriasis have increased risks of experiencing developing anxiety disorders (). [Jaggar et al., 2020] [Bobo et al., 2022] [Meier et al., 2019] [Cai et al., 2025] [Mac Giollabhui et al., 2025] [Lee et al., 2025]

Emerging evidence highlights the MGBA as a critical contributor to anxiety pathophysiology (). Genetic studies further showed that several loci associated with GI disorder such as IBS, namely, andalso correlate with anxiety and mood disorders (). Moreover, Mendelian randomization analyses support a causal role for specific gut microbes: Actinobacteria andtaxa appear protective, whileincrease anxiety risk (). Animal research and scarce human studies confirm these findings, showing that disruptions in microbiota composition or metabolite profiles can induce anxiety-like behaviors via MGBA (). [Abautret-Daly et al., 2018] [Eijsbouts et al., 2021] [Lai and Xiong, 2025] [Cai et al., 2025] NCAM1, CADM2 PHF2/FAM120A Bifidobacterium Lactobacillaceae

Gut microbiota alterations are constantly found in individuals with anxiety disorders (). For instance, whilst beta diversity (reflecting differences in microbial community composition) is consistently altered across anxiety disorders, alpha diversity patterns show disorder type and sex-specific patterns (;;). Sex-dependent effects emerged specifically in a large Korean study with anxious population, where men exhibited reduced alpha diversity while women showed no changes (). However, self-reported anxiety symptoms may limit the generalizability of the findings. Furthermore, a small study with GAD diagnosed patients showed reduced microbial richness among males and females () while SAD patients maintained normal diversity (). One hypothesis for these observed differences is that biological sex influences gut microbial composition through hormone-regulated immune and metabolic pathways, with sex steroid hormones and sex-linked genetic factors shaping the immune environment and selectively supporting the growth of certain microbial taxa (). [Chen et al., 2019] [Jiang et al., 2018] [Butler et al., 2023] [Kim et al., 2023] [Kim et al., 2023] [Jiang et al., 2018] [Butler et al., 2023] [Jaggar et al., 2020]

SCFA producing taxa is depleted in anxiety disorders (), mirroring patterns observed in other psychiatric conditions (). Anxious men showed reduced abundance of butyrate-producing(), which is essential for epithelial barrier integrity and microglial regulation (). GAD patients demonstrated broader SCFA depletion, with decreased levels of, and, bacteria integral to maintaining mucosal homeostasis and modulating host-microbiota immune interactions. Interestingly, in the remission state, increased levels ofandwere observed (). Similarly, SAD control group showed an abundance of—a symbiont that supports intestinal mucosal stability with a potential protective role in anxiety (;). [Burton et al., 2023] [Bruun et al., 2024] [Kim et al., 2023] [Erny et al., 2015] [Jiang et al., 2018] [Butler et al., 2023] [Yao et al., 2023] Lachnospiraceae_NK4A136 Faecalibacterium, Eubacterium rectale, Butyricicoccus Lachnospira Faecalibacterium Eubacterium rectale Parasutterella

Pro-inflammatory and pathobiont taxa showed disorder-specific enrichment patterns. GAD patients exhibited increased, and(), with the latter linked to epithelial disruption, gut inflammation and IBS pathogenesis (). Interestingly, about one third of people with IBS have anxiety symptoms, suggesting a potential shared gut–brain inflammatory axis between GAD and IBS (). SAD patients showed enrichment of novel generaand, whereaswas linked to autism spectrum disorder—a condition with high SAD comorbidity (). Interestingly, the gut metabolic module aspartate degradation I, which converts L-aspartate to oxaloacetate by aspartate aminotransferase, was elevated in SAD patients and the authors hypothesized that bacterial aspartate aminotransferase enzyme activity may represent a link between gut microbiome function and the tryptophan-kynurenine pathway, a key physiological system in psychiatric disorders (). The tryptophan-kynurenine pathway functions as a stress-activated metabolic system that diverts tryptophan from serotonin synthesis toward kynurenic acid production, which acts as a glutamate receptor antagonist and may contribute to anxiety pathophysiology through altered glutamatergic neurotransmission (). Despite consistent patterns of SCFA depletion, the heterogeneity in microbial signatures across anxiety subtypes suggests disorder-specific pathophysiological mechanisms. Small sample sizes and different anxiety types limit clinical translation. Future studies should standardize methodological approaches across populations and increase sample sizes. Bacteroides, Ruminococcus gnavus Fusobacterium Anaeromassilibacillus Gordonibacter Anaeromassilibacillus [Jiang et al., 2018] [Zhou, 2016] [Grover et al., 2021] [Butler et al., 2023] [Butler et al., 2023] [Butler et al., 2022]

Rodent models of anxiety disorders provide causal evidence that stress exposure disrupts the MGBA, leading to microbiota alterations, compromised gut barrier integrity, immune activation and neurotransmitter imbalance (). Alterations in the Firmicutes and Bacteroidetes (F/B) ratio—a key marker of gut dysbiosis—have been reported in male mice exposed to chronic mild stress (CMS;) and humid heat environment stress models () Enrichment of the phylum Proteobacteria was observed across multiple stress paradigms (;). Proteobacteria enrichment in the gut serves as a dysbiosis marker (). Moreover, 6 weeks of chronic stress also revealed decreased relative abundance of Bacteroidetes and(). [Bear et al., 2021] [Tyagi et al., 2025] [Weng et al., 2024] [Jia et al., 2024] [Tyagi et al., 2025] [Shin et al., 2015] [Jia et al., 2024] Deferribacteres

Across preclinical anxiety models, there was a consistent enrichment of pathogenic or dysbiosis-associated bacteria. Male mice exposed to CMS for 2 weeks showed increased pathogenic bacteria including, and(). Similarly, chronic stress elevatedandcompared to controls (). Similarly, a systematic depletion of beneficial and anti-inflammatory taxa, many of which are involved in SCFA production, was observed in stress-exposed animals., and()., and() as well as, and(). These losses occurred irrespective of stress model or duration. These microbial alterations were accompanied by functional impairments, with CMS significantly reducing SCFA production, particularly acetic and propionic acid concentrations (). Acinetobacter, Proteus Enterococcus Kineothrix alysoides Helicobacter bilis Lactobacillus murinus, L. intestinalis, L. reuteri Akkermansia muciniphila Oscillibacter, Muribaculum, Roseburia Alistipes Muribaculum intestinale, Ligilactobacillus murinus, Duncaniella Prevotella [Tyagi et al., 2025] [Jia et al., 2024] [Weng et al., 2024] [Tyagi et al., 2025] [Jia et al., 2024] [Tyagi et al., 2025]

Anxiety involves MGBA alterations that create cascading pathophysiological changes (). Chronic stress activates the HPA axis, resulting in increased cortisol production (). Mice exposed to chronic unpredictable mild stress (CUMS) for 6 weeks showed increased hypothalamic corticotropin-releasing hormone concentrations, elevated corticosterone levels and increased blood ammonia, which corresponded with anxiety-like behaviors, demonstrating HPA axis involvement in anxiety pathogenesis (). Interestingly, Ammonia (a neurotoxic by-product) can impair the nervous system even at low levels and it has been associated with anxiety disorders—potentially serving as a biomarker (). Furthermore, chronic stress impairs inhibitory neurotransmitter systems. Both GABA and serotonin availability declined with reduced receptor expression for GABAα2 and GABAB1β in prefrontal cortex in the 2 week CMS (). Dysregulation in these receptors is linked to anxiety behaviors and it may be considered as a potential therapeutic pathway in anxiety treatment (). Moreover, 6 week exposure to CUMS showed further GABA level reductions in tissues such as hippocampus, blood and feces, suggesting that more widespread neurotransmitter depletion may be stress type and duration dependant (). Furthemore, an increased serotonin metabolism was demonstrated by diminished hypothalamic serotonin levels, lowered 5-hydroxytryptamine (5-HT)/tryptophan ratios and elevated 5-hydroxyindoleacetic acid/5-HT ratios, indicating dysregulated serotonergic system (). Altered serotonergic signaling is considered a hallmark neurochemical feature of anxiety disorders (). [Rogers et al., 2016] [Faravelli, 2012] [Jia et al., 2024] [Duan et al., 2015] [Tyagi et al., 2025] [Solati et al., 2013] [Jia et al., 2024] [Jia et al., 2024] [Yohn et al., 2017] A

Moreover, chronic stress exposure triggers systemic inflammatory activation through upregulation of pro-inflammatory cytokine cascades (). Elevated IL-6 and TNF-α concentrations in CMS exposed mice demonstrate stress-induced inflammatory signaling contribution toward anxiety-like behaviors (). Similarly, mice exposed to CUMS for 6 weeks showed an increased interferon-gamma (IFN-γ) and decreased anti-inflammatory IL-10 levels, demonstrating anti-inflammatory suppression with further pro-inflammatory activation (). Intriguingly, correlation analyses linked microbiota changes to alterations in stress hormones, neurotransmitters, inflammatory markers and anxiety-like behaviors, suggesting a gut–brain contribution to the observed behavioral manifestations in anxiety pathology (;;). [Ravi et al., 2021] [Tyagi et al., 2025] [Jia et al., 2024] [Jia et al., 2024] [Tyagi et al., 2025] Figure 7

PTSD is a chronic neuropsychiatric condition affecting 1.3–12.2% of the global population (). PTSD is triggered by exposure to a traumatic event involving actual or threatened death, injury or sexual violence (). Remission is achieved by less than 30% of patients and pharmacological interventions remain slow-acting and lack effectiveness (). Core symptoms span intrusive memories, hyperarousal, avoidance and negative shifts in mood and cognition (), yet clinical presentation is highly heterogeneous—shaped by trauma type and individual neurobiology (). Structural and functional abnormalities in the amygdala, hippocampus and medial prefrontal cortex underlie persistent, overgeneralized fear responses (). Not everyone exposed to trauma would develop PTSD. Risk of developing PTSD is influenced by adverse childhood experiences, younger age and socioeconomic disadvantage () with prevalence rates twice as high in females than in males (). Furthermore, heritability estimates range from 30 to 40% () with genome-wide studies implicating immune-linked loci such asamong others (;). At the systems level, PTSD is characterized by heightened peripheral inflammation, impaired regulatory T cell function (), dysregulation of the HPA axis, neurotransmitter systems and neuroinflammation (;). Elevated pre-existing inflammation has emerged as a predictive factor for PTSD onset. Individuals with high baseline CRP are more likely to develop PTSD symptoms following trauma exposure (). [Hu et al., 2024] [Al Jowf et al., 2023] [Kelmendi et al., 2016] [Petakh et al., 2024] [Huckins et al., 2020] [Harnett et al., 2020] [Xue et al., 2015] [Perrin et al., 2014] [Girgenti et al., 2021] [Stein et al., 2016] [Ugidos et al., 2019] [Jergović et al., 2014] [Michopoulos et al., 2015] [Aliev et al., 2020] [Eraly et al., 2014] ANKRD55

A growing body of evidence implicates the MGBA as a key modulator of PTSD vulnerability. Given that gut microbiota regulate immune function and inflammation, both key features of PTSD pathophysiology, this axis represents a promising therapeutic target. Early-life gut microbiota imbalances may predispose individuals to PTSD susceptibility after trauma exposure (). Supporting this hypothesis, PTSD is more prevalent in individuals with GI inflammatory disorders including, IBD and Crohn's disease (;). Recent Mendelian randomization findings further validate this framework:andappear protective, whereasandare associated with increased PTSD risk (). Multiple clinical studies have characterized the gut microbiome in PTSD patients, revealing patterns of microbial dysbiosis (;;;;). An early study found decreased abundance of Actinobacteriaand Verrucomicrobia in PTSD patients vs. trauma-exposed controls (). Decreased Verrucomicrobia (which includes the beneficial bacterium, important for gut barrier function) correlated with greater PTSD symptom severity in 26 Iraq/Afghanistan War Veterans from different ethnic backgrounds, though findings were based on self-reported behavioral symptoms (). [Leclercq et al., 2016] [Katrinli et al., 2022] [Kent, 2024] [He et al., 2024] [Hemmings et al., 2017] [Bajaj et al., 2019] [O'Hare et al., 2024] [Yirmiya et al., 2024] [Li Y. I. et al., 2025] [Hemmings et al., 2017] [Li Y. I. et al., 2025] Dorea Sellimonas Phascolarctobacterium Ruminococcaceae UCG-004 , Lentisphaerae Akkermansia muciniphila

SCFA-producing bacteria are consistently depleted among PTSD patients along with increased pathobionts indicate a shift toward inflammatory environment. SCFA producingandwere reduced in US combat veterans with cirrhosis and PTSD compared to those without PTSD, together with increased pathobiontsand(), suggesting these microbial changes may reflect or even exacerbate inflammation-driven psychiatric vulnerability. Moreover, a longitudinal study following war-exposed Israeli children for over 15 years found that clinically diagnosed PTSD youth exhibited significantly lower α-diversity, decreased SCFA-producing bacteria () and increased pro-inflammatory pathobionts () compared to controls, along with increased nitrate reductase-associated metabolites linked to nitrogen metabolism pathways. Fecal microbiome transplantation from PTSD adolescents into germ-free mice induced significant anxiety behaviors, confirming functional contribution of gut microbiota to psychiatric symptomatology (). However, the study used only one behavioral test (Elevated Plus Maze). Future studies should employ multiple paradigms to capture the broader spectrum of PTSD-related phenotypes. These findings collectively highlight that PTSD is associated with reproducible patterns of gut dysbiosis, characterized by reduced SCFA-producing taxa and increased inflammatory pathobionts, supporting a functional link between microbial imbalance and psychiatric vulnerability. Lachnospiraceae Ruminococcaceae Enterococcus Escherichia/Shigella Dialister, Eubacterium Collinsella, Veillonella [Bajaj et al., 2019] [Yirmiya et al., 2024]

Bacteria changes may be linked to geographic location where the study was carried. PTSD-diagnosed South African individuals showed higher levels of, andcompared to controls, positively correlating with childhood trauma severity. Intriguingly, these four genera are found in oral microbiota of patients with periodontitis. The authors hypothesized that early life adversity may alter oral microbiome composition, which can shift to gut via saliva, potentially creating a pro-inflammatory state that increases vulnerability to PTSD following subsequent trauma exposure ().was also identified in another South African study with self-assessed PTSD symptoms (), indicating potential geographic location-specific associations (). Higher levels of, andalso correlated with higher symptom severity (). These bacteria produce lactic acid. Lactate (the ionized active form of lactic acid) has been linked to PTSD through unclear mechanisms. One proposed mechanism is that lactate enhances hippocampal neuronal firing, potentially contributing to panic symptoms (). Moreover, elevatedhas been associated with reduced right amygdala and hippocampal volumes () brain regions consistently reduced in PTSD individuals (). Future functional studies should assess whether associations between these bacteria concentrations and brain volumes reflect causal relationships. Together, these findings suggest that microbiome shifts associated with trauma exposure and geography may influence PTSD risk by modulating brain structure and neuroinflammatory signaling. Mitsuokella, Odoribacter, Olsenella Catenibacterium Catenibacterium Catenibacterium, Collinsella Holdemanella Holdemanella [Malan-Muller et al., 2022] [O'Hare et al., 2024] [Parizadeh and Arrieta, 2023] [O'Hare et al., 2024] [Bergold et al., 2009] [Wanapaisan et al., 2022] [Ben-Zion et al., 2023]

Additional population studies have expanded these findings. Whole-genome sequencing of 191 American nurses identified specific bacterial alterations in self-reported PTSD: increased, andunclassified, decreasedand(). ParaBacteroides goldsteinii, Barnesiella intestinihominis Paraprevotella Eubacterium eligens Akkermansia muciniphila [Ke et al., 2023]

Differences in findings could be attributed to the fact that participants were from different geographic locations, which are known to influence gut microbiota composition through factors such as diet, environment, and lifestyle-potentially contributing to the observed variation. Furthermore, small sample sizes, different trauma types and symptom assessment methods limit clinical translation. Future studies should standardize methodological approaches across populations and increase sample sizes in order to distinguish between geographic and pathological microbiome variations.

Rodent models of PTSD provide causal evidence that psychological trauma disrupts the MGBA, leading to microbiota alterations, compromised gut barrier integrity, immune activation and neurotransmitter imbalance. Alterations in the Firmicutes and Bacteroidetes (F/B) ratio—a key marker of gut dysbiosis, have been reported in PTSD model rodents, exposed to psychological trauma using Repeated Social Defeat Stress and Single Prolonged Stress (SPS;;). [Zhou et al., 2020] [Yadav et al., 2023]

Across preclinical PTSD models, there is consistent enrichment of pathogenic or dysbiosis-associated bacteria. For instance,reported elevated levels ofand Proteobacteria in SPS exposed male rats. Similarly, female rats exposed to trauma exhibited increased abundance ofand, latter being associated with GABA disruption (). In male mice,observed elevatedandfamilies—taxa known to influence dopaminergic signaling and myelination via production of the neurotoxic metabolite-cresol, a compound implicated in PTSD related neuropathology (;). Similarly, a systematic depletion of beneficial and anti-inflammatory taxa was observed in trauma exposed animals. In female rats, trauma led to reduced abundance of, and—genera some of which are involved in short-chain fatty acid (SCFA) production and serotonergic () regulation (;) reported reduced levels of Actinobacteria, Proteobacteria, Verrucomicrobia andin male mice with PTSD-like behaviors, consistent with findings from human studies linking similar depletions to PTSD symptomatology (). Interestingly, protective baseline microbiome signatures were identified in stress-resilient rodents. Females resilient to trauma exhibited higher pre-trauma levels of, and, suggesting that baseline enrichment of SCFA-producing bacteria may confer resistance to PTSD onset (). [Zhou et al. (2020)] [Tanelian et al., 2023] [Laudani et al. (2023)] [Torrisi et al., 2019] [Jak et al., 2020] [Laudani et al., 2023] [Tanelian et al., 2023] [Hemmings et al., 2017] [Tanelian et al., 2023] Cyanobacteria Anaerovorax Flavonifractor Ruminococcaceae Lachnospiraceae p Bifidobacterium, Clostridium sensu stricto, Turicibacter Barnesiella Turicibacter Bacteroides Roseburia, Oscillibacter Lachnospiraceae

PTSD involves gut–brain axis alterations that create cascading pathophysiological effects. Altered regulation of the HPA axis has been observed in PTSD pathology. Female rats exposed to predator-based psychosocial stress exhibited significantly reduced baseline corticosterone levels and enhanced dexamethasone suppression compared to controls, demonstrating that PTSD is characterized by altered HPA axis function (). Furthermore, gut microbiota regulates HPA axis responsiveness. Germ-free mice exhibited exaggerated plasma corticosterone responses compared to specific pathogen-free controls, demonstrating that microbiota regulates HPA axis function (). Moreover, psychological trauma compromises gut barrier function and increases inflammation through stress hormone signaling (). In PTSD mice models, trauma exposure increased tyrosine hydroxylase expression (the rate-limiting enzyme in catecholamine biosynthesis), elevating stress hormones epinephrine and norepinephrine in serum and colon, which upregulated claudin-2 expression, confirming gut barrier dysfunction (). Trauma exposure also induces intestinal inflammation (increased CD45leukocytes, CD68macrophages, and CD3T cells and upregulated phosphorylated Stat3 and NF-κB) signaling. This shows the causal pathway whereby psychological trauma compromises gut barrier function and intestinal inflammation through stress hormone signaling. The study hypothesized that pro-inflammatory gut environment further promotes changes in microbiota (). Furthermore, significantly elevated branch-chain fatty acids (BCFA), which are metabolic products of protein breakdown have been hypothesized to induce epithelium inflammation (). [Zoladz et al., 2021] [Vagnerová et al., 2019] [Sherin and Nemeroff, 2011] [Yadav et al., 2023] [Yadav et al., 2023] [Aguirre et al., 2016] + + +

These microbial alterations coincided with PTSD symptomatology, BBB dysfunction and hippocampal neuroinflammation, which was confirmed by increased proinflammatory cytokine levels IL-1β and IL-6 (). Collectively, these studies confirm that PTSD involves gut–brain axis disruption. [Tanelian et al., 2023]

Alterations in gut microbiota can disrupt neurotransmitter homeostasis, particularly affecting serotonin (5-HT), norepinephrine (NE), and dopamine (DA) systems that are dysregulated in PTSD (). Microbial shifts in a PTSD male rat study coincided with a significant decrease in brain 5-HT and increases in DA and NE, indicating a potential hyperaroused state. Spearman correlation analysis linked the microbiota changes to fear- and anxiety-like behaviors, suggesting a gut–brain contribution to the observed neurotransmitter imbalance in PTSD rat models (). Intriguingly, serotonin regulation may be particular sensitive to the decreased levels of(particularly) as this genus influences gut-derived serotonin (), which is partly controlled by the microbiota () and is known contributor to PTSD symptoms (). Similarly, trauma induced increasedmay potentially compromise GABA availability, since these bacteria primarily utilize GABA for metabolism () potentially affecting this key inhibitory neurotransmitter and contributing to anxiety symptoms observed in PTSD (). Similarly, dopaminergic dysfunction was observed. Male rats with PTSD-like behaviors showed elevated-cresol (a neurotoxic metabolite linked to overgrowth ofand) in prefrontal cortex, leading to dopaminergic dysfunction with increased DA, increased dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), and significantly elevated DA D3 receptor expression compared to controls (). The prefrontal cortex is highly sensitive to DA and even minor fluctuations can impair prefrontal cortex-dependent functions, making it particularly relevant in PTSD, as it plays a central role in suppressing fear responses, regulating stress reactivity, and enabling emotional control (). Collectively, these findings demonstrate that psychological trauma initiates a cascade of interconnected MGBA disruptions in PTSD, encompassing HPA axis dysregulation, microbial dysbiosis, compromised gut barrier integrity, chronic inflammation and neurotransmitter imbalances across serotonergic, dopaminergic, and GABAergic systems. Collectively, these findings demonstrate that PTSD arises through a complex interplay of gut dysbiosis, neuroendocrine disruption, immune activation, and altered neurotransmission, firmly implicating the microbiota–MGBA in the pathophysiology of trauma-related disorders. [Zhou et al., 2020] [Zhou et al., 2020] [Tanelian et al., 2023] [Fung et al., 2017] [Tanelian et al., 2023] [Tanelian et al., 2023] [Strandwitz et al., 2018] [Laudani et al., 2023] [Cools and D'Esposito, 2011] Turicibacter T. sanguinis Flavonifractor p Ruminococcaceae Lachnospiraceae

CFS, also known as Myalgic Encephalomyelitis (CFS/ME), is a complex disorder marked by persistent fatigue, cognitive impairment, and a range of physical symptoms that are not alleviated by rest (;). The underlying mechanisms are multifactorial and not fully understood, but increasing evidence highlights the gut–brain axis and the intestinal microbiome as critical contributors to disease onset and progression (;). Recent advances in microbiome research have opened new avenues for prevention and intervention, focusing on how gut microbial communities influence immune, metabolic, and neural pathways relevant to CFS/ME. Taken together, these studies underscore the potential of gut-targeted therapies in managing the multi-systemic symptoms of CFS/ME. [König et al., 2021] [Wang J.-H. et al., 2024] [He et al., 2023] [El-Sehrawy et al., 2025]

Multiple studies have established that individuals with CFS/ME exhibit significant alterations in their gut microbiome composition compared to healthy controls. Dysbiosis in CFS/ME is characterized by reduced microbial diversity and a shift in the abundance of specific bacterial taxa. For example, patients often have lower levels of anti-inflammatory bacteria such asand higher proportions of pro-inflammatory species, which may contribute to systemic inflammation and symptom severity (;). A recent meta-analysis confirmed that CFS/ME is associated with distinct gut microbial signatures, including reduced levels of butyrate-producing bacteria and increased abundance of(). These alterations are thought to impact gut barrier integrity and immune function, both of which are implicated in CFS/ME pathophysiology. In CFS/ME, disruptions in this axis are believed to play a central role in the manifestation of fatigue, cognitive dysfunction, and mood disturbances (). Microbial metabolites such as SCFAs and tryptophan catabolites can influence brain function directly or via modulation of systemic inflammation. For instance, butyrate, an SCFA produced by certain gut bacteria, supports the integrity of the intestinal barrier and exerts anti-inflammatory effects (;). Reduced butyrate levels in CFS/ME patients may contribute to increased gut permeability ("leaky gut"), allowing microbial products like LPS to enter the circulation and trigger systemic immune activation (). This immune activation may, in turn, affect the CNS, exacerbating fatigue and cognitive symptoms. This highlights the complexity of host–microbe interactions in CFS/ME and underscores the importance of personalized medicine approaches. Faecalibacterium Enterobacteriaceae [König et al., 2021] [Xiong R. et al., 2023] [Jurek and Castro-Marrero, 2024] [König et al., 2021] [Guo et al., 2023] [Jurek and Castro-Marrero, 2024] [Wang J.-H. et al., 2024]

Altered microbial metabolism in CFS/ME extends beyond SCFAs. Dysbiosis can affect the kynurenine pathway of tryptophan metabolism, leading to an imbalance in neuroactive metabolites that influence mood, cognition, and pain perception (). The gut microbiome modulates the balance of pro- and anti-inflammatory immune responses, which is crucial in light of the chronic low-grade inflammation observed in many CFS/ME patients (). Recent multi-omics studies have revealed that patients with CFS/ME, especially in early disease stages, display pronounced disruptions in both gut microbial composition and metabolic profiles (). These disruptions include a reduction in SCFA producers and an increase in bacteria associated with inflammation and metabolic endotoxemia, which may serve as potential biomarkers for disease progression and severity. As the disease progresses, some patients may experience a partial restoration of microbial balance (eubiosis); however, this restoration does not consistently correlate with clinical improvement, highlighting the importance of early intervention (). Moreover, GI comorbidities such as IBS are frequently observed in CFS/ME, further supporting the hypothesis that gut microbiota imbalances are not merely a consequence of illness but may actively contribute to its pathogenesis (). In addition, emerging data suggest that specific microbial taxa may be causally linked to CFS/ME risk. For example, reductions inand increases inhave been associated with greater disease severity (). Notably, animal models have demonstrated that transferring dysbiotic microbiota from CFS/ME patients to germ-free mice can induce fatigue-like behaviors, supporting a causal role for the microbiome in disease pathogenesis (). Taken together, these studies demonstrate that alterations in the gut microbiome and its metabolic products are consistently associated with immune dysregulation and symptom severity in CFS/ME, suggesting that targeting the microbiome may offer promising new avenues for diagnosis and treatment. [He et al., 2023] [Seton et al., 2023] [Wang J.-H. et al., 2024] [Seton et al., 2023] [He et al., 2023] [Guo et al., 2023] [Bansal et al., 2025] Ruminococcaceae Paraprevotella

Stroke is a leading cause of adult-onset neuropsychiatric and neurodegenerative disability, with substantial global prevalence and profound long-term consequences (). PSCI affects a significant proportion of survivors, manifesting as deficits in memory, executive function, and attention that markedly diminish quality of life and functional independence. In addition to well-established cerebrovascular and inflammatory mechanisms, emerging research highlights the gut microbiota's role in shaping stroke outcomes through the MGBA, influencing neuroinflammation, BBB integrity, and neuronal recovery (). This chapter will examine how stroke and PSCI are increasingly understood within the context of gut–brain interactions, and explore potential opportunities for intervention by targeting gut dysbiosis to improve neurological recovery and cognitive health. [Elendu et al., 2023] [Wang et al., 2023a]

Growing evidence reveals that stroke not only disrupts CNS homeostasis but also profoundly alters the MGBA, leading to bidirectional interactions that can exacerbate neuroinflammation and hinder recovery. A systematic review of 18 studies highlighted the critical role of aging, inflammation, and shifts in gut microbiota, particularly involving Firmicutes, Bacteroidetes, SCFAs, and TMAO, in the pathogenesis and outcomes of ischemic stroke. This underscores how microbiome alterations may both predispose individuals to stroke and influence recovery (). These findings collectively suggest that restoring gut microbial balance could become an integral component of stroke prevention and recovery strategies. In a mouse model of ischemic stroke,demonstrated that antibiotic-induced alterations of the gut microbiota significantly reduced brain infarct size. This neuroprotection was associated with increased intestinal regulatory T cells and reduced IL-17–producing γδ T cells, ultimately suppressing the trafficking of pro-inflammatory T cells from the gut to the leptomeninges after stroke. Their findings highlight a crucial MGBA in which intestinal immune modulation directly influences the severity of ischemic brain injury ().demonstrated in mouse models of middle cerebral artery occlusion that large ischemic strokes induce gut dysbiosis characterized by reduced diversity and Bacteroidetes overgrowth, leading to intestinal barrier dysfunction. Transplanting this dysbiotic microbiota into germ-free mice worsened stroke outcomes by driving proinflammatory T-cell responses and promoting lymphocyte migration to the injured brain. These findings underscore a bidirectional brain–gut–immune axis in stroke pathology (). These mechanistic studies emphasize that targeting gut-driven immune responses could modulate neuroinflammation and improve stroke outcomes. Dysbiosis-driven disruptions of the MGBA have been implicated in both the development of common stroke risk factors, such as obesity, diabetes, and atherosclerosis, and in poorer recovery post-stroke, with age-related changes further compounding MGBA dysfunction (). Recent research underscores that stroke-induced gut dysbiosis not only increases intestinal permeability and triggers systemic inflammation, but also facilitates translocation of microbes and immune cells across a compromised BBB, exacerbating neural injury; paradoxically, certain gut-derived metabolites may help limit post-stroke inflammation and support neurorepair (). This highlights the complex bidirectional relationship between the gut microbiota and stroke pathology. Gut microbiota-derived metabolites, particularly SCFAs like butyrate and acetate, play critical roles in maintaining metabolic and immune homeostasis, with dysbiosis-linked alterations implicated in the pathophysiology of numerous neurological disorders including stroke, AD, and PD (). Emerging evidence suggests that modulation of SCFA production may offer therapeutic avenues for neuroinflammatory and neurodegenerative conditions. Together, these insights point toward microbiota-centered interventions—including strategies to enhance SCFA production—as promising approaches to mitigate neuroinflammation and promote brain recovery. In summary, growing evidence underscores that gut microbiota dysbiosis plays a pivotal role in both the development and outcome of ischemic stroke through immune, barrier, and metabolic pathways, suggesting that restoring gut microbial balance could become an essential strategy for stroke prevention and recovery. [Lee Y. T. et al., 2021] [Benakis et al. (2016)] [Benakis et al., 2016] [Singh et al. (2016)] [Singh et al., 2016] [Honarpisheh et al., 2022] [Hu et al., 2022] [Mirzaei et al., 2021]

Radiation therapy (RT) has redefined the management principles of several types of cancer at various stages, whether a primary neoplasm or metastatic lesion. Although it is effective in targeting cancer cells, it can alter many other tissues like CNS and GI tissue (). The MGBA represents the mutual communication system between the GI tract and the CNS, using various mediators like neural and endocrine signals (). Recent evidence shows that gut microbiota plays a significant role in maintaining homeostasis and regulating the MGBA, which influences the neural and GI responses to RT (). This review focuses on the relationship between gut microbiota, MGBA, and RT, highlighting the microbiota's potential to influence RT-induced neural and intestinal side effects. [Bai et al., 2021] [Yang Q. et al., 2023] [Bai et al., 2021]

Using RT in the abdomino-pelvic region can cause gut dysbiosis, due to the reduction of Firmicutes and Bacteroidetes species accompanied by the surge in Proteobacteria species. This imbalance is strongly linked to the breakdown of the mucosal barrier and high systemic LPS levels (). The microbial translocation through the disrupted tight junctions of GI cells promotes systemic inflammation and can alter the BBB or cause other direct CNS effects via the Vagus nerve. Clinically, RT patients often report neuropsychological symptoms such as depression and fatigue, which may be mediated by microbiota-induced BBB dysfunction (). [Wang L. et al., 2021] [Liu X. et al., 2024]

did a pivotal experiment on rats using a 6 Gy pelvic irradiation causing a significant decrease in the microbiota's diversity, impaired GI morphology, neuroinflammation, and neuronal cell death. Moreover, they documented reduced hippocampal plasticity genes—alongside a change in the rodents behavior (). This study showed that pelvic irradiation can substantially promote pyknosis in the neurons of DG and CA2 regions of the hippocampus, which strongly supports that pelvic irradiation can cause memory and cognitive effects indirectly. Similarly, another study conducted by suggest that the use of antibiotics before cranial irradiation can be a contraindication. The study shows that applying cranial RT to mice after the administration of antibiotics reduced cytokine expression, especially IL-1β and TNF-α in the hippocampus and preserved cognitive functions (). The authors believe that the transmigration of some of the SCFA bacteria, like the Firmicutes and Bacteroidetes species across the damaged tight junctions may exacerbate radiation-induced neurotoxicity (). [Venkidesh et al. (2023)] [Venkidesh et al., 2023] [Luo et al., 2022] [Luo et al., 2022]

The gut microbiota produces key metabolites, such as SCFAs, neurotransmitter precursors, and tryptophan catabolites, which all influence the CNS. Butyrate and propionate, subtypes of SCFAs, are produced by anabolic commensals, such asand, when they ferment dietary fiber (). Butyrate has anti-inflammatory properties and serves as an epigenetic regulator by activating G-protein coupled receptors (GPR41 and GPR43) and inhibiting histone deacetylase activity (). Moreover, an experiment on rodents found that providing Butyrate supplementation effectively reduced hippocampus inflammation and preserved hippocampal neurogenesis following RT exposure (). Furthermore, species likehave been shown to produce tryptophan metabolites that influence serotonergic signaling (), whereasSpp. synthesize Gamma-aminobutyric acid (GABA), a crucial inhibitory neurotransmitter (). This suggests that any disruption of the microbial functions following RT may contribute to some neuropsychological symptoms like fatigue, depression, and cognitive dysfunction (). Faecelibacterium Roseburia Bifidobacterium longum Lactobacillus [Wang L. et al., 2021] [Du et al., 2024] [Lee et al., 2019a] [Tian et al., 2019a] [Zheng et al., 2023] [Zhang Y. et al., 2023]

The MGBA can be influenced by many other microbial-derived metabolites, not only SCFAs (). One example is indole-3-propionic acid (IPA), which is one of the iodole derivatives produced by the gut bacteria during tryptophan catabolism. IPA exhibits neuroprotective effects via activation of the aryl hydrocarbon receptor (AhR;). In preclinical models, IPA has been shown to enhance the expression of tight junction proteins in the BBB, reduce the severity of neuroinflammation, and preserve cognitive performance after CNS injury (). In the radiation setting, any depletion in the IPA-producing species (e.g.,Spp. and) strongly links to behavioral defects and the rise in pro-inflammatory cytokines in the CNS (;). Other microbial metabolites, like lactate and secondary bile, have the ability to modulate the neuroinflammatory response and influence synaptic plasticity, even though their roles in the post-radiation pathologies are still unspecified. Overall, microbially produced metabolites act as potent CNS regulators, either by modulating the vagus signaling and systemic immunity or by directly crossing the BBB (). Understanding these complex interactions will open the gates to more promising therapeutic venues to enhance the overall quality of life of patients undergoing RT. [Deng et al., 2024] [Xiao et al., 2020] [Deng et al., 2024] [Wlodarska et al., 2017] [Xiao et al., 2020] [Deng et al., 2024] Clostridium Peptostreptococcus

Radiation-induced injuries initiate local and systemic responses, which are closely related to the gut microbiome's integrity.found that the relation between gut microbiota and radiation-induced injuries could be direct and indirect. Direct interactions are related primarily to gut radiation and microbiota homeostasis, while indirect interactions are more related to other axes, like the MGBA. Pre-clinical studies done on C57BL/6J mice using total body irradiation (9 Gy) found that radiation reduced α-diversity of gut microbiota, while urolithin A (UroA), a gut microbial metabolite, helps in alleviating radiation-induced apoptosis in intestinal cells by suppressing P53 signaling pathway (;). This explains that the direct relationship between the gut microbiota and radiation-induced injuries is based on microbial homeostasis (). Also, clinical studies done on patients with cervical cancer using pelvic radiation explained that Firmicutes-Proteobacteria ratio (F/P) reflects the severity of radiation toxicity, where it showed that patients with chronic radiation enteritis exhibited a reduction in Firmicutes and an increase in Proteobacteria. Moreover, the same study found that patients with severe enteritis showed high abundance ofand. This supports a direct interaction, although their underlying mechanisms are still in the early stages of investigation and further studies with larger sample sizes or validation are required (). [Wang Q. et al. (2025)] [Zhang et al., 2021c] [Wang Q. et al., 2025] Figure 9 [Wang Q. et al., 2025] Shigella Lachnospiraceae Clostridium

Several pre-clinical studies illustrated the indirect interactions between gut microbiota and radiation injuries, especially brain injuries via the MGBA. A preclinical study used C57BL/6 J mice exposed to head radiation found that the predominet components of the subjects' gut microbiota following radiation were, and. Gut microbiota-derived metabolites, like SCFAs, were shown to play a pivotal role in the MGBA by elevating pro-inflammatory cytokines in the subjects' blood, worsening radiation-induced brain injury (;;). Another pre-clinical study done on C57BL/6J mice using abdominal irradiation (10 Gy) found that the expression level of miR-34a-5p in the small intestine tissue and peripheral blood significantly increased, which mediated distant cognition impairment. Cognitive functions can be maintained by intravenous administration of miR-34a-5p antagomic immediately post-radiation, which blocks miR-34a-5p upregulation in peripheral blood, resulting in restoring the hippocampal expression of BDNF (;). Bacteroidales, Muribaculaceae, Erysipelotrichales Ruminococcus [Luo et al., 2022] [Hu et al., 2023] [Wang Q. et al., 2025] [Cui et al., 2017a] [Wang Q. et al., 2025]

The communication between microbial dynamics and the host's immune system play a major role in determining the strength of the systemic inflammation during RT. Ionizing radiation has been proven to increase the expression of TLR on intestinal epithelial and immune cells, making them more sensitive to microbial ligands like LPS ad flagellins. In radiation settings, upregulated expression of TLR4 enhances the sensitivity and response to Proteobacteria-derived ligands, amplifying downstream NF-κB signaling and cytokine secretion (). Recent experiments showed a surge in IL-6, IL-1β, and TNF-α levels within irradiated mice serum, which is revoked in MyD88-deficient animals. This highlights the importance of the innate immune system responses in driving systemic inflammation following RT. Simultaneously, the upregulation of co-stimulatory molecules (CD80/86) of dendritic cells conditioned in the irradiated gut mucosa suggests a pro-inflammatory antigen-presenting phenotype. The previous interactions contribute to the activation of the peripheral immune system and primes CNS microglia, creating a neuroinflammatory environment that aggravate behavioral deficits (;). Notably, certain commensals, likecluster XIVa and segmented filamentous bacteria, have the ability to push the host immune system toward regulatory responses via regulatory Treg expansion and IL-10 production (). Deficiency in these taxa following RT is significantly connected with prolong tissue injury and impaired mucosal tolerance (). These findings show that microbial-immune interactions have dual role, mediators and potential modulators of radiation toxicity, along the MGBA. [Lu et al., 2020] [Manda et al., 2012] [Wolff et al., 2021] [Atarashi et al., 2011] [Touchefeu et al., 2014] Clostridium

Given the importance of gut microbiota and its mitigate radiation-induced toxicity., implementing preventative strategies focusing on preserving the microbial diversity and barrier quality is crucial. In murine models, FMT has shown therapeutic benefits by restoring Firmicutes species and attenuating systemic inflammation post-RT. Timing is pivotal; administering FMT pre-RT has been shown to provide more benefits compared to post-RT (). FMT is beginning to move toward clinical application. Pilot clinical trials found that FMT might be a safe and effective approach for patients that suffer from post-RT enteritis, although it can alter the patients' gut microbiota composition (). Dietary interventions enrich with microbial substrates, such as polyphenols and dietary fiber, may enhance endogenous synthesis of beneficial metabolites like SCFAs and IPA. Recent studies done on animals found that high fiber diets helped in mitigating hippocampal inflammation following abdominal radiation, while preserving goblet cell integrity and tight junction protein expression (;). Stress management techniques and exercising regularly have been shown to promote microbial diversity and cognitive resilience, potentially leading to improved neurocognitive outcomes following RT (). Limiting non-indicated use of antibiotics during RT is crucial to prevent excessive loss of microbiota (). Personalized multimodal strategies—integrating lifestyle, nutrition, and targeted therapies—require further development and validation in clinical trials. [Cui et al., 2017b] [Ding et al., 2020] [Church et al., 2023] [Lu et al., 2024] [Matei et al., 2023] [Poonacha et al., 2022]

Although pre-clinical studies are promising, several gaps remain in understanding the exact microbial species and metabolites responsible for reducing RT side effects on the gut and brain. Many clinical studies fail to incorporate longitudinal assessments of both microbiome and neurocognitive data. The limited incorporation of advanced 'omics platforms, like metabolomics and metatranscriptomics has yet to reliably identify biomarkers of RT response and toxicity (). Fourth industrial revolution tools, such as artificial intelligence and machine learning, are crucial in linking all the variables and further understand their mechanism of action. This is accomplished by developing generalized robust models, that minimize bias, along with explained machine learning techniques for multifactorial longitudinal data to analyze in more accurate manner and ensure future research success. Using these tools will aid the precision of radiation therapy, minimizing the risks of radiation-induced toxicities and injuries, and making medical care more personalized (). Moreover, most of the existing preclinical studies have relied on male rodents, neglecting sex-specific variants in gut microbiota compositions and neuroinflammatory responses (). The field currently lacks the application of standardized approaches for microbiota modulation, like FMT and precision nutrition, which further hinder reproducibility and clinical application (). Subsequent research must further clarify the role of the MGBA axis across varying malignancies, radiation site, and dose parameters (). Cross-disciplinary collaboration will be the key in achieving applicable realistic progress in personalized radiation oncology intervention (). [Liu et al., 2021] [Herrera-Quintana et al., 2024] [Chakraborty et al., 2025] [Lu et al., 2024] [Li et al., 2022] [Yi et al., 2023]

The MGBA represents a dynamic modulator, where microbiota can influence the host's pathophysiological responses to RT. Preclinical evidence shows the significance of microbial metabolites and immune signaling in driving these effects, and recent clinical studies further supports these findings (;). Implementing strategies that targets the MGBA axis can significantly reduce RT-associated morbidities. A clear Interdisciplinary approach containing microbiology, neuroimmunology, and behavioral sciences is needed to turn these theoretical data into realistic therapies. As we refine our knowledge about microbiota-RT interactions, microbiome modulation strategies are poised to play a key role in personalized oncology radiation treatments. [Touchefeu et al., 2014] [Wang et al., 2015]

Xenobiotics are chemical substances foreign to the human body, commonly found in pharmaceuticals, food additives, pesticides and environmental pollutants—making exposure unavoidable (). These compounds enter via ingestion, inhalation or dermal absorption and primarily accumulate in the GI tract (). The gut microbiota, comprising diverse bacterial species, plays a central role in metabolizing xenobiotics through detoxification, bio activation or conversion into excretable forms (). Given the vast number and variety of xenobiotics encountered by the gut microbiota—over 25,000 compounds, understanding these interactions is critical (). Xenobiotics can reshape microbial communities, alter spatial organization, and disrupt host–microbiota signaling (;). These disruptions have been found to impair communication in the MGBA, a pathway increasingly linked to psychiatric symptoms (). [Jin et al., 2023] [Hawkins et al., 2020] [Catron et al., 2019] [Lindell et al., 2022] [Sutherland et al., 2020] Figure 10 [De Filippis et al., 2024]

Although emerging evidence links xenobiotics, such as antibiotics (most commonly prescribed pharmaceuticals), glyphosate (most widely used herbicide), and microplastics (MPs)—(ubiquitous emerging environmental contaminant) with anxiety and depression, studies remain limited and mechanisms of action are poorly understood (;;). Given that these mental health conditions are projected to become the leading contributor to the global disease burden by 2030 (), understanding how xenobiotics disrupt gut–brain communication is urgently needed. This review examines how these three major xenobiotic classes disrupt gut–brain axis communication, potentially contributing to anxiety and depression-like symptoms. [Zhang et al., 2021a] [Hsiao et al., 2023] [Luo and Lin, 2025] [Liu J. et al., 2024]

Plastic manufacturing has undergone a rapid expansion since 1950. In 2022, global production reached 400 million tons, and it is expected to double by 2050 (). These materials degrade slowly, fragmenting into MPs (<5 mm) and nanoplastics (NPs; 1–100 nm), which have emerged as widespread environmental pollutants and a potential threat to human health (). MPs/NPs are either directly used in cosmetics, detergents, lotions, shampoos, synthetic textiles, and industrial processes, or formed secondarily through the degradation of larger plastic items such as packaging or tire (). Common polymers include polyethylene (PE), polypropylene (PP), polystyrene (PS), and polyvinyl chloride, often combined with additives such as plasticisers or flame retardants (). MPs/NPs have been detected across aquatic species including molluscs, fish, and crustaceans, raising concern about bioaccumulation in humans, with estimated intake ranging from 0.1 to 5 g/week via contaminated food, water and air (;). This exposure concern has been validated by direct tissue analysis. Postmortem human study demonstrated MPs/NPs were 7–30 times higher in frontal cortex than kidney or liver, with 75% of particles identified as PE (). Frontal cortex concentrations increased by 50% from 2016 to 2024, with dementia cases exhibiting higher accumulation than controls (). [Houssini et al., 2025] [Zheng et al., 2024] [Zheng et al., 2024] [Zheng et al., 2024] [Li G. et al., 2024] [Zheng et al., 2024] [Nihart et al., 2025] [Nihart et al., 2025]

Furthermore, a preclinical study demonstrated that circulating MPs may impair brain function via immune-mediated vascular occlusion (). Following MP phagocytosis, immune cells obstructed cortical capillaries, producing neurological deficits that persisted for 4 weeks (). The authors demonstrated that larger particles (5 μm) caused more severe obstruction than smaller ones (2 μm, 80 nm), suggesting size-dependent neurovascular toxicity. Interestingly, while maternal PE MPs/NPs exposure increased umbilical flow by 43% in mice, it did not affect fetal growth or brain circulation—suggesting effective compensatory mechanisms (). Collectively, these studies suggest MPs/NPs potentially exhibiting neurotoxic effects on cerebral tissue and vascular integrity, while negative effects during fetal exposure may be mitigated by placental adaptation. [Huang et al., 2025] [Huang et al., 2025] [Hanrahan et al., 2024]

Human exposure to microplastics can occur via respiratory inhalation, transdermal absorption and oral ingestion via food and plastic packaging () with the gut being a primary site of accumulation (). MPs were found in every stomach examined at autopsy, averaging 9.4 particles per person, with an estimated daily intake of 32.2 particles (). Recent preclinical studies found that gut microbiota participates in MPs and NPs induced anxiety and depression-like behaviors by modulating the gut–brain axis. MPs disrupt the Firmicutes/Bacteroidetes (F/B) ratio—a key marker of microbial balance in mice (;;) and zebrafish () suggesting a conserved disruption of dominant phyla across species in response to MPs exposure. This was often accompanied by enrichment of pro-inflammatory Proteobacteria and depletion of protective phyla such as Verrucomicrobia, indicating a shift toward inflammation and barrier dysfunction (). Furthermore, MPs induce gut dysbiosis by decreasing probiotic bacteria and increasing pro-inflammatory. In male mice even low-dose exposure to PS-MPs and PS-NPs (0.5 mg/day for 60 days) reduced, a genus important for epithelial maintenance (). Similar reductions followed in male mice study exposed to low-density polyethylene MPs (LDPE-MPs) and oxidized low-density polyethylene MPs (Ox-LDPE-MPs) for 28 days (;) suggesting microbial vulnerability across polymer types. Similarly, SCFA-producing genera were consistently depleted in male rodent models exposed to PS-MPs and PS-NPs includingand()and(), and(). These losses occurred irrespective of dose, duration, or particle size. Moreover, an overgrowth of pro-inflammatory gut bacteria was shown across rodent models and doses. This included(),, and(). Moreover, gut barrier dysfunction was consistently observed in rodent models following microplastics exposure, marked by reduced expression of tight junction proteins—ZO-1, Occludin, Claudin-1, and Claudin-5 (;;). This epithelial disruption was linked to elevated serum LPS, confirming increased intestinal permeability and microbial translocation. Increased levels of IL-1β, IL-6, and TNF-α further demonstrated systemic immune activation (;). Interestingly, Ox-LDPE-MPs showed greater inflammatory responses and intestinal damage compared to LDPE-MPs which was hypothesized to result from their easier cellular accumulation (). [Wu P. et al., 2022] [Sun et al., 2025] [Özsoy et al., 2024] [Chen et al., 2023] [Yang J.-Z. et al., 2023] [Wang J. et al., 2024] [Qian et al., 2025] [Stolfi et al., 2022] [Chen et al., 2023] [Wang et al., 2023b] [Wang J. et al., 2024] [Yang J.-Z. et al., 2023] [Jiang et al., 2023] [Chen et al., 2023] [Chen et al., 2023] [Yang J.-Z. et al., 2023] [Jiang et al., 2023] [Yang J.-Z. et al., 2023] [Wang J. et al., 2024] [Yang J.-Z. et al., 2023] [Wang J. et al., 2024] [Wang et al., 2023b] Lactobacillus Faecalibaculum Akkermansia , Oscillibacter Ruminococcus Lachno Clostridium Desulfovibrio Mucispirillum, Helicobacter, Paraprevotella Tuzzerella

Furthermore, peripheral immune changes were associated with neuroinflammatory responses in mood-related brain regions. Hippocampal TLR4/MyD88/NF-κB signaling was activated () the cAMP/PKA/p-CREB pathway was altered in the amygdala alongside neuronal apoptosis (), and cortical cytokines—including IL-1β, IL-6, and TNF-α were elevated (), each coinciding with anxiety- and depression-like behaviors. Exposure to MPs consistently disrupted monoaminergic and cholinergic signaling. In rats, long-term low-dose PS-NPs exposure reduced amygdalar metabolites-N-acetylserotonin, N-acetyl-L-tyrosine, and 4-aminobutyric acid, suggesting impaired neurotransmitter metabolism (). In mice, 28-day exposure to LDPE and Ox-LDPE MPs reduced acetylcholine levels in the cortex and hippocampus (). In zebrafish, 90-day exposure to Polyactic Acid (PLA) and Aged Polyactic Acid (APLA) MPs (1–20 mg/L) suppressed 5-HT and DA, decreased acetylcholinesterase activity in the brain and gut and downregulated BDNF/TrkB signaling, coinciding with neuronal apoptosis. Interestingly, these effects were more pronounced in the high-dose APLA group compared to PLA, suggesting dose- and type-dependent neurotoxicity (). Behavioral alterations from MPs exposure demonstrated clear dose-response and particle-specific patterns () reported no alteration in neuropsychiatric symptoms at 12 weeks but observed clear effects after 24 weeks of exposure, supporting cumulative neurotoxicity. There were greater impairments with higher-dose APLA vs. PLA, suggesting dose- and polymer-specific toxic effects on neuropsychiatric symptoms (). Furthermore, Ox-LDPE caused more pronounced anxiety-like behaviors compared to LDPE, with oxidized particles producing more severe behavioral impairments (). MPs caused more pronounced anxiety-like behaviors compared to NPs after 30 days of exposure, hypothesizing that NPs are more easily absorbed and removed due to their smaller size, resulting in less neurotoxicity than MPs (). The behavioral toxicity threshold of MPs remains to be defined. Future studies should investigate the effects across polymer types, doses and exposure durations. Several interventions have reversed MPs-induced neurotoxicity by targeting the gut microbiota, supporting a causal role of the MGBA (). A treatment with epigallocatechin gallate (EGCG), a polyphenol from green tea, restored microbial composition, preserved tight junction expression, and reduced systemic inflammation (). Moreover, rats treated with 1% neohesperidin dihydrochalcone for 1 month showed reduced amygdala neuroinflammation via suppression of cAMP/PKA pathway activity, restoration of cortical 5-HT, DA, and NE levels, and reversal of anxiety- and depression-like behaviors (). Similarly, bile acid treatment rescued microbial diversity and restored 5-HT, DA, acetylcholine, BDNF, and tropomyosin receptor kinase B levels in both brain and gut of zebrafish, alleviating behavioral symptoms (). Moreover, supplementation with(DP189) and GOS restored gut microbial composition, improved gut and BBB integrity, reduced cortical inflammation and elevated acetylcholinesterase activity, reversing anxiety and depression-like behaviors in mice (). [Yang J.-Z. et al., 2023] [Jiang et al., 2023] [Wang J. et al., 2024] [Jiang et al., 2023] [Wang J. et al., 2024] [Qian et al., 2025] [Jiang et al., 2023] [Qian et al., 2025] [Wang J. et al., 2024] [Chen et al., 2023] [Yang J.-Z. et al., 2023] [Yang J.-Z. et al., 2023] [Jiang et al., 2023] [Qian et al., 2025] [Wang J. et al., 2024] Lactobacillus plantarum

While human studies remain scarce, emergingmodels simulating human gut conditions reveal variable microbiota responses to MPs, ranging from dysbiosis and inflammatory metabolite production to probiotic enrichment and metabolic adaptation (;). In the M-ARCOL model (Mucosal Artificial Colon, an advancedsystem using microbiota from healthy donors), daily exposure to PE—MPs for 14 days increased pathobiont(). Elevated levels may contribute to the development of depression by promoting hydrogen sulfide–mediated inflammation (). Furthermore, donor-dependent rises in, alongside reductions in protective taxaandwere found ().exhibits a capacity to influence the HPA axis, a central regulator of the body's stress response () and depleted levels have been found in individuals with MDD, supporting their proposed role as protective taxa within the MGBA (). in vitro in vitro Desulfovibrionaceae Enterobacteriaceae Christensenellaceae Akkermansiaceae Christensenellaceae [Fournier et al., 2023] [Jiménez-Arroyo et al., 2023] [Fournier et al., 2023] [Yang et al., 2017] [Fournier et al., 2023] [Agusti et al., 2024] [Liu R. T. et al., 2020]

Moreover, skatole, a tryptophan-derived metabolite typically low in healthy individuals, was also elevated, suggesting disruption of gut homeostasis (). However, biodegradable plastics show contrasting effects. Interestingly, certain MPs may be metabolically processed by the human gut microbiota without causing detrimental alterations. In the SIMGImodel (ansimulator of human digestion), a single dose of 0.166 g of PLA—a widely used biodegradable plastic was followed by 72-h colonic fermentation. An increase in probioticwas detected in all donors (). During this process, PLA particles were colonized by gut microbes, forming surface biofilms and increasing pullulanase activity—an enzyme that degrades branched polysaccharides—the authors suggested this may have broken down PLA into smaller carbon-rich molecules, potentially supportinggrowth, without triggering pathogenic overgrowth or inflammatory responses (). These findings were challenged by a more recentstudy, using fecal microbiota from healthy donors (). Biodegradable MPs such as PLA and Poly(ε-caprolactone) underwent degradation and oligomerization while significantly depleting beneficial bacteria including, and(). These play a significant role in neurotransmitter production, inflammation control and barrier regulation and their depletion is frequently observed in individuals with depression and anxiety further suggesting their relevance to mental health (;). Moreover, biodegradable MPs increased potentially harmfulandwith SCFA production impairment, authors hypothesizing that biodegradable plastics may cause greater harm than conventional plastics because their degradation creates oligomers—smaller breakdown products that can more easily penetrate biological barriers and further exhibit detrimental effects on gut microbiota (). However, small donor sample sizes limit generalizability, as they may not capture donor-dependent shifts or reflect broader diversity in age, diet, or health. Moreover, these models used adult microbiota, despite evidence that infants are found to contain higher levels of MPs in fecal samples (). Future studies should include larger, diverse cohorts and age-relevant microbiota. [Fournier et al., 2023] [Jiménez-Arroyo et al., 2023] [Jiménez-Arroyo et al., 2023] [Peng et al., 2024] [Peng et al., 2024] [Borkent et al., 2022] [Xiong R.-G. et al., 2023] [Peng et al., 2024] [Zhang et al., 2021b] ® in vitro Bifidobacterium Bifidobacterium in vitro Bifidobacterium, Lactobacillus, Faecalibacterium, Blautia Ruminococcus Megamonas Prevotella

Glyphosate is a widely used herbicide acting via inhibition of the enzyme 5-enolpyruvylshikimate-3-phosphate synthase, which blocks the shikimate pathway responsible for synthesizing aromatic amino acids including phenylalanine, tyrosine and tryptophan (). These are known precursors to neurotransmitters that modulate mood, behavior and cognition. The shikimate pathway is absent in mammals; therefore, glyphosate has been considered safe for human health, however, this pathway is present in plants and many microorganisms, including members of the gut microbiota (). As some gut bacteria rely on the shikimate pathway for nutrient synthesis or metabolic cross-feeding, glyphosate exposure may alter microbial composition, as 12–26% of human gut bacterial species may be sensitive to glyphosate (;). Therefore, GBA may be proposed as a potential mediator of glyphosate-associated neuropsychiatric effects in humans (). Although glyphosate has been classified as a potentially carcinogenic substance () and has been linked to psychiatric symptoms and neurotoxicity () the debate on glyphosate's detrimental effects on human health continuously persists in the scientific community with scarce number of studies and inconsistent findings. [Chiantia et al., 2025] [Mesnage et al., 2021] [Leino et al., 2021] [Puigbò et al., 2022] [Lehman et al., 2023] [Guyton et al., 2015] [Costas-Ferreira et al., 2022]

Preclinical studies found that glyphosate exposure can induce anxiety and depression-like behaviors by disrupting gut microbiome composition, impairing neurotransmitter levels and increasing neuroinflammation (). Adult mice exposed to low-dose glyphosate exposure at environmentally relevant levels (10 μg/ml) for 90 days showed reduced levels of beneficial bacteriaand(). These bacteria are found to exhibit a greater sensitivity to glyphosate exposure () and are often found at reduced levels in individuals with MDD and may play a role in the development of mood disorders (). Moreover, detrimental effects of glyphosate on gut–brain axis exhibit transgenerational effects. Reduced beneficial bacteriaandand overgrowth of Alistipes and Blautia were found in offspring of mice exposed to glyphosate during pregnancy and lactation (). This microbial shift disrupts multiple gut–brain pathways simultaneously: these shifts coincided with gut barrier disruption (elevated serum endotoxin), triggering elevated hippocampal cytokines (IL-6, TNF-α), which in turn suppress Tph2 expression and induce Tph2 hypermethylation (suggesting neuroinflammation and serotonergic suppression), ultimately manifesting as anxiety and depression-like behaviors (). These effects were dose-dependent, emerging only at 50 mg/kg/day—a level still classified as safe in animals by regulatory standards. Furthermore, the effects were sex-dependant—recorded in female offspring only. The selective vulnerability in females led the authors to hypothesize a role for estrogen-linked mechanisms, although this was not tested. Future studies should determine whether hormonal factors mediate this sex-specific sensitivity (). Moreover, exposing mice to a low dose which reflects a typical American diet (0.01 mg/kg/day), caused gut microbiota alterations across two generations-consistent with earlier findings,was depleted, whileandwere elevated in the second generation (). Interestingly,responses appear to vary between studies, asobserveddepletion rather than enrichment, suggesting exposure timing or generation-dependent effects. Whilst these microbial shifts coincided with gut barrier disruption (loss of ZO-2 tight junction protein and goblet cell depletion), colonic immune activation (elevated pro-inflammatory cytokines), and altered levels of gut-derived metabolites relevant to neuropsychiatric function (reduced GLP-1 and serum kynurenine), affective symptoms were not detected at the time of testing (), possibly due to delayed onset of behavioral abnormalities (). Future studies should employ longitudinal study designs to clarify the delayed effects of glyphosate on gut–brain interactions. [Aitbali et al., 2018] [Lehman et al., 2023] [Shehata et al., 2013] [Aizawa et al., 2019] [Buchenauer et al., 2023] [Buchenauer et al., 2023] [Buchenauer et al., 2023] [Barnett et al., 2024] [Buchenauer et al. (2023)] [Barnett et al., 2024] [Del Castilo et al., 2022] Lactobacillus Bifidobacterium Akkermansia ParaBacteroides Akkermansia muciniphila ParaBacteroides distasonis Christensenellaceae ParaBacteroides ParaBacteroides

Antibiotics are commonly prescribed medications in clinical settings and may represent one of the most powerful disruptors of the MGBA (). Antibiotic-induced depression followed by an attempt to suicide was first reported in 2010 (). Since then, large human cohort studies have linked antibiotic exposure to increased risk of depression and anxiety, with disruption of the MGBA proposed as a key mechanism (;). This proposed mechanism has been directly validated in animal models where the surgically severed vagus nerve attenuated anxiety- and depression-like behaviors in mice after oral antibiotic administration, providing direct evidence for neuropsychiatric effects induced by antibiotics through the gut–brain axis (). Preclinical studies have demonstrated that antibiotic treatment induces gut dysbiosis-marked by reduced alpha diversity, a decreased Firmicutes/Bacteroidetes ratio, depletion of beneficial genera, and enrichment of pro-inflammatory taxa (;). These microbial shifts trigger cascading gut–brain disruption by impairing neurotransmitter signaling, suppressing SCFA production, weakening epithelial barrier integrity, and activating neuroimmune pathways, ultimately resulting in anxiety- and depression-like behaviors in rodent models (;;). In mice treated with amoxicillin or ciprofloxacin, depletion of(Firmicutes) led to reduced brain and serum GABA, downregulation of GABA-A receptors, and diminished 5-HT and DA, neurochemical changes that coincided with anxiety- and depression-like behaviors (). Intergenerational exposure to vancomycin and streptomycin resulted in progressive microbial loss, with the most pronounced shifts observed in third-generation offspring (). Depletion of beneficial taxa such as(Bacteroidetes) and(Firmicutes), along with increased abundance of pro-inflammatory taxa includingand, was associated with reduced SCFA gene expression, downregulation of tight junction proteins (occludin and claudin-1), and microglial activation in the amygdala and arcuate nucleus, indicating gut barrier disruption and neuroinflammation that coincided with anxiety-like behavior. Soil microbiota restoration reversed anxiety-like behavior, attenuated microgliosis, and restored gut microbial composition in affected mice (). However, findings remain inconsistent across studies. A recent two-hit rat model study found that antibiotic-induced dysbiosis, including increasedand reduced, failed to amplify anxiety-like behaviors in immune-primed rodents, contradicting prior evidence and highlighting the complexity of gut–brain interactions (). Future studies should clarify the role of immune priming in modulating behavioral responses to antibiotic-induced gut–brain effects. [Hao et al., 2021] [Ahmed et al., 2011] [Gudnadottir et al., 2024] [Lee et al., 2024] [Joo et al., 2023] [Tejkalová et al., 2023] [Thabet et al., 2024] [Tejkalová et al., 2023] [Li N. et al., 2024] [Bibi et al., 2025] [Bibi et al., 2025] [Li N. et al., 2024] [Li N. et al., 2024] [Tejkalová et al., 2023] Lactobacillus reuteri Odoribacter Lachno Clostridium Ileibacterium Olsenella Proteobacteria Bacteroidetes