How gut bacteria may affect brain diseases by changing immune system signals through the gut-brain connection

The gut microbiota refers to the vast microbial community residing within the human gastrointestinal tract, comprising bacteria, viruses, fungi, and archaea, numbering in the trillions (16). These microorganisms not only participate in digestion, nutrient absorption, and vitamin synthesis but also interact with the host's immune, nervous, and metabolic systems through complex signaling networks, forming the so-called "gut-microbiota-host axis" (17). Through symbiosis with the host, gut microbes interact via metabolites, neurotransmitters, and immune signals. Metabolic products of gut microbes include short-chain fatty acids (SCFAs), secondary bile acids, indole compounds, trimethylamine N-oxide (TMAO), and various gas molecules (e.g., H₂S, NO, and CO) (18, 19). In addition to metabolic roles, the gut microbiota is essential for immune regulation. It guides the differentiation and function of immune cells—including T cells and dendritic cells-thereby upholding systemic immune homeostasis (20). Furthermore, by reinforcing the integrity of the intestinal epithelial barrier, the microbiota helps prevent translocation of pathogenic organisms and harmful agents, playing a critical role in host defense and overall health (21).

The intestinal epithelial barrier constitutes the primary physical and immunological line of defense, selectively restricting the passage of harmful agents into systemic circulation while actively communicating with the gut microbiota via chemosensory receptors and tight junction proteins (22). Its structural and functional integrity is essential for sustaining a stable host-microbiota relationship and preventing aberrant immune activation (23).

A second critical component is the ENS, a subdivision of the peripheral nervous system composed of intrinsic neurons and glial cells that autonomously regulate gut motility, secretion, and absorption (24). The ENS maintains bidirectional communication with the CNS through vagal and spinal pathways, forming a key neural relay within the MGBA (25). The CNS, encompassing the brain and spinal cord, receives and integrates signals from the gut through neural, endocrine, and immune pathways, thereby influencing behavior and cognitive function (26). Simultaneously, the gut-resident immune system engages in continuous interaction with commensal microbiota, deploying cytokines and inflammatory mediators that influence both local intestinal function and central nervous integrity. Dysregulation of this crosstalk has been associated with the pathophysiology of several neuropsychiatric conditions, including anxiety, depression, Major Depressive Disorder (MDD), and bipolar disorder (BD) (27, 28). Furthermore, systemic immune and endocrine pathways contribute to gut–brain signaling through circulating cytokines, hormones, and neuropeptides, collectively enabling multi-level communication across the MGBA (26).

The MGBA exerts broad influence on neurodevelopment, behavioral modulation, and disease susceptibility through multiple interconnected pathways. One primary mechanism involves the microbial production of signaling molecules—such as short-chain fatty acids (e.g., butyrate), neurotransmitters (e.g., serotonin and GABA), and indole-derived metabolites—that directly or indirectly shape neuronal plasticity and synaptic function (29). Research indicates that the gut microbiota influences serotonin synthesis by regulating the tryptophan metabolic pathway, thereby modulating mood and cognitive function (30).

Additionally, the gut microbiota regulates neuroinflammatory tone and neuroprotective mechanisms through vagus nerve activation and immune modulation. For example, in AD models, altered gut microbiota reduced neuroinflammation and cognitive impairment by increasing indole-3-acetic acid levels (31). The microbiota also contribute to neurodegenerative pathology by dynamically regulating BBB permeability, thereby controlling the CNS exposure to circulating metabolites and neurotransmitters (32).

When the composition of the gut microbiota changes-a condition known as dysbiosis-it may trigger a series of pathophysiological responses (33). This process promotes systemic immune activation (21, 34). Inflammatory signals are then relayed to the CNS via immune and neuroendocrine routes, ultimately driving neuroinflammation and neurodegeneration (33). Accumulating evidence underscores a strong association between gut microbiome dysbiosis and the pathogenesis of several neurodegenerative disorders, including AD, PD, and multiple sclerosis (MS) (35).

MGBA constitutes a complex bidirectional communication network that facilitates information exchange between gut microbiota and the CNS through multiple pathways (Figure 1). These core pathways include neural, immune, metabolic, and endocrine mechanisms, which together mediate gut-brain crosstalk.

Gut microbiota dysbiosis is considered a key driver of neuroinflammation and immune dysfunction in NDDs (49). For example, mutations in the GBA1 gene can induce microbial imbalance, which in turn exacerbates PD pathology through neuroimmune activation (50). Supporting this, preclinical studies show that microbiota depletion markedly reduces neuroinflammation and ameliorates motor deficits in disease models (51).

In NDDs, the gut microbiota influences the immune system through multiple pathways. First, gut microbiota directly shape the phenotype and function of immune cells (52, 53). Furthermore, the gut microbiota influences neuronal survival and function by modulating the activity of myeloid cells such as macrophages and microglia (54). These cells play critical roles in clearing neurotoxic substances like amyloid plaques and regulating neuroinflammation (55). Studies have demonstrated that microglia, as the primary immune effector cells in the central nervous system, display an over - activated phenotype under conditions of intestinal flora imbalance. This results in the release of a substantial quantity of pro - inflammatory factors (e.g., IL - 1β, TNF - α), which in turn leads to neuronal damage and the specific loss of dopaminergic neurons (56). For example, in AD, amyloid proteins secreted by the gut microbiota can cross-aggregate with Aβ in the brain via a molecular mimicry mechanism, which exacerbates neuroinflammation and synaptic damage (57, 58).

From an immunological perspective, dysbiosis of the gut microbiota can result in the impairment of intestinal barrier function, which facilitates the translocation of bacteria and their metabolic products (e.g., lipopolysaccharides) into the circulatory system. Subsequently, this activates peripheral immune cells and initiates a systemic inflammatory response. These inflammatory mediators can impact the central nervous system through multiple pathways. Firstly, the disruption of the integrity of the BBB enables cytokines and immune cells to infiltrate the brain parenchyma. Secondly, peripheral immune signals can be transmitted to the central nervous system via the vagus nerve or directly act on brainstem circumventricular organs (e.g., the area postrema) (59). For example, in PD, the age-associated decline in immune system function, combined with long-term exposure to environmental factors like pesticides or pathogens, can be further aggravated by gut microbiota dysbiosis, creating an ideal situation that facilitates the pathological spread of α-synuclein (49). It is noteworthy that the gut microbiota also influences the production of kynurenine through the regulation of the tryptophan metabolic pathway. This metabolic product can not only exert an effect on the enteric nervous system, leading to intestinal dysfunction, but also cross the BBB to directly modulate the immune balance of the central nervous system (50, 60).

The gut microbiota also modulates bile acid and tryptophan metabolism, with downstream effects on neurotransmitter synthesis and neuronal viability (61). Specific tryptophan metabolites such as indole-3-acetaldehyde (I3AA) have been shown to regulate TGFβ signaling and CD4⁺ T cell differentiation, thereby exacerbating intestinal and neuroinflammation (62).

Collectively, the gut microbiota influences the MGBA through multiple core communication pathways-encompassing neural, immune, metabolic, endocrine, microbial metabolite, and barrier functions. These pathways are highly interconnected, forming an integrated network that collectively regulates bidirectional gut–brain communication and ultimately shapes host physiology and disease susceptibility. A deeper understanding of these mechanisms will not only help clarify the pathogenesis of NDDs but also provide a scientific rationale for developing novel microbiota-targeted therapeutic strategies.

As a NDDs, AD involves a complex pathogenesis encompassing multiple factors such as chronic neuroinflammation, Aβ, and abnormal tau phosphorylation. In AD, the gut microbiota influences disease progression by regulating Aβ deposition and tau hyperphosphorylation (55, 64). Gut microbiota dysbiosis has been demonstrated to be closely associated with AD pathogenesis. In AD patients, the abundance of Firmicutes and Bifidobacteria in the gut is reduced, while the abundance of Bacteroidetes and Proteobacteria is increased (65). This imbalance may induce "Leaky Gut" syndrome, allowing pathogen-associated molecular patterns (PAMPs) such as LPS to enter the bloodstream and trigger systemic low-grade inflammation (66). Research indicates that gut dysbiosis-induced intestinal permeability facilitates bacterial LPS and Aβ entry into the bloodstream, further activating microglia and exacerbating AD-associated neuroinflammation (67). Microglia, the primary immune cells of the CNS, exhibit dysfunction that constitutes a core pathological feature of AD. Certain gut microbial metabolites may induce abnormal activation of microglia and cross-seeding of amyloid through molecular mimicry mechanisms, further exacerbating AD pathology (68). Additionally, gut dysbiosis can cause astrocyte dysfunction, thereby impairing neuronal energy metabolism and antioxidant capacity, promoting neuronal degeneration (20). Microbial metabolites-including SCFAs, LPS, and trimethylamine N-oxide (TMAO)-also contribute to AD progression by enhancing systemic inflammation, disturbing cerebral Aβ clearance, and directly activating microglia, which intensifies neuroinflammation and neuronal injury (69 –72). Moreover, gut microbes influence cognitive function in AD through the regulation of glutamate metabolism. Specific bacteria, such as Bacteroides vulgatus and Campylobacter jejuni, can lower levels of the glutamate metabolite 2-ketoglutarate, potentially altering NMDA receptor function and synaptic plasticity (73). Other microbiota-derived molecules, including secondary bile acids and tryptophan metabolites, may also modulate brain function and immune activity, thereby shaping AD trajectory (74).

Additionally, the interaction between the gut microbiota and the immune system constitutes a key mechanism in the onset and progression of AD. Research indicates that the efficacy of AD immunotherapies may partially depend on the regulatory role of the gut microbiota. For example, in AD mouse models, tau-targeted immunotherapy significantly alters the composition of the gut microbiota, thereby influencing treatment outcomes (75).

Dysbiosis of the gut microbiota has been demonstrated to be closely associated with PD. In the research on biodiversity, the Simpson's Index and the Species Evenness Index are frequently employed for assessment (76). Specifically, the Simpson's Index is utilized to quantify the concentration or dominance within a community (77), while the Species Evenness Index is designed to measure the uniformity of the distribution of individual numbers of various species within a community (78). Studies report reduced Simpson and species evenness indices in PD patients, reflecting decreased microbial diversity and ecological imbalance (79). Characteristic shifts include a decline in Firmicutes abundance with concomitant increases in Bacteroidetes and Proteobacteria. The expansion of pro-inflammatory taxa can elevate circulating lipopolysaccharide (LPS), promoting systemic inflammation and potentially accelerating PD pathology (80, 81). These alterations may compromise intestinal barrier function, thereby promoting gut inflammation and systemic inflammatory responses that ultimately affect the CNS via the gut-brain axis (82). Indirectly, they regulate BBB permeability and neuroinflammatory responses, thereby affecting neuronal survival. For instance, probiotic supplementation with Bifidobacterium lactis MH-022 has been shown to improve motor function and neuronal integrity in PD models by enhancing antioxidant defenses and suppressing neuroinflammation (83). A central pathological feature of PD is the aggregation of α-synuclein. Gut dysbiosis may promote the misfolding and aggregation of α-synuclein in the ENS (84, 85). These pathological forms can potentially propagate to the CNS via the vagus nerve, leading to Lewy body formation and PD-related neurodegeneration (86, 87).

Microbial metabolites-including SCFAs, H₂S, and tryptophan derivatives-also contribute to PD progression. SCFAs exhibit anti-inflammatory and neuroprotective effects; for instance, propionic acid exerts neuroprotection by activating the FFAR3 receptor, alleviating motor dysfunction and dopaminergic neuron loss in PD models (88). However, their levels are significantly reduced in PD patients, potentially diminishing their inhibitory effect on neuroinflammation (89). Other microbial metabolites, including H₂S, Adenosine (ADO) and Quinolinic acid (QA) may promote oxidative stress and mitochondrial dysfunction, exacerbating neuronal injury (90 –95).

Immune regulation represents another key mechanism by which the gut microbiota influences PD. Research indicates that in PD, the gut microbiota affects immune responses and neuronal function by regulating amino acid metabolism (e.g., branched-chain amino acids and aromatic amino acids) (96). Alterations in microbial composition can activate innate and adaptive immunity, leading to sustained neuroinflammation and neuronal damage (83). For example, certain gut bacteria (e.g., Ruminococcaceae) can enhance immune responses by activating dendritic cells (DCs) and CD8⁺ T cells (97). Furthermore, dysbiosis may promote α-synuclein aggregation and propagation by modulating Toll-like receptor (TLR) signaling pathways (98).

ALS is a progressive NDDs characterized by the selective loss of motor neurons. Its pathogenesis is multifactorial, involving a complex interplay of genetic, epigenetic, and environmental influences (99). In recent years, the gut microbiota has emerged as a key modulator in ALS pathophysiology, primarily through its role in the bidirectional GBA that links the gastrointestinal tract with the CNS (100).

Patients with ALS exhibit decreased gut microbial diversity and significant compositional shifts, including an increased abundance of Enterobacteriaceae and reduced levels of beneficial genera such as Bifidobacterium and Clostridium sensu stricto (101 –103). This dysbiotic state can trigger non-cell-autonomous neuroinflammation by activating microglia and astrocytes, thereby accelerating motor neuron injury (99). Furthermore, impaired intestinal barrier integrity-driven by microbial imbalance-facilitates the systemic translocation of bacterial metabolites and pro-inflammatory mediators, which may subsequently compromise CNS immune homeostasis (104).

Notably, microbial metabolites play a dual role in ALS progression. SCFAs such as butyrate exert anti-inflammatory and neuroprotective effects, yet their levels are often diminished in ALS patients (105). Similarly, SCFAs can directly stimulate the vagus nerve, thereby regulating inflammatory responses and neuroprotective mechanisms within the CNS (106). The gut microbiota further influences ALS by shaping peripheral immune responses. Dysregulation promotes the infiltration and skewed differentiation of T cell populations-such as an imbalance between Th17 and Treg cells-which amplifies neuroinflammation and motor neuron damage (99).

Metagenomic analyses also reveal marked alterations in microbial metabolic pathways in ALS, particularly those involved in neurotransmitter synthesis and neuroprotection (107). For instance, tryptophan metabolites produced by the gut microbiota-such as serotonin and kynurenine-exhibit dysregulation in ALS patients, with elevated kynurenine levels closely linked to neuroinflammation and oxidative stress (108).

In summary, the gut microbiota contributes to NDDs pathogenesis through metabolite signaling, immune modulation, and gut-brain communication. However, given the rapid progression and heterogeneity of NDDs, the precise causal role of microbial communities remains incompletely defined. Future studies should focus on elucidating the specific mechanisms underlying gut-brain interactions in NDDs and evaluating the translational potential of microbiota-targeted interventions.