Role of the microbiota in inflammation-related related psychiatric disorders

In major depressive disorder (MDD), the most affected bacterial phyla include Firmicutes, Actinobacteria, and Bacteroidetes, leading to an elevated Bacteroidetes/Firmicutes ratio (24). Characteristic changes involve the enrichment of Bacteroides and depletion of Blautia, Faecalibacterium, and Coprococcus. In addition, an increased abundance of Eggerthella and reduced abundance of Sutterella are consistently observed in patients with MDD. A pathological vicious cycle is supported by evidence revealing an elevated abundance of pro-inflammatory genera (e.g., Escherichia) in depression (25). These microbial shifts could drive MDD pathogenesis. Research on post-intervention outcomes of intestinal probiotics demonstrated that supplementation with Bre1025 (Bifidobacterium longum) restores 5-HT levels in the brain while concurrently suppressing serum corticosterone and pro-inflammatory cytokine expression (e.g., IL-1β, IL-6) and elevating the expression of the anti-inflammatory cytokine IL-10 (26). Furthermore, JB-1 (Lactobacillus rhamnosus) supplementation alters gamma-aminobutyric acid (GABA) neurotransmission via the vagus nerve, thereby ameliorating depressive symptoms (27).

Patients with anxiety disorders exhibit an increased Firmicutes/Bacteroidetes ratio, marked by the overgrowth of Clostridium and Desulfovibrio alongside reductions in the abundance of SCFA-producing genera (e.g., Bifidobacterium, Lactobacillus) (28). Clostridium species can exacerbate anxiety-like behaviors by generating neurotoxic metabolites (e.g., p-cresol), which disrupt dopamine and 5-HT metabolism. Recent studies revealed distinct gut microbial community structures across anxiety states, with the abundance of Akkermansia being inversely correlated with anxiety severity (29, 30). Akkermansia muciniphila synergizes with lactate to restore the tryptophan metabolic balance, promoting 5-HT synthesis and alleviating anxiety (29).

Schizophrenia is associated with distinct gut microbiota alterations characterized by reduced α-diversity, featuring an increased abundance of Proteobacteria and Lactobacillus alongside diminished levels of anti-inflammatory commensals such as Prevotella (31). The condition exhibits a pro-inflammatory microbial profile with an increased abundance of Lachnoclostridium and a decreased abundance of SCFA-producing Blautia spp. and Ruminococcus spp (32)., corresponding with elevated lipopolysaccharide (LPS) (32) and reduced superoxide dismutase-1 levels (33). Notably, the abundance of Lachnoclostridium might predict poor cognitive improvement (34), whereas acute-phase patients display Streptococcus vestibularis enrichment associated with cognitive decline (35). Mechanistically, impaired SCFA synthesis (butyrate/propionate) compromises immunomodulation, and dysregulated tryptophan metabolism (via the kynurenine pathway) reduces 5-HT content, exacerbating the neurotransmitter imbalance (36). Gut dysbiosis further activates the vagus nerve–hypothalamic–pituitary–adrenal axis, inducing hippocampal microglial M1 polarization, whereas SCFA deficiency directly impairs neuronal mitochondrial function, amplifying oxidative stress (37). These findings collectively suggest that gut microbiota dysbiosis plays a multifaceted role in schizophrenia pathogenesis through immune–metabolic–neural pathways.

Patients with BD exhibit gut dysbiosis, including disrupted Firmicutes/Bacteroidetes ratios, reduced α-diversity, and altered β-diversity. The elevated abundance of Streptococcaceae and Bacteroidaceae contrasts with the depletion of A. muciniphila and F. prausnitzii (38). Functional analyses revealed significant differences in amino acid metabolism and vitamin synthesis pathways (39). Notably, the abundance of Faecalibacterium (an anti-inflammatory, gram-positive commensal) is reduced in BD, IBD, and depression, suggesting gut dysbiosis can broadly disrupt CNS physiology.

PD is associated with gut microbial dysbiosis characterized by an increased abundance of Lactobacillus and Bifidobacterium but reduced levels of Faecalibacterium, Coprococcus, and Blautia (40, 41). Probiotic interventions (e.g., L. casei) mitigate β-amyloid deposition and cognitive decline, highlighting microbial metabolites as potential therapeutic targets (42, 43). Altered branched-chain and aromatic amino acid levels in fecal samples are correlated with PD progression (44, 45). Recent clinical studies indicated that patients with PD exhibit a reduced abundance of Blautia and diminished fecal levels of the SCFA butyrate. The abundance of Blautia is correlated with the clinical severity of PD. The RAS-related pathway, a pivotal inflammatory signaling pathway modulated by butyrate, has emerged as a key mechanism inhibiting microglial activation in PD. Alterations in the RAS–NF-κB pathway have been observed in patients with PD. Furthermore, butyrate derived from B. producta inhibited microglial activation by regulating the RAS–NF-κB pathway (46).

The gut microbiota drives AD pathology through the "leaky gut–systemic inflammation–neuroimmune activation" axis, in which intestinal barrier dysfunction triggers systemic inflammation, which ultimately activates neuroimmune responses (47). In patients with AD, this process is characterized by reduced microbial diversity, with decreased levels of probiotics (e.g., Bifidobacterium) and increased levels of opportunistic pathogens (e.g., E. coli, Clostridium) and poly-unsaturated fatty acids (PUFAs), along with diminished levels of anti-inflammatory SCFAs, thereby exacerbating neuroinflammation (48, 49). Therapeutic strategies targeting this axis include probiotic supplementation (e.g., Lactobacillus) and high-fiber diets to boost SCFAs and suppress pro-inflammatory pathways, short-term antibiotic regimens or fecal microbiota transplantation (FMT), which has displayed efficacy in murine models (although long-term safety validation is required), and gut–brain axis-targeted drugs such as GV-971 that remodel the microbial balance while inhibiting neuroinflammation and improving cognitive function (50). These microbiota-modulating approaches represent promising strategies for delaying AD progression.

ASD, a neurodevelopmental disorder marked by social deficits and repetitive behaviors, is linked to gut–brain crosstalk via microbial metabolites (51). Higher concentrations of p-cresol exhibit a significant link to increased symptom severity in ASD, demonstrating a strong correlation with both intensified behavioral symptoms and developmental regression patterns. P-cresol contributes to the pathogenesis of ASD by inducing dopamine accumulation and enhancing dopamine metabolism in the brain. This effect is partly explained by evidence identifying p-cresol as an inhibitor of dopamine β-hydroxylase (DBH)—the enzyme responsible for converting dopamine (DA) into norepinephrine (NE). By blocking dopamine's transformation into norepinephrine, p-cresol further amplifies dopamine accumulation and promotes heightened dopaminergic metabolic activity within neural systems and reward circuitry (52, 53). Emerging evidence indicates that Candida spp. contribute to immune dysregulation, behavioral abnormalities, and alterations in brain activity, corroborated by their elevated prevalence in the feces of individuals with ASD. This genus might exacerbate hyperserotonemia through enhanced peripheral 5-HT production coupled with impaired brain 5-HT synthesis from tryptophan, thereby aggravating neurobehavioral symptoms (54). Biomarkers include brain-derived neurotrophic factor (BDNF), calprotectin, S100B, and dysregulated cytokines (e.g., CCL5, eotaxin), underscoring the role of gut–microbiota–immune interactions in ASD pathogenesis (55, 56). Specific ASD-related microbial shifts and potential differential mechanisms are summarized in Table 1.

Probiotic interventions demonstrate multifaceted therapeutic potential. Bifidobacterium enhances SCFA production, lowers intestinal pH to suppress pathogenic overgrowth, and upregulates BDNF to improve hippocampal neuroplasticity. L. casei mitigates cognitive decline by inhibiting β-amyloid aggregation and slowing disease progression in PD. F. prausnitzii, a keystone anti-inflammatory species, ameliorates CNS dysfunction in both IBD and depression. A. muciniphila synergizes with lactate to restore tryptophan metabolic balance, promoting 5-HT synthesis and alleviating anxiety.

FMT and probiotic formulations hold promise as alternatives to conventional pharmacotherapies, particularly in restoring tryptophan homeostasis and reducing peripheral IL-6 levels. Given their mechanistic versatility and safety profile, microbiota-targeted therapies are poised to gain clinical traction.

With more than 6.8 million patients globally affected by Crohn's disease and ulcerative colitis, current therapies (e.g., immunosuppressants, biologics) remain palliative, often causing drug resistance and opportunistic infections with prolonged use (97). Notably, approximately 30% of patients with IBD develop anxiety or depression, underscoring the urgent need for dual-action therapies that concurrently resolve gut inflammation and modulate the gut–brain axis.

Preclinical evidence has highlighted the potential of synergistic strategies. Lamotrigine, a mood stabilizer, attenuates neuroinflammation by suppressing glutamatergic hyperactivity. Duloxetine, when co-administered with lamotrigine, potentiates 5-HT/norepinephrine reuptake inhibition, disrupting the inflammation–depression cycle. Such combinatorial approaches exemplify the paradigm shift toward targeting gut–brain axis dysregulation in psychiatric comorbidities. Future innovations could combine anti-inflammatory biologics (e.g., IL-6/IL-17 inhibitors) with neuromodulatory agents to achieve sustained remission.