Jul 20 2026

From short-chain fatty acids to bile acids, researchers trace how microbial chemistry could influence brain signaling and point to potential adjunctive treatments that still require stronger human evidence.

Study: Gut microbiota-driven metabolites modulate the development of stress-related mental disorders. Image Credit: Corona Borealis Studio / Shutterstock

A recent review published online as an 'article in press' in the journal Translational Psychiatry suggests that gut dysbiosis may contribute to stress-related psychiatric disorders. Alterations in the gut microbiome may change the production of metabolites that influence neural, endocrine, immune, and epigenetic gut-brain signaling, affecting cognitive and emotional function and potentially contributing to stress-related psychiatric disorders.

Chronic stress may predispose individuals to psychiatric conditions such as anxiety, depression, or post-traumatic stress disorder (PTSD). Together, these conditions impose a substantial global health burden. Current diagnostic and treatment approaches remain largely empirical, resulting in relatively limited diagnostic accuracy and therapeutic efficacy. Further investigations are required to improve the understanding of biological mechanisms underlying the association between stress and psychiatric disorders to help develop more targeted strategies and ultimately improve patient outcomes.

In the present review, researchers discuss the association between gut dysbiosis and stress-related psychiatric disorders and summarize preclinical and clinical evidence concerning the association.

Gut Dysbiosis and Mental Health

An increasing body of preclinical as well as clinical evidence suggests that disruptions in the structure and function of the intestinal microbiome are associated with the onset and progression of stress-related psychiatric disorders. Gut microbes produce or transform several classes of metabolites, including bile acids (BAs), short-chain fatty acids (SCFAs), monoamine-related metabolites, and amino acid-related metabolites. These substances influence signaling pathways that link the gut and the brain. These pathways are involved in several immunological, endocrine, neural, and epigenetic processes, alterations in which may predispose individuals to psychiatric disorders.

Altered metabolite profiles may affect intestinal permeability and regulate serotonin release. Increased intestinal permeability may allow microbial products such as lipopolysaccharide (LPS), an endotoxin, to cross the intestinal barrier and enter the circulation. These microbial products may promote peripheral and central inflammatory signaling and influence activation of the NLRP3 inflammasome in the brain. Gut metabolites may also alter epigenetic regulation linked to depression. Gut microbial imbalance could adversely affect cognitive and emotional functions through the hypothalamic-pituitary-adrenal (HPA) axis, autonomic nervous system, neurotransmitter systems, and immune-inflammatory pathways. While the vagus nerve may transmit signals to the brain, stress responses may also alter the gut microbiome.

Evidence from Human and Animal Studies

Gut-derived SCFAs help maintain intestinal barrier integrity and promote epithelial repair. Several clinical and preclinical studies have associated lower butyrate levels with depression, although findings vary across populations and experimental conditions. Butyrate also helps regulate immune activity. SCFAs can suppress pro-inflammatory signaling through several mechanisms. For example, propionate may inhibit the nuclear factor kappa B (NF-κB) pathway, while butyrate can regulate immune tolerance through epigenetic pathways. These beneficial metabolites could also enhance the transcriptional activity of antioxidant and anti-inflammatory genes. Animal studies suggest that reduced butyrate and beneficial gut microbes are associated with depressive behaviors, while butyrate or acetate supplementation can improve mood-related behaviors and cognitive function.

In preclinical studies, SCFAs can also cross the blood-brain barrier to regulate neuroplasticity, while low-dose propionate reduced depression-like behaviors, whereas high-dose propionate promoted these behaviors in one model. In correlation studies, gut microbiome composition has been linked with several tryptophan (Trp)-derived metabolites. Bacterial taxa within the Bacteroidetes, Firmicutes, and Proteobacteria phyla have been associated with 5-hydroxyindoleacetic acid (5-HIAA) and serotonin. These taxa have also been associated with kynurenine pathway metabolites involved in immune function. Murine stress models receiving Trp supplementation have shown a reduction in anxiety- and depression-like behaviors.

In depressed mice, supplementation with a psychobiotic Bifidobacterium breve strain restored indole-3-lactic acid (ILA) levels in hippocampal and intestinal tissues. Baseline gut microbiome composition and indole-3-propionic acid (I3PA) levels have also been associated with response to escitalopram treatment. In rats, rifaximin ameliorated depression-like behavior by altering the intestinal microbiota and hippocampal kynurenine and serotonin metabolism. Altered glutamate and proline metabolism has been linked to depression, with studies also reporting associations involving Actinobacteria, Firmicutes, and Bacteroidetes. Preclinical fecal microbiota transplantation (FMT) studies suggest that alterations in the gut microbiome can modulate central proline levels and matrix metalloproteinase (MMP) activity, changes associated with depression-like behavior.

Gut dysbiosis may also contribute to the development of psychiatric disorders through bile acid (BA) dysregulation and alterations in dopamine-related metabolites. Preclinical studies suggest that TGR5 activation can produce antidepressant-like effects, with secondary BAs acting as particularly potent TGR5 agonists. Although these findings are promising, excessively high bile acid levels could lead to neurotoxicity. Elevated levels of deoxycholic acid (DCA) have been associated with cognitive impairment and decline in patients with chronic kidney disease.

Most of the clinical evidence concerns depression, while direct evidence for anxiety and PTSD remains more limited.

Conclusions

The reviewed evidence suggests that gut microbiome alterations may enhance vulnerability to stress-related psychiatric disorders. Dietary interventions, exercise, probiotics, prebiotics, traditional Chinese medicine, and FMT are being investigated as potential adjunctive approaches that may modulate the gut-brain axis. Their clinical efficacy, however, remains uncertain. Clinical interpretation remains challenging because of pronounced inter-individual variability, inconsistent microbial findings, methodological heterogeneity, and limited direct validation in humans.

Looking ahead, researchers should conduct longitudinal investigations integrating multi-omics data to support the clinical development of personalized microbiome-based interventions. Large prospective human studies are needed to establish whether microbiome-related alterations track clinical disease trajectories and to clarify causal and predictive relationships.