Microbiome-driven alterations in tryptophan metabolism contribute to behavioral comorbidities in the Muc2 knockout mouse model of chronic colitis.

چکیده اصلی

Globally, the incidence of inflammatory bowel disease (IBD) is projected to reach 0.5% of the population by 2030, with increasing recognition of neurobehavioral comorbidities, including anxiety, depression, and cognitive dysfunction. The mechanisms underlying these comorbidities remain unclear but may involve interacting pathways, including microbial dysbiosis, inflammation and imbalanced neurometabolite production. Here, we investigated whether microbiome-associated alterations in neurometabolites are correlated with behavioral changes in a chronic colitis model. Specific pathogen-free (SPF) and germ-free (GF) mucin 2 knockout mice (Muc2-/-) alongside mucin 2 expressing mice (Muc2+/+) were evaluated for behavioral patterns of anxiety, depressive-like patterns and memory dysfunction. Tryptophan and metabolite concentrations were measured in the colon, serum and brain. Blood-brain barrier integrity and neuroimmune activation were assessed through tight-junction protein claudin-5 expression, glial fibrillary acid protein (GFAP) and ionized calcium-binding adaptor molecule 1 (IBA-1) protein expression. Microbiome composition was characterized in relation to the tryptophan utilization pathways. To assess causality, early-life nutrient supplementation was used to address potential metabolite depletion. Female Muc2-/- displayed reduced anxiety-like behavior, while males displayed memory dysfunction. These changes coincided with decreased intestinal tryptophan, kynurenine, and serotonin within the gastrointestinal tract. GF Muc2-/- mice displayed normalized intestinal metabolite levels without concurrent brain metabolite changes. Notably, behavioral phenotypes were lost in GF Muc2-/- mice, revealing a key role for the microbiome played in these comorbidities. Muc2-/- exhibited reduced claudin-5, suggesting impaired blood‒brain barrier integrity. Microbiome analysis revealed a shift towards indole production and NAD+ salvage pathways with reduced abundance of Anaerotruncus, Enterocloster and Intestinimonas. Although early-life nutrient supplementation partially restored colonic tryptophan, it failed to fully rescue behavioral outcomes. Collectively, these findings demonstrate that chronic colitis is associated with microbiome-mediated disruption of host tryptophan metabolism, which correlates with neurobehavioral dysfunction. Targeting microbiome-driven metabolic alterations may represent a therapeutic strategy for both intestinal and neurobehavioral manifestations of IBD.

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