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Disease Models, Animal / Chronic Disease · Journal article
Gut Microbes · June 24, 2026
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This preclinical study in Muc2−/− mice demonstrates that chronic colitis-associated microbiome dysbiosis correlates with altered tryptophan metabolism and sex-specific behavioral abnormalities (reduced anxiety in females, memory dysfunction in males), with evidence implicating microbiome-mediated disruption of the tryptophan-kynurenine pathway and impaired blood–brain barrier integrity. The loss of behavioral phenotypes in germ-free mice confirms microbiome involvement, but the failure of early-life nutrient supplementation to fully rescue behavior and the absence of quantified effect sizes limit mechanistic clarity and clinical applicability.
Preclinical mechanistic study with controlled comparisons (specific pathogen-free, germ-free, and wild-type groups). Female and male Muc2−/− (mucin 2 knockout) mice with chronic colitis and Muc2+/+ (mucin 2 expressing wild-type) control mice.. Intervention: Muc2−/− mice with chronic colitis; germ-free condition; early-life nutrient supplementation. Compared with: Muc2+/+ wild-type mice; specific pathogen-free condition; non-supplemented controls.
Female Muc2−/− displayed reduced anxiety-like behavior; males displayed memory dysfunction Muc2−/− exhibited decreased intestinal tryptophan, kynurenine, and serotonin within the gastrointestinal tract Germ-free Muc2−/− mice displayed normalized intestinal metabolite levels without concurrent brain metabolite changes and behavioral phenotypes were lost
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These findings suggest microbiome-driven tryptophan metabolism disruption may contribute to neurobehavioral comorbidities in IBD, but human studies are needed before any therapeutic intervention targeting these pathways can be recommended. Sex-specific differences warrant consideration in future clinical studies.
Mechanistic mouse model study demonstrating microbiome-mediated tryptophan metabolism disruption correlates with behavioral changes, but lacks human validation, quantified effect sizes, and comparative statistics necessary for clinical translation.
As stated by the source record.
These findings suggest microbiome-driven tryptophan metabolism disruption may contribute to neurobehavioral comorbidities in IBD, but human studies are needed before any therapeutic intervention targeting these pathways can be recommended. Sex-specific differences warrant consideration in future clinical studies.
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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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