Background: Serotonin (5-HT) is a vital neurotransmitter essential for neural communication. It arises from tryptophan metabolism through two forms of tryptophan hydroxylase (TPH): TPH1 in the gut, and TPH2 in the CNS. Notably, the gut is the source of 90% of 5-HT production, underlining its central role in influencing both mental and physical health. This project provides novel data on the interplay between gut-derived 5-HT and the gut-brain-microbiota axis concerning body metabolism and behavioral shifts. Methods: This study used TPH1 knockout (KO) mice to determine the impact of gut-derived 5-HT on neuropsychological health, including depression and anxiety. TPH1KO mice lack the TPH1 enzyme in the gastrointestinal tract, preventing the production of gut serotonin. The evaluation included five standard anxiety and depression tests. Metabolic assessments utilized Promethion metabolic cages, which assessed food and water intake, sleep duration, and physical activity. In addition, microbiota profiling through DNA sequencing was analyzed, as well as High-Performance Liquid Chromatography (HPLC) to quantify tryptophan metabolites in the brain and gut. Results: TPH1KO mice showed a significant reduction in anxiety-like behavior (P<0.05), with decreases in 8 out of 11 parameters. Metabolic assessments indicated a 35% increase in food and water intake in TPH1KO mice compared to controls, along with a 55% extension in sleep duration and a remarkable 65% increase in physical activity (P<0.01). Notably, TPH1KO mice displayed a reduced lean-to-fat ratio, suggesting alterations in body composition. Tryptophan metabolite analysis revealed elevated l-kynurenine and quinolinic acid levels in colon tissue (P<0.01) but reduced levels in the brain. Conversely, melatonin and 3-hydroxykynurenine levels increased in the brain (P<0.01), while colon tissue showed significantly reduced melatonin levels (P<0.01). Gut microbiota profiling revealed a disrupted microbial composition in TPH1KO mice, with significant reductions in Actinobacteria and Erysipelotrichi, including their respective orders, families, and genera (P<0.01). Actinobacteria's order Bifidobacteriales, the family Bifidobacteriaceae, and the genus Bifidobacterium showed marked reductions in TPH1KO mice. Furthermore, Erysipelotrichales, a Firmicutes order, and Erysipelotrichaceae, a Firmicutes family, were significantly diminished in TPH1KO mice. Conclusions: This study showed the intricate role of gut-derived 5-HT in shaping behavior, metabolism, and microbiota composition, offering novel potential therapeutic avenues for neuropsychiatric disorders. By mapping the contributions of gut-derived 5-HT, this research will lead to the development of innovative treatments addressing anxiety, depression, and broader health challenges.

Niloufar Rashidi

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