TGR5 deficiency-induced anxiety and depression-like behaviors: The role of gut microbiota dysbiosis

Anxiety and depression have been associated with imbalances in the gut microbiota and bile acid metabolism. Takeda G protein-coupled receptor 5 (TGR5), a bile acid receptor involved in metabolism, is influenced by the gut microbiota. This study aimed to investigate the relationship between anxiety, depression, and microbiota using TGR5 knockout mice. We employed the following methods: (1) Assessment of behavioral changes, (2) Measurement of 5-HT levels and protein expression, (3) Analysis of stool samples, (4) Utilization of gene sequencing and statistical analysis to identify microbial signatures, (5) Examination of correlations between microbial signatures and 5-HT levels, and (6) Fecal microbiota transplantation experiments of TGR5−/− mice. The deletion of TGR5 was found to result in increased anxiety- and depression-like behaviors in mice. TGR5 knockout mice exhibited significant reductions in 5-hydroxytryptamine (5-HT) levels in both serum and hippocampus, accompanied by a decrease in the expression of 5-HT1A receptor in the hippocampus. Moreover, TGR5 deficiency was associated with a decrease in the species richness of the gut microbiota. Specifically, the gut microbiota compositions of TGR5 knockout mice displayed distinct differences compared to their littermates, characterized by higher abundances of Anaeroplasma, Prevotella, Staphylococcus, Jeotgalicoccus, and Helicobacter, and a lower abundance of Bifidobacterium. Notably, a strong association between Jeotgalicoccus as well as Staphylococcus and serum 5-HT levels was observed in co-occurrence network. Furthermore, mice that received fecal microbiota transplants from TGR5−/− mice displayed anxiety and depression -like behaviors, accompanied by alterations in 5-HT levels in the hippocampus and serum. Study limitations for gut bacteria were analyzed at the genus level only. TGR5 deletion in mice induces anxiety and depression-like behaviors, linked to reduced 5-HT levels in serum and the hippocampus. Gut microbiota changes play a direct role in these behaviors and serotonin alterations. This implicates TGR5 and gut bacteria in mood regulation, with potential therapeutic implications.