TGR5 is essential for protecting from chronic stress-induced learning and memory impairments in mice by modulating inflammation associated with the gut-brain axis

作者：S Z Zhang, Xiaoyang Liu, Hao Xu, Wenqian Zhang, Chenchen Shi, Meimei Wang, Guangmin Zhang, Xin Cheng, Xuanpan Ding, Haoyang Tan, Yuan Zhao, Honggang Fan, Guiyan Yang · 发表于：Journal of Neuroinflammation · 年份：2026 · DOI：10.1186/s12974-026-03898-w · 被引用次数：1 · 研究领域：Gut microbiota and health、Tryptophan and brain disorders、Barrier Structure and Function Studies

BACKGROUND: CS impairs brain function, causing long-term changes in neural systems linked to anxiety, depression, and cognition. TGR5 is a key receptor crucial for modulating various physiological processes, impacting metabolic homeostasis and inflammation. However, the role of TGR5 in regulating CS-induced learning and memory impairments along the gut-brain axis remains incompletely understood. METHODS: WT and TGR5 KO male C57BL/6J mice underwent 21-day chronic restraint stress to model stress-induced memory deficit. Stress severity and cognitive function were evaluated by behavioral tests. Hippocampal and intestinal integrity were assessed by H&E, Nissl, AB-PAS staining, and TEM ultrastructural analysis. CORT and 5-HT levels were quantified by ELISA. BAs and gut microbiota were profiled by UPLC-MS/MS and 16S rRNA sequencing. Hippocampal and colonic transcriptomes were analyzed by RNA-seq. Electrophysiological LTP was recorded in hippocampal CA1. Inflammatory cytokines were detected by qPCR. Fkbp51, TGR5, and LCN2 proteins were quantified by Western blot, while TGR5 and LCN2 were localized by IHC/IF. RESULTS: This study found that 21 days of CRS suppressed body weight gain, triggered anxiety-like behaviors, and impaired spatial learning and memory in mice. CS induced significant damage to the hippocampal CA1 region and colon, accompanied by elevated TGR5 expression in both tissues. Moreover, CS altered gut microbiota composition and BAs metabolism (most notably increasing TC...