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

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 TCDCA levels) potentially contributing to neuroinflammation along the gut-brain axis. Using TGR5 KO mice, this study demonstrated that TGR5 deficiency exacerbated CS-induced hippocampal neuroinflammation, as evidenced by increased expression of pro-inflammatory markers including IL-1β, IL-6, TNF-α, and LCN2. CS also induced decreased 5‑HT levels and severely impaired LTP, disrupting synaptic plasticity and neurotransmission, which ultimately led to learning and memory deficits. In the colon, TGR5 deficiency similarly worsened CS-induced tissue injury. These findings highlight a protective role of TGR5 in both the hippocampus and the colon. CONCLUSIONS: In summary, TGR5 is essential for protecting from CS-induced learning and memory impairments in mice by modulating inflammation associated with the gut-brain axis.