Abstract

BackgroundHigh-fat diet (HFD)-associated anxiety- and depression-like behaviors are closely linked to disturbances in the gut–brain axis; however, the peripheral signaling mechanisms and key metabolites involved remain to be elucidated. Deoxycholic acid (DCA), a bile acid elevated by a HFD, has been reported to be associated with abnormal cognitive behaviors in mice. This study aimed to investigate whether HFD-induced anxiety- and depression-like behaviors are regulated by intestinal DCA and its underlying mechanisms.MethodsFour mouse models were established with different interventions: a low-fat diet (LFD), a HFD, a LFD plus DCA, and a HFD plus the bile acid binder cholestyramine. We performed behavioral phenotyping, brain tissue transcriptome sequencing, fecal 16S rRNA gene sequencing, fecal and serum metabolomics, and intestinal barrier function assessment to clarify the phenotypes and underlying mechanisms. In vitro cell experiments, ileal organoid assays, and in vivo fecal microbiota transplantation (FMT) were further used for validation.ResultsDCA intervention induced HFD-like anxiety- and depression-like behaviors in the mice, accompanied by reduced levels of the key gut bacterium Clostridium_sensu_stricto_1 and its metabolite indole-3-propionic acid (IPA) in the gut and serum. IPA supplementation restored circulating IPA levels, upregulated the expression of key genes (Cyp3a11 and Abcb1a) in the cerebral pregnane X receptor (PXR) signaling, ameliorated DCA-induced emotional and behavioral abnormalities, and reversed related gut–brain axis impairments, including downregulated brain barrier-related proteins, morphological changes associated with microglial activation, intestinal barrier damage (reduced goblet cells, downregulated Claudin-1/Occludin), intestinal epithelial oxidative stress and injury, and impaired ileal organoid budding. FMT induced behavioral phenotypes, barrier impairments, reduced serum IPA, and cerebral pathological changes in recipient m