{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T06:01:32Z","timestamp":1781157692900,"version":"3.54.1"},"reference-count":67,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>High-fat diet (HFD)-associated anxiety- and depression-like behaviors are closely linked to disturbances in the gut\u2013brain 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Four 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.\n                      <jats:italic>In vitro<\/jats:italic>\n                      cell experiments, ileal organoid assays, and\n                      <jats:italic>in vivo<\/jats:italic>\n                      fecal microbiota transplantation (FMT) were further used for validation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      DCA intervention induced HFD-like anxiety- and depression-like behaviors in the mice, accompanied by reduced levels of the key gut bacterium\n                      <jats:italic>Clostridium_sensu_stricto_1<\/jats:italic>\n                      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 (\n                      <jats:italic>Cyp3a11<\/jats:italic>\n                      and\n                      <jats:italic>Abcb1a<\/jats:italic>\n                      ) in the cerebral pregnane X receptor (PXR) signaling, ameliorated DCA-induced emotional and behavioral abnormalities, and reversed related gut\u2013brain 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 mice similar to those observed in DCA model mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings support a potential gut\u2013brain pathway linking HFD-associated luminal DCA elevation to anxiety- and depression-like behaviors in mice. The reduction in IPA levels resulting from the remodeling of gut microbiota triggered by DCA might be the key mediating factor. Targeting abnormal bile acid metabolism or restoring IPA function is a promising intervention strategy for HFD-related emotional and behavioral abnormalities.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1840574","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T05:48:50Z","timestamp":1781156930000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Deoxycholic acid promotes anxiety- and depression-like behaviors in mice via modulation of the gut microbial metabolite indole-3-propionic acid"],"prefix":"10.3389","volume":"17","author":[{"given":"Yulun","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]},{"name":"Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of 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