{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T16:13:47Z","timestamp":1785860027972,"version":"3.56.0"},"reference-count":32,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T00:00:00Z","timestamp":1757894400000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC3605700"],"award-info":[{"award-number":["2023YFC3605700"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Although a key intervention for advanced Prostate Cancer, Androgen Deprivation Therapy has been associated with cognitive dysfunction, a phenomenon that has been largely attributed to systemic metabolic alterations and neuroinflammation. Nonetheless, the precise role of gut microbiota in ADT\u2010induced cognitive impairment remains unclear, forming the basis of this study. Our aim is to explore the correlation between changes in gut metabolism and cognitive dysfunction following ADT in prostate cancer.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A subcutaneous PC3 tumor\u2010bearing mouse model of ADT\u2010induced cognitive dysfunction was established. Behavioral tests (OFT, NORT, and Y\u2010maze) were conducted to assess cognitive performance. Gut microbiota composition, fecal, and hippocampal bile acid profiles were analyzed by 16S rRNA sequencing and targeted metabolomics. To investigate potential mechanisms, we further supplemented ADT\u2010susceptible (ADT\u2010su) mice with Taurodeoxycholic acid (TDCA) via oral gavage and inhibited ERK1\/2 signaling with PD98059, followed by behavioral testing and Western blot analysis of hippocampal Takeda G\u2010protein coupled Receptor 5 (TGR5) and ERK1\/2 expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Hierarchical clustering analysis revealed ADT\u2010induced cognitive impairment in a subset of mice (ADT\u2010susceptible and ADT\u2010unsusceptible). These mice exhibited gut microbiota dysbiosis, featuring the depletion of bile acid\u2010transforming taxa, including\n                      <jats:italic>Bacteroides<\/jats:italic>\n                      spp. and\n                      <jats:styled-content style=\"fixed-case\">\n                        <jats:italic>Clostridium scindens<\/jats:italic>\n                      <\/jats:styled-content>\n                      . Additionally, FMT from ADT\u2010su mice to pseudo\u2010germ\u2010free mice efficiently transferred cognitive deficits and altered hippocampal bile acid profiles, confirming gut microbiota's causal role in ADT\u2010induced neurocognitive decline. Notably, both gut and hippocampal TDCA levels were significantly decreased in ADT\u2010su mice. Mechanistically, TDCA supplementation improved cognitive performance and upregulated hippocampal TGR5 and p\u2010ERK1\/2 expression, while ERK1\/2 inhibition by PD98059 partially reversed these effects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings suggest that gut microbiota\u2010mediated bile acid dysregulation, particularly reduced TDCA, contributes to ADT\u2010induced cognitive dysfunction via impaired TGR5\u2010ERK1\/2 signaling. Targeting this pathway may represent a novel therapeutic strategy to mitigate cognitive impairment in prostate cancer patients undergoing ADT.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/cns.70608","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T06:00:33Z","timestamp":1758002433000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Gut Microbiota\u2013Bile Acid\u2013Brain Axis and\n                    <scp>TGR5<\/scp>\n                    \u2010\n                    <scp>ERK1<\/scp>\n                    \/2 Signaling Mediate\n                    <scp>ADT<\/scp>\n                    \u2010Induced Cognitive Impairment"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3460-1379","authenticated-orcid":false,"given":"Fan","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Urology, Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1042-4961","authenticated-orcid":false,"given":"Yanbo","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Plastic Surgery Hospital Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhien","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Urology, Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Plastic Surgery Hospital Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7406-4694","authenticated-orcid":false,"given":"Weigang","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Urology, Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing 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