Gut microbiome-produced bile acid metabolite lengthens the circadian period in host intestinal cells

• 成果类型: Article
• 署名作者: Powell, Chelsea E.; McSween, Alana M.; Dohnalova, Lenka; Kim, Cecilia H.; Eisert, Robyn J.; Sun, Zhen-Yu J.; Seo, Hyuk-Soo; Marquardt, Vincent; Dhe-Paganon, Sirano; Thaiss, Christoph A.; Devlin, A. Sloan; Hooper, Lora
• 署名单位: Harvard University; Harvard Medical School; Stanford University; Stanford Medicine; University of Pennsylvania; Pennsylvania Medicine; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2506313123
• 发表日期: 2026-03-17
• 页码: e2506313123
• 关键词: circadian rhythm; bile acids; microbiome; CHAIN FATTY-ACIDS; CASEIN KINASE 1; clock; rhythms; phase; phosphorylation; inhibition; melatonin; sleep; time

摘要

Host circadian signaling, feeding, and the gut microbiome are tightly interconnected. Changes in the gut microbial community can affect the expression of core clock genes, but the specific metabolites and molecular mechanisms that mediate this relationship remain largely unknown. Here, we sought to identify gut microbial metabolites that impact circadian signaling. Through a phenotypic screen of a focused library of gut microbial metabolites, we identified a bile acid metabolite, lithocholic acid (LCA), as a circadian modulator. LCA lengthened the circadian period of core clock gene hPer2 transcription in a dose-responsive manner in human colonic cells. We found evidence that loop and stabilizes core clock protein cryptochrome 2 (CRY2). Furthermore, we showed that LCA feeding alters circadian transcription in mouse distal ileum and colon. Taken together, our work identifies LCA as a molecular link between host circadian biology and the microbiome. Because bile acids are secreted in response to feeding, our work provides potential mechanistic insight into the molecular nature of the food-entrainable oscillator (FEO) by which peripheral clocks adapt to the timing of food intake. Given the association between circadian rhythm, feeding, and metabolic disease, our insights may offer an avenue for modulating host health.