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

Mar 11, 2026Proceedings of the National Academy of Sciences of the United States of America

Gut bacteria-produced bile acid changes the daily rhythm length in intestinal cells

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Abstract

Lithocholic acid (LCA) lengthened the circadian period of core clock gene transcription in human colonic cells in a dose-responsive manner.

LCA was identified as a circadian modulator through a phenotypic screen of gut microbial metabolites.
LCA may influence the feedback loop involving casein kinase 1 δ/ε and protein phosphatase 1.
Evidence suggests that LCA stabilizes the core clock protein cryptochrome 2.
LCA feeding altered circadian transcription in the distal ileum and colon of mice.
The findings indicate a potential link between host circadian biology and the gut microbiome.

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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 genetranscription in a dose-responsive manner in human colonic cells. We found evidence that LCA modulates the casein kinase 1 δ/ε (CK1δ/ε)-protein phosphatase 1 (PP1) feedback 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. hPer2