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

A phenotypic screen of a focused library of gut microbial metabolites identified lithocholic acid (LCA) as a circadian modulator.

• The screen was conducted using a focused library of gut microbial metabolites.
• LCA was identified from this unbiased phenotypic screen as capable of modulating circadian signaling.
• LCA is a secondary bile acid metabolite produced by the gut microbiome.

LCA lengthened the circadian period of core clock gene hPer2 transcription in a dose-responsive manner in human colonic cells.

• The effect was observed in human colonic cells.
• The period lengthening was dose-responsive.
• The circadian readout was transcription of the core clock gene hPer2.

LCA modulates the casein kinase 1 δ/ε (CK1δ/ε)-protein phosphatase 1 (PP1) feedback loop.

• Evidence was found that LCA acts on the CK1δ/ε-PP1 feedback loop, a known regulator of circadian period length.
• This mechanism provides a molecular basis for the period-lengthening effect of LCA.
• CK1δ/ε phosphorylates core clock proteins and PP1 counteracts this phosphorylation in the feedback loop.

LCA stabilizes the core clock protein cryptochrome 2 (CRY2).

• CRY2 is a core clock protein involved in transcriptional repression in the circadian feedback loop.
• Stabilization of CRY2 by LCA was identified as part of the molecular mechanism by which LCA lengthens the circadian period.
• CRY2 stability is regulated by phosphorylation, consistent with LCA's proposed effect on CK1δ/ε-PP1 activity.

LCA feeding alters circadian transcription in mouse distal ileum and colon in vivo.

• The in vivo experiment involved LCA feeding in mice.
• Circadian transcription was assessed in two intestinal compartments: distal ileum and colon.
• These findings extend the in vitro results to an in vivo physiological context.

Because bile acids are secreted in response to feeding, LCA may provide mechanistic insight into the food-entrainable oscillator (FEO) by which peripheral clocks adapt to food intake timing.

• The food-entrainable oscillator (FEO) links feeding timing to peripheral circadian clock entrainment.
• Bile acids, including LCA, are released postprandially, providing a feeding-responsive circadian signal.
• The authors propose that LCA represents a molecular link between host circadian biology and the microbiome.
• This mechanism may be relevant to understanding circadian rhythm disruption in metabolic disease.