Microbial inositol phosphates orchestrate host diurnal metabolism and energy homeostasis via HDAC3

The gut microbiota programs mammalian circadian metabolism, yet the mechanisms remain unclear. Because feeding behavior is inherently rhythmic and strongly influences microbial metabolism, we hypothesized that the microbiota translates feeding timing into host circadian programs. We show that gut commensal Bacteroides thetaiotaomicron (Bt), in concert with feeding schedules, promotes diurnal chromatin-binding activity of the histone deacetylase 3 (HDAC3) in intestinal epithelial cells. Bt produces inositol triphosphate (InsP3) in a feeding-entrained diurnal manner that enhances HDAC3 activity. Colonization with wild-type Bt, but not an inositol phosphatase mutant, enhanced genome-wide rhythms in epithelial histone acetylation and metabolic gene expression. InsP3-activated HDAC3 deacetylates the transcriptional coactivator PGC-1α, resulting in enhanced expression of nutrient transporter genes. This Bt-InsPs-HDAC3 axis worsens diet-induced obesity in overnourished mice while improving growth in undernourished juvenile mice. These findings reveal a co-evolved microbial-epigenetic-circadian axis that orchestrates nutrient absorption and impacts energy homeostasis across nutritional states.