Gut microbiota-derived extracellular vesicles exhibit diurnal regulation and activate hepatic gluconeogenesis

The circadian clock regulates tissue-specific homeostasis, and its disruption is associated with metabolic disorders. Both host metabolic processes and the gut microbiota exhibit diurnal regulation, and both contribute to the maintenance of glucose homeostasis (Thaiss et al., 2014; Bishehsari et al., 2020; Frazier et al., 2023) [1-3]. However, how the gut microbiota and the circadian rhythm interplay to control host glucose homeostasis is not fully understood. Here, we identified gut microbiota-derived extracellular vesicles (MEV) as a potential peripheral Zeitgeber (time cue) for the hepatic circadian clock, controlling hepatic gluconeogenesis. Host feeding patterns influence the gut microbiota, driving the diurnal production of MEV. Gut MEV levels coincide with the activity of hepatic gluconeogenesis, with overnight fasting associated with increased production of MEV by gut bacteria. MEV directly activates hepatic gluconeogenesis and chronic increase in MEV exposure impairs glucose homeostasis in vivo. Our finding highlights a mechanism by which the gut microbiota has co-evolved with the host to support its glucose needs during periods of energy demands (such as during fasting or starvation). On the contrary, an abnormal increase in MEV production, leading to dysregulated gluconeogenesis, may underlie various glucose-associated disorders, such as type 2 or gestational diabetes. Together, our data reconcile the gut microbiota and circadian rhythm in the control of host glucose homeostasis and metabolic health.