Rapid modulation of gut microbiota composition by hypothalamic circuits in mice.

In recent years, the gut microbiota and derived metabolites have emerged as relevant players in modulating several brain functions, including energy balance control. This form of distant communication mirrors that of metabolic hormones (e.g., leptin, ghrelin), that convey information about the organism's energy status by exerting effects on diverse brain regions including the master homeostatic centre the hypothalamus. However, whether the hypothalamus is also able to influence gut microbiota composition remains enigmatic. Here, we present a proof-of-concept study designed to unravel this challenging question. To this aim, we employed chemogenetics (to selectively activate or inhibit the activity of hypothalamic POMC or AgRP neurons) or administered leptin or ghrelin centrally to mice. Subsequently, we conducted microbiota composition analysis throughout the gut using 16S rRNA gene sequencing. Our results showed that these brain interventions significantly changed the gut microbiota in an anatomical and short-term (2-4h) fashion. Transcriptomic analysis indicated that these changes were associated with the reconfiguration of neuronal and synaptic pathways in the duodenum concomitant with increased sympathetic tone. Interestingly, diet-induced obesity attenuated brain-mediated changes induced by leptin in gut microbiota communities and sympathetic activation. Our findings reveal a novel and unanticipated brain-to-gut axis that acutely attunes microbiota composition at fast timescales, with potential implications for meal-to-meal adjustments and systemic energy balance control.