The gut-brain axis mechanism of normal appetite induced by kynurenic acid

Feeding is essential for both host-organism survival and gut-microbiota maintenance. Our research focuses on how kynurenic acid (KYNA), a gut-microbiota metabolite, regulates appetite during fasting. We find that fasting significantly raises KYNA levels in the intestine, which increases short-term food intake by inhibiting vagal afferent nerve in the nodose ganglion (NG) and activating AgRP neurons in arcuate nucleus (ARC^AgRP). The orexigenic effects of KYNA are abolished by subdiaphragmatic vagotomy (sdVx), chemogenetic activation/inhibition of glutamatergic NG/ARC^AgRP neurons, inhibiting the nucleus of the solitary tract (NTS) to ARC^AgRP inputs, or knockdown of GPR35 (a KYNA receptor) in the intestinal vagal afferent nerve. Our data support a model in which KYNA acts through the GPR35 receptor to inhibit vagal afferent signaling and subsequently activate ARC^AgRP neurons, which leads to increased food intake. These findings reveal a mechanism by which gut microbiota controls appetite during fasting, highlighting the complex relationship between microbial and host feeding behavior.