THE GUT MICROBIOTA MODULATE LOCOMOTION VIA VAGUS-DEPENDENT GLUCAGON-LIKE PEPTIDE-1 SIGNALING

Abstract Background Locomotor activity is an innate behavior that can be triggered by gut-motivated conditions, such as appetite and metabolic condition. Various nutrient-sensing receptors distributed in the vagal terminal in the gut are crucial for signal transduction from the gut to the brain. The levels of gut hormones are closely associated with the colonization status of the gut microbiota, suggesting a complicated interaction among gut bacteria, gut hormones, and the brain. However, the detailed mechanism underlying gut microbiota-mediated endocrine signaling in the modulation of locomotion is still unclear. Aims & Objectives We hypothesize that the vagus-dependent enteroendocrine signaling serves as a mediator for the gut microbiome to modulate locomotor behavior. Methods To assess the association among gut microbiome, gut hormone glucagon-like peptide-1 (GLP-1) levels, and locomotion in mice, we depleted the gut microbiome by administrating the cocktail of a broad- spectrum antibiotic (ABX) in the drinking water for C57BL/6J mice and tested for their locomotor activity. The brain, serum, and fecal samples were analyzed by immunohistochemistry staining, ELISA, and 16S rRNA sequencing, respectively. On the other hand, the vagus nerve is one of the promising neural connections bidirectionally innervating in the GI tract and the brain. The subdiaphragmatic vagotomy (SDV) and transcranial focused ultrasound (FUS) was performed to understand the contributions of gut- associated vagal signaling involved in the microbiota-mediated GLP-1-induced locomotion alteration. Results Herein, we show that ABX-treated mice displayed hypolocomotion and elevated levels of the gut hormone GLP-1. Blockade of the GLP-1 receptor and subdiaphragmatic vagal transmission rescued the deficient locomotor phenotype in ABX-treated mice. Activation of the GLP-1 receptor and vagal projecting brain regions led to hypolocomotion. Finally, selective antibiotic treatment dramatically increased serum GLP- 1 levels and decreased locomotion. Colonizing Lactobacillus reuteri and Bacteroides thetaiotaomicron in microbiota-deficient mice suppressed GLP-1 levels and restored the hypolocomotor phenotype. Discussion & Conclusion Our findings identify a mechanism by which specific gut microbes mediate host motor behavior via the enteroendocrine and vagal-dependent neural pathways.