Microbial density and diversity increase towards the distal intestine, affecting tissue physiology, metabolism, and function of both immune and nervous systems. Intrinsic enteric-associated neurons (iEAN) continuously monitor and modulate intestinal functions, including nutrient absorption and motility.Through molecular, anatomic and functional approaches, we characterized the influence of the microbiota on iEAN. We found that iEAN are functionally adapted to the intestinal segment they occupy, with a stronger microbiota influence on distal intestine neurons. Chemogenetic characterization of microbiotainfluenced iEAN identified a subset of viscerofugal CART+ neurons, enriched in the distal intestine, able to modulate feeding through insulin-glucose levels. Retro-and anterograde tracing revealed that CART+ viscerofugal neurons send axons to the gut sympathetic ganglion and are synaptically connected to the liver and pancreas. Our results demonstrate a region-specific adaptation of enteric neurons and indicate that specific iEAN subsets are capable of regulating host physiology independently from the central nervous system.
One Sentence Summary:Microbes impact regionally defined intrinsic enteric neuron translatomes, including a novel CART+ glucoregulatory viscerofugal population.
Main Text:EAN comprise a numerous and heterogeneous population of neurons within the gastrointestinal (GI) tract that monitor and respond to various environmental cues such as mechanical stretch and luminal metabolites (1, 2). The vast majority of luminal stimuli are derived from the diet and commensal microbes, which may be sensed directly by EAN fibers positioned along the intestinal epithelium. Luminal perturbations can also be transmitted to EAN indirectly, via signals derived from epithelial, glial, or immune cells inhabiting the same compartment (1, 3). Intrinsic EAN (iEAN), which comprise a component of the enteric nervous system (ENS), are neural crest-derived and organized in two distinct layers, the myenteric or Auerbach's plexus and submucosal or Meissner's plexus (2). iEAN can operate autonomously and are primarily tasked with modulation of intestinal motility and secretory function (2). Recent studies have demonstrated that the gut microbiota influence the basal activity of intestine-associated cells, including the excitability of EAN and the activation state of immune cells (2-5). Additionally, microbial dysbiosis has a potential role in a host of metabolic disorders including obesity and diabetes (6, 7). Yet, whether the metabolic effects of the microbiota are mediated through the nervous system is still not known. These studies highlight the impact of the gut microbiota on EAN and key mammalian physiological processes, however the cellular circuits and molecular components that mediate gut-EAN or gut-brain communication remain poorly understood. We sought to determine how the microbiota impacts iEAN to better characterize their role in host physiology.To profile iEAN, we opted for a translating ribosomal affinity purificat...