Abstract
An intact gut epithelium preserves the immunological exclusion of “non-self” entities in the external environment of the gut lumen. Nonetheless, information flows continuously across this interface, with the host immune, endocrine, and neural systems all involved in monitoring the luminal environment of the gut. Both pathogenic and commensal gastrointestinal (GI) bacteria can modulate centrally-regulated behaviors and brain neurochemistry and, although the vagus nerve has been implicated in the microbiota-gut-brain signaling axis, the cellular and molecular machinery that facilitates this communication is unclear. Studies were carried out in healthy Sprague–Dawley rats to understand cross-barrier communication in the absence of disease. A novel colonic-nerve electrophysiological technique was used to examine gut-to-brain vagal signaling by bacterial products. Calcium imaging and immunofluorescent labeling were used to explore the activation of colonic submucosal neurons by bacterial products. The findings demonstrate that the neuromodulatory molecule, glucagon-like peptide-1 (GLP-1), secreted by colonic enteroendocrine L-cells in response to the bacterial metabolite, indole, stimulated colonic vagal afferent activity. At a local level indole modified the sensitivity of submucosal neurons to GLP-1. These findings elucidate a cellular mechanism by which sensory L-cells act as cross-barrier signal transducers between microbial products in the gut lumen and the host peripheral nervous system.
Highlights
The peripheral nervous system innervating the colon has evolved in the continued presence of over a 100 trillion microbial organisms, mostly bacteria
Sprague–Dawley rats were used to determine if indole, a bacterial metabolite of tryptophan, which stimulates L-cells (Chimerel et al, 2014), can induce cross-barrier signaling in healthy, non-leaky colons (Gareau et al, 2007)
Direct application of Ex-4 to a tissue preparation with exposed colonic submucosal neurons and afferent nerve endings resulted in increased vagal firing (n = 3, p = 0.0219, Figure 1E), in the absence of single-unit recordings it is not possible to determine if the same fibers are activated by both indole and Ex-4
Summary
The peripheral nervous system innervating the colon has evolved in the continued presence of over a 100 trillion microbial organisms, mostly bacteria. These microbes are predominantly beneficial, scavenging additional calories, secreting vitamins and ensuring normal immune and gastrointestinal (GI) development, but it appears that they may manipulate host physiology and behavior to their benefit (Stilling et al, 2016). Stimulation of vagal nerve activity (Perez-Burgos et al, 2013) and activation of intrinsic primary afferent neurons (Mao et al, 2013) in response to the exposure of mouse jejunum mucosa to Lactobacillus Rhamnosus JB-1 have been reported. A mechanistic understanding of how these bacterial signals are interpreted by the host is yet to be established
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