Glucagon-Like Peptide-1 Secreting L-Cells Coupled to Sensory Nerves Translate Microbial Signals to the Host Rat Nervous System

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.

The Role of Gut Bacterial Metabolites in Brain Development, Aging and Disease

“…Probable pathways by which these effects occur are the activation of vagal afferences by indole and on the other hand, accumulation of oxidized indole derivatives like oxindole and isatin in the brain. Indole has been shown to activate gut mucosal L-cells to secrete glucagon-like peptide-1 (GLP-1), which then stimulates vagal afferent fibres, therefore presenting an indirect impact of indole on the CNS [156]. Oxindole is known to inhibit motor activity [155], invoke hypotension, loss of righting reflex and a reversible comatose state, while isatin is proposed an anxiogenic role by inhibiting monoamine oxidase (MAO) B and by producing antagonistic effects on benzodiazepine receptors in rodents [70].…”

The specification and function of enteroendocrine cells in Drosophila and mammals: a comparative review

“…A study combining biophysics, genetics, pharmacology, and cell co-culture methods in organoids showed that enterochromaffin cells can sense microbial metabolites in the intestinal lumen and regulate the release of 5-HT to directly communicate with neurons through synaptic interactions [7]. Microbial metabolites and other derivatives produced by food fermentation (e.g., SCFAs and bile acids) can impact intestinal peptide hormone secretion from EECs and through the microbial-gut-brain axis, affect the nervous system, and regulate the host metabolism [96,97,128,129]. There is also evidence that microbiota composition is closely associated with many psychiatric disorders such as anxiety and depression, autism spectrum and neurodegenerative diseases including Parkinson's disease and Alzheimer's disease, and with [130][131][132].…”

Divergent effects of exendin‐4 and interleukin‐6 on rat colonic secretory and contractile activity are associated with changes in regional vagal afferent signaling

“…As application of Ex‐4 in the presence of IL‐6 resulted in enhanced calcium responses in submucosal neurons, 9 Ussing chamber studies were used to investigate the effects of Ex‐4, either alone or with IL‐6 on short‐circuit current (I Sc ), a measure of net ion transport across the colonic epithelium. Separately, addition of IL‐6 7 (103.6 ± 39.2, n = 7) and Ex‐4 30 (65.04 ± 26.3, n = 7) to the basolateral reservoir resulted in secretory currents with amplitudes larger than saline controls (16.87 ± 12.7 µA/cm 2 , n = 7). The secretory currents evoked by Ex‐4 with IL‐6 (161 ± 108.5 µA/cm 2 , n = 7) were larger than currents evoked by Ex‐4 alone ( p = 0.0016, Figure 1A).…”

“…We have reproduced the positive effects of GLP‐1 on gut function in the Wistar‐Kyoto rat model of IBS 9 and used healthy Sprague‐Dawley rats colons to further explore the mechanisms of action underlying these beneficial effects. We found that exendin 4 (Ex‐4), a longer‐lasting GLP‐1 receptor agonist, 29 decreased the amplitude of circular smooth muscle contractions, increased the amplitude of colonic secretory currents, and decreased barrier permeability 30 …”