Peripheral Neuronal Activation Shapes the Microbiome and Alters Gut Physiology

Abstract

The enteric nervous system (ENS) integrates cues from the brain and from local signals in the gut to coordinate responses that shape the intestinal milieu. Tools to study, and knowledge of, the ENS lag behind brain research. Herein, we deploy novel recombinant adeno-associated viral (rAAV) vectors with enhanced tropism for the gut to map and activate enteric neurons with spatial and temporal resolution. rAAV-mediated fluorescent labelling coupled with whole-tissue clearing methods in the small intestine and colon of mice enables efficient and thorough characterization of the neuronal architecture of the ENS. We also delivered "designer receptors exclusively activated by designer drugs" (DREADDs) to specifically activate gut neurons that express choline acetyltransferase (ChAT+) and tyrosine hydroxylase (TH+). Targeted activation of ChAT+ or TH+ neuronal populations associated with the gastrointestinal (GI) tract altered the intestinal transcriptome of mice, host and microbial proteome, metagenome, and fecal metabolome. We reveal previously unknown and broad roles for neurons in modulating intestinal physiology, mucosal immunity, and gut microbiome structure, and propose novel interactions for the ENS such as regulating fungal colonization and shaping of bile acid profiles. Experimental tools and rich datasets with multi-parameter characterization of the gut ecosystem may enable further study of the ENS.

Sympathetic Denervation Alters the Inflammatory Response of Resident Muscularis Macrophages upon Surgical Trauma and Ameliorates Postoperative Ileus in Mice

“…However, we did not detect a reduction of TH + fibers in the muscularis externa of the TH-Cre;TrkA f/f mutant mice. Due to the successful use of TH-Cre mouse lines in GI research [26], we speculate that TrkA deficiency might not be required for the survival of sympathetic nerves innervating the GI tract or that compensatory mechanism to TrkA action might exist in the intestine compared to the pancreas. The alternatively tested surgical approach [27] is selective and site-specific, although surgical transection is at risk of also disturbing the fine bundles of vagal afferent fibers that are dividing and reassembling along the superior mesenteric artery [21].…”

The Role of Morphine-Induced Impairment of Intestinal Epithelial Antibacterial Activity in Dysbiosis and its Impact on the Microbiota-Gut-Brain Axis

“…There is increasing evidence that enteric neurons can modulate the response of the intestinal epithelial barrier to gut microbiota. Chemogenetic activation of cholinergic enteric neurons altered the intestinal transcriptome, including the expression of genes responsible for mucosal immunity and antimicrobial responses, and produced effects on the gut microbiome and metabolome 35 . Approximately half of the μ-opioid receptor-expressing neurons in the enteric nervous system are cholinergic 25 , 34 .…”

The Role of Morphine-Induced Impairment of Intestinal Epithelial Antibacterial Activity in Dysbiosis and its Impact on the Microbiota-Gut-Brain Axis

“…There is increasing evidence that enteric neurons can modulate the response of the intestinal epithelial barrier to gut microbiota. Chemogenetic activation of cholinergic enteric neurons altered the intestinal transcriptome, including the expression of genes responsible for mucosal immunity and antimicrobial responses, and produced effects on the gut microbiome and metabolome 32 . Approximately half of the µ-opioid receptor-expressing neurons in the enteric nervous system are cholinergic 31,33 .…”