Intestinal Microbiota Shapes Gut Physiology and Regulates Enteric Neurons and Glia

Abstract

Background: The intestinal microbiota plays an important role in regulating gastrointestinal (GI) physiology in part through interactions with the enteric nervous system (ENS). Alterations in the gut microbiome frequently occur together with disturbances in enteric neural control in pathophysiological conditions. However, the mechanisms by which the microbiota regulates GI function and the structure of the ENS are incompletely understood. Using a mouse model of antibiotic (Abx)-induced bacterial depletion, we sought to determine the molecular mechanisms of microbial regulation of intestinal function and the integrity of the ENS. Spontaneous reconstitution of the Abx-depleted microbiota was used to assess the plasticity of structure and function of the GI tract and neuronal survival and neurogenesis in the ENS. Results: Adult male and female Abx-treated mice exhibited alterations in GI structure and function, including a longer small intestine, slower transit time, increased carbachol-stimulated ion transport and increased intestinal permeability. These alterations were accompanied by the loss of enteric neurons in the ileum and proximal colon in both submucosal and myenteric plexuses. A reduction in the number of enteric glia were only observed in the ileal myenteric plexus. Recovery of the microbiota restored intestinal function and stimulated enteric neurogenesis leading to increases in the number of enteric glia and neurons. Lipopolysaccharide (LPS) supplementation enhanced neuronal survival alongside bacterial depletion but had no effect on neuronal recovery once the Abx-induced neuronal loss was established. In contrast, SCFA were able to restore neuronal numbers after Abx-induced neuronal loss, demonstrating that SCFA stimulate enteric neurogenesis in vivo. Conclusions: Our results demonstrate a role for the gut microbiota in regulating the structure function of the GI tract in a sex-independent manner. Moreover, the microbiota is essential for the maintenance of ENS integrity, by regulating enteric neuronal survival and promoting neurogenesis. Molecular determinants of the microbiota, LPS and SCFA, regulate enteric neuronal survival, while SCFA also stimulates neurogenesis. Our data reveal new insights into the role of the gut microbiota that could lead to therapeutic developments for the treatment of enteric neuropathies.

Direct and indirect mechanisms by which the gut microbiota influence host serotonin systems

“…Mice treated with antibiotics exhibit lower levels of colonic 5-HT and decreased Tph1 expression, 5,21 which parallel the findings of GF-associated deficits to the gut 5-HT system. Furthermore, these alterations in 5-HT levels result in functional changes to intestinal transit, as antibiotic-treated mice display slower whole gut transit [21][22][23][24] and slower colonic motility times 21,24 compared with controls. In addition, these functional deficits are accompanied by loss of enteric neurons.…”

“…In addition, these functional deficits are accompanied by loss of enteric neurons. 22 Interestingly, antibiotic-induced changes are reversible. Following reconstitution of the microbiota, mice display restored GI motility and enteric neurogenesis.…”

TLR2 and TLR4 in Parkinson’s disease pathogenesis: the environment takes a toll on the gut

“…In mice, loss of TLR4 signalling through genetic models, or as a consequence of microbiome depletion results in delayed gastrointestinal motility and reduces nitrergic neuronal counts, with subsequent in vitro experiments demonstrating that LPS exposure improves primary enteric neuron survival in a TLR4-dependent mechanism [ 133 ]. More recently, TLR4 activation by LPS administration during antibiotic treatment prevents the antibiotic-induced enteric neuronal loss in mice, but has no benefit if administered 14 days after antibiotic treatment, supporting a role for LPS-TLR4 signalling in enteric neuronal survival, but not in neurogenesis or differentiation [ 134 ]. TLR4 is also expressed by enteric glial cells [ 132 ], which protect enteric neurons and facilitate ENS signalling, and TLR4 knock-out mice exhibit altered ileal dysmotility and reactive gliosis [ 135 , 136 ].…”

Role of the Endocannabinoid System in the Regulation of Intestinal Homeostasis

“…Studies using germ-free mice, or mice treated with antibiotics to deplete the gut microbiota, have revealed that the microbiota shapes gut function and enteric neural control mechanisms. [140][141][142][143][144][145] Microbial dysbiosis is associated with a breakdown in epithelial barrier function and is associated with both local GI diseases, eg, IBD, and various systemic conditions, eg, obesity and diabetes. Investigations into the regulation of the ECS by the gut microbiome and vice versa are at an early stage, but some intriguing results have emerged that support the general hypothesis that the ECS regulates intestinal homeostasis through interactions with the microbiota.…”