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 ENS. Microbiota-dependent molecular mechanisms of ENS neuronal survival and neurogenesis were also assessed. 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 secretion, 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 was 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, short-chain fatty acids (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 and 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.

Myenteric Neurons Do Not Replicate in Small Intestine Under Normal Physiological Conditions in Adult Mouse

“…Limited in vivo neurogenic potential in the ENS has been observed only after injury 6 , 8 , 9 , 10 , 12 , 13 ( Table 1 ). Kulkarni et al 11 challenged this dogma, suggesting that almost 70% of myenteric neurons are replaced within 1 week under normal physiological conditions.…”

“…Belkind-Gerson et al 8 , 9 used EdU labelling to analyze the distal colon and found no evidence of neuronal replication in adult mice. Similarly, Vicentini et al 10 found no evidence of neuronal replication after EdU labelling. Kulkarni et al 11 observed ∼70% turnover rate of enteric neurons after 1 week and 88% turnover rate after 2 weeks using IdU and CldU labelling in the ileum.…”

“…Several past studies using various techniques to label sites of DNA replication have suggested that under normal physiological conditions, robust neurogenesis does not occur in the adult gut 4 , 5 , 6 , 7 , 8 , 9 , 10 ; however, a recent study by Kulkarni et al 11 challenged these results and suggested that not only are enteric neurons born in the adult gut, but also almost 70% of them are replaced within 1 week under normal physiological conditions. This is an important conclusion with a possibly far-reaching impact on future research.…”

“…EdU-based quantification of ENS replication in the small intestine is currently lacking, and published results have been limited to the colon. 8 , 9 , 10 …”

Communication between the gut microbiota and peripheral nervous system in health and chronic disease

“…Finally, interneurons link the activity of ascending and descending motor networks to allow the “little brain” of the gut to function autonomously ( Figure 3 ). 39 , 51 The enteric nervous system is also supported by local glial cells, which also respond to changes in gut microbiota signaling, 52 but we will focus on enteric neurons in this review.

Figure 3.

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