Gastrointestinal neuromuscular apparatus: An underestimated target of gut microbiota

Abstract

Over the last few years, the importance of the resident intestinal microbiota in the pathogenesis of several gastro-intestinal diseases has been largely investigated. Growing evidence suggest that microbiota can influence gastro-intestinal motility. The current working hypothesis is that dysbiosis-driven mucosal alterations induce the production of several inflammatory/immune mediators which affect gut neuro-muscular functions. Besides these indirect mucosal-mediated effects, the present review highlights that recent evidence suggests that microbiota can directly affect enteric nerves and smooth muscle cells functions through its metabolic products or bacterial molecular components translocated from the intestinal lumen. Toll-like receptors, the bacterial recognition receptors, are expressed both on enteric nerves and smooth muscle and are emerging as potential mediators between microbiota and the enteric neuromuscular apparatus. Furthermore, the ongoing studies on probiotics support the hypothesis that the neuromuscular apparatus may represent a target of intervention, thus opening new physiopathological and therapeutic scenarios.

Keywords: Enteric nervous system; Gastrointestinal motility; Irritable bowel syndrome; Microbiota; Probiotics; Smooth muscle.

Figure 1

Dysbiosis and intestinal motility disorders. One hypothesis regarding the pathogenesis of functional intestinal disorders suggests that dysbiosis increases paracellular permeability leading to translocation of luminal contents with activation of immunocytes, cytokines and inflammatory mediators release. The activation of this state of inflammation and the presence of bacterial components, such as LPS, lead to nociceptive hypersensitivity, thus explaining the pain, and to enteric nervous system (ENS) or muscle impairment, thus explaining the intestinal motor disorders. LPS: Lipopolysaccharide.

Figure 2

Role of toll-like receptors on human colonic smooth muscle cells. LPS affects intestinal contractility by activating oxidative stress in the mucosa and, once translocated, by activating TLR4 expressed in colonic muscle cells. Activation of muscular TLR4 impairs cell contractility by activation of the nuclear factor kB transcription with intracellular increase of oxidative stress and by prostaglandin E2 (PGE2) that block intracellular calcium release. The oxygen free radicals, produced in the mucosa, impair cell contractility with a similar mechanism and also by de-regulation of contractile receptors. The activation of TLR2, whose ligands are the components of the outer membrane of Gram-positive bacteria, such Lactobacillus rhamnosus GG (LGG), prevents LPS-induced muscular alterations. TLR4: Toll-like receptor 4; LPS: Lipopolysaccharide.