Role of Muscarinic Acetylcholine Receptors in Intestinal Epithelial Homeostasis: Insights for the Treatment of Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, is an intestinal disorder that causes prolonged inflammation of the gastrointestinal tract. Currently, the etiology of IBD is not fully understood and treatments are insufficient to completely cure the disease. In addition to absorbing essential nutrients, intestinal epithelial cells prevent the entry of foreign antigens (micro-organisms and undigested food) through mucus secretion and epithelial barrier formation. Disruption of the intestinal epithelial homeostasis exacerbates inflammation. Thus, the maintenance and reinforcement of epithelial function may have therapeutic benefits in the treatment of IBD. Muscarinic acetylcholine receptors (mAChRs) are G protein-coupled receptors for acetylcholine that are expressed in intestinal epithelial cells. Recent studies have revealed the role of mAChRs in the maintenance of intestinal epithelial homeostasis. The importance of non-neuronal acetylcholine in mAChR activation in epithelial cells has also been recognized. This review aimed to summarize recent advances in research on mAChRs for intestinal epithelial homeostasis and the involvement of non-neuronal acetylcholine systems, and highlight their potential as targets for IBD therapy.

The parasitic worm product ES-62 protects against collagen-induced arthritis by resetting the gut-bone marrow axis in a microbiome-dependent manner

“…Finally, given the increasing evidence that non-neuronal sources of ACh suppress gut inflammation and promote intestinal barrier integrity ( 57 ), it is tempting to speculate that by resetting the BM myeloid/lymphoid bias to protect lymphopoiesis, ES-62 may harness ACh-producing B (and T) cells ( 46 ) to resolve inflammation and promote tissue repair resulting from disruption of the gut BM axis. Of relevance, it is well established that neuronal-derived ACh suppresses production of inflammatory cytokines, stimulates mucus production by goblet cells and acts on cryptic basal and stem cells to effect gut barrier repair ( 57 ). Indeed, ACh confers resistance to IL-1β-mediated gut pathology, as exemplified by disruption of tight junctions and loss of colon fucosylation and intestinal barrier integrity ( 28 , 58 ).…”

“…Indeed, ACh confers resistance to IL-1β-mediated gut pathology, as exemplified by disruption of tight junctions and loss of colon fucosylation and intestinal barrier integrity ( 28 , 58 ). However, there is also increasing evidence that ACh release by ChAT-expressing haematopoietic and stromal cells plays roles in fighting bacterial infection and promoting epithelial barrier formation in the gut ( 57 ). Thus, ES-62 could potentially counteract the CIA-induced microbiome dysbiosis and associated loss of colon fucosylation and accompanying increase in IL-1β production and consequent cellular infiltration and gut pathology by promoting influx of ChAT-expressing ACh-secreting lymphoid cells.…”

The Role of Mast Cells in Maintaining Homeostasis of the Colon Mucosa

“…The relationship between manifestations of stress and reactions from the gastrointestinal tract is mediated by the interaction of the brain and mast cells with the participation of the vagus nerve [56,57]. The further process of mast cell degranulation increases the permeability of the intestinal barrier, and pharmacological inhibition of their activation eliminates this effect in animal stress models [58][59][60].…”

“…Взаємозв'язок між проявами стресу та реакціями з боку шлунково-кишкового тракту опосередковується взаємодією мозку і мастоцитів за участі блукаючого нерва [56,57]. Подальший процес дегрануляції мастоцитів посилює проникність кишкового бар'єру, а фармакологічне інгібування їх активації нівелює цей ефект на моделях стресу у тварин [58][59][60].…”

Exploring the microscopic terrain of the small intestinal epithelium: a comprehensive overview of general architecture and the present understanding of intestinal stem cells

“…By regulating the transcription of cyclin D1 and suppressing the expression of the M3 receptor gene in Lgr5-positive cells, acetylcholine restrains their proliferative activity and differentiation. This mechanism contributes to the overall equilibrium within the intestine, emphasizing the interplay between neural signaling, cellular processes, and the maintenance of intestinal function [37]. Recent research has uncovered the impact of innate lymphoid cells (ILC) through the secretion of interleukin 22 .…”