New insights into irritable bowel syndrome pathophysiological mechanisms: contribution of epigenetics

Abstract

Irritable bowel syndrome (IBS) is a complex multifactorial condition including alterations of the gut-brain axis, intestinal permeability, mucosal neuro-immune interactions, and microbiota imbalance. Recent advances proposed epigenetic factors as possible regulators of several mechanisms involved in IBS pathophysiology. These epigenetic factors include biomolecular mechanisms inducing chromosome-related and heritable changes in gene expression regardless of DNA coding sequence. Accordingly, altered gut microbiota may increase the production of metabolites such as sodium butyrate, a prominent inhibitor of histone deacetylases. Patients with IBS showed an increased amount of butyrate-producing microbial phila as well as an altered profile of methylated genes and micro-RNAs (miRNAs). Importantly, gene acetylation as well as specific miRNA profiles are involved in different IBS mechanisms and may be applied for future diagnostic purposes, especially to detect increased gut permeability and visceromotor dysfunctions. In this review, we summarize current knowledge of the role of epigenetics in IBS pathophysiology.

Keywords: DNA methylation; Epigenetic; Irritable bowel syndrome; miRNA.

Fig. 1

Epigenetic factors involved in gut–brain axis dysregulation – Histone acetylation and miRNA expression triggering biomolecular pathways involved in IBS. The underlying hypothesis envisages miRNA such as miR-24 and miR-29a having a direct involvement in pain perception and increased IP. An akin effect is induced by SB, a great HDAC inhibitor, produced at high levels by Firmicutes. In contrast, high SB levels were shown to restore IP and dysbiosis. Increased histone acetylation elicits NGF production by enteric glial cells resulting in higher SM contractility and pain perception. High SB levels reduce TLR4-mediated inflammation and, allegedly by a dose-dependent mechanism, both impair and restore intestinal permeability. AHR aromatic hydrocarbon receptor, IEC intestinal epithelial cells, NGF nerve growth factor, SB sodium butyrate, VIP vasoactive intestinal protein

Fig. 2

Epigenetic factors involved in brain-gut axis dysregulation. The scheme reports gene acetylation and miRNAs evoking visceral pain by interacting with key players of serotonergic (i.e., 5-HT3, 5-HT4, SERT), cholinergic, HPA response, and neurogenesis. SERT serotonin transporter, SB sodium butyrate, GR glucocorticoid receptor, CRF corticotropin-releasing factor, BDNF brain-derived neurotrophic factor, GRM glutamate receptor genes