Role of microRNAs in Disorders of Gut-Brain Interactions: Clinical Insights and Therapeutic Alternatives

Abstract

Disorders of gut-brain interactions (DGBIs) are heterogeneous in nature and intertwine with diverse pathophysiological mechanisms. Regular functioning of the gut requires complex coordinated interplay between a variety of gastrointestinal (GI) cell types and their functions are regulated by multiple mechanisms at the transcriptional, post-transcriptional, translational, and post-translational levels. MicroRNAs (miRNAs) are small non-coding RNA molecules that post-transcriptionally regulate gene expression by binding to specific mRNA targets to repress their translation and/or promote the target mRNA degradation. Dysregulation of miRNAs might impair gut physiological functions leading to DGBIs and gut motility disorders. Studies have shown miRNAs regulate gut functions such as visceral sensation, gut immune response, GI barrier function, enteric neuronal development, and GI motility. These biological processes are highly relevant to the gut where neuroimmune interactions are key contributors in controlling gut homeostasis and functional defects lead to DGBIs. Although extensive research has explored the pathophysiology of DGBIs, further research is warranted to bolster the molecular mechanisms behind these disorders. The therapeutic targeting of miRNAs represents an attractive approach for the treatment of DGBIs because they offer new insights into disease mechanisms and have great potential to be used in the clinic as diagnostic markers and therapeutic targets. Here, we review recent advances regarding the regulation of miRNAs in GI pacemaking cells, immune cells, and enteric neurons modulating pathophysiological mechanisms of DGBIs. This review aims to assess the impacts of miRNAs on the pathophysiological mechanisms of DGBIs, including GI dysmotility, impaired intestinal barrier function, gut immune dysfunction, and visceral hypersensitivity. We also summarize the therapeutic alternatives for gut microbial dysbiosis in DGBIs, highlighting the clinical insights and areas for further exploration. We further discuss the challenges in miRNA therapeutics and promising emerging approaches.

Keywords: functional dyspepsia; gastroparesis; gut barrier function; irritable bowel syndrome; miRNA therapeutics; neuroimmune interaction; serotonin; slow transit constipation; visceral hypersensitivity.

Figure 1

miRNA mediated pathophysiological mechanisms and potential therapeutic alternatives for DGBIs. (A). miRNA biogenesis and miRNA therapeutic approaches to reduce or enhance miRNA levels leading to mRNA restoration or mRNA degradation/translational repression, respectively, (B). Dysregulated miRNAs are evidenced in gastrointestinal pacemaking cells, immune cells, intestinal epithelial cells, and enteric neurons, (C). Possible miRNA therapeutics based on pathophysiological mechanisms. Abbreviations: AGO, argonaute; CLDN1, claudin-1; EC cell, enterochromaffin cell; ICC, interstitial cell of Cajal; miRNA, microRNA, mRNA, messenger RNA; RISC, RNA-induced silencing complex; SMC, smooth muscle cell; ZO-1, zonula occludens; 5-HT, 5-hydroxytryptamine.