miRNA effects on gut homeostasis: therapeutic implications for inflammatory bowel disease

Inflammatory bowel disease (IBD) pathogenesis is poorly understood due to its multifactorial nature which comprises genetic as well as environmental factors, making miRNAs ideal candidates for etiological studies. miRNAs can modulate multiple aspects of mammalian gut homeostasis (sometimes simultaneously), ranging from intestinal barrier function, to microbial homeostasis, to damage or pathogen recognition, activating innate and adaptive immune responses. miRNAs have been recently implicated in shaping the gut microbiota of mice and/or humans, whereby miRNAs from intestinal epithelial cells can promote the growth of certain bacteria and vice versa. Emerging preclinical studies in mouse models of IBD have demonstrated the potential of candidate miRNA-based therapies, such as those involving antagomirs (miRNA inhibitors) and agomirs (miRNA mimetics). Inflammatory bowel disease (IBD) spans a range of chronic conditions affecting the gastrointestinal (GI) tract, which are marked by intermittent flare-ups and remissions. IBD results from microbial dysbiosis or a defective mucosal barrier in the gut that triggers an inappropriate immune response in a genetically susceptible person, altering the immune–microbiome axis. In this review, we discuss the regulatory roles of miRNAs, small noncoding RNAs with gene regulatory functions, in the stability and maintenance of the gut immune–microbiome axis, and detail the challenges and recent advances in the use of miRNAs as putative therapeutic agents for treating IBD. Inflammatory bowel disease (IBD) spans a range of chronic conditions affecting the gastrointestinal (GI) tract, which are marked by intermittent flare-ups and remissions. IBD results from microbial dysbiosis or a defective mucosal barrier in the gut that triggers an inappropriate immune response in a genetically susceptible person, altering the immune–microbiome axis. In this review, we discuss the regulatory roles of miRNAs, small noncoding RNAs with gene regulatory functions, in the stability and maintenance of the gut immune–microbiome axis, and detail the challenges and recent advances in the use of miRNAs as putative therapeutic agents for treating IBD. positioned immediately below TJs, AJs are characterized by intercellular E-cadherin chains, which are crucial for the initiation and maintenance of intercellular adhesion. molecules released by cells to signal injury or infection and mount appropriate immune response. mediate strong intercellular adhesion between adjacent cells and provide firm support to the epithelium during extreme mechanical stress. members of the RNAse III family; cleave kilobyte-long primary miRNAs and 60–90 nucleotide-long pre-miRNAs, respectively, giving rise to 20–22 nucleotide-long mature miRNAs. most-rapidly proliferating adult stems cells residing in intestinal crypts and marked by the G-protein-coupled receptor LGR5. cytosolic receptors recognizing molecular signatures associated with pathogens or dying cells that enter the cell via phagocytosis. evolutionarily conserved small molecular motifs associated with pathogens or microbes; in general, recognized by the immune system of the host. proteins recognizing specific molecular motifs on the surface of pathogens, damaged or senescent cells, or apoptotic host cells. determine paracellular transport in epithelial tight junctions; the pore pathway is charge and size selective (<8 Å), unlike the leak pathway. conserved post-transcriptional mechanism of suppressing the expression of double-stranded RNA in a sequence-specific way that can be activated by two effector small RNA molecules: miRNA and small interfering RNA (siRNA). pathological abnormality marked by narrowing of blood vessels due to lesions, resulting in pain and inflammation. multiprotein junctional complexes forming a tight seal between adjacent intestinal epithelial cells; they monitor paracellular transport. single-pass membrane-spanning receptors expressed by dendritic cells, macrophages, and most intestinal epithelial cells; help recognize conserved molecular motifs on microbes to activate innate immunity in the host.