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miR-10b Rescues Diabetes and GI Dysmotility Associated with a Leaky Gut
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Of all microorganisms in the human body, the largest and most complex population resides in the gastrointestinal (GI) tract. The gut microbiota continuously adapts to the host environment and serves multiple critical functions for their hosts, including regulating host immunity, procuring energy from food, and preventing the colonization of pathogens. Mounting evidence has suggested gut immune dysfunction, impaired barrier function, and gut dysmotility play a key role in the development of metabolic disorders and disorders of gut-brain interactions (DGBIs). In reference to the Rome IV criteria, the most common DGBIs, include functional dyspepsia (FD) and irritable bowel syndrome (IBS). Additionally, there is substantial overlap of these disorders and other specific GI motility disorders such as gastroparesis. These disorders are heterogeneous and are intertwined with several proposed pathophysiological mechanisms, such as altered gut motility, intestinal barrier dysfunction, gut immune dysfunction, visceral hypersensitivity, altered GI secretion, presence and degree of bile acid malabsorption, microbial dysbiosis, and alterations to the gut-brain axis. The currently available therapies lack long-term effectiveness and safety for their use to treat motility disorders and DGBIs. Additionally, currently available treatment options simply treat the symptoms and not the pathological mechanism causing the disorder. Pharmacological agents that are developed based on the cellular and molecular mechanisms underlying the pathologies of these disorders might provide the best avenue for future pharmaceutical development. Current advances in RNA-based therapies have substantial promise in treating and preventing many human diseases and disorders through fixing the pathology instead of merely treating the symptomology, like traditional therapeutics. Although many RNA therapeutics have made it to clinical trials, only a few have been FDA-approved thus far. Additionally, the results of clinical trials for RNA therapeutics have been ambivalent to date, with some studies demonstrating potent efficacy, whereas others have limited effectiveness and/or toxicity. Momentum is building in the clinic for RNA therapeutics; future clinical care of human diseases will likely be comprised of promising RNA therapeutics. There has been phenomenal progress in understanding the cellular and molecular mechanisms of DGBIs. However, the precise cellular and molecular pathogeneses of gut dysfunctions are yet enigmatic. Important regulatory mechanisms are mediated through mircoRNAs (miRNAs) and they play an essential role in gut health. 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. 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. Additionally, miRNAs might be beneficial for the treatment of DGBIs because they might be able to return functionality of key cells in the maintenance of normal gut homeostasis such as interstitial cells of Cajal (ICCs), enterochromaffin (EC cells), enteric neurons, smooth muscle cells, gut immune cells, etc. that are normally dysregulated in these conditions. Our previous studies demonstrated that depletion of miR-10b in KIT+ cells has been shown to cause the development of diabetes and gut dysmotility through the KLF11-KIT pathway. Recent studies have also shown that the leaky gut is connected to both diabetes and gut dysmotility; however, there is no direct evidence indicating whether or not the leaky gut is the linking mechanism between these conditions. Here we aimed to elucidate if global loss of miR-10b leads to the development of the leaky gut and if this is the linking mechanism between hyperglycemia and gut dysmotility. First, we created a mir-10b global KO (gKO) mouse model using CRISPR-Mb3Cas12a/Mb3Cpf1. Using both loss-of-function and gain-of-function studies we found that the leaky gut phenotype is a core pathophysiological mechanism linking the hyperglycemic and gut dysmotility phenotypes. Finally, we found that treating the mice with a miR-10b mimic rescues these phenotypes and might have substantial therapeutic potential for the treatment of diabetes, gut dysmotility, and the leaky gut.