Obesity and Roux-en-Y gastric bypass drive changes in miR-31 and miR-215 expression in the human rectal mucosa

Abstract

Background/Objectives Obesity increases colorectal cancer (CRC) risk. However, the effects of weight loss on CRC risk are unclear. Epigenetic mechanisms involving microRNAs that lead to dysregulated gene expression may mediate the effects of obesity and weight loss on CRC risk. We examined the effects of obesity and weight loss following Roux-en-Y gastric bypass (RYGB) on microRNA expression in the human rectal mucosa. Subjects/Methods We collected rectal mucosal biopsies from obese patients (n = 22) listed for RYGB and age- and sex-matched healthy non-obese Controls (n = 20), at baseline and six months post-surgery. We quantified microRNA expression in rectal mucosal biopsies using Next Generation Sequencing and bioinformatics analysis to investigate the likely functional consequences of these epigenetic changes. Results Compared with non-obese individuals, obese individuals showed differential expression of 112 microRNAs (p < 0.05). At six-months post-RYGB, when mean body mass had fallen by 27 kg, 60 microRNAs were differentially expressed, compared with baseline (p < 0.05). The expression of 36 microRNAs differed significantly between both i) obese and non-obese individuals and ii) obese individuals pre- and post-RYGB. Quantitative polymerase chain reaction (qPCR) demonstrated that expression of miR-31 and miR-215 was significantly (p < 0.05) higher, 143-fold and 15-fold respectively, in obese than in non-obese individuals. Weight loss, following RYGB, reduced expression of miR-31 and miR-215 to levels comparable with Controls. These differentially expressed microRNAs are implicated in pathways linked with inflammation, obesity and cancer. Conclusion Our findings show, for the first time, that obesity is associated with dysregulated microRNA expression in the human rectal mucosa. Further, surgically-induced weight loss may normalise microRNA expression in this tissue.

Epigenetic modifications in obesity‐associated diseases

“…Differentially expressed miRNAs in obese patients tended to be normalized after bariatric surgery, which was thought to reduce the risk of colorectal cancer. 273 Gastric sleeve surgery can prompt the upregulation of tumor suppressor miR-122 in serum, thus reducing the risk of cancer. 274 In addition, the marked upregulation of lncRNA Gm19619 triggered by a HFD can enhance hepatic gluconeogenesis and lipid accumulation.…”

“…This analysis of changes can help identify potential therapeutic targets for T2D. Differentially expressed miRNAs in obese patients tended to be normalized after bariatric surgery, which was thought to reduce the risk of colorectal cancer 273 . Gastric sleeve surgery can prompt the upregulation of tumor suppressor miR‐122 in serum, thus reducing the risk of cancer 274 .…”

Using ncRNAs as Tools in Cancer Diagnosis and Treatment—The Way towards Personalized Medicine to Improve Patients’ Health

“…A recent study compared the ncRNAs in obese people, colorectal cancer patients, and healthy controls, showing that there is a significant overlap in dysregulated ncRNAs in obese people and cancer patients [ 207 ]. Moreover, another group showed that dysregulated miRs (especially miR-31 and miR-215) are a hallmark of obesity, and that weight loss can change the expression profile of these patients, showing a highly dynamic response of miR expression related to weight [ 208 ]. Leptin is a hormone that is predominantly made by adipose cells and enterocytes in the small intestine; it helps to regulate energy balance by inhibiting hunger, which in turn diminishes fat storage in adipocytes.…”

Circulating microRNAs Showed Specific Responses according to Metabolic Syndrome Components and Sex of Adults from a Population-Based Study

“…MicroRNAs (miRNAs), a subclass of short non-coding RNAs, mediate post-transcriptional regulation of gene expression. The miRNAs function through pairing with a target messenger RNA inducing different responses according to the level of complementarity, resulting in degradation or translational repression [ 3 , 4 ]. In addition, some miRNAs regulate the translation of proteins, histone modifications and DNA methylation [ 3 ].…”

“…Moreover, miRNAs packaged within cell-secreted exosomes can modulate local or systemic cell-to-cell communication, and regulate several metabolic pathways [ 3 , 5 , 6 ]. It should be noted that altered miRNA levels are associated with the development of cardiometabolic risk factors [ 4 , 5 ].…”