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

Stella Panagio Breininger,Laura Sabater,Fiona Caroline Malcomson,Jelena Mann,John Cummings Mathers,Sorena Afshar

doi:10.1038/s41366-021-01005-y

Stella Panagio Breininger, Laura Sabater + Show 4 more

Open Access

https://doi.org/10.1038/s41366-021-01005-y

Copy DOI

Abstract

Background/ObjectivesObesity 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/MethodsWe 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.ResultsCompared 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.ConclusionOur 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.

Highlights

The prevalence of obesity has doubled in more than 70 countries since 1980 and the incidence continues to rise [1]
We examined the effects of obesity and weight loss following Roux-en-Y gastric bypass (RYGB) on microRNA expression in the human rectal mucosa
We show that miRNA expression quantitative polymerase chain reaction using validated profiles are altered with excess obesity and following RYGB, primers

Summary

INTRODUCTION

The prevalence of obesity has doubled in more than 70 countries since 1980 and the incidence continues to rise [1]. Using the 82 miRNAs for which expression differed by absolute logFC >1 between obese individuals before RYGB and non-obese Controls, IPA predicted a network that involved 31 molecules (Fig. 1D). Using the 45 miRNAs for which expression differed by logFC >1 between obese individuals preRYGB and following RYGB, IPA analysis yielded a network that predicted interactions between 33 molecules (Fig. 2D). AGO2 emerged as a central player that is implicated in both obesity and in weight loss and which shows the highest number (n = 15) of interactions It is targeted by 7 network members (CCNE1, UPF1, miR-9, miR-9-5p, miR-196a-5p, miR-203a-3p and miR-3150b-3p), targets four network members (miR-126-3p, miR-204-5p, miR-2103p, miR-455-3p) and is associated with a further 4 molecules in this network (DELTA133P53, DICER1, miR-7-5p and miR-15a-5p). The remaining six miRNAs (miR-204, miR-671, miR-892c, miR-1247, miR3196 and miR-4516) were unrelated to changes of adiposity, or their role is unknown, and will not be discussed further (Table S10)

DISCUSSION

Findings

CONCLUSION

ETHICS APPROVAL