Obese adipose tissue extracellular vesicles inhibit recovery from dextran sulphate sodium (DSS)‐induced colitis

Abstract

Similar to the general American population, approximately 1/3rd of inflammatory bowel disease (IBD) patients are overweight and an additional 1/3rd are obese. Obesity in IBD patients is associated with increased difficulty in achieving remission, higher risk of disease relapse, higher hospitalization costs, and difficult surgical management. Adipose tissue is the largest endocrine organ producing and secreting cytokines, hormones, growth factors, and extracellular vesicles. Adipose tissue cellular composition, function, and secretion is strikingly altered during obesity. Alteration of adipose tissue‐derived EVs, including exosomes, during obesity is less understood. EVs carry molecular cargo that is actively taken up by other cell types and mediate phenotypic changes in recipient cells, resulting in intra‐organ communication. Since obesity is associated with abnormalities in gastrointestinal epithelial turnover, increased gut permeability, enhanced stemness, and decreased goblet cells, further studies are needed to elucidate the influence of obesity on pathomechanisms of underlying IBD. Here, we aim to investigate whether obese adipose tissue EVs alter acute disease or recovery in a model of induced colitis. As EV donor mice, C57BL/6 mice were fed from 4‐20 weeks of age a purified high fat diet (HFD) containing 45% kcal fat, a well‐established model of obesity, or purified matched diet (MD) containing 10% kcal fat. Visceral adipose tissue was cultured ex vivo, secreted EVs were isolated by ultracentrifugation, and concentration was determined by Nanoparticle Tracking Analysis. As EV recipient mice, a separate set of C57BL/6 mice were treated with 2.5% (wt/vol) dextran sodium sulfate (DSS) in drinking water for 6 days to induce acute colitis and were i.p. injected with MD EVs, HFD EVs, or vehicle (1xPBS) at a concentration of 10^8 EVs/g body weight every 2 days of DSS treatment. To test recovery from colitis, C57BL/6 mice were treated with 2.5% DSS for 6 days, were allowed to recover for an additional 6 days by removing DSS, and were treated with EVs every 2 days beginning on day 4 of DSS. Body weight and disease activity index (DAI) scores were measured daily. Colon was collected and swiss‐rolled for histology scoring (inflammation, extent, crypt damage, percent involvement) or RNA isolation for quantitative real‐time PCR analysis of Lcn2 as an indicator of inflammation. During acute DSS, body weights, DAI, colon length, and histology scoring did not change between mice injected with HFD EVs or MD EVs compared to vehicle. However, HFD EV treated mice exhibited delayed recovery from DSS colitis as evidenced by significantly higher DAI scores, colon shortening, and elevated levels of Lcn2 mRNA following recovery from DSS. These results suggest that EVs released by obese adipose tissue inhibit colitis recovery and provide insight on adipose‐to‐intestinal tissue communication elicited by EVs.