High-fat diet aggravates colitis via mesenteric adipose tissue derived exosome metastasis-associated lung adenocarcinoma transcript 1

Abstract

BACKGROUND

Obesity is associated with an increased risk of developing Crohn’s disease (CD), higher disease activity, and comparatively worse clinical outcomes.

AIM

To investigate the role of mesenteric adipose tissue-derived exosomes in the pathogenesis of CD aggravation in obese individuals.

METHODS

First, we induced colitis in mice initiated on high-fat and normal diets and compared the severity of colitis. We then extracted and identified exosomes from mesenteric adipose tissue and determined the levels of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in mesenteric adipose tissue-derived exosomes and the colon. Next, we demonstrated an interaction between MALAT1 and the miR-15a-5p/activating transcription factor 6 (ATF6) axis. Finally, we explored the effects of mesenteric adipose tissue-derived exosomes extracted from mice fed a high-fat or normal diet on the severity of 2,4,6-trinitrobe-nzenesulfonic acid (TNBS)-induced colitis and ATF6-related endoplasmic reticulum stress pathways.

RESULTS

High-fat diet was found to aggravate TNBS-induced colitis in mice. The expression of MALAT1 in mesenteric adipose tissue-derived exosomes of high-fat diet-fed mice increased. The increased expression of MALAT1 in colon tissue exacerbated TNBS-induced colitis and activated the ATF6 endoplasmic reticulum stress pathway. This effect was partially reversed by the reduced expression of MALAT1 and overexpression of miR-15a-5p.

CONCLUSION

Mesenteric adipose tissue-derived exosome-encapsulated long noncoding RNAs MALAT1 targets the colon and aggravates TNBS-induced colitis in obese mice, which may potentially act on the miR-15a-5p/ATF6 axis and activate endoplasmic reticulum stress.

Keywords: Metastasis-associated lung adenocarcinoma transcript; Crohn’s disease; miR-15a-5p; Mesenteric adipose tissue; Obesity; Colitis; Inflammatory bowel disease

Core Tip: A higher visceral adipose tissue ratio has been associated with increased disease activity in patients with Crohn’s disease. However, the mechanisms underlying this effect remain unclear. Our study indicates that a high-fat diet increases the mesenteric adipose tissue content and aggravates colitis in mice. Mesenteric adipose tissue-derived exosome long noncoding RNAs metastasis-associated lung adenocarcinoma transcript 1 can be absorbed by the colon, leading to the activation of the endoplasmic reticulum stress pathway by targeting the miR-15a-5p/activating transcription factor 6 axis to aggravate colitis.