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

ARTICLE HIGHLIGHTS

Research background

Obesity is associated with an increased risk of developing Crohn’s disease (CD), higher disease activity, and comparatively worse clinical outcomes, especially in CD patients with a high visceral adipose tissue ratio. However, the underlying mechanisms remain unclear.

Research motivation

Exosomes contain multiple non-coding RNAs such as long non-coding RNAs (lncRNAs), which serve as messengers in cell-cell communication. Visceral adipose tissue derived exosomes display tissue affinity and preferentially target the colonic lamina propria. We hypothesized that obesity exacerbates inflammatory bowel disease, partially through mesenteric adipose tissue-derived exosomes.

Research objectives

To investigate the role of mesenteric adipose tissue-derived exosomes in CD aggravation through obesity, thereby providing a potential therapeutic target for CD in this subpopulation.

Research methods

A 2,4,6-trinitrobe-nzenesulfonic acid (TNBS) was used to induce colitis in mice fed a high-fat diet (HFD) and normal diet (ND). Exosomes from the mesenteric adipose tissue were extracted and identified, followed by the investigation of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) expression. Luciferase reporter and RNA pull-down assays were performed to verify the interaction between MALAT1 and miR-15a-5p/activating transcription factor 6 (ATF6) axis. Finally, mesenteric adipose tissue-derived exosomes extracted from HFD-fed mice were isolated and treated with either a short hairpin RNA targeting MALAT1 (shMALAT) or an miR-15a-5p mimic before being injected into mice to explore their influence on TNBS-induced colitis.

Research results

HFD can aggravate TNBS-induced colitis in mice, and increase the expression of MALAT1 in mesenteric adipose tissue-derived exosomes. Increased expression of MALAT1 in the colon tissue exacerbated TNBS-induced colitis and activated the ATF6-related endoplasmic reticulum stress pathway. Moreover, this effect was partially reversed by the reduced expression of MALAT1 and overexpression of miR-15a-5p.

Research conclusions

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

Research perspectives

Obesity-mediated aggravation of colitis might involve the mesenteric adipose tissue-derived exosome lncRNA MALAT1, but the specific cells of the intestine targeted by MALAT1 deserve further exploration.