Abstract
Prolonged high fat diets (HFD) induce low-grade chronic intestinal inflammation in mice, and diets high in saturated fat are a risk factor for the development of human inflammatory bowel diseases. We hypothesized that HFD-induced endoplasmic reticulum (ER)/oxidative stress occur in intestinal secretory goblet cells, triggering inflammatory signaling and reducing synthesis/secretion of proteins that form the protective mucus barrier. In cultured intestinal cells non-esterified long-chain saturated fatty acids directly increased oxidative/ER stress leading to protein misfolding. A prolonged HFD elevated the intestinal inflammatory cytokine signature, alongside compromised mucosal barrier integrity with a decrease in goblet cell differentiation and Muc2, a loss in the tight junction protein, claudin-1 and increased serum endotoxin levels. In Winnie mice, that develop spontaneous colitis, HFD-feeding increased ER stress, further compromised the mucosal barrier and increased the severity of colitis. In obese mice IL-22 reduced ER/oxidative stress and improved the integrity of the mucosal barrier, and reversed microbial changes associated with obesity with an increase in Akkermansia muciniphila. Consistent with epidemiological studies, our experiments suggest that HFDs are likely to impair intestinal barrier function, particularly in early life, which partially involves direct effects of free-fatty acids on intestinal cells, and this can be reversed by IL-22 therapy.
Highlights
A dense mucus layer prevents inflammation in the intestine by shielding the underlying epithelium from luminal microbes and the external environment
We show that high fat diets (HFD)-feeding leads to spontaneous goblet cell dysfunction, impaired mucosal barrier function and inflammation, and exacerbates the development of pathology in mice predisposed to endoplasmic reticulum (ER) stress-induced colitis
Corroborating the increase in gene expression, we found an increase in ER resident proteins Grp[78] and Ire-1β(ER resident endoribonuclease that drives the unfolded protein response (UPR)) proteins in epithelial cells isolated from the distal colon of HFD mice compared to control mice (Fig. 1j)
Summary
A dense mucus layer prevents inflammation in the intestine by shielding the underlying epithelium from luminal microbes and the external environment. High fat diets (HFD) have been shown to exacerbate chemically-induced dextran sodium sulphate (DSS) colitis by up-regulating pro-inflammatory cytokines[18,19,20] and exacerbate mucosal tissue damage in mouse models of spontaneous colitis (Muc2−/−, TNFΔARE mice)[21] and ileitis (Mdr1a−/− mice)[22,23]. Consistent with this pro-inflammatory response to the HFD, epidemiological studies have implicated high dietary fat intake with an increased risk of IBD24. We show that HFD-induced intestinal epithelial stress, inflammation and the associated shifts in the microbiome are reversed by IL-22
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