High Fat Diets Induce Colonic Epithelial Cell Stress and Inflammation that is Reversed by IL-22

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.

Functional Interactions between Gut Microbiota Transplantation, Quercetin, and High‐Fat Diet Determine Non‐Alcoholic Fatty Liver Disease Development in Germ‐Free Mice

“…In this regard, increased Akkermansia spp. relative abundance in HFD‐fed receivers could exert a protective effect in a mechanism involving the improvement of intestinal bacterial imbalance and barrier integrity, as previously proposed, suggesting that this genus can play a role as a potential strategy for preventing NAFLD development. Moreover, an increase in Akkermansia spp.…”

Gut Microbiota Contribute to Age-Related Changes in Skeletal Muscle Size, Composition, and Function: Biological Basis for a Gut-Muscle Axis

“…In addition, circulating levels of lipopolysaccharide (LPS), a component of the outer membrane of gram negative bacteria, were 2- to-3-fold elevated in high-fat fed mice when compared with control fed animals. Pertinently, high-fat feeding is shown to compromise epithelial tight junctions and increase intestinal permeability [34, 35], evidence that suggests a role for high-fat induced leak of LPS from the intestine into the circulation.…”

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

“…These antimicrobial peptides act to regulate spatial segregation of commensal bacteria from the epithelial barrier by establishing a gradient of bactericidal activity, which has been termed the ‘demilitarized zone’ 77. Production of IL‐22 further reinforces spatial segregation of commensal bacteria by driving transcription of membrane‐bound mucins and goblet cell hyperplasia 78, 79…”