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.

De novo expression of Muc5ac, a mucin not normally expressed in the intestinal tract, is induced in the cecum of mice resistant to Trichuris muris infection. In this study, we investigated the role of Muc5ac, which is detected shortly before worm expulsion and is associated with the production of interleukin-13 (IL-13), in resistance to this nematode. Muc5ac-deficient mice were incapable of expelling T. muris from the intestine and harbored long-term chronic infections, despite developing strong T_H2 responses. Muc5ac-deficient mice had elevated levels of IL-13 and, surprisingly, an increase in the T_H1 cytokine IFN-γ. Because T_H1 inflammation is thought to favor chronic nematode infection, IFN-γ was neutralized in vivo, resulting in an even stronger T_H2-type immune response. Nevertheless, despite a more robust T_H2 effector response, the Muc5ac-deficient mice remained highly susceptible to chronic T. muris infection. Importantly, human MUC5AC had a direct detrimental effect on nematode vitality. Moreover, the absence of Muc5ac caused a significant delay in the expulsion of two other gut-dwelling nematodes (Trichinella spiralis and Nippostrongylus brasiliensis). Thus, for the first time, we identify a single mucin, Muc5ac, as a direct and critical mediator of resistance during intestinal nematode infection.

The inability of pancreatic β-cells to make sufficient insulin to control blood sugar is a central feature of the aetiology of most forms of diabetes. In this review we focus on the deleterious effects of oxidative stress and endoplasmic reticulum (ER) stress on β-cell insulin biosynthesis and secretion and on inflammatory signalling and apoptosis with a particular emphasis on type 2 diabetes (T2D). We argue that oxidative stress and ER stress are closely entwined phenomena fundamentally involved in β-cell dysfunction by direct effects on insulin biosynthesis and due to consequences of the ER stress-induced unfolded protein response. We summarise evidence that, although these phenomenon can be driven by intrinsic β-cell defects in rare forms of diabetes, in T2D β-cell stress is driven by a range of local environmental factors including increased drivers of insulin biosynthesis, glucolipotoxicity and inflammatory cytokines. We describe our recent findings that a range of inflammatory cytokines contribute to β-cell stress in diabetes and our discovery that interleukin 22 protects β-cells from oxidative stress regardless of the environmental triggers and can correct much of diabetes pathophysiology in animal models. Finally we summarise evidence that β-cell dysfunction is reversible in T2D and discuss therapeutic opportunities for relieving oxidative and ER stress and restoring glycaemic control.