High Fat Diets Induce Colonic Epithelial Cell Stress and Inflammation that is Reversed by IL-22.
High Fat Diets Induce Colonic Epithelial Cell Stress and Inflammation that is Reversed by IL-22.
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DOI：
10.1038/srep28990
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发表时间：
2016-06-28
影响因子：
4.6
通讯作者：
Hasnain SZ
中科院分区：
文献类型：
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作者：
Gulhane M;Murray L;Lourie R;Tong H;Sheng YH;Wang R;Kang A;Schreiber V;Wong KY;Magor G;Denman S;Begun J;Florin TH;Perkins A;Cuív PÓ;McGuckin MA;Hasnain SZ
长期高脂饮食(HFD)可引起小鼠低度慢性肠炎，高饱和脂肪饮食是人类炎症性肠病的危险因素。我们假设HFD诱导的内质网(ER)/氧化应激发生在肠道分泌杯状细胞中，触发炎症信号并减少形成保护性粘液屏障的蛋白质的合成/分泌。在培养的肠道细胞中，非酯化的长链饱和脂肪酸直接增加氧化/内质网应激，导致蛋白质错误折叠。长时间的HFD增加了肠道炎症细胞因子的信号，同时损害了粘膜屏障的完整性，杯状细胞分化和Muc2减少，紧密连接蛋白Claudin-1丢失，血清内毒素水平上升。在患有自发性结肠炎的Winnie小鼠中，喂食HFD增加了ER应激，进一步损害了粘膜屏障，增加了结肠炎的严重程度。在肥胖小鼠中，IL-22降低了ER/氧化应激，改善了粘膜屏障的完整性，并逆转了与肥胖相关的微生物变化，增加了粘性阿克曼氏菌。与流行病学研究一致，我们的实验表明，HFDs可能损害肠道屏障功能，特别是在生命早期，这部分涉及游离脂肪酸对肠道细胞的直接影响，这可以被IL-22治疗逆转。
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.