Western diet reduces small intestinal intraepithelial lymphocytes via FXR-Interferon pathway

IF 7.9 2区 医学 Q1 IMMUNOLOGY
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Abstract

The prevalence of obesity in the United States has continued to increase over the past several decades. Understanding how diet-induced obesity modulates mucosal immunity is of clinical relevance. We previously showed that consumption of a high fat, high sugar “Western” diet (WD) reduces the density and function of small intestinal Paneth cells, a small intestinal epithelial cell type with innate immune function. We hypothesized that obesity could also result in repressed gut adaptive immunity. Using small intestinal intraepithelial lymphocytes (IEL) as a readout, we found that in non-inflammatory bowel disease (IBD) subjects, high body mass index correlated with reduced IEL density. We recapitulated this in wild type (WT) mice fed with WD. A 4-week WD consumption was able to reduce IEL but not splenic, blood, or bone marrow lymphocytes, and the effect was reversible after another 2 weeks of standard diet (SD) washout. Importantly, WD-associated IEL reduction was not dependent on the presence of gut microbiota, as WD-fed germ-free mice also showed IEL reduction. We further found that WD-mediated Farnesoid X Receptor (FXR) activation in the gut triggered IEL reduction, and this was partially mediated by intestinal phagocytes. Activated FXR signaling stimulated phagocytes to secrete type I IFN, and inhibition of either FXR or type I IFN signaling within the phagocytes prevented WD-mediated IEL loss. Therefore, WD consumption represses both innate and adaptive immunity in the gut. These findings have significant clinical implications in the understanding of how diet modulates mucosal immunity.
西式饮食通过 FXR- 干扰素途径减少小肠上皮内淋巴细胞。
过去几十年来,美国的肥胖症发病率持续上升。了解饮食引起的肥胖如何调节粘膜免疫具有临床意义。我们以前的研究表明,摄入高脂肪、高糖的 "西式 "饮食(WD)会降低小肠帕奈斯细胞的密度和功能,帕奈斯细胞是一种具有先天性免疫功能的小肠上皮细胞类型。我们假设肥胖也会导致肠道适应性免疫功能受抑制。利用小肠上皮内淋巴细胞(IEL)作为读数,我们发现在非炎症性肠病(IBD)受试者中,高体重指数与 IEL 密度降低相关。我们在喂食 WD 的野生型(WT)小鼠身上重现了这一点。连续 4 周摄入 WD 能够减少 IEL,但不会减少脾脏、血液或骨髓淋巴细胞,而且这种影响在标准饮食(SD)间隔 2 周后是可逆的。重要的是,WD 相关的 IEL 减少并不依赖于肠道微生物群的存在,因为喂食 WD 的无菌小鼠也会出现 IEL 减少。我们进一步发现,WD 介导的肠道类囊体 X 受体(FXR)激活引发了 IEL 减少,而这部分是由肠道吞噬细胞介导的。激活的 FXR 信号刺激吞噬细胞分泌 I 型 IFN,抑制吞噬细胞内的 FXR 或 I 型 IFN 信号可防止 WD 介导的 IEL 损失。因此,摄入 WD 会抑制肠道内的先天性免疫和适应性免疫。这些发现对于了解饮食如何调节粘膜免疫具有重要的临床意义。
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来源期刊
Mucosal Immunology
Mucosal Immunology 医学-免疫学
CiteScore
16.60
自引率
3.80%
发文量
100
审稿时长
12 days
期刊介绍: Mucosal Immunology, the official publication of the Society of Mucosal Immunology (SMI), serves as a forum for both basic and clinical scientists to discuss immunity and inflammation involving mucosal tissues. It covers gastrointestinal, pulmonary, nasopharyngeal, oral, ocular, and genitourinary immunology through original research articles, scholarly reviews, commentaries, editorials, and letters. The journal gives equal consideration to basic, translational, and clinical studies and also serves as a primary communication channel for the SMI governing board and its members, featuring society news, meeting announcements, policy discussions, and job/training opportunities advertisements.
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