Objective

Obesity is characterized by systemic and low-grade tissue inflammation. In the intestine, alteration of the intestinal barrier and accumulation of inflammatory cells in the epithelium are important contributors of gut inflammation. Recent studies demonstrated the role of the aryl hydrocarbon receptor (AhR) in the maintenance of immune cells at mucosal barrier sites. A wide range of ligands of external and local origin can activate this receptor. We studied the causal relationship between AhR activation and gut inflammation in obesity.

Methods

Jejunum samples from subjects with normal weight and severe obesity were phenotyped according to T lymphocyte infiltration in the epithelium from lamina propria and assayed for the mRNA level of AhR target genes. The effect of an AhR agonist was studied in mice and Caco-2/TC7 cells. AhR target gene expression, permeability to small molecules and ions, and location of cell-cell junction proteins were recorded under conditions of altered intestinal permeability.

Results

We showed that a low AhR tone correlated with a high inflammatory score in the intestinal epithelium in severe human obesity. Moreover, AhR activation protected junctional complexes in the intestinal epithelium in mice challenged by an oral lipid load. AhR ligands prevented chemically induced damage to barrier integrity and cytokine expression in Caco-2/TC7 cells. The PKC and p38MAPK signaling pathways were involved in this AhR action.

Conclusions

The results of these series of human, mouse, and cell culture experiments demonstrate the protective effect of AhR activation in the intestine targeting particularly tight junctions and cytokine expression. We propose that AhR constitutes a valuable target to protect intestinal functions in metabolic diseases, which can be achieved in the future via food or drug ligands.

中文翻译：

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AhR激活可防御肠屏障的完整性，防止肥胖发生。

目的

肥胖症的特征是全身性和低度组织炎症。在肠中，肠屏障的改变和上皮中炎性细胞的积累是肠道炎症的重要因素。最近的研究表明芳基烃受体（AhR）在黏膜屏障位点的免疫细胞维持中的作用。多种外部和局部来源的配体均可激活该受体。我们研究了肥胖中AhR激活与肠道炎症之间的因果关系。

方法

根据来自固有层的上皮中的T淋巴细胞浸润，对正常体重和严重肥胖的受试者的空肠样品进行表型分析，并检测AhR靶基因的mRNA水平。在小鼠和Caco-2 / TC7细胞中研究了AhR激动剂的作用。在肠道通透性改变的条件下记录了AhR靶基因的表达，对小分子和离子的通透性以及细胞间连接蛋白的位置。

结果

我们显示，在严重的肥胖症患者中，低的AhR值与肠道上皮的高炎症评分相关。此外，AhR激活保护了口服脂质负荷激发的小鼠肠上皮的连接复合物。AhR配体可防止化学诱导的Caco-2 / TC7细胞屏障完整性和细胞因子表达受损。PKC和p38MAPK信号通路参与了该AhR的作用。

结论

这些人类，小鼠和细胞培养系列实验的结果表明，AhR激活在肠中的保护作用特别针对紧密连接和细胞因子表达。我们建议，AhR是保护代谢疾病中肠功能的重要靶标，将来可以通过食物或药物配体实现。