Maternal high-fat diet disrupts intestinal mucus barrier of offspring by regulating gut immune receptor LRRC19
Yue Sun, Shumin Huang, Mengfan Li, Yunwei Yang, Jiahui Ma, Runxiang Xie, Jingyi Wang, Qianjing Zhao, Siqi Qin, Linlin He, Jiaying Jiang, Qingliang Zhao, Ge Jin, Xiang Liu, Huan Huang, Yazheng Yang, Jianmei Wei, Wentian Liu, Bangmao Wang, Rongcun Yang, Xiaomin Su, Hailong Cao
Abstract
Maternal high fat diet (MHFD) increased colitis susceptibility in adulthood. However, the mechanism remains unclear. We sought to explore whether novel gut immune receptor leucine-rich repeat C19 (LRRC19) contributed to the impaired mucus barrier of offspring exposed to MHFD via gut immune response and microbiota. The results showed that MHFD significantly impaired the intestinal mucus barrier of offspring, and up-regulated the expression of LRRC19. Lrrc19 deletion alleviated the mucus barrier disruption. Mechanistically, metagenome sequencing revealed that the MHFD-induced gut microbiota alteration was partly restored in Lrrc19−/− offspring. Muc2-associated bacteria were decreased in the MHFD group, such as Akkermansia_muciniphila_CAG_154, which increased in the Lrrc19-deficient offspring. Moreover, Lrrc19−/− offspring had a higher rate of indole-3-acetic acid (IAA)-producing bacterium, such as Lactobacillus reuteri. A targeted metabolomics analysis revealed that IAA emerged as the top candidate that might mediate the protective effects. IAA was found to improve the mucus barrier function by increasing the ratio of interleukin-22 (IL-22)+ ILC3 cells in an aryl hydrocarbon receptor (AhR)-dependent manner. These results suggest that MHFD disrupts the intestinal mucus barrier of offspring through regulating gut immune receptor LRRC19 and inducing an imbalance of gut microbiota and microbiota-derived metabolites. Maternal high-fat diet alters the gut microbiota of offspring, reduces tryptophan metabolites and disrupts the intestinal mucus barrier via LRRC19, while LRRC19 deletion restores barrier function.