Gut microbiota–derived metabolite 3-idoleacetic acid together with LPS induces IL-35+ B cell generation
Lei Su, Minying Zhang, Houbao Qi, Yunhuan Gao, Yazheng Yang, Huan Yun, Qianjing Zhang, Xiaorong Yang, Yuan Zhang, Jiangshan He, Yaqi Fan, Yuxue Wang, Pei Guo, Chunze Zhang, Rongcun Yang
Abstract
Abstract Background IL-35–producing Bregs and Treg cells critically regulate chronic illnesses worldwide via mechanisms related to disrupting the gut microbiota composition. However, whether the gut microbiota regulates these IL-35 + cells remains elusive. We herein investigated the regulatory effects of the gut microbiota on IL-35 + cells by using genetically modified mouse models of obesity. Results We first found that gut Reg4 promoted resistance to high-fat diet-induced obesity. Using 16S rRNA sequencing combined with LC-MS (liquid chromatography–mass spectrometry)/MS, we demonstrated that gut Reg4 associated with bacteria such as Lactobacillus promoted the generation of IL-35 + B cells through 3-idoleacetic acid (IAA) in the presence of LPS. HuREG4 IECtg mice fed a high-fat diet exhibited marked IL-35 + cell accumulation in not only their adipose tissues but also their colons, whereas decreased IL-35 + cell accumulation was observed in the adipose and colon tissues of Reg4 knockout (KO) mice. We also found that Reg4 mediated HFD-induced obesity resistance via IL-35. Lower levels of IAA were also detected in the peripheral blood of individuals with obesity compared with nonobese subjects. Mechanistically, IAA together with LPS mediated IL-35 + B cells through PXR and TLR4. KO of PXR or TLR4 impaired the generation of IL-35 + B cells. Conclusion Together, IAA and LPS induce the generation of IL-35 + B cells through PXR and TLR4.