Background IL-35 producing B and Treg cells are critical regulators in worldwide chronic illnesses, which are related to disruptions of gut microbiota composition. Whether gut microbiota regulate these IL-35+ cells maintains elusive. Here we investigated the regulation of gut microbiota in the IL-35+ cells through genetically modified mouse models against obesity. Results Here, we first found that gut Reg4 can promote resistance to high-fat diet induced obesity. Using 16S rRNA gene-based microbiota analysis combined with LC-MS (Liquid chromatography-mass spectrometry)/MS, we demonstrate that gut Reg4 associated microbiota such as lactobacillus can promote generation of the IL-35+ B cells through producing 3-idoleacetic acid (IAA) in the presence of LPS. HuREG4IECtg mice had accumulation of IL-35+ cells not only in adipose but also in colon after feeding high-fat diet; whereas decreased IL-35+ cells in adipose and colon tissues could be detected in Reg4 knockout (KO) mice. Lower levels of IAA were also detected in the peripheral blood of individuals with obesity. Mechanistically, IAA with LPS mediated IL35+ B cells are through PXR and TLR4. PXR KO or TLR4 KO impaired generation of IL-35+B cells. Conclusion IAA with LPS can induce generation of the IL-35+B cells through PXR and TLR4.
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