Gut microbiota–derived metabolite 3-idoleacetic acid together with LPS induces IL-35(+) B cell generation

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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40168-021-01205-8.