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

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. Video Abstract.

Keywords: Gut microbiota; IAA; IL-35+ B cells; Lactobacillus; PXR; Reg4; TLR4.