Abstract
BackgroundIL-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.ResultsWe 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. HuREG4IECtg 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.ConclusionTogether, IAA and LPS induce the generation of IL-35+ B cells through PXR and TLR4.ESFDmA-1LKhrrc6QfnM_pPVideo
Highlights
The gut microbiota can influence essential human functions, including inflammation, digestion, and energy metabolism, by modulating the immune pathways and neural and endocrine systems of the host [1,2,3,4]
Since alteration of the gut microbiota is related to the occurrence and development of multiple diseases, such as obesity [37,38,39], we further investigated the role of Reg4 in high-fat diet (HFD)–mediated obesity using Reg4 knockout (KO) mice
We found that these Reg4 KO mice showed more sensitivity to HFD-induced obesity, including a higher body weight, higher fat pad tissue weight, decreased insulin sensitivity and reduced glucose tolerance (Fig. 1a–d)
Summary
The gut microbiota can influence essential human functions, including inflammation, digestion, and energy metabolism, by modulating the immune pathways and neural and endocrine systems of the host [1,2,3,4]. IL-35, a potent anti-inflammatory cytokine, is a newly identified member of the IL-12 family of heterodimeric cytokines comprised of p35 (IL-12A), which is shared by both IL-35 and IL-12, and Epstein–Barr virus-induced gene 3 (Ebi3), which is shared by IL-27 and IL-35 [21] This cytokine has strong suppressive properties both in vivo and in vitro [22,23,24]. It can exert wide-ranging effects on multiple types of immune cells, such as T cells, B cells, macrophages, and dendritic cells (DCs) [19], promote the generation of Treg cells and anti-inflammatory macrophage 2 (M2) [25, 26], and impede the differentiation of Th1 cells [27]. We investigated the regulatory effects of the gut microbiota on IL-35+ cells by using genetically modified mouse models of obesity
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