Gut microbiota-derived metabolite 3-idoleacetic acid together with LPS induces IL-35(+) B cell generation.
Gut microbiota-derived metabolite 3-idoleacetic acid together with LPS induces IL-35(+) B cell generation.
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肠道微生物群衍生的代谢物 3-吲哚乙酸与 LPS 一起诱导 IL-35 B 细胞生成
DOI：
10.1186/s40168-021-01205-8
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发表时间：
2022-01-24
期刊：
影响因子：
15.5
通讯作者：
Yang R
中科院分区：
文献类型：
--
作者：
Su X;Zhang M;Qi H;Gao Y;Yang Y;Yun H;Zhang Q;Yang X;Zhang Y;He J;Fan Y;Wang Y;Guo P;Zhang C;Yang R
产生白细胞介素 - 35（IL - 35）的调节性B细胞（Bregs）和调节性T细胞（Treg细胞）通过与破坏肠道微生物群组成相关的机制，在全球范围内对慢性疾病起着关键的调节作用。然而，肠道微生物群是否对这些IL - 35⁺细胞有调控作用仍不明确。在此，我们利用肥胖的转基因小鼠模型，研究肠道微生物群对IL - 35⁺细胞的调节作用。
我们首先发现，肠道中的Reg4蛋白可促进对高脂饮食诱导的肥胖的抵抗。通过16S rRNA测序结合液相色谱 - 质谱联用（LC - MS）/质谱分析，我们证明在脂多糖（LPS）存在的情况下，肠道Reg4与诸如乳杆菌等细菌相关联，通过3 - 吲哚乙酸（IAA）促进IL - 35⁺ B细胞的生成。喂食高脂饮食的HuREG4IECtg小鼠不仅在其脂肪组织中，而且在结肠中均表现出显著的IL - 35⁺细胞积累，而在Reg4基因敲除（KO）小鼠的脂肪和结肠组织中观察到IL - 35⁺细胞积累减少。我们还发现，Reg4通过IL - 35介导对高脂饮食诱导的肥胖的抵抗。与非肥胖个体相比，肥胖个体外周血中的IAA水平也较低。从机制上讲，IAA与LPS通过孕烷X受体（PXR）和Toll样受体4（TLR4）介导IL - 35⁺ B细胞的生成。PXR或TLR4基因敲除会损害IL - 35⁺ B细胞的生成。
总之，IAA和LPS通过PXR和TLR4诱导IL - 35⁺ B细胞的生成。
视频摘要
在线版本包含补充材料，网址为10.1186/s40168 - 021 - 01205 - 8。
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. 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. 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. Together, IAA and LPS induce the generation of IL-35+ B cells through PXR and TLR4. Video Abstract The online version contains supplementary material available at 10.1186/s40168-021-01205-8.
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1016/j.bbadis.2013.05.017
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2016-09
期刊：
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通讯作者：
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影响因子：
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