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. 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. Conclusion Together, IAA and LPS induce the generation of IL-35+ B cells through PXR and TLR4.

Gut Microbiota-Derived Tryptophan Metabolites Maintain Gut and Systemic Homeostasis

“…CD19 + IgM + IgD + IL10 + CD1d high CD5 low CD11b low CD21/CD35 Low CD23 Low CD25 Low CD72 low CD69 − CD138 low/− CD40 low/− CD86 low/− cells [ 112 ], which are different from IgG-producing Bregs but similar to IgM + IgD + Bregs [ 110 ]. These Bregs restrain excessive inflammatory responses [ 113 ] and contribute to the maintenance of immunological tolerance [ 114 ].…”

“…The relationship between IL-35 and NFκB has been reported. IAA by the gut microbiota, together with LPS, can activate NF-κB through TLR4 to induce the generation of IL-35 + cells [ 112 ]. IAA with LPS promotes the activity of transcription factors PXR, RXR and CAR, which are necessary for the expression of IL-35 [ 112 ].…”

Myristica fragrans Extract Regulates Gut Microbes and Metabolites to Attenuate Hepatic Inflammation and Lipid Metabolism Disorders via the AhR–FAS and NF-κB Signaling Pathways in Mice with Non-Alcoholic Fatty Liver Disease

“…The abundance of Akkermansia, Blautia, and Bifidobacterium was positively correlated with tryptophan levels, indicating that there were more probiotics and more tryptophan in the MFE group to activate AhR. A previous study suggested that tryptophan metabolites of the gut microbiota suppress liver inflammation [7], and the 3-indoleacetic acid produced by the intestinal flora helps mice lose weight [45].…”

Dual Role of Indoles Derived From Intestinal Microbiota on Human Health

“…Still, no research on Bacteroides, indole synthesis, and IL-22 secretion has been conducted, so further studies are needed to verify the possibility that IAA produced by other Bacteroides activates IL-22 and reduces colitis. In the presence of LPS, Reg4 expressed in intestinal epithelial cells maintains immune homeostasis by increasing the proportion of Lactobacillus and its metabolite IAA, which promotes the production and accumulation of IL-35 + B regulatory (Breg) cells in intestinal tissues (71). IL-35-producing Breg cells are key immune regulators of many diseases, including autoimmune and infectious diseases and cancer progression (89).…”

“…It has been found that IPA acts as a ligand for PXR in vivo, and IPA downregulates enterocyte TNF-a while upregulating ligand-encoding mRNA and increasing the manifestation of TJs that regulate intestinal barrier function in terms of intestinal permeability and inflammation (74). IAA combined with the PXR receptor can cause the production of IL-35 + B cells, promoting potent antiinflammatory cytokine IL-35, which maintains intestinal homeostasis (71). In addition, indole and indole-3-acetamide have also been suggested as PXR agonists (110) (Table 2).…”