Dubosiella newyorkensis modulates immune tolerance in colitis via the L-lysine-activated AhR-IDO1-Kyn pathway

Yanan Zhang, Shuyu Tu, Xingwei Ji, Jianan Wu, Jinxin Meng, Jinsong Gao, Xian Shao, Shuai Shi, Gan Wang, Jingjing Qiu, Zhuobiao Zhang, Chengang Hua, Ziyi Zhang, Shuxian Chen, Li Zhang and Shu Jeffrey Zhu ()
Additional contact information
Yanan Zhang: Zhejiang University
Shuyu Tu: The First Affiliated Hospital of Guangdong Pharmaceutical University
Xingwei Ji: Zhejiang University
Jianan Wu: Zhejiang University School of Medicine
Jinxin Meng: Qingdao Agricultural University
Jinsong Gao: Zhejiang University
Xian Shao: Zhejiang University Shaoxing Hospital
Shuai Shi: Zhejiang University Shaoxing Hospital
Gan Wang: Zhejiang University
Jingjing Qiu: Jilin Agricultural University
Zhuobiao Zhang: Zhejiang University
Chengang Hua: Zhejiang University
Ziyi Zhang: Zhejiang University
Shuxian Chen: Zhejiang University
Li Zhang: The First Affiliated Hospital of Guangdong Pharmaceutical University
Shu Jeffrey Zhu: Zhejiang University

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Commensal bacteria generate immensely diverse active metabolites to maintain gut homeostasis, however their fundamental role in establishing an immunotolerogenic microenvironment in the intestinal tract remains obscure. Here, we demonstrate that an understudied murine commensal bacterium, Dubosiella newyorkensis, and its human homologue Clostridium innocuum, have a probiotic immunomodulatory effect on dextran sulfate sodium-induced colitis using conventional, antibiotic-treated and germ-free mouse models. We identify an important role for the D. newyorkensis in rebalancing Treg/Th17 responses and ameliorating mucosal barrier injury by producing short-chain fatty acids, especially propionate and L-Lysine (Lys). We further show that Lys induces the immune tolerance ability of dendritic cells (DCs) by enhancing Trp catabolism towards the kynurenine (Kyn) pathway through activation of the metabolic enzyme indoleamine-2,3-dioxygenase 1 (IDO1) in an aryl hydrocarbon receptor (AhR)-dependent manner. This study identifies a previously unrecognized metabolic communication by which Lys-producing commensal bacteria exert their immunoregulatory capacity to establish a Treg-mediated immunosuppressive microenvironment by activating AhR-IDO1-Kyn metabolic circuitry in DCs. This metabolic circuit represents a potential therapeutic target for the treatment of inflammatory bowel diseases.

Date: 2024
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DOI: 10.1038/s41467-024-45636-x

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