2. Academic Validation
  3. Dubosiella newyorkensis modulates immune tolerance in colitis via the L-lysine-activated AhR-IDO1-Kyn pathway

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

  • Nat Commun. 2024 Feb 13;15(1):1333. doi: 10.1038/s41467-024-45636-x.
Yanan Zhang 1,  Shuyu Tu 2,  Xingwei Ji 1,  Jianan Wu 3,  Jinxin Meng 4,  Jinsong Gao 1,  Xian Shao 5,  Shuai Shi 5,  Gan Wang 1,  Jingjing Qiu 6,  Zhuobiao Zhang 1,  Chengang Hua 1,  Ziyi Zhang 1,  Shuxian Chen 1,  Li Zhang 2,  Shu Jeffrey Zhu 7 8 9
Affiliations

Affiliations

  • 1 Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, PR China.
  • 2 Department of Cardiology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510080, PR China.
  • 3 Department of Critical Care Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, PR China.
  • 4 College of Veterinary Medicine, Qingdao Agricultural University, Qingdao, Shandong, 266109, PR China.
  • 5 Shaoxing People's Hospital, Zhejiang University Shaoxing Hospital, Shaoxing, Zhejiang, 312000, PR China.
  • 6 College of Veterinary Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, 130118, PR China.
  • 7 Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, PR China. shuzhu@zju.edu.cn.
  • 8 Department of Critical Care Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, PR China. shuzhu@zju.edu.cn.
  • 9 Shaoxing People's Hospital, Zhejiang University Shaoxing Hospital, Shaoxing, Zhejiang, 312000, PR China. shuzhu@zju.edu.cn.
PMID: 38351003 DOI: 10.1038/s41467-024-45636-x
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.

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