Gut microbe-derived metabolite trimethylamine N-oxide activates PERK to drive fibrogenic mesenchymal differentiation
Seok-Jo Kim,
Swarna Bale,
Priyanka Verma,
Qianqian Wan,
Feiyang Ma,
Johann E. Gudjonsson,
Stanley L. Hazen,
Paul W. Harms,
Pei-Suen Tsou,
Dinesh Khanna,
Lam C. Tsoi,
Nilaksh Gupta,
Karen J. Ho,
John Varga
Affiliations
Seok-Jo Kim
Division of Rheumatology, Department of Internal Medicine, The University of Michigan, Suite 7C27, 300 North Ingalls Building, Ann Arbor, MI, USA; SCM Lifescience Co. Ltd., Incheon, Republic of Korea
Swarna Bale
Division of Rheumatology, Department of Internal Medicine, The University of Michigan, Suite 7C27, 300 North Ingalls Building, Ann Arbor, MI, USA
Priyanka Verma
Division of Rheumatology, Department of Internal Medicine, The University of Michigan, Suite 7C27, 300 North Ingalls Building, Ann Arbor, MI, USA
Qianqian Wan
Division of Rheumatology, Department of Internal Medicine, The University of Michigan, Suite 7C27, 300 North Ingalls Building, Ann Arbor, MI, USA
Feiyang Ma
Department of Dermatology, The University of Michigan, 300 North Ingalls Building, Ann Arbor, MI, USA; Department of Computational Medicine & Bioinformatics, The University of Michigan, Ann Arbor, MI, USA
Johann E. Gudjonsson
Division of Rheumatology, Department of Internal Medicine, The University of Michigan, Suite 7C27, 300 North Ingalls Building, Ann Arbor, MI, USA; Department of Dermatology, The University of Michigan, 300 North Ingalls Building, Ann Arbor, MI, USA
Stanley L. Hazen
Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH, USA; Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH, USA
Paul W. Harms
Department of Dermatology, The University of Michigan, 300 North Ingalls Building, Ann Arbor, MI, USA; Department of Pathology, The University of Michigan, Ann Arbor, MI, USA
Pei-Suen Tsou
Division of Rheumatology, Department of Internal Medicine, The University of Michigan, Suite 7C27, 300 North Ingalls Building, Ann Arbor, MI, USA
Dinesh Khanna
Division of Rheumatology, Department of Internal Medicine, The University of Michigan, Suite 7C27, 300 North Ingalls Building, Ann Arbor, MI, USA; Michigan Scleroderma Program, The University of Michigan, 300 North Ingalls Building, Ann Arbor, MI, USA
Lam C. Tsoi
Department of Dermatology, The University of Michigan, 300 North Ingalls Building, Ann Arbor, MI, USA; Department of Computational Medicine & Bioinformatics, The University of Michigan, Ann Arbor, MI, USA
Nilaksh Gupta
Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH, USA
Karen J. Ho
Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
John Varga
Division of Rheumatology, Department of Internal Medicine, The University of Michigan, Suite 7C27, 300 North Ingalls Building, Ann Arbor, MI, USA; Department of Dermatology, The University of Michigan, 300 North Ingalls Building, Ann Arbor, MI, USA; Michigan Scleroderma Program, The University of Michigan, 300 North Ingalls Building, Ann Arbor, MI, USA; Corresponding author
Summary: Intestinal dysbiosis is prominent in systemic sclerosis (SSc), but it remains unknown how it contributes to microvascular injury and fibrosis that are hallmarks of this disease. Trimethylamine (TMA) is generated by the gut microbiome and in the host converted by flavin-containing monooxygenase (FMO3) into trimethylamine N-oxide (TMAO), which has been implicated in chronic cardiovascular and metabolic diseases. Using cell culture systems and patient biopsies, we now show that TMAO reprograms skin fibroblasts, vascular endothelial cells, and adipocytic progenitor cells into myofibroblasts via the putative TMAO receptor protein R-like endoplasmic reticulum kinase (PERK). Remarkably, FMO3 was detected in skin fibroblasts and its expression stimulated by TGF-β1. Moreover, FMO3 was elevated in SSc skin biopsies and in SSc fibroblasts. A meta-organismal pathway thus might in SSc link gut microbiome to vascular remodeling and fibrosis via stromal cell reprogramming, implicating the FMO3-TMAO-PERK axis in pathogenesis, and as a promising target for therapy.
