Evidence map›Paper›PMID 35856022›Full record

ArticleiScience2022

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 and 4 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in iScience, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.

0numbers the graph read from it
0cells of the map it votes in
23citing papers in PubMed
4.0field-weighted citation impact, top 5% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

23 citing papers in PubMed, 30 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors at 3 institutions in 1 country.

Seok-Jo KimDivision of Rheumatology, Department of Internal Medicine, The University of Michigan, Suite 7C27, 300 North Ingalls Building, Ann Arbor, MI, USA.
Swarna BaleDivision of Rheumatology, Department of Internal Medicine, The University of Michigan, Suite 7C27, 300 North Ingalls Building, Ann Arbor, MI, USA.
Priyanka VermaDivision of Rheumatology, Department of Internal Medicine, The University of Michigan, Suite 7C27, 300 North Ingalls Building, Ann Arbor, MI, USA.
Qianqian WanDivision of Rheumatology, Department of Internal Medicine, The University of Michigan, Suite 7C27, 300 North Ingalls Building, Ann Arbor, MI, USA.
Feiyang MaDepartment of Dermatology, The University of Michigan, 300 North Ingalls Building, Ann Arbor, MI, USA.
Johann E GudjonssonDivision of Rheumatology, Department of Internal Medicine, The University of Michigan, Suite 7C27, 300 North Ingalls Building, Ann Arbor, MI, USA.
Stanley L HazenDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Paul W HarmsDepartment of Dermatology, The University of Michigan, 300 North Ingalls Building, Ann Arbor, MI, USA.
Pei-Suen TsouDivision of Rheumatology, Department of Internal Medicine, The University of Michigan, Suite 7C27, 300 North Ingalls Building, Ann Arbor, MI, USA.
Dinesh KhannaDivision of Rheumatology, Department of Internal Medicine, The University of Michigan, Suite 7C27, 300 North Ingalls Building, Ann Arbor, MI, USA.
Lam C TsoiDepartment of Dermatology, The University of Michigan, 300 North Ingalls Building, Ann Arbor, MI, USA.
Nilaksh GuptaDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Karen J HoDepartment of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
John VargaDivision of Rheumatology, Department of Internal Medicine, The University of Michigan, Suite 7C27, 300 North Ingalls Building, Ann Arbor, MI, USA.
University of Michigan · USCleveland Clinic · USNorthwestern University · US

Funding

University of Michigan Skin Biology and Diseases Resource-based CenterP30AR075043 · NIAMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI ANDRZEJ A. DLUGOSZ · 2019 to 2026
$6.6M
The Role of Gut Microbiota in Neointimal Hyperplasia After Vascular InjuryK08HL130601 · NHLBI · NORTHWESTERN UNIVERSITY AT CHICAGO · PI HO, KAREN J. · 2016 to 2020
$801k
Metaorganismal TMAO pathway driving scleroderma pathogenesis: novel gene-environment interaction paradigm and therapeutic targetR61AR076821 · NIAMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI VARGA, JOHN · 2019 to 2021
$590k
Epigenetic regulation of the Klotho / Miz 1 axis in smoking-induced emphysema.R21AG060211 · NIA · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI KIM, SEOK-JO, LIU, JING · 2019 to 2020
$407k
Metaorganismal TMAO pathway driving scleroderma pathogenesis: novel gene-environment interaction paradigm and therapeutic targetR33AR076821 · NIAMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI VARGA, JOHN · 2022 to 2022
$341k
NHLBI NIH HHS K08 HL130601NIAMS NIH HHS P30 AR075043NIAMS NIH HHS R33 AR076821NIAMS NIH HHS R61 AR076821NIA NIH HHS R21 AG060211
6 · The paper itself

Abstract

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.

Indexed as

Cell biologyMicrobial metabolismMicrobiome

Identifiers

PMID35856022
PMCPMC9287188
OpenAlexW4283522577

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.