{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T10:00:56Z","timestamp":1791021656460,"version":"4.1.0"},"reference-count":51,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T00:00:00Z","timestamp":1728345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["R33AR076821"],"award-info":[{"award-number":["R33AR076821"]}]},{"name":"National Institutes of Health","award":["R03HL146880"],"award-info":[{"award-number":["R03HL146880"]}]},{"name":"National Institutes of Health","award":["R21AG081706"],"award-info":[{"award-number":["R21AG081706"]}]},{"name":"National Institutes of Health","award":["R01HL153306"],"award-info":[{"award-number":["R01HL153306"]}]},{"name":"National Institutes of Health","award":["R21AG060211"],"award-info":[{"award-number":["R21AG060211"]}]},{"name":"National Institutes of Health","award":["R01HL103866"],"award-info":[{"award-number":["R01HL103866"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background\/Objectives: Alterations in fecal microbial communities in patients with systemic sclerosis (SSc) are common, but the clinical significance of this observation is poorly understood. Gut microbial production of trimethylamine (TMA), and its conversion by the host to trimethylamine N-oxide (TMAO), has clinical and mechanistic links to cardiovascular and renal diseases. Direct provision of TMAO has been shown to promote fibrosis and vascular injury, hallmarks of SSc. We sought to determine levels of TMAO and related metabolites in SSc patients and investigate associations between the metabolite levels with disease features. Methods: This is an observational case:control study. Adults with SSc (n = 200) and non-SSc controls (n = 400) were matched for age, sex, indices of renal function, diabetes mellitus, and cardiovascular disease. Serum TMAO, choline, betaine, carnitine, \u03b3-butyrobetaine, and crotonobetaine were measured using stable isotope dilution liquid chromatography tandem mass spectrometry. Results: Median TMAO concentration was higher (p = 0.020) in SSc patients (3.31 [interquartile range 2.18, 5.23] \u00b5M) relative to controls (2.85 [IQR 1.88, 4.54] \u00b5M). TMAO was highest among obese and male SSc participants compared to all other groups. Following adjustment for sex, BMI, age, race, and eGFR in a quantile regression model, elevated TMAO levels remained associated with SSc at each quantile of TMAO. Conclusions: Patients with SSc have increased circulating levels of TMAO independent of comorbidities including age, sex, renal function, diabetes mellitus, and cardiovascular disease. As a potentially modifiable factor, further studies examining the link between TMAO and SSc disease severity and course are warranted.<\/jats:p>","DOI":"10.3390\/jcm13195984","type":"journal-article","created":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T12:01:54Z","timestamp":1728388914000},"page":"5984","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Elevated Circulating Levels of Gut Microbe-Derived Trimethylamine N-Oxide Are Associated with Systemic Sclerosis"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7514-8953","authenticated-orcid":false,"given":"Karen J.","family":"Ho","sequence":"first","affiliation":[{"name":"Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8655-1484","authenticated-orcid":false,"given":"Lutfiyya N.","family":"Muhammad","sequence":"additional","affiliation":[{"name":"Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linh Ngo","family":"Khanh","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Houston Methodist Hospital, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4946-4271","authenticated-orcid":false,"given":"Xinmin S.","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5063-156X","authenticated-orcid":false,"given":"Mary","family":"Carns","sequence":"additional","affiliation":[{"name":"Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4770-2643","authenticated-orcid":false,"given":"Kathleen","family":"Aren","sequence":"additional","affiliation":[{"name":"Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seok-Jo","family":"Kim","sequence":"additional","affiliation":[{"name":"Institute of Basic Science, Sungkyunkwan University, Suwon 16419, Republic of Korea"},{"name":"Mondrian AI Co., Ltd., Incheon 21985, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priyanka","family":"Verma","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley L.","family":"Hazen","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA"},{"name":"Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Varga","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15002","DOI":"10.1038\/nrdp.2015.2","article-title":"Systemic sclerosis","volume":"1","author":"Allanore","year":"2015","journal-title":"Nat. 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