The Gut Microbe-Derived Metabolite Trimethylamine N-Oxide in Patients With Systemic Lupus Erythematosus
TMAO as a potential biomarker in lupus nephritis.
Abstract
Background/Aim: Both human and animal studies suggest that the gut microbe-derived metabolite trimethylamine N-oxide (TMAO) is strongly associated with several autoimmune diseases including systemic lupus erythematosus (SLE) and correlates to disease severity. The study aimed to investigate the diagnostic and prognostic validity of TMAO as a potential biomarker in patients with SLE, particularly focusing on lupus nephritis patients and its relation to disease activity.
Methods: A total of 90 patients were included and assigned into either: group I (SLE without nephritis (NN)), group II (lupus nephritis (LN)) and group III (healthy controls). Serum TMAO levels were compared between the study groups, and correlated to the clinical, laboratory and histopathological criteria.
Results: Unpredictably, TMAO levels were significantly higher in healthy controls compared to the total SLE population (p = 0.003), to LN and NN groups individually (p = 0.01). TMAO levels did not significantly vary between (NN) and (LN) patients and only correlated to anti-dsDNA titres (p = 0.02) and red blood cells count (p = 0.02) among LN patients.
Conclusion: Contrary to previous studies, TMAO levels were found to be higher in healthy controls. A possible confounding effect of the dietary pattern and ingested drugs on the gut microbiome limits the utility of TMAO as a potential marker in different diseases.
References
Hevia A, Milani C, López P, Cuervo A, Arboleya S, Duranti S, et al. Intestinal dysbiosis associated with systemic lupus erythematosus. mBio. 2014 Sep 30;5(5):e01548-14. doi: 10.1128/mBio.01548-14.
Mu Q, Zhang H, Luo XM. SLE: another autoimmune disorder influenced by microbes and diet? Front Immunol. 2015 Nov 30;6:608. doi: 10.3389/fimmu.2015.00608.
Gul'neva M, Romanov V, Shilkina N. [Intestinal microecology in some systemic connective tissue diseases]. Z mikrobiol Epidemiol immunobiol 2007(4):38-41. PMID: 17886374. Russian.
van der Meulen TA, Harmsen HJM, Vila AV, Kurilshikov A, Liefers SC, Zhernakova A, et al. Shared gut, but distinct oral microbiota composition in primary Sjögren's syndrome and systemic lupus erythematosus. J Autoimm. 2019;97:77-87. doi: 10.1016/j.jaut.2018.10.009.
Okada H, Kuhn C, Feillet H, Bach JF. The ‘hygiene hypothesis’ for autoimmune and allergic diseases: an update. Clin Exp Immunol. 2010;160(1):1-9. doi: 10.1111/j.1365-2249.2010.04139.x.
Zhang H, Liao X, Sparks JB, Luo XM. Dynamics of gut microbiota in autoimmune lupus. Appl Environ Microbiol. 2014 Dec;80(24):7551-60. doi: 10.1128/AEM.02676-14.
Kasselman LJ, Vernice NA, DeLeon J, Reiss AB. The gut microbiome and elevated cardiovascular risk in obesity and autoimmunity. Atherosclerosis. 2018;271:203-13. doi: 10.1016/j.atherosclerosis.2018.02.036.
Dong L, Wang S, Chen M, Li H, Bi W. The activation of macrophage and upregulation of CD40 costimulatory molecule in lipopolysaccharide-induced acute lung injury. J Biomed Biotechnol. 2008;2008:852571. doi: 10.1155/2008/852571.
Kinoshita K, Kishimoto K, Shimazu H, Nozaki Y, Sugiyama M, Ikoma S, et al. Successful treatment with retinoids in patients with lupus nephritis. Am J Kidney Dis. 2010 Feb;55(2):344-7. doi: 10.1053/j.ajkd.2009.06.012.
Tong Y, Marion T, Schett G, Luo Y, Liu Y. Microbiota and metabolites in rheumatic diseases. Autoimmun Rev. 2020 Aug;19(8):102530. doi: 10.1016/j.autrev.2020.102530.
Narasimhan R, Coras R, Rosenthal SB, Sweeney SR, Lodi A, Tiziani S, et al. Serum metabolomic profiling predicts synovial gene expression in rheumatoid arthritis. Arthritis Res Ther. 2018 Aug 3;20(1):164. doi: 10.1186/s13075-018-1655-3.
Coras R, Kavanaugh A, Boyd T, Huynh D, Lagerborg KA, Xu Y-J, et al. Choline metabolite, trimethylamine N-oxide (TMAO), is associated with inflammation in psoriatic arthritis. Clin Exp Rheumatol. 2019;37:481-4. PMID: 30620278.
Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, et al. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nature Med. 2013;19(5):576-85. doi: 10.1038/nm.3145.
Bennett BJ, de Aguiar Vallim TQ, Wang Z, Shih DM, Meng Y, Gregory J, et al. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 2013;17(1):49-60. doi: 10.1016/j.cmet.2012.12.011.
Romano KA, Vivas EI, Amador-Noguez D, Rey FE. Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide. mBio. 2015 Mar 17;6(2):e02481. doi: 10.1128/mBio.02481-14.
Brown JM, Hazen SL. Microbial modulation of cardiovascular disease. Nature Rev Microbiol. 2018;16(3):171-81. doi: 10.1038/nrmicro.2017.149.
Rhee EP, Clish CB, Ghorbani A, Larson MG, Elmariah S, McCabe E, et al. A combined epidemiologic and metabolomic approach improves CKD prediction. J Am Soc Nephrol. 2013;24(8):1330-8. doi: 10.1681/ASN.2012101006.
Bell JD, Lee J, Lee H, Sadler PJ, Wilkie D, Woodham RH. Nuclear magnetic resonance studies of blood plasma and urine from subjects with chronic renal failure: identification of trimethylamine-N-oxide. Biochim Biophys Acta. 1991 Feb 22;1096(2):101-7. doi: 10.1016/0925-4439(91)90046-c.
Tang WW, Wang Z, Kennedy DJ, Wu Y, Buffa JA, Agatisa-Boyle B, et al. Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circulation Res. 2015;116(3):448-55. doi: 10.1161/CIRCRESAHA.116.305360.
Dambrova M, Latkovskis G, Kuka J, Strele I, Konrade I, Grinberga S, et al. Diabetes is associated with higher trimethylamine N-oxide plasma levels. Exp Clin Endocrinol Diabetes. 2016;124(04):251-6. doi: 10.1055/s-0035-1569330.
Risk T, Zhu W, Gregory J, Org E, Brown J, Lusis A, et al. Gut microbial metabolite TMAO enhances platelet article gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell. 2016;165(1):111-24. doi: 10.1016/j.cell.2016.02.011.
Seldin MM, Meng Y, Qi H, Zhu W, Wang Z, Hazen SL, et al. Trimethylamine N‐oxide promotes vascular inflammation through signaling of mitogen‐activated protein kinase and nuclear factor‐κB. J Am Heart Assoc. 2016 Feb 22;5(2):e002767. doi: 10.1161/JAHA.115.002767.
Dörner T, Furie R. Novel paradigms in systemic lupus erythematosus. Lancet. 2019 Jun 8;393(10188):2344-58. doi: 10.1016/S0140-6736(19)30546-X.
Stoll T, Stucki G, Malik J, Pyke S, Isenberg DA. Association of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index with measures of disease activity and health status in patients with systemic lupus erythematosus. J Rheumatol. 1997 Feb;24(2):309-13. PMID: 9034988.
Lam GK, Petri M. Assessment of systemic lupus erythematosus. Clin Exp Rheumatol. 2005 Sep-Oct;23(5 Suppl 39):S120-32. PMID: 16273796.
Almaani S, Prokopec SD, Zhang J, Yu L, Avila-Casado C, Wither J, et al. Rethinking lupus nephritis classification on a molecular level. J Clin Med. 2019 Sep 23;8(10):1524. doi: 10.3390/jcm8101524.
Narváez J, Ricse M, Gomà M, Mitjavila F, Fulladosa X, Capdevila O, et al. The value of repeat biopsy in lupus nephritis flares. Medicine (Baltimore). 2017 Jun;96(24):e7099. doi: 10.1097/MD.0000000000007099.
Schroeder BO, Bäckhed F. Signals from the gut microbiota to distant organs in physiology and disease. Nat Med. 2016;22(10):1079-89. doi: 10.1038/nm.4185.
Koh JH, Park Y-J, Lee S, Hong Y-S, Hong KS, Yoo S-A, et al. Distinct urinary metabolic profile in rheumatoid arthritis patients: a possible link between diet and arthritis phenotype. J Rheum Dis. 2019;26(1):46-56. doi: 10.4078/jrd.2019.26.1.46.
Carlström M, Moretti CH, Weitzberg E, Lundberg JO. Microbiota, diet and the generation of reactive nitrogen compounds. Free Radic Biol Med. 2020 Dec;161:321-5. doi: 10.1016/j.freeradbiomed.2020.10.025.
Landfald B, Valeur J, Berstad A, Raa J. Microbial trimethylamine-N-oxide as a disease marker: something fishy? Microb Ecol Health Dis. 2017 May 19;28(1):1327309. doi: 10.1080/16512235.2017.1327309.
Jia J, Dou P, Gao M, Kong X, Li C, Liu Z, et al. Assessment of causal direction between gut microbiota-dependent metabolites and cardiometabolic health: a bidirectional mendelian randomization analysis. Diabetes. 2019 Sep;68(9):1747-55. doi: 10.2337/db19-0153.
Manzo VE, Bhatt AS. The human microbiome in hematopoiesis and hematologic disorders. Blood. 2015 Jul 16;126(3):311-8. doi: 10.1182/blood-2015-04-574392.
Al-Ani B, Fitzpatrick M, Al-Nuaimi H, Coughlan AM, Hickey FB, Pusey CD, et al. Changes in urinary metabolomic profile during relapsing renal vasculitis. Sci Rep. 2016 Dec 1;6:38074. doi: 10.1038/srep38074.
Weis M. Impact of the gut microbiome in cardiovascular and autoimmune diseases. Clin Sci (Lond). 2018 Nov 19;132(22):2387-9. doi: 10.1042/CS20180410.
Manfredo Vieira S, Hiltensperger M, Kumar V, Zegarra-Ruiz D, Dehner C, et al. Translocation of a gut pathobiont drives autoimmunity in mice and humans. Science. 2018 Mar 9;359(6380):1156-61. doi: 10.1126/science.aar7201.
Yurkovetskiy L, Burrows M, Khan AA, Graham L, Volchkov P, Becker L, et al. Gender bias in autoimmunity is influenced by microbiota. Immunity. 2013 Aug 22;39(2):400-12. doi: 10.1016/j.immuni.2013.08.013.
Paolino S, Pacini G, Patanè M, Alessandri E, Cattelan F, Goegan F, et al. Interactions between microbiota, diet/nutrients and immune/inflammatory response in rheumatic diseases: focus on rheumatoid arthritis. Reumatologia. 2019;57(3):151-7. doi: 10.5114/reum.2019.86425.
Lin H, Liu T, Li X, Gao X, Wu T, Li P. The role of gut microbiota metabolite trimethylamine N-oxide in functional impairment of bone marrow mesenchymal stem cells in osteoporosis disease. Ann Transl Med. 2020 Aug;8(16):1009. doi: 10.21037/atm-20-5307.
Miguel DF, Terreri MT, Pereira RMR, Bonfá E, Silva CAA, Corrente JE, Magalhaet al; Brazilian Childhood-onset Systemic Lupus Erythematosus Group. Comparison of urinary parameters, biomarkers, and outcome of childhood systemic lupus erythematosus early onset-lupus nephritis. Adv Rheumatol. 2020 Feb 1;60(1):10. doi: 10.1186/s42358-020-0114-4.
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).