Kronik Hepatit B'de bağırsak mikrobiyota bağımlı bir metabolit olan Trimetilamin-N-oksit

Yıl 2024, Cilt: 34 Sayı: 6, 853 - 860, 31.12.2024

Esra Paydaş Hataysal , Muslu Kazım Körez , Nuray Heydar Kasar Turan Aslan , Fatma Şengül Bağ , Hifa Gülru Çağlar , Alev Kural , Hüsamettin Vatansev

https://doi.org/10.54005/geneltip.1539275

Öz

Özet
Giriş: Bağırsak mikrobiyota metaboliti olan Trimetilamin-N-oksit (TMAO), kolin, betain ve L-karnitin gibi besin kaynaklarından karaciğerde üretilir. TMAO, hepatit ilerlemesinde kritik faktörler olan inflamatuar süreçler ve oksidatif stres ile ilişkilendirilmiştir. Bu çalışma, TMAO'nun Kronik Hepatit B (KHB) üzerindeki etkisini incelemeyi amaçlamaktadır.
Gereç ve Yöntemler: Çalışmaya, HBV DNA düzeyleri 2000 IU/mL'nin üzerinde olan 41 tedavi-naif KHB hastası ve yaş ve cinsiyet açısından eşleştirilmiş 46 kontrol grubu dahil edilmiştir. Serum TMAO seviyeleri, Sıvı Kromatografi-Tandem Kütle Spektrometrisi (LC/MS/MS) kullanılarak ölçülmüştür. Tüm istatistiksel analizler R versiyon 4.2.1 ile gerçekleştirilmiştir.
Bulgular: KHB hastalarında serum TMAO düzeyleri, sağlıklı kontrollere göre anlamlı derecede daha yüksektir (1860 [IQR, 808 – 2720] vs. 552.5 [IQR, 252 – 876.5], p<0.001). Serum ALT ve AST düzeyleri KHB hastalarında daha yüksekti (p<0.001 ve p<0.001). TMAO düzeyleri, ALT ve AST seviyeleri ile pozitif korelasyon göstermiştir (r=0.466, p<0.001; r=0.376, p<0.001) ve KHB tanısı için eğri altındaki alan 0.808’di.
Tartışma: Sonuçlarımız, bağırsak mikrobiyota bağımlı bir metabolit olan TMAO ile KHB hastalığı arasında bir bağlantı olduğunu göstermektedir. TMAO esas olarak karaciğerde sentezlendiğinden, artmış seviyeleri karaciğer hastalıklarıyla ilişkili olabilir.

Anahtar Kelimeler

TMAO, mikrobiota, HBV, LC/MS/MS

Proje Numarası

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Trimethylamine N-oxide, a gut microbiota-dependent metabolite in Chronic Hepatitis B

Öz

Background: Trimethylamine N-oxide (TMAO), a gut microbiota metabolite is produced in the liver from dietary precursors such as choline, betaine, and L-carnitine. TMAO has been linked to inflammatory processes and oxidative stress, both of which are critical factors in the progression of hepatitis. This article aims to examine the impact of TMAO on Chronic hepatitis B (CHB).
Materials and Methods: The study included 41 treatment-naïve CHB patients with HBV DNA levels above 2000 IU/mL, as well as 46 age and gender-matched controls. Serum TMAO levels were measured using Liquid Chromatography-Tandem Mass Spectrometry (LC/MS/MS). All statistical analysis was performed with R version 4.2.1.
Results: Patients with CHB have a more significant increase in serum level of TMAO than healthy controls (1860 [IQR, 808 – 2720] vs. 552.5 [IQR, 252 – 876.5], p<0.001). Serum ALT and AST were higher in patients with CHB (p<0.001 and p<0.001). TMAO levels were positively correlated with ALT and AST levels (r=0.466, p<0.001; r=0.376, p<0.001) and had predictive power for CHB with an area under curve of 0.808.
Conclusions: Our results indicate that there is a link between TMAO, a gut microbiota-dependent metabolite, and CHB disease. Since TMAO is synthesized mainly in the liver, its raised levels may be associated with liver-related diseases.

Anahtar Kelimeler

TMAO, LC/MS/MS, HBV, microbiota

Etik Beyan

The research received approval from the Ethics Committee at Selcuk University Faculty of Medicine (2024/176)

Destekleyen Kurum

none

Proje Numarası

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Teşekkür

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Kaynakça

• 1. Gatarek P, Kaluzna-Czaplinska J. Trimethylamine N-oxide (TMAO) in human health. Excli j. 2021;20:301-19.
• 2. Li D, Lu Y, Yuan S, Cai X, He Y, Chen J, et al. Gut microbiota-derived metabolite trimethylamine-N-oxide and multiple health outcomes: an umbrella review and updated meta-analysis. Am J Clin Nutr. 2022;116(1):230-43.
• 3. Heianza Y, Ma W, DiDonato JA, Sun Q, Rimm EB, Hu FB, et al. Long-Term Changes in Gut Microbial Metabolite Trimethylamine N-Oxide and Coronary Heart Disease Risk. J Am Coll Cardiol. 2020;75(7):763-72.
• 4. Mei Z, Chen GC, Wang Z, Usyk M, Yu B, Baeza YV, et al. Dietary factors, gut microbiota, and serum trimethylamine-N-oxide associated with cardiovascular disease in the Hispanic Community Health Study/Study of Latinos. Am J Clin Nutr. 2021;113(6):1503-14.
• 5. 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(4):251-6.
• 6. Shan Z, Sun T, Huang H, Chen S, Chen L, Luo C, et al. Association between microbiota-dependent metabolite trimethylamine-N-oxide and type 2 diabetes. Am J Clin Nutr. 2017;106(3):888-94.
• 7. Tang WH, Wang Z, Kennedy DJ, Wu Y, Buffa JA, Agatisa-Boyle B, et al. Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both the development of renal insufficiency and mortality risk in chronic kidney disease. Circ Res. 2015;116(3):448-55.
• 8. Liu X, Liu H, Yuan C, Zhang Y, Wang W, Hu S, et al. Preoperative serum TMAO level is a new prognostic marker for colorectal cancer. Biomark Med. 2017;11(5):443-7.
• 9. Berger M, Kleber ME, Delgado GE, März W, Andreas M, Hellstern P, et al. Trimethylamine N-Oxide and Adenosine Diphosphate-Induced Platelet Reactivity Are Independent Risk Factors for Cardiovascular and All-Cause Mortality. Circ Res. 2020;126(5):660-2.
• 10. Florea CM, Rosu R, Moldovan R, Vlase L, Toma V, Decea N, et al. The impact of chronic Trimethylamine N-oxide administration on liver oxidative stress, inflammation, and fibrosis. Food and Chemical Toxicology. 2024;184:114429.
• 11. Yang W, Zhao Q, Yao M, Li X, Shan Z, Wang Y. The transformation of atrial fibroblasts into myofibroblasts is promoted by trimethylamine N-oxide via the Wnt3a/β-catenin signaling pathway. Journal of Thoracic Disease. 2022;14(5):1526-36.
• 12. Kapetanaki S, Kumawat AK, Persson K, Demirel I. The Fibrotic Effects of TMAO on Human Renal Fibroblasts Is Mediated by NLRP3, Caspase-1 and the PERK/Akt/mTOR Pathway. International Journal of Molecular Sciences. 2021;22(21):11864.
• 13. Liu X, Shao Y, Tu J, Sun J, Li L, Tao J, et al. Trimethylamine-N-oxide-stimulated hepatocyte-derived exosomes promote inflammation and endothelial dysfunction through nuclear factor-kappa B signaling. Ann Transl Med. 2021;9(22):1670.
• 14. Shanmugham M, Bellanger S, Leo CH. Gut-Derived Metabolite, Trimethylamine-N-oxide (TMAO) in Cardio-Metabolic Diseases: Detection, Mechanism, and Potential Therapeutics. Pharmaceuticals (Basel). 2023;16(4).
• 15. Yan Z, Chen Q, Xia Y. Oxidative Stress Contributes to Inflammatory and Cellular Damage in Systemic Lupus Erythematosus: Cellular Markers and Molecular Mechanism. J Inflamm Res. 2023;16:453-65.
• 16. Chou RH, Chen CY, Chen IC, Huang HL, Lu YW, Kuo CS, et al. Trimethylamine N-Oxide, Circulating Endothelial Progenitor Cells, and Endothelial Function in Patients with Stable Angina. Sci Rep. 2019;9(1):4249.
• 17. Zhen J, Zhou Z, He M, Han HX, Lv EH, Wen PB, et al. The gut microbial metabolite trimethylamine N-oxide and cardiovascular diseases. Front Endocrinol (Lausanne). 2023;14:1085041.
• 18. Li T, Chen Y, Gua C, Li X. Elevated Circulating Trimethylamine N-Oxide Levels Contribute to Endothelial Dysfunction in Aged Rats through Vascular Inflammation and Oxidative Stress. Front Physiol. 2017;8:350.
• 19. Singh GB, Zhang Y, Boini KM, Koka S. High Mobility Group Box 1 Mediates TMAO-Induced Endothelial Dysfunction. Int J Mol Sci. 2019;20(14).
• 20. Pflughoeft KJ, Versalovic J. Human Microbiome in Health and Disease. Annual Review of Pathology: Mechanisms of Disease. 2012;7(Volume 7, 2012):99-122.
• 21. Chen ML, Yi L, Zhang Y, Zhou X, Ran L, Yang J, et al. Resveratrol Attenuates Trimethylamine-N-Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota. mBio. 2016;7(2):e02210-15.
• 22. Mehedint MG, Zeisel SH. Choline's role in maintaining liver function: new evidence for epigenetic mechanisms. Curr Opin Clin Nutr Metab Care. 2013;16(3):339-45.
• 23. Fischer LM, daCosta KA, Kwock L, Stewart PW, Lu TS, Stabler SP, et al. Sex and menopausal status influence human dietary requirements for the nutrient choline. Am J Clin Nutr. 2007;85(5):1275-85.
• 24. Butler LM, Arning E, Wang R, Bottiglieri T, Govindarajan S, Gao YT, et al. Prediagnostic levels of serum one-carbon metabolites and risk of hepatocellular carcinoma. Cancer Epidemiol Biomarkers Prev. 2013;22(10):1884-93.
• 25. Bae S, Ulrich CM, Neuhouser ML, Malysheva O, Bailey LB, Xiao L, et al. Plasma choline metabolites and colorectal cancer risk in the Women's Health Initiative Observational Study. Cancer Res. 2014;74(24):7442-52.
• 26. Xu R, Wang Q, Li L. A genome-wide systems analysis reveals a strong link between colorectal cancer and trimethylamine N-oxide (TMAO), a gut microbial metabolite of dietary meat and fat. BMC Genomics. 2015;16 Suppl 7(Suppl 7):S4.
• 27. Tanase DM, Gosav EM, Neculae E, Costea CF, Ciocoiu M, Hurjui LL, et al. Role of Gut Microbiota on Onset and Progression of Microvascular Complications of Type 2 Diabetes (T2DM). Nutrients. 2020;12(12).
• 28. Barrea L, Annunziata G, Muscogiuri G, Di Somma C, Laudisio D, Maisto M, et al. Trimethylamine-N-oxide (TMAO) as Novel Potential Biomarker of Early Predictors of Metabolic Syndrome. Nutrients. 2018;10(12).
• 29. Rohrmann S, Linseisen J, Allenspach M, von Eckardstein A, Müller D. Plasma Concentrations of Trimethylamine-N-oxide Are Directly Associated with Dairy Food Consumption and Low-Grade Inflammation in a German Adult Population. J Nutr. 2016;146(2):283-9.
• 30. Ma R, Shi G, Li Y, Shi H. Trimethylamine N-oxide, choline and its metabolites are associated with the risk of non-alcoholic fatty liver disease. British Journal of Nutrition. 2024;131(11):1915-23.
• 31. Chen Y-m, Liu Y, Zhou R-f, Chen X-l, Wang C, Tan X-y, et al. Associations of gut-flora-dependent metabolite trimethylamine-N-oxide, betaine, and choline with non-alcoholic fatty liver disease in adults. Scientific Reports. 2016;6(1):19076.
• 32. Liu Z-Y, Tan X-Y, Li Q-J, Liao G-C, Fang A-P, Zhang D-M, et al. Trimethylamine N-oxide, a gut microbiota-dependent metabolite of choline, is positively associated with the risk of primary liver cancer: a case-control study. Nutrition & Metabolism. 2018;15(1):81.
• 33. Huang H, Ren Z, Gao X, Hu X, Zhou Y, Jiang J, et al. Integrated analysis of microbiome and host transcriptome reveals correlations between gut microbiota and clinical outcomes in HBV-related hepatocellular carcinoma. Genome Medicine. 2020;12(1):102.
• 34. Cox IJ, Aliev AE, Crossey MM, Dawood M, Al-Mahtab M, Akbar SM, et al. Urinary nuclear magnetic resonance spectroscopy of a Bangladeshi cohort with hepatitis-B hepatocellular carcinoma: A biomarker corroboration study. World J Gastroenterol. 2016;22(16):4191-200.
• 35. Shi C, Wu C-q, Cao A-m, Sheng H-Z, Yan X-z, Liao M-y. NMR-spectroscopy-based metabonomic approach to the analysis of Bay41-4109, a novel anti-HBV compound, induced hepatotoxicity in rats. Toxicology Letters. 2007;173(3):161-7.
• 36. Wu Q, Zhang X, Zhao Y, Yang X. High l-Carnitine Ingestion Impairs Liver Function by Disordering Gut Bacteria Composition in Mice. J Agric Food Chem. 2020;68(20):5707-14.
• 37. Sun X, Jiao X, Ma Y, Liu Y, Zhang L, He Y, et al. Trimethylamine N-oxide induces inflammation and endothelial dysfunction in human umbilical vein endothelial cells via activating ROS-TXNIP-NLRP3 inflammasome. Biochem Biophys Res Commun. 2016;481(1-2):63-70.
• 38. Chen S, Henderson A, Petriello MC, Romano KA, Gearing M, Miao J, et al. Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction. Cell Metab. 2019;30(6):1141-51.e5.
• 39. Tan X, Liu Y, Long J, Chen S, Liao G, Wu S, et al. Trimethylamine N-Oxide Aggravates Liver Steatosis through Modulation of Bile Acid Metabolism and Inhibition of Farnesoid X Receptor Signaling in Nonalcoholic Fatty Liver Disease. Mol Nutr Food Res. 2019;63(17):e1900257.
• 40. Zhao ZH, Xin FZ, Zhou D, Xue YQ, Liu XL, Yang RX, et al. Trimethylamine N-oxide attenuates high-fat high-cholesterol diet-induced steatohepatitis by reducing hepatic cholesterol overload in rats. World J Gastroenterol. 2019;25(20):2450-62.
• 41. Masarone M, Rosato V, Dallio M, Gravina AG, Aglitti A, Loguercio C, et al. Role of Oxidative Stress in Pathophysiology of Nonalcoholic Fatty Liver Disease. Oxidative Medicine and Cellular Longevity. 2018;2018(1):9547613.
• 42. Li X, Geng J, Zhao J, Ni Q, Zhao C, Zheng Y, et al. Trimethylamine N-Oxide Exacerbates Cardiac Fibrosis via Activating the NLRP3 Inflammasome. Front Physiol. 2019;10:866.
• 43. Xiong Z, Li J, Huang R, Zhou H, Xu X, Zhang S, et al. The gut microbe-derived metabolite trimethylamine-N-oxide induces aortic valve fibrosis via PERK/ATF-4 and IRE-1α/XBP-1s signaling in vitro and in vivo. Atherosclerosis. 2024;391:117431.
• 44. Stefania K, Ashok KK, Geena PV, Katarina P, Isak D. TMAO enhances TNF-α mediated fibrosis and release of inflammatory mediators from renal fibroblasts. Scientific Reports. 2024;14(1):9070.
• 45. Zhou D, Zhang J, Xiao C, Mo C, Ding B-S. Trimethylamine-N-oxide (TMAO) mediates the crosstalk between the gut microbiota and hepatic vascular niche to alleviate liver fibrosis in nonalcoholic steatohepatitis. Frontiers in Immunology. 2022;13.
• 46. Yang W, Zhao Q, Yao M, Li X, Shan Z, Wang Y. The transformation of atrial fibroblasts into myofibroblasts is promoted by trimethylamine N-oxide via the Wnt3a/β-catenin signaling pathway. J Thorac Dis. 2022;14(5):1526-36.