Gut-derived uremic toxin trimethylamine-N-oxide in cardiovascular disease under end-stage renal disease: an injury mechanism and therapeutic target_Journal of Biomedical Engineering

Authors：

REN Yuan , WANG Zuoyuan ,  XUE Jun

Department of Nephrology, Huashan Hospital, Fudan University, Shanghai 200040, P. R. China;

Corresponding author：

Keywords：

End-stage renal disease; Cardiovascular disease; Trimethylamine-N-oxide; Atherosclerosis

DOI：

10.7507/1001-5515.202110017

Video：

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The main cause of death in patients with end-stage renal disease (ESRD) is cardiovascular disease, and trimethylamine-N-oxide (TMAO) has been found to be one of the specific risk factors in the pathogenic process in recent years. TMAO is derived from intestinal bacterial metabolism of dietary choline, carnitine and other substances and subsequently catalyzed by flavin monooxygenase enzymes in the liver. The changes of intestinal bacteria in ESRD patients have contributed to the accumulation of gut-derived uremic toxins such as TMAO, indoxyl sulfate and indole-3-acetic acid. While elevated TMAO concentration accelerates atherosclerosis through mechanisms such as inflammation, increased scavenger receptor expression, and inhibition of reverse cholesterol transport. In this review, this research introduces the biological function, metabolic processes of TMAO and mechanisms by which TMAO promotes the progression of cardiovascular disease in ESRD patients and summarizes current interventions that may be used to reverse gut microbiota disturbances, such as activated carbon, fecal microbial transplantation, dietary improvement, probiotic and probiotic introduction. It also focuses on exploring intervention targets to reduce the gut-derived uremic toxin TMAO in order to explore the possibility of more cardiovascular disease treatments for ESRD patients.

Citation： REN Yuan, WANG Zuoyuan, XUE Jun. Gut-derived uremic toxin trimethylamine-N-oxide in cardiovascular disease under end-stage renal disease: an injury mechanism and therapeutic target. Journal of Biomedical Engineering, 2022, 39(4): 848-852. doi: 10.7507/1001-5515.202110017 Copy

1.	Düsing P, Zietzer A, Goody P R, et al. Vascular pathologies in chronic kidney disease: pathophysiological mechanisms and novel therapeutic approaches. J Mol Med (Berl), 2021, 99(3): 335-348.
2.	Pugh D, Gallacher P J, Dhaun N. Management of hypertension in chronic kidney disease. Drugs, 2019, 79(4): 365-379.
3.	Song J Y, Shen T C, Hou Y C, et al. Influence of resveratrol on the cardiovascular health effects of chronic kidney disease. Int J Mol Sci, 2020, 21(17): 6294.
4.	Ravid J D, Chitalia V C. Molecular mechanisms underlying the cardiovascular toxicity of specific uremic solutes. Cells, 2020, 9(9): 2024.
5.	Gupta N, Buffa J A, Roberts A B, et al. Targeted inhibition of gut microbial trimethylamine N-oxide production reduces renal tubulointerstitial fibrosis and functional impairment in a murine model of chronic kidney disease. Arterioscler Thromb Vasc Biol, 2020, 40(5): 1239-1255.
6.	Duttaroy A K. Role of gut microbiota and their metabolites on atherosclerosis, hypertension and human blood platelet function: a review. Nutrients, 2021, 13(1): 144.
7.	Prokopienko A J, West R E 3rd, Schrum D P, et al. Metabolic activation of flavin monooxygenase-mediated trimethylamine-N-oxide formation in experimental kidney disease. Sci Rep, 2019, 9(1): 15901.
8.	Ganguly P, Polák J, van der Vegt N F A, et al. Protein stability in TMAO and mixed urea-TMAO solutions. J Phys Chem B, 2020, 124(29): 6181-6197.
9.	Wang Z, Zhao Y. Gut microbiota derived metabolites in cardiovascular health and disease. Protein Cell, 2018, 9(5): 416-431.
10.	Wu W K, Chen C C, Liu P Y, et al. Identification of TMAO-producer phenotype and host-diet-gut dysbiosis by carnitine challenge test in human and germ-free mice. Gut, 2019, 68(8): 1439-1449.
11.	Schmidt A C, Leroux J C. Treatments of trimethylaminuria: where we are and where we might be heading. Drug Discov Today, 2020, 25(9): 1710-1717.
12.	Li D Y, Wang Z, Jia X, et al. Loop diuretics inhibit renal excretion of trimethylamine N-oxide. JACC Basic Transl Sci, 2021, 6(2): 103-115.
13.	Teft W A, Morse B L, Leake B F, et al. Identification and characterization of trimethylamine-N-oxide uptake and efflux transporters. Mol Pharm, 2017, 14(1): 310-318.
14.	Pelletier C C, Croyal M, Ene L, et al. Elevation of Trimethylamine-N-oxide in chronic kidney disease: contribution of decreased glomerular filtration rate. Toxins (Basel), 2019, 11(11): 635.
15.	Zeng Y, Guo M, Fang X, et al. Gut microbiota-derived trimethylamine N-oxide and kidney function: a systematic review and meta-analysis. Adv Nutr, 2021, 12(4): 1286-1304.
16.	Komazawa H, Yamaguchi H, Hidaka K, et al. Renal uptake of substrates for organic anion transporters Oat1 and Oat3 and organic cation transporters Oct1 and Oct2 is altered in rats with adenine-induced chronic renal failure. J Pharm Sci, 2013, 102(3): 1086-1094.
17.	Adak A, Khan M R. An insight into gut microbiota and its functionalities. Cell Mol Life Sci, 2019, 76(3): 473-493.
18.	Wang X, Yang S, Li S, et al. Aberrant gut microbiota alters host metabolome and impacts renal failure in humans and rodents. Gut, 2020, 69(12): 2131-2142.
19.	Taguchi K, Fukami K, Elias B C, et al. Dysbiosis-related advanced glycation endproducts and trimethylamine N-oxide in chronic kidney disease. Toxins (Basel), 2021, 13(5): 361.
20.	Wang Zeneng, Klipfell E, Bennett B J, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature, 2011, 472(7341): 57-63.
21.	Li Z, Wu Z, Yan J, et al. Gut microbe-derived metabolite trimethylamine N-oxide induces cardiac hypertrophy and fibrosis. Lab Invest, 2019, 99(3): 346-357.
22.	Chou R H, Chen C Y, Chen I C, et al. Trimethylamine N-oxide, circulating endothelial progenitor cells, and endothelial function in patients with stable angina. Sci Rep, 2019, 9(1): 4249.
23.	Yamagata K, Hashiguchi K, Yamamoto H, et al. Dietary apigenin reduces induction of LOX-1 and NLRP3 expression, leukocyte adhesion, and acetylated low-density lipoprotein uptake in human endothelial cells exposed to trimethylamine-N-oxide. J Cardiovasc Pharmacol, 2019, 74(6): 558-565.
24.	Krüger-Genge A, Jung F, Hufert F, et al. Effects of gut microbial metabolite trimethylamine N-oxide (TMAO) on platelets and endothelial cells. Clin Hemorheol Microcirc, 2020, 76(2): 309-316.
25.	Tang W H, Wang Zeneng, Kennedy D J, et al. Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ Res, 2015, 116(3): 448-455.
26.	Zhang X, Li Y, Yang P, et al. Trimethylamine-N-oxide promotes vascular calcification through activation of NLRP3(nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3)inflammasome and NF-KB (nuclear factor KB) signals. Arterioscler Thromb Vasc Biol, 2020, 40(3): 751-765.
27.	Kapetanaki S, Kumawat A K, Persson K, et al. The fibrotic effects of TMAO on human renal fibroblasts is mediated by NLRP3, caspase-1 and the PERK/Akt/mTOR pathway. Int J Mol Sci, 2021, 22(21): 11864.
28.	Myhrstad M W, Tunsjø H, Charnock C, et al. Dietary fiber, gut microbiota, and metabolic regulation-current status in human randomized trials. Nutrients, 2020, 12(3): 859.
29.	Lau W L, Savoj J, Nakata M B, et al. Altered microbiome in chronic kidney disease: systemic effects of gut-derived uremic toxins. Clin Sci (Lond), 2018, 132(5): 509-522.
30.	Sato E, Hosomi K, Sekimoto A, et al. Effects of the oral adsorbent AST-120 on fecal p-cresol and indole levels and on the gut microbiota composition. Biochem Biophys Res Commun, 2020, 525(3): 773-779.
31.	Hatakeyama S, Yamamoto H, Okamoto A, et al. Effect of an oral adsorbent, AST-120, on dialysis initiation and survival in patients with chronic kidney disease. Int J Nephrol, 2012: 376128.
32.	Schulman G, Berl T, Beck G J, et al. Randomized placebo-controlled EPPIC trials of AST-120 in CKD. J Am Soc Nephrol, 2015, 26(7): 1732-1746.
33.	Din A U, Hassan A, Zhu Y, et al. Amelioration of TMAO through probiotics and its potential role in atherosclerosis. Appl Microbiol Biotechnol, 2019, 103(23-24): 9217-9228.
34.	DeMartino P, Cockburn D W. Resistant starch: impact on the gut microbiome and health. Curr Opin Biotechnol, 2020, 61: 66-71.
35.	Karaduta O, Glazko G, Dvanajscak Z, et al. Resistant starch slows the progression of CKD in the 5/6 nephrectomy mouse model. Physiol Rep, 2020, 8(19): e14610.
36.	Hu X F, Zhang W Y, Wen Q, et al. Fecal microbiota transplantation alleviates myocardial damage in myocarditis by restoring the microbiota composition. Pharmacol Res, 2019, 139: 412-421.
37.	Lai C Y, Sung J, Cheng F, et al. Systematic review with meta-analysis: review of donor features, procedures and outcomes in 168 clinical studies of faecal microbiota transplantation. Aliment Pharmacol Ther, 2019, 49(4): 354-363.
38.	Liu J, Lai L, Lin J, et al. Ranitidine and finasteride inhibit the synthesis and release of trimethylamine N-oxide and mitigates its cardiovascular and renal damage through modulating gut microbiota. Int J Biol Sci, 2020, 16(5): 790-802.
39.	Lin Jiajia, Nie Xiaoli, Xiong Ying, et al. Fisetin regulates gut microbiota to decrease CCR9⁺/CXCR3⁺/CD4⁺ T-lymphocyte count and IL-12 secretion to alleviate premature ovarian failure in mice. Am J Transl Res, 2020, 12(1): 203-247.
40.	Macpherson M E, Hov J R, Ueland T, et al. Gut microbiota-dependent trimethylamine N-oxide associates with inflammation in common variable immunodeficiency. Front Immunol, 2020, 11: 574500.
41.	Wang Zeneng, Roberts A B, Buffa J A, et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell, 2015, 163(7): 1585-1595.

1. Düsing P, Zietzer A, Goody P R, et al. Vascular pathologies in chronic kidney disease: pathophysiological mechanisms and novel therapeutic approaches. J Mol Med (Berl), 2021, 99(3): 335-348.
2. Pugh D, Gallacher P J, Dhaun N. Management of hypertension in chronic kidney disease. Drugs, 2019, 79(4): 365-379.
3. Song J Y, Shen T C, Hou Y C, et al. Influence of resveratrol on the cardiovascular health effects of chronic kidney disease. Int J Mol Sci, 2020, 21(17): 6294.
4. Ravid J D, Chitalia V C. Molecular mechanisms underlying the cardiovascular toxicity of specific uremic solutes. Cells, 2020, 9(9): 2024.
5. Gupta N, Buffa J A, Roberts A B, et al. Targeted inhibition of gut microbial trimethylamine N-oxide production reduces renal tubulointerstitial fibrosis and functional impairment in a murine model of chronic kidney disease. Arterioscler Thromb Vasc Biol, 2020, 40(5): 1239-1255.
6. Duttaroy A K. Role of gut microbiota and their metabolites on atherosclerosis, hypertension and human blood platelet function: a review. Nutrients, 2021, 13(1): 144.
7. Prokopienko A J, West R E 3rd, Schrum D P, et al. Metabolic activation of flavin monooxygenase-mediated trimethylamine-N-oxide formation in experimental kidney disease. Sci Rep, 2019, 9(1): 15901.
8. Ganguly P, Polák J, van der Vegt N F A, et al. Protein stability in TMAO and mixed urea-TMAO solutions. J Phys Chem B, 2020, 124(29): 6181-6197.
9. Wang Z, Zhao Y. Gut microbiota derived metabolites in cardiovascular health and disease. Protein Cell, 2018, 9(5): 416-431.
10. Wu W K, Chen C C, Liu P Y, et al. Identification of TMAO-producer phenotype and host-diet-gut dysbiosis by carnitine challenge test in human and germ-free mice. Gut, 2019, 68(8): 1439-1449.
11. Schmidt A C, Leroux J C. Treatments of trimethylaminuria: where we are and where we might be heading. Drug Discov Today, 2020, 25(9): 1710-1717.
12. Li D Y, Wang Z, Jia X, et al. Loop diuretics inhibit renal excretion of trimethylamine N-oxide. JACC Basic Transl Sci, 2021, 6(2): 103-115.
13. Teft W A, Morse B L, Leake B F, et al. Identification and characterization of trimethylamine-N-oxide uptake and efflux transporters. Mol Pharm, 2017, 14(1): 310-318.
14. Pelletier C C, Croyal M, Ene L, et al. Elevation of Trimethylamine-N-oxide in chronic kidney disease: contribution of decreased glomerular filtration rate. Toxins (Basel), 2019, 11(11): 635.
15. Zeng Y, Guo M, Fang X, et al. Gut microbiota-derived trimethylamine N-oxide and kidney function: a systematic review and meta-analysis. Adv Nutr, 2021, 12(4): 1286-1304.
16. Komazawa H, Yamaguchi H, Hidaka K, et al. Renal uptake of substrates for organic anion transporters Oat1 and Oat3 and organic cation transporters Oct1 and Oct2 is altered in rats with adenine-induced chronic renal failure. J Pharm Sci, 2013, 102(3): 1086-1094.
17. Adak A, Khan M R. An insight into gut microbiota and its functionalities. Cell Mol Life Sci, 2019, 76(3): 473-493.
18. Wang X, Yang S, Li S, et al. Aberrant gut microbiota alters host metabolome and impacts renal failure in humans and rodents. Gut, 2020, 69(12): 2131-2142.
19. Taguchi K, Fukami K, Elias B C, et al. Dysbiosis-related advanced glycation endproducts and trimethylamine N-oxide in chronic kidney disease. Toxins (Basel), 2021, 13(5): 361.
20. Wang Zeneng, Klipfell E, Bennett B J, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature, 2011, 472(7341): 57-63.
21. Li Z, Wu Z, Yan J, et al. Gut microbe-derived metabolite trimethylamine N-oxide induces cardiac hypertrophy and fibrosis. Lab Invest, 2019, 99(3): 346-357.
22. Chou R H, Chen C Y, Chen I C, et al. Trimethylamine N-oxide, circulating endothelial progenitor cells, and endothelial function in patients with stable angina. Sci Rep, 2019, 9(1): 4249.
23. Yamagata K, Hashiguchi K, Yamamoto H, et al. Dietary apigenin reduces induction of LOX-1 and NLRP3 expression, leukocyte adhesion, and acetylated low-density lipoprotein uptake in human endothelial cells exposed to trimethylamine-N-oxide. J Cardiovasc Pharmacol, 2019, 74(6): 558-565.
24. Krüger-Genge A, Jung F, Hufert F, et al. Effects of gut microbial metabolite trimethylamine N-oxide (TMAO) on platelets and endothelial cells. Clin Hemorheol Microcirc, 2020, 76(2): 309-316.
25. Tang W H, Wang Zeneng, Kennedy D J, et al. Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ Res, 2015, 116(3): 448-455.
26. Zhang X, Li Y, Yang P, et al. Trimethylamine-N-oxide promotes vascular calcification through activation of NLRP3(nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3)inflammasome and NF-KB (nuclear factor KB) signals. Arterioscler Thromb Vasc Biol, 2020, 40(3): 751-765.
27. Kapetanaki S, Kumawat A K, Persson K, et al. The fibrotic effects of TMAO on human renal fibroblasts is mediated by NLRP3, caspase-1 and the PERK/Akt/mTOR pathway. Int J Mol Sci, 2021, 22(21): 11864.
28. Myhrstad M W, Tunsjø H, Charnock C, et al. Dietary fiber, gut microbiota, and metabolic regulation-current status in human randomized trials. Nutrients, 2020, 12(3): 859.
29. Lau W L, Savoj J, Nakata M B, et al. Altered microbiome in chronic kidney disease: systemic effects of gut-derived uremic toxins. Clin Sci (Lond), 2018, 132(5): 509-522.
30. Sato E, Hosomi K, Sekimoto A, et al. Effects of the oral adsorbent AST-120 on fecal p-cresol and indole levels and on the gut microbiota composition. Biochem Biophys Res Commun, 2020, 525(3): 773-779.
31. Hatakeyama S, Yamamoto H, Okamoto A, et al. Effect of an oral adsorbent, AST-120, on dialysis initiation and survival in patients with chronic kidney disease. Int J Nephrol, 2012: 376128.
32. Schulman G, Berl T, Beck G J, et al. Randomized placebo-controlled EPPIC trials of AST-120 in CKD. J Am Soc Nephrol, 2015, 26(7): 1732-1746.
33. Din A U, Hassan A, Zhu Y, et al. Amelioration of TMAO through probiotics and its potential role in atherosclerosis. Appl Microbiol Biotechnol, 2019, 103(23-24): 9217-9228.
34. DeMartino P, Cockburn D W. Resistant starch: impact on the gut microbiome and health. Curr Opin Biotechnol, 2020, 61: 66-71.
35. Karaduta O, Glazko G, Dvanajscak Z, et al. Resistant starch slows the progression of CKD in the 5/6 nephrectomy mouse model. Physiol Rep, 2020, 8(19): e14610.
36. Hu X F, Zhang W Y, Wen Q, et al. Fecal microbiota transplantation alleviates myocardial damage in myocarditis by restoring the microbiota composition. Pharmacol Res, 2019, 139: 412-421.
37. Lai C Y, Sung J, Cheng F, et al. Systematic review with meta-analysis: review of donor features, procedures and outcomes in 168 clinical studies of faecal microbiota transplantation. Aliment Pharmacol Ther, 2019, 49(4): 354-363.
38. Liu J, Lai L, Lin J, et al. Ranitidine and finasteride inhibit the synthesis and release of trimethylamine N-oxide and mitigates its cardiovascular and renal damage through modulating gut microbiota. Int J Biol Sci, 2020, 16(5): 790-802.
39. Lin Jiajia, Nie Xiaoli, Xiong Ying, et al. Fisetin regulates gut microbiota to decrease CCR9⁺/CXCR3⁺/CD4⁺ T-lymphocyte count and IL-12 secretion to alleviate premature ovarian failure in mice. Am J Transl Res, 2020, 12(1): 203-247.
40. Macpherson M E, Hov J R, Ueland T, et al. Gut microbiota-dependent trimethylamine N-oxide associates with inflammation in common variable immunodeficiency. Front Immunol, 2020, 11: 574500.
41. Wang Zeneng, Roberts A B, Buffa J A, et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell, 2015, 163(7): 1585-1595.

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