Association of gut microbiota metabolite sulfate with cardiovascular disease: a review of mechanisms and clinical implications_West China Medical Journal

Authors：

LIAO Yuanhong ¹ , CHEN Tingting ¹ , LU Jingkun ² , TAN Xin ² , LIU Chengdong ¹ ,  WANG Yuewu ¹

1. School of Pharmacy, Inner Mongolia Medical University, Hohhot, Inner Mongolia 010010, P. R. China;
2. School of Basic Medical Sciences, Inner Mongolia Medical University, Hohhot, Inner Mongolia 010010, P. R. China;

Corresponding author：

WANG Yuewu, Email: wywimmu@163.com

Keywords：

Gut microbiota; metabolites; sulfate; cardiovascular disease; mechanism

DOI：

10.7507/1002-0179.202410290

Video：

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In recent years, the diversity of gut microbiota and the role of its metabolites in cardiovascular disease (CVD) have attracted widespread attention. Gut microbiota metabolites not only play an important role in maintaining gut health, but may also influence cardiovascular health through a variety of mechanisms. As one of the important products of gut microbiota metabolism, sulfate’s biosynthetic pathway, metabolic dynamics and potential effects on cardiovascular system have become the focus of research. However, the current research on the relationship between sulfate and cardiovascular disease still has some shortcomings, including the mechanism is not clear, and clinical data are limited. This article reviewed the biosynthesis of sulfate and its mechanism of action in cardiovascular diseases, and combined with the existing clinical research results, aimed to provide new perspectives and ideas for future research, in order to promote the in-depth exploration and development of this field.

1.	Zhou W, Cheng Y, Zhu P, et al. Implication of gut microbiota in cardiovascular diseases. Oxid Med Cell Longev, 2020: 5394096.
2.	Hills RD Jr, Pontefract BA, Mishcon HR, et al. Gut microbiome: profound implications for diet and disease. Nutrients, 2019, 11(7): 1613.
3.	Wei L, Xu Y, Du M, et al. A novel 4-O-endosulfatase with high potential for the structure-function studies of chondroitin sulfate/dermatan sulfate. Carbohydr Polym, 2023, 305: 120508.
4.	Liukkonen M, Muriel J, Martínez-Padilla J, et al. Seasonal and environmental factors contribute to the variation in the gut microbiome: a large-scale study of a small bird. J Anim Ecol, 2024, 93(10): 1475-1492.
5.	Jia Q, Li H, Zhou H, et al. Role and effective therapeutic target of gut microbiota in heart failure. Cardiovasc Ther, 2019, 2019: 5164298.
6.	Lu D, Zou X, Zhang H. The relationship between atrial fibrillation and intestinal flora with its metabolites. Front Cardiovasc Med, 2022, 9: 948755.
7.	Li J, Yang X, Zhou X, et al. The role and mechanism of intestinal flora in blood pressure regulation and hypertension development. Antioxid Redox Signal, 2021, 34(10): 811-830.
8.	Luo W, Zhao M, Dwidar M, et al. Microbial assimilatory sulfate reduction-mediated H₂S: an overlooked role in Crohn’s disease development. Microbiome, 2024, 12(1): 152.
9.	Zhu Z, Han Y, Ding Y, et al. Health effects of dietary sulfated polysaccharides from seafoods and their interaction with gut microbiota. Compr Rev Food Sci Food Saf, 2021, 20(3): 2882-2913.
10.	Wu S, Liu Y, Jiang P, et al. Effect of sulfate group on sulfated polysaccharides-induced improvement of metabolic syndrome and gut microbiota dysbiosis in high fat diet-fed mice. Int J Biol Macromol, 2020, 164: 2062-2072.
11.	Sun L, Zhang X, Zhang Y, et al. Antibiotic-induced disruption of gut microbiota alters local metabolomes and immune responses. Front Cell Infect Microbiol, 2019, 9: 99.
12.	Sun X, Sun W, Huang Y, et al. Traditional chinese medicine: an exogenous regulator of crosstalk between the gut microbial ecosystem and CKD. Evid Based Complement Alternat Med, 2022, 2022: 7940684.
13.	Li R, Huang X, Liang X, et al. Integrated omics analysis reveals the alteration of gut microbe-metabolites in obese adults. Brief Bioinform, 2021, 22(3): bbaa165.
14.	Abo H, Muraki A, Harusato A, et al. N-acetylglucosamine-6-O sulfation on intestinal mucins prevents obesity and intestinal inflammation by regulating gut microbiota. JCI Insight, 2023, 8(16): e165944.
15.	Kuchel O, Buu NT, Racz K, et al. Role of sulfate conjugation of catecholamines in blood pressure regulation. Fed Proc, 1986, 45(8): 2254-2259.
16.	Zhao P, Liu G, Cui Y, et al. Propylene glycol alginate sodium sulphate attenuates LPS-induced acute lung injury in a mouse model. Innate Immun, 2019, 25(8): 513-521.
17.	Aldini R, Micucci M, Cevenini M, et al. Antiinflammatory effect of phytosterols in experimental murine colitis model: prevention, induction, remission study. PLoS One, 2014, 9(9): e108112.
18.	Mohr AE, Jasbi P, van Woerden I, et al. Microbial ecology and metabolism of emerging adulthood: gut microbiome insights from a college freshman cohort. Gut Microbes Rep, 2024, 1(1): 1-23.
19.	Blake MR, Parrish DC, Staffenson MA, et al. Loss of chondroitin sulfate proteoglycan sulfation allows delayed sympathetic reinnervation after cardiac ischemia-reperfusion. Physiol Rep, 2023, 11(10): e15702.
20.	唐田, 王彦青, 王海全, 等. 氯吡格雷硫酸氢盐的合成. 中国医药工业杂志, 2009, 40(5): 324-326.
21.	Apostu D, Lucaciu O, Mester A, et al. Systemic drugs with impact on osteoarthritis. Drug Metab Rev, 2019, 51(4): 498-523.
22.	Azim A, Murray J, Beddhu S, et al. Urinary sulfate, kidney failure, and death in CKD: the African American study of kidney disease and hypertension. Kidney360, 2022, 3(7): 1183-1190.
23.	Das SK, Ainsworth HC, Dimitrov L, et al. Metabolomic architecture of obesity implicates metabolonic lactone sulfate in cardiometabolic disease. Mol Metab, 2021, 54: 101342.
24.	Carecho R, Figueira I, Terrasso AP, et al. Circulating (poly) phenol metabolites: neuroprotection in a 3D cell model of Parkinson’s disease. Mol Nutr Food Res, 2022, 66(21): e2100959.
25.	Fernandes Silva L, Hokkanen J, Vangipurapu J, et al. Metabolites as risk factors for diabetic retinopathy in patients with type 2 diabetes: a 12-year follow-up study. J Clin Endocrinol Metab, 2023, 109(1): 100-106.
26.	汉辉. 尿毒症毒素硫酸盐对甲酚促进心血管疾病的发生及其毒性作用机制的研究. 上海: 上海交通大学, 2016.
27.	李佳莹, 刘艳阳. 脱氢表雄酮及其硫酸盐与动脉粥样硬化关系的研究现状. 医学综述, 2013, 19(24): 4439-4441.
28.	Qi H, Sheng J. The antihyperlipidemic mechanism of high sulfate content ulvan in rats. Mar Drugs, 2015, 13(6): 3407-3421.
29.	Fernandes S, Ribeiro C, Paiva-Martins F, et al. Protective effect of olive oil polyphenol phase Ⅱ sulfate conjugates on erythrocyte oxidative-induced hemolysis. Food Funct, 2020, 11(10): 8670-8679.
30.	Verlangieri AJ, Hollis TM, Mumma RO. Effects of ascorbic acid and its 2-sulfate on rabbit aortic intimal thickening. Blood Vessels, 1977, 14(3): 157-174.
31.	Pretorius D, Richter RP, Anand T, et al. Alterations in heparan sulfate proteoglycan synthesis and sulfation and the impact on vascular endothelial function. Matrix Biol Plus, 2022, 16: 100121.
32.	Patil NP, Gómez-Hernández A, Zhang F, et al. Rhamnan sulfate reduces atherosclerotic plaque formation and vascular inflammation. Biomaterials, 2022, 291: 121865.
33.	Ribeiro A, Liu F, Srebrzynski M, et al. Uremic toxin indoxyl sulfate promotes macrophage-associated low-grade inflammation and epithelial cell senescence. Int J Mol Sci, 2023, 24(9): 8031.
34.	Yamaguchi K, Yisireyili M, Goto S, et al. Indoxyl sulfate activates nlrp3 inflammasome to induce cardiac contractile dysfunction accompanied by myocardial fibrosis and hypertrophy. Cardiovasc Toxicol, 2022, 22(4): 365-377.
35.	Almeida HV, Tenreiro MF, Louro AF, et al. Human extracellular-matrix functionalization of 3D hiPSC-based cardiac tissues improves cardiomyocyte maturation. ACS Appl Bio Mater, 2021, 4(2): 1888-1899.
36.	Zhang R, Bryson TD, Fogo GM, et al. Rapid treatment with intramuscular magnesium sulfate during cardiopulmonary resuscitation does not provide neuroprotection following cardiac arrest. Mol Neurobiol, 2022, 59(3): 1872-1881.
37.	Sivertsson E, Ceder S, Nangaku M, et al. AST-120 to target protein-bound uremic toxins improves cardiac output and kidney oxygenation in experimental chronic kidney disease. Kidney Blood Press Res, 2023, 48(1): 114-123.
38.	Tsai MH, Chang CH, Liou HH, et al. Inverted u-curve association between serum indoxyl sulfate levels and cardiovascular events in patients on chronic hemodialysis. J Clin Med, 2021, 10(4): 744.
39.	Takkavatakarn K, Phannajit J, Udomkarnjananun S, et al. Association between indoxyl sulfate and dialysis initiation and cardiac outcomes in chronic kidney disease patients. Int J Nephrol Renovasc Dis, 2022, 15: 115-126.
40.	Caillard P, Bennis Y, Six I, et al. The role of gut-derived, protein-bound uremic toxins in the cardiovascular complications of acute kidney injury. Toxins (Basel), 2022, 14(5): 336.
41.	Zhao Y, Chen L. Effects of intestinal bacteria on cardiovascular disease. Biotechnol Genet Eng Rev, 2022, 38(2): 270-287.
42.	Rodríguez-López A, Pimentel-Vera LN, Espejo-Mojica AJ, et al. Characterization of human recombinant N-acetylgalactosamine-6-sulfate sulfatase produced in pichia pastoris as potential enzyme for mucopolysaccharidosis IVA treatment. J Pharm Sci, 2019, 108(8): 2534-2541.
43.	Kühne M, Lindemann H, Grune C, et al. Biocompatible sulfated valproic acid-coupled polysaccharide-based nanocarriers with HDAC inhibitory activity. J Control Release, 2021, 329: 717-730.
44.	Liao YE, Liu J, Arnold K. Heparan sulfates and heparan sulfate binding proteins in sepsis. Front Mol Biosci, 2023, 10: 1146685.
45.	March DS, Jones AW, Bishop NC, et al. The efficacy of prebiotic, probiotic, and synbiotic supplementation in modulating gut-derived circulatory particles associated with cardiovascular disease in individuals receiving dialysis: a systematic review and Meta-analysis of randomized controlled trials. J Ren Nutr, 2020, 30(4): 347-359.
46.	Niu Y, Gao T, Ouyang H, et al. Chondroitin sulfate-derived micelles for adipose tissue-targeted delivery of celastrol and phenformin to enhance obesity treatment. ACS Appl Bio Mater, 2024, 7(2): 1271-1289.
47.	El Daibani AA, Alherz FA, Abunnaja MS, et al. Impact of human SULT1E1 polymorphisms on the sulfation of 17β-estradiol, 4-hydroxytamoxifen, and diethylstilbestrol by SULT1E1 allozymes. Eur J Drug Metab Pharmacokinet, 2021, 46(1): 105-118.
48.	Rasool MI, Bairam AF, Gohal SA, et al. Effects of the human SULT1A1 polymorphisms on the sulfation of acetaminophen, O-desmethylnaproxen, and tapentadol. Pharmacol Rep, 2019, 71(2): 257-265.
49.	Guthrie L, Spencer SP, Perelman D, et al. Impact of a 7-day homogeneous diet on interpersonal variation in human gut microbiomes and metabolomes. Cell Host Microbe, 2022, 30(6): 863-874. e4.
50.	Johansen J, Atarashi K, Arai Y, et al. Centenarians have a diverse gut virome with the potential to modulate metabolism and promote healthy lifespan. Nat Microbiol, 2023, 8(6): 1064-1078.
51.	Xu Z, Liu Y, Liu J, et al. Integrated chemoenzymatic synthesis of a comprehensive sulfated ganglioside glycan library to decipher functional sulfoglycomics and sialoglycomics. Nat Chem, 2024, 16(6): 881-892.
52.	Wang T, Tang L, Lin R, et al. Individual variability in human urinary metabolites identifies age-related, body mass index-related, and sex-related biomarkers. Mol Genet Genomic Med, 2021, 9(8): e1738.
53.	卢文婷, 姚远, 熊静, 等. 机器学习在心血管疾病辅助诊断模型中的效果. 中华全科医学, 2023, 23(1): 112-117.

1. Zhou W, Cheng Y, Zhu P, et al. Implication of gut microbiota in cardiovascular diseases. Oxid Med Cell Longev, 2020: 5394096.
2. Hills RD Jr, Pontefract BA, Mishcon HR, et al. Gut microbiome: profound implications for diet and disease. Nutrients, 2019, 11(7): 1613.
3. Wei L, Xu Y, Du M, et al. A novel 4-O-endosulfatase with high potential for the structure-function studies of chondroitin sulfate/dermatan sulfate. Carbohydr Polym, 2023, 305: 120508.
4. Liukkonen M, Muriel J, Martínez-Padilla J, et al. Seasonal and environmental factors contribute to the variation in the gut microbiome: a large-scale study of a small bird. J Anim Ecol, 2024, 93(10): 1475-1492.
5. Jia Q, Li H, Zhou H, et al. Role and effective therapeutic target of gut microbiota in heart failure. Cardiovasc Ther, 2019, 2019: 5164298.
6. Lu D, Zou X, Zhang H. The relationship between atrial fibrillation and intestinal flora with its metabolites. Front Cardiovasc Med, 2022, 9: 948755.
7. Li J, Yang X, Zhou X, et al. The role and mechanism of intestinal flora in blood pressure regulation and hypertension development. Antioxid Redox Signal, 2021, 34(10): 811-830.
8. Luo W, Zhao M, Dwidar M, et al. Microbial assimilatory sulfate reduction-mediated H₂S: an overlooked role in Crohn’s disease development. Microbiome, 2024, 12(1): 152.
9. Zhu Z, Han Y, Ding Y, et al. Health effects of dietary sulfated polysaccharides from seafoods and their interaction with gut microbiota. Compr Rev Food Sci Food Saf, 2021, 20(3): 2882-2913.
10. Wu S, Liu Y, Jiang P, et al. Effect of sulfate group on sulfated polysaccharides-induced improvement of metabolic syndrome and gut microbiota dysbiosis in high fat diet-fed mice. Int J Biol Macromol, 2020, 164: 2062-2072.
11. Sun L, Zhang X, Zhang Y, et al. Antibiotic-induced disruption of gut microbiota alters local metabolomes and immune responses. Front Cell Infect Microbiol, 2019, 9: 99.
12. Sun X, Sun W, Huang Y, et al. Traditional chinese medicine: an exogenous regulator of crosstalk between the gut microbial ecosystem and CKD. Evid Based Complement Alternat Med, 2022, 2022: 7940684.
13. Li R, Huang X, Liang X, et al. Integrated omics analysis reveals the alteration of gut microbe-metabolites in obese adults. Brief Bioinform, 2021, 22(3): bbaa165.
14. Abo H, Muraki A, Harusato A, et al. N-acetylglucosamine-6-O sulfation on intestinal mucins prevents obesity and intestinal inflammation by regulating gut microbiota. JCI Insight, 2023, 8(16): e165944.
15. Kuchel O, Buu NT, Racz K, et al. Role of sulfate conjugation of catecholamines in blood pressure regulation. Fed Proc, 1986, 45(8): 2254-2259.
16. Zhao P, Liu G, Cui Y, et al. Propylene glycol alginate sodium sulphate attenuates LPS-induced acute lung injury in a mouse model. Innate Immun, 2019, 25(8): 513-521.
17. Aldini R, Micucci M, Cevenini M, et al. Antiinflammatory effect of phytosterols in experimental murine colitis model: prevention, induction, remission study. PLoS One, 2014, 9(9): e108112.
18. Mohr AE, Jasbi P, van Woerden I, et al. Microbial ecology and metabolism of emerging adulthood: gut microbiome insights from a college freshman cohort. Gut Microbes Rep, 2024, 1(1): 1-23.
19. Blake MR, Parrish DC, Staffenson MA, et al. Loss of chondroitin sulfate proteoglycan sulfation allows delayed sympathetic reinnervation after cardiac ischemia-reperfusion. Physiol Rep, 2023, 11(10): e15702.
20. 唐田, 王彦青, 王海全, 等. 氯吡格雷硫酸氢盐的合成. 中国医药工业杂志, 2009, 40(5): 324-326.
21. Apostu D, Lucaciu O, Mester A, et al. Systemic drugs with impact on osteoarthritis. Drug Metab Rev, 2019, 51(4): 498-523.
22. Azim A, Murray J, Beddhu S, et al. Urinary sulfate, kidney failure, and death in CKD: the African American study of kidney disease and hypertension. Kidney360, 2022, 3(7): 1183-1190.
23. Das SK, Ainsworth HC, Dimitrov L, et al. Metabolomic architecture of obesity implicates metabolonic lactone sulfate in cardiometabolic disease. Mol Metab, 2021, 54: 101342.
24. Carecho R, Figueira I, Terrasso AP, et al. Circulating (poly) phenol metabolites: neuroprotection in a 3D cell model of Parkinson’s disease. Mol Nutr Food Res, 2022, 66(21): e2100959.
25. Fernandes Silva L, Hokkanen J, Vangipurapu J, et al. Metabolites as risk factors for diabetic retinopathy in patients with type 2 diabetes: a 12-year follow-up study. J Clin Endocrinol Metab, 2023, 109(1): 100-106.
26. 汉辉. 尿毒症毒素硫酸盐对甲酚促进心血管疾病的发生及其毒性作用机制的研究. 上海: 上海交通大学, 2016.
27. 李佳莹, 刘艳阳. 脱氢表雄酮及其硫酸盐与动脉粥样硬化关系的研究现状. 医学综述, 2013, 19(24): 4439-4441.
28. Qi H, Sheng J. The antihyperlipidemic mechanism of high sulfate content ulvan in rats. Mar Drugs, 2015, 13(6): 3407-3421.
29. Fernandes S, Ribeiro C, Paiva-Martins F, et al. Protective effect of olive oil polyphenol phase Ⅱ sulfate conjugates on erythrocyte oxidative-induced hemolysis. Food Funct, 2020, 11(10): 8670-8679.
30. Verlangieri AJ, Hollis TM, Mumma RO. Effects of ascorbic acid and its 2-sulfate on rabbit aortic intimal thickening. Blood Vessels, 1977, 14(3): 157-174.
31. Pretorius D, Richter RP, Anand T, et al. Alterations in heparan sulfate proteoglycan synthesis and sulfation and the impact on vascular endothelial function. Matrix Biol Plus, 2022, 16: 100121.
32. Patil NP, Gómez-Hernández A, Zhang F, et al. Rhamnan sulfate reduces atherosclerotic plaque formation and vascular inflammation. Biomaterials, 2022, 291: 121865.
33. Ribeiro A, Liu F, Srebrzynski M, et al. Uremic toxin indoxyl sulfate promotes macrophage-associated low-grade inflammation and epithelial cell senescence. Int J Mol Sci, 2023, 24(9): 8031.
34. Yamaguchi K, Yisireyili M, Goto S, et al. Indoxyl sulfate activates nlrp3 inflammasome to induce cardiac contractile dysfunction accompanied by myocardial fibrosis and hypertrophy. Cardiovasc Toxicol, 2022, 22(4): 365-377.
35. Almeida HV, Tenreiro MF, Louro AF, et al. Human extracellular-matrix functionalization of 3D hiPSC-based cardiac tissues improves cardiomyocyte maturation. ACS Appl Bio Mater, 2021, 4(2): 1888-1899.
36. Zhang R, Bryson TD, Fogo GM, et al. Rapid treatment with intramuscular magnesium sulfate during cardiopulmonary resuscitation does not provide neuroprotection following cardiac arrest. Mol Neurobiol, 2022, 59(3): 1872-1881.
37. Sivertsson E, Ceder S, Nangaku M, et al. AST-120 to target protein-bound uremic toxins improves cardiac output and kidney oxygenation in experimental chronic kidney disease. Kidney Blood Press Res, 2023, 48(1): 114-123.
38. Tsai MH, Chang CH, Liou HH, et al. Inverted u-curve association between serum indoxyl sulfate levels and cardiovascular events in patients on chronic hemodialysis. J Clin Med, 2021, 10(4): 744.
39. Takkavatakarn K, Phannajit J, Udomkarnjananun S, et al. Association between indoxyl sulfate and dialysis initiation and cardiac outcomes in chronic kidney disease patients. Int J Nephrol Renovasc Dis, 2022, 15: 115-126.
40. Caillard P, Bennis Y, Six I, et al. The role of gut-derived, protein-bound uremic toxins in the cardiovascular complications of acute kidney injury. Toxins (Basel), 2022, 14(5): 336.
41. Zhao Y, Chen L. Effects of intestinal bacteria on cardiovascular disease. Biotechnol Genet Eng Rev, 2022, 38(2): 270-287.
42. Rodríguez-López A, Pimentel-Vera LN, Espejo-Mojica AJ, et al. Characterization of human recombinant N-acetylgalactosamine-6-sulfate sulfatase produced in pichia pastoris as potential enzyme for mucopolysaccharidosis IVA treatment. J Pharm Sci, 2019, 108(8): 2534-2541.
43. Kühne M, Lindemann H, Grune C, et al. Biocompatible sulfated valproic acid-coupled polysaccharide-based nanocarriers with HDAC inhibitory activity. J Control Release, 2021, 329: 717-730.
44. Liao YE, Liu J, Arnold K. Heparan sulfates and heparan sulfate binding proteins in sepsis. Front Mol Biosci, 2023, 10: 1146685.
45. March DS, Jones AW, Bishop NC, et al. The efficacy of prebiotic, probiotic, and synbiotic supplementation in modulating gut-derived circulatory particles associated with cardiovascular disease in individuals receiving dialysis: a systematic review and Meta-analysis of randomized controlled trials. J Ren Nutr, 2020, 30(4): 347-359.
46. Niu Y, Gao T, Ouyang H, et al. Chondroitin sulfate-derived micelles for adipose tissue-targeted delivery of celastrol and phenformin to enhance obesity treatment. ACS Appl Bio Mater, 2024, 7(2): 1271-1289.
47. El Daibani AA, Alherz FA, Abunnaja MS, et al. Impact of human SULT1E1 polymorphisms on the sulfation of 17β-estradiol, 4-hydroxytamoxifen, and diethylstilbestrol by SULT1E1 allozymes. Eur J Drug Metab Pharmacokinet, 2021, 46(1): 105-118.
48. Rasool MI, Bairam AF, Gohal SA, et al. Effects of the human SULT1A1 polymorphisms on the sulfation of acetaminophen, O-desmethylnaproxen, and tapentadol. Pharmacol Rep, 2019, 71(2): 257-265.
49. Guthrie L, Spencer SP, Perelman D, et al. Impact of a 7-day homogeneous diet on interpersonal variation in human gut microbiomes and metabolomes. Cell Host Microbe, 2022, 30(6): 863-874. e4.
50. Johansen J, Atarashi K, Arai Y, et al. Centenarians have a diverse gut virome with the potential to modulate metabolism and promote healthy lifespan. Nat Microbiol, 2023, 8(6): 1064-1078.
51. Xu Z, Liu Y, Liu J, et al. Integrated chemoenzymatic synthesis of a comprehensive sulfated ganglioside glycan library to decipher functional sulfoglycomics and sialoglycomics. Nat Chem, 2024, 16(6): 881-892.
52. Wang T, Tang L, Lin R, et al. Individual variability in human urinary metabolites identifies age-related, body mass index-related, and sex-related biomarkers. Mol Genet Genomic Med, 2021, 9(8): e1738.
53. 卢文婷, 姚远, 熊静, 等. 机器学习在心血管疾病辅助诊断模型中的效果. 中华全科医学, 2023, 23(1): 112-117.

West China Medical Journal

Latest ArticlesAssociation of gut microbiota metabolite sulfate with cardiovascular disease: a review of mechanisms and clinical implications

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