REFERENCES
1. United Nations. World population prospects 2024: summary of results. Available from: https://desapublications.un.org/publications/world-population-prospects-2024-summary-results [Last accessed on 26 May 2026].
2. Ghosh TS, Shanahan F, O’toole PW. The gut microbiome as a modulator of healthy ageing. Nat Rev Gastroenterol Hepatol. 2022;19:565-84.
3. He S, Huang B, Xu F, et al. Functions and application of circRNAs in vascular aging and aging-related vascular diseases. J Nanobiotechnol. 2025;23:216.
4. Witkowski M, Weeks TL, Hazen SL. Gut microbiota and cardiovascular disease. Circ Res. 2020;127:553-70.
5. Fan Y, Pedersen O. Gut microbiota in human metabolic health and disease. Nat Rev Microbiol. 2020;19:55-71.
6. Lynch SV, Pedersen O. The human intestinal microbiome in health and disease. N Engl J Med. 2016;375:2369-79.
8. Ling Z, Liu X, Cheng Y, Yan X, Wu S. Gut microbiota and aging. Crit Rev Food Sci Nutr. 2020;62:3509-34.
9. Wilmanski T, Diener C, Rappaport N, et al. Gut microbiome pattern reflects healthy ageing and predicts survival in humans. Nat Metab. 2021;3:274-86.
10. Francini E, Badillo Pazmay GV, Fumarola S, Procopio AD, Olivieri F, Marchegiani F. Bi-directional relationship between bile acids (BAs) and gut microbiota (GM): UDCA/TUDCA, probiotics, and dietary interventions in elderly people. Int J Mol Sci. 2025;26:1759.
11. Biagi E, Franceschi C, Rampelli S, et al. Gut microbiota and extreme longevity. Curr Biol. 2016;26:1480-5.
12. Longtine AG, Greenberg NT, Gonzalez A, et al. Oral supplementation with the short-chain fatty acid acetate ameliorates age-related arterial dysfunction in mice. Aging Biol. 2024;2:20240033.
13. Malik M, Suboc TM, Tyagi S, et al. Lactobacillus plantarum 299v supplementation improves vascular endothelial function and reduces inflammatory biomarkers in men with stable coronary artery disease. Circ Res. 2018;123:1091-102.
14. Yang H, Wang T, Qian C, et al. Gut microbial-derived phenylacetylglutamine accelerates host cellular senescence. Nat Aging. 2025;5:401-18.
15. Chen W, Li M, Zeng G, et al. Gut microbiota-derived metabolite phenylacetylglutamine in cardiovascular and metabolic diseases. Pharmacol Res. 2025;217:107794.
16. Chen B, Wirawan KF, Luo L, Zhang J, Li T. Mapping arterial stiffness metabolic biomarkers: a bibliometric analysis. Front Med. 2025;12:1557731.
17. Ungvari Z, Tarantini S, Sorond F, Merkely B, Csiszar A. Mechanisms of vascular aging, a geroscience perspective: JACC focus seminar. J Am Coll Cardiol. 2020;75:931-41.
18. Couteur DG, Lakatta EG. A vascular theory of aging. J Gerontol A Biol Sci Med Sci. 2010;65A:1025-7.
19. Grunewald M, Kumar S, Sharife H, et al. Counteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span. Science. 2021;373:eabc8479.
20. Lacolley P, Avril S, Gáll T, et al. Aging in the vascular system: lessons from mechanobiology, computational approaches, and oxidative stress. Cardiovasc Res. 2025;121:1566-81.
21. Climie RE, Alastruey J, Mayer CC, et al. Vascular ageing: moving from bench towards bedside. Eur J Prev Cardiol. 2023;30:1101-17.
22. Wang M, Monticone RE, Mcgraw KR. Proinflammatory arterial stiffness syndrome: a signature of large arterial aging. J Vasc Res. 2018;55:210-23.
23. Donato AJ, Machin DR, Lesniewski LA. Mechanisms of dysfunction in the aging vasculature and role in age-related disease. Circ Res. 2018;123:825-48.
24. Herzog MJ, Müller P, Lechner K, et al. Arterial stiffness and vascular aging: mechanisms, prevention, and therapy. Sig Transduct Target Ther. 2025;10:282.
25. Hooglugt A, Klatt O, Huveneers S. Vascular stiffening and endothelial dysfunction in atherosclerosis. Curr Opin Lipidol. 2022;33:353-63.
26. Regnault V, Lacolley P, Laurent S. Arterial stiffness: from basic primers to integrative physiology. Annu Rev Physiol. 2024;86:99-121.
27. Li Q, Qian Z, Huang Y, et al. Mechanisms of endothelial senescence and vascular aging. Biogerontology. 2025;26:128.
28. Xu S, Ilyas I, Little PJ, et al. Endothelial dysfunction in atherosclerotic cardiovascular diseases and beyond: from mechanism to pharmacotherapies. Pharmacol Rev. 2021;73:924-67.
29. Paulus WJ, Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013;62:263-71.
30. Carnagarin R, Matthews V, Zaldivia MTK, Peter K, Schlaich MP. The bidirectional interaction between the sympathetic nervous system and immune mechanisms in the pathogenesis of hypertension. Br J Pharmacol. 2018;176:1839-52.
31. Drüppel V, Kusche‐vihrog K, Grossmann C, et al. Long‐term application of the aldosterone antagonist spironolactone prevents stiff endothelial cell syndrome. FASEB J. 2013;27:3652-9.
32. Peng X, Haldar S, Deshpande S, Irani K, Kass DA. Wall stiffness suppresses Akt/eNOS and cytoprotection in pulse-perfused endothelium. Hypertension. 2003;41:378-81.
33. Méndez-Barbero N, Gutiérrez-Muñoz C, Blanco-Colio L. Cellular crosstalk between endothelial and smooth muscle cells in vascular wall remodeling. Int J Mol Sci. 2021;22:7284.
34. Liu X, Liu H, Lin Y, et al. Deletion of METTL14, a key methylation regulator, attenuates vascular ageing. Eur Heart J. 2025;46:4953-68.
35. Pang J, Pan L, Shen W, et al. Endothelial LRRC8A delays vascular ageing in natural and accelerated ageing mouse models. Cardiovasc Res. 2025;121:2549-64.
36. Cao G, Xuan X, Hu J, Zhang R, Jin H, Dong H. How vascular smooth muscle cell phenotype switching contributes to vascular disease. Cell Commun Signal. 2022;20:180.
37. Qiu H, Zhu Y, Sun Z, et al. Short communication: vascular smooth muscle cell stiffness as a mechanism for increased aortic stiffness with aging. Circ Res. 2010;107:615-9.
38. Badi I, Mancinelli L, Polizzotto A, et al. miR-34a promotes vascular smooth muscle cell calcification by downregulating SIRT1 (Sirtuin 1) and Axl (AXL receptor tyrosine kinase). Arterioscler Thromb Vasc Biol. 2018;38:2079-90.
39. Chen L, Fukuda N, Otsuki T, et al. Increased complement 3 with suppression of miR‐145 induces the synthetic phenotype in vascular smooth muscle cells from spontaneously hypertensive rats. J Am Heart Assoc. 2019;8:e012327.
40. Yuan X, Bhat OM, Samidurai A, Das A, Zhang Y, Li P. Reversal of endothelial extracellular vesicle-induced smooth muscle phenotype transition by hypercholesterolemia stimulation: role of NLRP3 inflammasome activation. Front Cell Dev Biol. 2020;8:597423.
41. Yan W, Li T, Yin T, et al. M2 macrophage-derived exosomes promote the c-KIT phenotype of vascular smooth muscle cells during vascular tissue repair after intravascular stent implantation. Theranostics. 2020;10:10712-28.
42. Grootaert MO, Finigan A, Figg NL, Uryga AK, Bennett MR. SIRT6 protects smooth muscle cells from senescence and reduces atherosclerosis. Circ Res. 2021;128:474-91.
43. Chi C, Fu H, Li Y, et al. Exerkine fibronectin type-III domain-containing protein 5/irisin-enriched extracellular vesicles delay vascular ageing by increasing SIRT6 stability. Eur Heart J. 2022;43:4579-95.
44. Nie H, Ji T, Wan Z, et al. ATF3 deficiency exacerbates ageing‐induced atherosclerosis and clinical intervention strategy. Adv Sci. 2025;12:e02249.
45. Li X, Chen M, Chen X, et al. TRAP1 drives smooth muscle cell senescence and promotes atherosclerosis via HDAC3-primed histone H4 lysine 12 lactylation. Eur Heart J. 2024;45:4219-35.
46. Sun S, Zhang Z, Zhang G, et al. GSDME-dependent pyroptosis drives abdominal aortic aneurysm via promoting vascular senescence. Nat Commun. 2025;16:11248.
47. Sun D, Wu W, Wu J, et al. Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence. Nat Commun. 2024;15:1429.
48. Ajoolabady A, Pratico D, Tang D, Zhou S, Franceschi C, Ren J. Immunosenescence and inflammaging: mechanisms and role in diseases. Ageing Res Rev. 2024;101:102540.
49. Dong R, Ji Z, Wang M, Ma G. Role of macrophages in vascular calcification: from the perspective of homeostasis. Int Immunopharmacol. 2025;144:113635.
50. Deconne TM, Buckley DJ, Trott DW, Martens CR. The role of T cells in vascular aging, hypertension, and atherosclerosis. Am J Physiol Heart Circ Physiol. 2024;327:H1345-60.
51. Pattarabanjird T, Li C, Mcnamara C. B cells in atherosclerosis: Mechanisms and Potential Clinical Applications. JACC Basic Transl Sci. 2021;6:546-63.
52. Fusco W, Adolph T, Cammarota G, Gasbarrini A, Ianiro G, Tilg H. Gut microbiota and atherosclerosis. Gut. 2026;75:1067-77.
53. Sender R, Fuchs S, Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol. 2016;14:e1002533.
54. Hul M, Cani PD, Petitfils C, De Vos WM, Tilg H, El-Omar EM. What defines a healthy gut microbiome? Gut. 2024;73:1893-908.
55. Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut microbiota. Nature. 2012;489:220-30.
56. Odamaki T, Kato K, Sugahara H, et al. Age-related changes in gut microbiota composition from newborn to centenarian: a cross-sectional study. BMC Microbiol. 2016;16:90.
57. Ticinesi A, Maggi S, Nouvenne A, Zuliani G, Franceschi C. The gut microbiome and ageing trajectories: mechanisms and clinical implications. Nat Rev Endocrinol. 2026;22:323-37.
58. Untersmayr E, Brandt A, Koidl L, Bergheim I. The intestinal barrier dysfunction as driving factor of inflammaging. Nutrients. 2022;14:949.
59. Menni C, Lin C, Cecelja M, et al. Gut microbial diversity is associated with lower arterial stiffness in women. Eur Heart J. 2018;39:2390-7.
60. Battson ML, Lee DM, Jarrell DK, et al. Suppression of gut dysbiosis reverses Western diet-induced vascular dysfunction. Am J Physiol Endocrinol Metab. 2018;314:E468-77.
61. Trikha SRJ, Lee DM, Ecton KE, et al. Transplantation of an obesity-associated human gut microbiota to mice induces vascular dysfunction and glucose intolerance. Gut Microbes. 2021;13:1940791.
62. Cuadrat RRC, Goris T, Birukov A, et al. Association of the human gut microbiota with vascular stiffness. Sci Rep. 2023;13:13348.
63. Luo S, Zhao Y, Zhu S, et al. Flavonifractor plautii protects against elevated arterial stiffness. Circ Res. 2023;132:167-81.
64. Rahman S, Trone K, Kelly C, Stroud A, Martindale R. All fiber is not fiber. Curr Gastroenterol Rep. 2022;25:1-12.
65. Koh A, De Vadder F, Kovatcheva-Datchary P, Bäckhed F. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell. 2016;165:1332-45.
66. Hu T, Wu Q, Yao Q, Jiang K, Yu J, Tang Q. Short-chain fatty acid metabolism and multiple effects on cardiovascular diseases. Ageing Res Rev. 2022;81:101706.
67. Canfora EE, Jocken JW, Blaak EE. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat Rev Endocrinol. 2015;11:577-91.
68. Mann ER, Lam YK, Uhlig HH. Short-chain fatty acids: linking diet, the microbiome and immunity. Nat Rev Immunol. 2024;24:577-95.
69. Rekha K, Venkidasamy B, Samynathan R, et al. Short-chain fatty acid: an updated review on signaling, metabolism, and therapeutic effects. Crit Rev Food Sci Nutr. 2022;64:2461-89.
70. Zhao Y, Chen F, Wu W, et al. GPR43 mediates microbiota metabolite SCFA regulation of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3. Mucosal Immunol. 2018;11:752-62.
71. Kasahara K, Krautkramer KA, Org E, et al. Interactions between Roseburia intestinalis and diet modulate atherogenesis in a murine model. Nat Microbiol. 2018;3:1461-71.
72. Zheng L, Kelly CJ, Battista KD, et al. Microbial-derived butyrate promotes epithelial barrier function through IL-10 receptor-dependent repression of claudin-2. J Immunol. 2017;199:2976-84.
73. Kaiko GE, Ryu SH, Koues OI, et al. The colonic crypt protects stem cells from microbiota-derived metabolites. Cell. 2016;165:1708-20.
74. Kim S, Shin Y, Kim T, et al. Mucin degrader Akkermansia muciniphila accelerates intestinal stem cell-mediated epithelial development. Gut Microbes. 2021;13:1892441.
75. Parada Venegas D, De La Fuente MK, Landskron G, et al. Short chain fatty acids (SCFAs)-mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Front Immunol. 2019;10:277.
76. Singh N, Gurav A, Sivaprakasam S, et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity. 2014;40:128-39.
77. Smith PM, Howitt MR, Panikov N, et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science. 2013;341:569-73.
78. Furusawa Y, Obata Y, Fukuda S, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013;504:446-50.
79. Chen L, Sun M, Wu W, et al. Microbiota metabolite butyrate differentially regulates Th1 and Th17 cells’ differentiation and function in induction of colitis. Inflamm Bowel Dis. 2019;25:1450-61.
80. Park J, Kim M, Kang S, et al. Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway. Mucosal Immunol. 2015;8:80-93.
81. Yang W, Yu T, Huang X, et al. Intestinal microbiota-derived short-chain fatty acids regulation of immune cell IL-22 production and gut immunity. Nat Commun. 2020;11:4457.
82. Kim M, Qie Y, Park J, Kim CH. Gut microbial metabolites fuel host antibody responses. Cell Host Microbe. 2016;20:202-14.
83. Zhao Y, Liu J, Hao W, et al. Structure-specific effects of short-chain fatty acids on plasma cholesterol concentration in male syrian hamsters. J Agric Food Chem. 2017;65:10984-92.
84. Haghikia A, Zimmermann F, Schumann P, et al. Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism. Eur Heart J. 2022;43:518-33.
85. Tayyeb JZ, Popeijus HE, Mensink RP, Konings MCJM, Mokhtar FBA, Plat J. Short-chain fatty acids (except hexanoic acid) lower NF-kB transactivation, which rescues inflammation-induced decreased apolipoprotein A-I transcription in HepG2 cells. Int J Mol Sci. 2020;21:5088.
86. Tayyeb JZ, Popeijus HE, Mensink RP, Plat J. Butyric acid added apically to intestinal Caco-2 cells elevates hepatic ApoA-I transcription and rescues lower ApoA-I expression in inflamed HepG2 cells co-cultured in the basolateral compartment. Biomolecules. 2021;11:71.
87. Du Y, Li X, Su C, et al. Butyrate protects against high‐fat diet‐induced atherosclerosis via up‐regulating ABCA1 expression in apolipoprotein E‐deficiency mice. Br J Pharmacol. 2020;177:1754-72.
88. Woollett LA, Wang Y, Buckley DD, et al. Micellar solubilisation of cholesterol is essential for absorption in humans. Gut. 2006;55:197-204.
89. Farr S, Stankovic B, Hoffman S, et al. Bile acid treatment and FXR agonism lower postprandial lipemia in mice. Am J Physiol Gastrointest Liver Physiol. 2020;318:G682-93.
90. Roessler J, Zimmermann F, Schumann P, et al. Modulation of the serum metabolome by the short-chain fatty acid propionate: potential implications for its cholesterol-lowering effect. Nutrients. 2024;16:2368.
91. Li M, Van Esch BCAM, Henricks PAJ, Folkerts G, Garssen J. The anti-inflammatory effects of short chain fatty acids on lipopolysaccharide- or tumor necrosis factor α-stimulated endothelial cells via activation of GPR41/43 and inhibition of HDACs. Front Pharmacol. 2018;9:533.
92. Liu T, Li J, Liu Y, et al. Short-chain fatty acids suppress lipopolysaccharide-induced production of nitric oxide and proinflammatory cytokines through inhibition of NF-κB pathway in RAW264.7 cells. Inflammation. 2012;35:1676-84.
93. Wu J, Jiang Z, Zhang H, et al. Sodium butyrate attenuates diabetes-induced aortic endothelial dysfunction via P300-mediated transcriptional activation of Nrf2. Free Radic Biol Med. 2018;124:454-65.
94. González-bosch C, Boorman E, Zunszain PA, Mann GE. Short-chain fatty acids as modulators of redox signaling in health and disease. Redox Biol. 2021;47:102165.
95. Saeedi Saravi SS, Pugin B, Constancias F, et al. Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging. Nat Aging. 2025;5:1025-45.
96. Mathew OP, Ranganna K, Mathew J, et al. Cellular effects of butyrate on vascular smooth muscle cells are mediated through disparate actions on dual targets, histone deacetylase (HDAC) activity and PI3K/Akt signaling network. Int J Mol Sci. 2019;20:2902.
97. Pewowaruk R, Jaeger BC, Hughes TM, et al. Effects of blood pressure control on arterial stiffness mechanisms in SPRINT: a randomized controlled trial. Hypertension. 2025;82:1004-11.
98. Natarajan N, Hori D, Flavahan S, et al. Microbial short chain fatty acid metabolites lower blood pressure via endothelial G protein-coupled receptor 41. Physiol Genomics. 2016;48:826-34.
99. Kaye DM, Shihata WA, Jama HA, et al. Deficiency of prebiotic fiber and insufficient signaling through gut metabolite-sensing receptors leads to cardiovascular disease. Circulation. 2020;141:1393-403.
100. Nakai M, Ribeiro RV, Stevens BR, et al. Essential hypertension is associated with changes in gut microbial metabolic pathways: a multisite analysis of ambulatory blood pressure. Hypertension. 2021;78:804-15.
101. Dinakis E, Nakai M, Gill PA, et al. The gut microbiota and their metabolites in human arterial stiffness. Heart Lung Circ. 2021;30:1716-25.
102. Pluznick JL, Protzko RJ, Gevorgyan H, et al. Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation. Proc Natl Acad Sci USA. 2013;110:4410-5.
103. Wu Y, Xu H, Tu X, Gao Z. The role of short-chain fatty acids of gut microbiota origin in hypertension. Front Microbiol. 2021;12:730809.
104. Xu J, Moore BN, Pluznick JL. Short-chain fatty acid receptors and blood pressure regulation: council on hypertension mid-career award for research excellence 2021. Hypertension. 2022;79:2127-37.
105. R. Muralitharan R, Zheng T, Dinakis E, et al. Gut microbiota metabolites sensed by host GPR41/43 protect against hypertension. Circ Res. 2025;136:e20-33.
106. Salvado R, Lugones-Sánchez C, Santos-Minguez S, et al. Sex differences in gut microbiota and their relation to arterial stiffness (MIVAS study). Nutrients. 2024;17:53.
107. Tsai H, Tsai W, Yu P, Hung W, Hung W, Tsai Y. Circulating short-chain fatty acids and subclinical cardiovascular disease in type 2 diabetes mellitus. Pol Arch Intern Med. 2025;135:17128.
109. Cai J, Rimal B, Jiang C, Chiang JY, Patterson AD. Bile acid metabolism and signaling, the microbiota, and metabolic disease. Pharmacol Ther. 2022;237:108238.
110. Collins SL, Stine JG, Bisanz JE, Okafor CD, Patterson AD. Bile acids and the gut microbiota: metabolic interactions and impacts on disease. Nat Rev Microbiol. 2022;21:236-47.
111. Zhang Z, Lv T, Wang X, et al. Role of the microbiota-gut-heart axis between bile acids and cardiovascular disease. Biomed Pharmacother. 2024;174:116567.
112. Liu T, Kern JT, Jain U, et al. Western diet induces Paneth cell defects through microbiome alterations and farnesoid X receptor and type I interferon activation. Cell Host Microbe. 2021;29:988-1001.e6.
113. Fu T, Coulter S, Yoshihara E, et al. FXR regulates intestinal cancer stem cell proliferation. Cell. 2019;176:1098-112.e18.
114. Sorrentino G, Perino A, Yildiz E, et al. Bile acids signal via TGR5 to activate intestinal stem cells and epithelial regeneration. Gastroenterology. 2020;159:956-68.e8.
115. Li T, Ding N, Guo H, et al. A gut microbiota-bile acid axis promotes intestinal homeostasis upon aspirin-mediated damage. Cell Host Microbe. 2024;32:191-208.e9.
116. Chen L, Jiao T, Liu W, et al. Hepatic cytochrome P450 8B1 and cholic acid potentiate intestinal epithelial injury in colitis by suppressing intestinal stem cell renewal. Cell Stem Cell. 2022;29:1366-81.e9.
117. Sorribas M, Jakob MO, Yilmaz B, et al. FXR modulates the gut-vascular barrier by regulating the entry sites for bacterial translocation in experimental cirrhosis. J Hepatol. 2019;71:1126-40.
118. Cai J, Sun L, Gonzalez FJ. Gut microbiota-derived bile acids in intestinal immunity, inflammation, and tumorigenesis. Cell Host Microbe. 2022;30:289-300.
119. Guo C, Xie S, Chi Z, et al. Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome. Immunity. 2016;45:802-16.
120. Yang Y, Hao C, Jiao T, et al. Osteoarthritis treatment via the GLP-1-mediated gut-joint axis targets intestinal FXR signaling. Science. 2025;388:eadt0548.
121. Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell. 2000;102:731-44.
122. Watanabe M, Houten SM, Wang L, et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Investig. 2004;113:1408-18.
123. Claudel T, Inoue Y, Barbier O, et al. Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression. Gastroenterology. 2003;125:544-55.
124. Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev. 2009;89:147-91.
125. De Boer JF, Schonewille M, Boesjes M, et al. Intestinal farnesoid X receptor controls transintestinal cholesterol excretion in mice. Gastroenterology. 2017;152:1126-38.e6.
126. Huang F, Zheng X, Ma X, et al. Theabrownin from Pu-erh tea attenuates hypercholesterolemia via modulation of gut microbiota and bile acid metabolism. Nat Commun. 2019;10:4971.
127. Joyce SA, Macsharry J, Casey PG, et al. Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut. Proc Natl Acad Sci USA. 2014;111:7421-6.
128. Clifford BL, Sedgeman LR, Williams KJ, et al. FXR activation protects against NAFLD via bile-acid-dependent reductions in lipid absorption. Cell Metab. 2021;33:1671-84.e4.
129. Chan AP, Jarrett KE, Lai RW, et al. Bile acids regulate lipid metabolism through selective actions on fatty acid absorption. Cell Metab. 2026;38:263-80.e10.
130. Velazquez-villegas LA, Perino A, Lemos V, et al. TGR5 signalling promotes mitochondrial fission and beige remodelling of white adipose tissue. Nat Commun. 2018;9:245.
131. Watanabe M, Houten SM, Mataki C, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006;439:484-9.
132. Broeders EP, Nascimento EB, Havekes B, et al. The bile acid chenodeoxycholic acid increases human brown adipose tissue activity. Cell Metab. 2015;22:418-26.
133. She J, Tuerhongjiang G, Guo M, et al. Statins aggravate insulin resistance through reduced blood glucagon-like peptide-1 levels in a microbiota-dependent manner. Cell Metab. 2024;36:408-21.e5.
134. He F, Li J, Mu Y, et al. Downregulation of endothelin-1 by farnesoid X receptor in vascular endothelial cells. Circ Res. 2006;98:192-9.
135. Voiosu A, Wiese S, Voiosu T, Bendtsen F, Møller S. Bile acids and cardiovascular function in cirrhosis. Liver Int. 2017;37:1420-30.
136. Kida T, Tsubosaka Y, Hori M, Ozaki H, Murata T. Bile acid receptor TGR5 agonism induces NO production and reduces monocyte adhesion in vascular endothelial cells. Arterioscler Thromb Vasc Biol. 2013;33:1663-9.
137. Bennett BJ, Vallim TQDA, Wang Z, et al. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 2013;17:49-60.
138. Wahlström A, Sayin SI, Marschall H, Bäckhed F. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 2016;24:41-50.
139. Lu H, Wu Z, Wan M, et al. Taurochenodeoxycholic acid alleviates obesity-induced endothelial dysfunction. Eur Heart J. 2026;47:1221-38.
140. Liu H, Tian R, Wang H, et al. Gut microbiota from coronary artery disease patients contributes to vascular dysfunction in mice by regulating bile acid metabolism and immune activation. J Transl Med. 2020;18:382.
141. Battson ML, Lee DM, Jarrell DK, et al. Tauroursodeoxycholic acid reduces arterial stiffness and improves endothelial dysfunction in type 2 diabetic mice. J Vasc Res. 2017;54:280-7.
142. Kaffe E, Roulis M, Zhao J, et al. Humanized mouse liver reveals endothelial control of essential hepatic metabolic functions. Cell. 2023;186:3793-809.e26.
143. Lichtenstein L, Cheng CW, Bajarwan M, et al. Endothelial force sensing signals to parenchymal cells to regulate bile and plasma lipids. Sci Adv. 2024;10:eadq3075.
144. Zhang P, Li X, Liang J, et al. Chenodeoxycholic acid modulates cholestatic niche through FXR/Myc/P-selectin axis in liver endothelial cells. Nat Commun. 2025;16:2093.
145. Qu Q, Chen Y, Wang Y, et al. Lithocholic acid phenocopies anti-ageing effects of calorie restriction. Nature. 2024;643:192-200.
146. Zhu Y, Dwidar M, Nemet I, et al. Two distinct gut microbial pathways contribute to meta-organismal production of phenylacetylglutamine with links to cardiovascular disease. Cell Host Microbe. 2023;31:18-32.e9.
147. Song Y, Wei H, Zhou Z, et al. Gut microbiota-dependent phenylacetylglutamine in cardiovascular disease: current knowledge and new insights. Front Med. 2024;18:31-45.
148. Poesen R, Claes K, Evenepoel P, et al. Microbiota-derived phenylacetylglutamine associates with overall mortality and cardiovascular disease in patients with CKD. J Am Soc Nephrol. 2016;27:3479-87.
149. Nemet I, Saha PP, Gupta N, et al. A cardiovascular disease-linked gut microbial metabolite acts via adrenergic receptors. Cell. 2020;180:862-77.e22.
150. Li Z, Gu M, Zaparte A, et al. Alcohol-induced gut microbial reorganization and associated overproduction of phenylacetylglutamine promotes cardiovascular disease. Nat Commun. 2024;15:10788.
151. Su I, Wu T, Liu C, Lin Y, Hsu B. Serum phenylacetylglutamine is a potential risk factor for aortic stiffness in patients with chronic hemodialysis. Diagnostics. 2025;15:3123.
152. Yang H, Chen Y, Ho C, Hsu B. Serum phenylacetylglutamine among potential risk factors for arterial stiffness measuring by carotid-femoral pulse wave velocity in patients with kidney transplantation. Toxins. 2024;16:111.
153. Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472:57-63.
154. Xue C, Li G, Zheng Q, et al. Tryptophan metabolism in health and disease. Cell Metab. 2023;35:1304-26.
155. Suzuki K, Susaki EA, Nagaoka I. Lipopolysaccharides and cellular senescence: involvement in atherosclerosis. Int J Mol Sci. 2022;23:11148.
156. Liu W, Wang J, Yang H, et al. The metabolite indole‐3‐acetic acid of Bacteroides Ovatus improves atherosclerosis by restoring the polarisation balance of M1/M2 macrophages and inhibiting inflammation. Adv Sci. 2025;12:2413010.
157. Alsulami M, Alamri H, Barhoumi T, Munawar N, Alghanem B. The effect of TMAO on aging-associated cardiovascular and metabolic pathways and emerging therapies. Mol Cell Biochem. 2025;480:5659-69.
158. Xue H, Chen X, Yu C, et al. Gut microbially produced indole-3-propionic acid inhibits atherosclerosis by promoting reverse cholesterol transport and its deficiency is causally related to atherosclerotic cardiovascular disease. Circ Res. 2022;131:404-20.
159. Zhu W, Gregory JC, Org E, et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell. 2016;165:111-24.
160. Brunt VE, Gioscia-ryan RA, Casso AG, et al. Trimethylamine-N-oxide promotes age-related vascular oxidative stress and endothelial dysfunction in mice and healthy humans. Hypertension. 2020;76:101-12.
161. Lu Y, Yang W, Qi Z, et al. Gut microbe-derived metabolite indole-3-carboxaldehyde alleviates atherosclerosis. Sig Transduct Target Ther. 2023;8:378.
162. Merk D, Cox FF, Jakobs P, Prömel S, Altschmied J, Haendeler J. Dose-dependent effects of lipopolysaccharide on the endothelium—sepsis versus metabolic endotoxemia-induced cellular senescence. Antioxidants. 2024;13:443.
163. Ciesielska A, Matyjek M, Kwiatkowska K. TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling. Cell Mol Life Sci. 2020;78:1233-61.
164. Ecton KE, Graham EL, Risk BD, et al. Toll-like receptor 4 deletion partially protects mice from high fat diet-induced arterial stiffness despite perturbation to the gut microbiota. Front Microbiomes. 2023;2:1095997.
165. Sakura T, Morioka T, Shioi A, et al. Lipopolysaccharide-binding protein is associated with arterial stiffness in patients with type 2 diabetes: a cross-sectional study. Cardiovasc Diabetol. 2017;16:62.
166. Brunt VE, Casso AG, Gioscia-Ryan RA, et al. Gut microbiome-derived metabolite trimethylamine N-oxide induces aortic stiffening and increases systolic blood pressure with aging in mice and humans. Hypertension. 2021;78:499-511.
167. Huang P, Lin Y, Chen Y, et al. The association between serum trimethylamine N-oxide and arterial stiffness in chronic peritoneal dialysis patients: a cross-sectional study. Toxins. 2024;16:523.
168. Huang P, Hsu B, Lai Y, Wang C, Tsai J. Serum trimethylamine N-Oxide level is positively associated with aortic stiffness measured by carotid-femoral pulse wave velocity in patients undergoing maintenance hemodialysis. Toxins. 2023;15:572.
169. Hsu B, Wang C, Lin Y, Lai Y, Tsai J. Serum trimethylamine N-oxide level is associated with peripheral arterial stiffness in advanced non-dialysis chronic kidney disease patients. Toxins. 2022;14:526.
170. Wang Q, Lv H, Ainiwan M, et al. Untargeted metabolomics identifies indole-3-propionic acid to relieve Ang II-induced endothelial dysfunction in aortic dissection. Mol Cell Biochem. 2024;479:1767-86.
171. Shaheen N, Miao J, Li D, et al. Indole-3-acetic acid protects against lipopolysaccharide-induced endothelial cell dysfunction and lung injury through the activation of USP40. Am J Respir Cell Mol Biol. 2024;71:307-17.
172. Jia Y, He M, Wang F, et al. Indole-3-lactic acid protects the gut vascular barrier following intestinal ischemia injury through AhR/Nrf2/STAT3 mediated claudin 2 downregulation. Cell Commun Signal. 2025;23:447.
174. Ungvari Z, Tarantini S, Donato AJ, Galvan V, Csiszar A. Mechanisms of vascular aging. Circ Res. 2018;123:849-67.
175. Jie Z, Xia H, Zhong S, et al. The gut microbiome in atherosclerotic cardiovascular disease. Nat Commun. 2017;8:845.
176. Hua R, Ding N, Hua Y, et al. Ligilactobacillus murinus and lactobacillus johnsonii suppress macrophage pyroptosis in atherosclerosis through butyrate‐GPR109A‐GSDMD axis. Adv Sci. 2025;12:e01707.
177. Qi Z, Zhang W, Zhang P, et al. The gut microbiota-bile acid-TGR5 axis orchestrates platelet activation and atherothrombosis. Nat Cardiovasc Res. 2025;4:584-601.
178. Li B, Fan H, Wu H, et al. Targeting FXR in hepatocytes: a promising approach to enhance fibrinolysis and reduce deep vein thrombosis risk. Blood. 2025;146:2464-78.
179. Hutchison ER, Mallikarjun J, Byun JH, et al. GPR41 deficiency alters the gut microbiota-bile acid axis, reduces ileal expression of Npc1l1, and attenuates hypercholesterolemia in male mice. Gut Microbes. 2025;17:2598957.
180. Mian O, Santi N, Boodhwani M, et al. Arterial age and early vascular aging, but not chronological age, are associated with faster thoracic aortic aneurysm growth. J Am Heart Assoc. 2023;12:e029466.
181. Quintana RA, Taylor WR. Cellular mechanisms of aortic aneurysm formation. Circ Res. 2019;124:607-18.
182. Song T, Zhao S, Luo S, et al. SLC44A2 regulates vascular smooth muscle cell phenotypic switching and aortic aneurysm. J Clin Investig. 2024;134:e173690.
183. Tian Z, Zhang Y, Zheng Z, et al. Gut microbiome dysbiosis contributes to abdominal aortic aneurysm by promoting neutrophil extracellular trap formation. Cell Host Microbe. 2022;30:1450-63.e8.
