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Front. Med.    2024, Vol. 18 Issue (1) : 31-45    https://doi.org/10.1007/s11684-024-1055-9
Gut microbiota-dependent phenylacetylglutamine in cardiovascular disease: current knowledge and new insights
Yaonan Song, Haoran Wei, Zhitong Zhou, Huiqing Wang, Weijian Hang, Junfang Wu(), Dao Wen Wang
Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
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Abstract

Phenylacetylglutamine (PAGln) is an amino acid derivate that comes from the amino acid phenylalanine. There are increasing studies showing that the level of PAGln is associated with the risk of different cardiovascular diseases. In this review, we discussed the metabolic pathway of PAGln production and the quantitative measurement methods of PAGln. We summarized the epidemiological evidence to show the role of PAGln in diagnostic and prognostic value in several cardiovascular diseases, such as heart failure, coronary heart disease/atherosclerosis, and cardiac arrhythmia. The underlying mechanism of PAGln is now considered to be related to the thrombotic potential of platelets via adrenergic receptors. Besides, other possible mechanisms such as inflammatory response and oxidative stress could also be induced by PAGln. Moreover, since PAGln is produced across different organs including the intestine, liver, and kidney, the cross-talk among multiple organs focused on the function of this uremic toxic metabolite. Finally, the prognostic value of PAGln compared to the classical biomarker was discussed and we also highlighted important gaps in knowledge and areas requiring future investigation of PAGln in cardiovascular diseases.
Keywords PAGln      cardiovascular disease      gut microbiota      uremic metabolite      biomarker     
Corresponding Author(s): Junfang Wu   
About author: Li Liu and Yanqing Liu contributed equally to this work.
Just Accepted Date: 23 January 2024   Online First Date: 29 February 2024    Issue Date: 22 April 2024
 Cite this article:   
Yaonan Song,Haoran Wei,Zhitong Zhou, et al. Gut microbiota-dependent phenylacetylglutamine in cardiovascular disease: current knowledge and new insights[J]. Front. Med., 2024, 18(1): 31-45.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-024-1055-9
https://academic.hep.com.cn/fmd/EN/Y2024/V18/I1/31
Fig.1  The metabolic pathway of phenylacetylglutamine. The PAGln comes from the dietary protein, phenylalanine. Under the existence of gut microbiota in large intestine, the dietary phenylalanine converts into phenylpyruvic acid. The conversion of phenylpyruvic acid into phenylacetic acid could be achieved through two microbial pathways that produce two intermediates, phenylacealdehyde and phenylacetyl-CoA, respectively. The phenylacetate is converted to either phenylacetylglutamine (PAGln, dominant pathway in human) or phenyalcetylglycine (PAGly, dominant pathway in rodents) by host liver enzymes. The PAGln/PAGly take effects on cardiac dysfunction by its uremic toxicity and platelet hyperreactivity activation in cardiovascular diseases.
Sample Pathology No. of subjects Reported ConC (μmol/L) Methodology References
Plasma HF Con = 2820
HF = 1265		 2.5 (0.5–14) LC-MS/MS [91]
Plasma HF Con = 1955
HF = 3152		 0.87 (0.47–1.69)
1.56 (0.76–3.11)		 LC-MS/MS [40]
Plasma CAD Con = 35
CAD = 68		 0.20–0.30 ELISA [43]
Plasma AF Con = 42
AF = 92		 0.18–0.30 ELISA [44]
Plasma Healthy rhesus monkey N = 5 2.5–6 GC-MS/MS [42]
Urine NMR database – 34.0 (4.5–70.0) μM/mM creatinine 1H NMR [23]
Urine IC Con = 10
IC = 10		 47.03 (3.84–85.51) μM/mM creatinine 1H NMR [36]
Urine Healthy rhesus monkey N = 5 21.6 μM/mM creatinine GC-MS/MS [42]
Saliva Healthy subjects N = 18 0.04–0.08 LC-MS/MS [46]
Tab.1  Selected metabolomic approaches for PAGln quantification
Subjects No. of patients Study type Sample type; assay method Main results/findings References
Cardiovascular disease
Subjects with cardiac evaluation Discovery cohort (n = 1162); Validated cohort (n = 4000) Prospective study, 3-year follow-up Plasma; untargeted and targeted LC-MSMS The increased PAGln is to be associated with cardiovascular disease (CVD) and incident major adverse cardiovascular events [16]
Subjects with cardiac evaluation US cohort (n = 4000); EU cohort (n = 833) Prospective study, 3-year follow-up Plasma; LCMS/MS Phenylalanine derived PAGln showed association with incident major adverse cardiovascular events and poorer survival risks [49]
Heart failure
HF patients 58 HF patients (control = 22, NYHAIII HF = 29, NYHAIV HF = 29) Retrospective study Plasma; LC-MS/MS The increased PAGln were altered with different grades of chronic heart failure [117]
HF patients Cohort 1: 712 HF patients (control = 2544, HF = 712). Cohort 2: 553 HF patients (control = 276, HF = 553) Retrospective study Plasma; LC-MS/MS PAGln is clinically and mechanistically linked to heart failure presence and severity [91]
HF patients 61 HF patients (HF with events = 31; HF without events = 30) Retrospective study Plasma; UPLC-TOFMS Increased PAGln predicted HF events. The PAGln has better discrimination than B-type natriuretic peptide (BNP) by AUC in HF patients [55]
HF patients 956 subjects (control = 485; HF = 471) Retrospective study Plasma; LCMS/MS Elevated PAGln levels are an independent risk factor for HF and are associated with higher risk of cardiac death [118]
HFrEF and HfpEF patients 3024 HF patients: HFpEF (n = 1724); HFrEF (n = 1300); control (n = 1955) Prospective study, 2-year follow-up Plasma; LCMS/MS Higher plasma PAGln is associated with a higher risk of events in both HF subtype patients. PAGln provides concurrent and complementary prognostic value for NT-proBNP in HF [40]
HFrEF with diabetes and chronic kidney diseases (CKD) 260 subjects (control = 23, HF = 48, prediabetes + HF = 83, diabetes + HF = 56, prediabetes/HF/CKD = 34, diabetes/HF/CKD = 16) Prospective study, 5-year follow-up Plasma; LCMS/MS PAGln is associated with both CHF and CKD but not diabetes [96]
Coronary artery disease
PCI patients n = 72 Retrospective study Plasma; LCMS/MS Plasma Phe and PAGln are valuable indices for predicting coronary in-stent restenosis [65]
Post-PCI patients n = 103 Retrospective study Plasma; ELISA kit Enhanced microbiota-derived PAGln synthesis-related functions and elevated plasma PAGln levels were associated with in-stent stenosis and hyperplasia in CAD [43]
CHD patients n = 686 Retrospective study Plasma;LCMS/MS An independent association between plasma PAG levels and the coronary atherosclerotic burden among patients with suspected CAD [58]
Incident coronary artery disease Total n = 5017: cohort 1 (n = 3361); cohort 2 (n = 880); cohort 3 (n = 776) Prospective study for cohort 1 Plasma; UPLC-TOFMS PAGln is associated with increased risk of incident coronary artery disease independently of other cardiovascular risk factors [59]
Atherosclerosis n = 316 Retrospective study Plasma; UPLC-TOFMS Increased PAGln was found in unexplained extreme atherosclerosis [66]
Ischemia/reperfusion Rodent model; n = 6 – Plasma; ELISA kit PAGly could suppress cardiomyocyte apoptosis caused by myocardial I/R injury and reduce the infarct size [76]
Arterial stiffness n = 617 women Retrospective study Plasma; LCMS/MS The increased PAGln is reported in low arterial stiffness women patients and microbiome factors explained 8.3% of the variance in arterial stiffness [61]
Cardiac arrhythmia
Atrial fibrillation 92 AF patients: contorl = 42; AF = 92 Retrospective study Plasma; ELISA kit PAGln increased apoptosis, reactive oxygen species production, CaMKII and RyR2 activation and decreased cell viability [44]
Ventricular arrhythmias Animal model, n = 6 – Plasma; LCMS/MS PAGln increased the susceptibility of VAs in HF mice by activating the TLR4/AKT/mTOR signaling pathway [69]
Tab.2  Epidemiological or animal evidences of PAGln/PAGly associated cardiovascular diseases
Fig.2  Effects of PAGln on the cardiovascular system and its different mechanisms. The inter-organ crosstalk among the intestine, heart, and kidney is critical for PAGln production in maintaining homeostasis. The increased PAGln could activate the G-protein adrenergic receptors, enhance apoptosis through the TLR4/AKT/mTOR signal pathway, and increase systematic inflammation. NOX, NADPH oxidase; ROS, reactive oxygen species; TLR4, Toll-like receptor 4; AKT, protein kinase; mTOR, mammalian target of rapamycin; IL-1β, interleukin-1β; IL-6, interleukin-6; TNF-α, tumor necrosis factor α; PAGln, phenylacetylglutamine.
1 F Bäckhed, RE Ley, JL Sonnenburg, DA Peterson, JI Gordon. Host-bacterial mutualism in the human intestine. Science 2005; 307(5717): 1915–1920
https://doi.org/10.1126/science.1104816
2 S Fromentin, SK Forslund, K Chechi, J Aron-Wisnewsky, R Chakaroun, T Nielsen, V Tremaroli, B Ji, E Prifti, A Myridakis, J Chilloux, P Andrikopoulos, Y Fan, MT Olanipekun, R Alves, S Adiouch, N Bar, Y Talmor-Barkan, E Belda, R Caesar, LP Coelho, G Falony, S Fellahi, P Galan, N Galleron, G Helft, L Hoyles, R Isnard, Chatelier E Le, H Julienne, L Olsson, HK Pedersen, N Pons, B Quinquis, C Rouault, H Roume, JE Salem, TSB Schmidt, S Vieira-Silva, P Li, M Zimmermann-Kogadeeva, C Lewinter, NB Søndertoft, TH Hansen, D Gauguier, JP Gøtze, L Køber, R Kornowski, H Vestergaard, T Hansen, JD Zucker, S Hercberg, I Letunic, F Bäckhed, JM Oppert, J Nielsen, J Raes, P Bork, M Stumvoll, E Segal, K Clément, ME Dumas, SD Ehrlich, O Pedersen. Microbiome and metabolome features of the cardiometabolic disease spectrum. Nat Med 2022; 28(2): 303–314
https://doi.org/10.1038/s41591-022-01688-4
3 Y Talmor-Barkan, N Bar, AA Shaul, N Shahaf, A Godneva, Y Bussi, M Lotan-Pompan, A Weinberger, A Shechter, C Chezar-Azerrad, Z Arow, Y Hammer, K Chechi, SK Forslund, S Fromentin, ME Dumas, SD Ehrlich, O Pedersen, R Kornowski, E Segal. Metabolomic and microbiome profiling reveals personalized risk factors for coronary artery disease. Nat Med 2022; 28(2): 295–302
https://doi.org/10.1038/s41591-022-01686-6
4 Z Wang, E Klipfell, BJ Bennett, R Koeth, BS Levison, B Dugar, AE Feldstein, EB Britt, X Fu, YM Chung, Y Wu, P Schauer, JD Smith, H Allayee, WH Tang, JA DiDonato, AJ Lusis, SL Hazen. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011; 472(7341): 57–63
https://doi.org/10.1038/nature09922
5 TWH Tang, HC Chen, CY Chen, CYT Yen, CJ Lin, RP Prajnamitra, LL Chen, SC Ruan, JH Lin, PJ Lin, HH Lu, CW Kuo, CM Chang, AD Hall, EI Vivas, JW Shui, P Chen, TA Hacker, FE Rey, TJ Kamp, PCH Hsieh. Loss of gut microbiota alters immune system composition and cripples postinfarction cardiac repair. Circulation 2019; 139(5): 647–659
https://doi.org/10.1161/CIRCULATIONAHA.118.035235
6 G Ettinger, K MacDonald, G Reid, JP Burton. The influence of the human microbiome and probiotics on cardiovascular health. Gut Microbes 2014; 5(6): 719–728
https://doi.org/10.4161/19490976.2014.983775
7 D Shalon, RN Culver, JA Grembi, J Folz, PV Treit, H Shi, FA Rosenberger, L Dethlefsen, X Meng, E Yaffe, A Aranda-Díaz, PE Geyer, JB Mueller-Reif, S Spencer, AD Patterson, G Triadafilopoulos, SP Holmes, M Mann, O Fiehn, DA Relman, KC Huang. Profiling the human intestinal environment under physiological conditions. Nature 2023; 617(7961): 581–591
https://doi.org/10.1038/s41586-023-05989-7
8 WH Tang, Z Wang, BS Levison, RA Koeth, EB Britt, X Fu, Y Wu, SL Hazen. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 2013; 368(17): 1575–1584
https://doi.org/10.1056/NEJMoa1109400
9 W Zhu, JC Gregory, E Org, JA Buffa, N Gupta, Z Wang, L Li, X Fu, Y Wu, M Mehrabian, RB Sartor, TM McIntyre, RL Silverstein, WHW Tang, JA DiDonato, JM Brown, AJ Lusis, SL Hazen. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 2016; 165(1): 111–124
https://doi.org/10.1016/j.cell.2016.02.011
10 G Charach, A Rabinovich, O Argov, M Weintraub, P Rabinovich. The role of bile acid excretion in atherosclerotic coronary artery disease. Int J Vasc Med 2012; 2012: 949672
https://doi.org/10.1155/2012/949672
11 XS Cao, J Chen, JZ Zou, YH Zhong, J Teng, J Ji, ZW Chen, ZH Liu, B Shen, YX Nie, WL Lv, FF Xiang, X Tan, XQ Ding. Association of indoxyl sulfate with heart failure among patients on hemodialysis. Clin J Am Soc Nephrol 2015; 10(1): 111–119
https://doi.org/10.2215/CJN.04730514
12 J Yan, Y Pan, W Shao, C Wang, R Wang, Y He, M Zhang, Y Wang, T Li, Z Wang, W Liu, Z Wang, X Sun, S Dong. Beneficial effect of the short-chain fatty acid propionate on vascular calcification through intestinal microbiota remodelling. Microbiome 2022; 10(1): 195
https://doi.org/10.1186/s40168-022-01390-0
13 Y Lu, W Yang, Z Qi, R Gao, J Tong, T Gao, Y Zhang, A Sun, S Zhang, J Ge. Gut microbe-derived metabolite indole-3-carboxaldehyde alleviates atherosclerosis. Signal Transduct Target Ther 2023; 8(1): 378
https://doi.org/10.1038/s41392-023-01613-2
14 BG Poll, J Xu, S Jun, J Sanchez, NA Zaidman, X He, L Lester, DE Berkowitz, N Paolocci, WD Gao, JL Pluznick. Acetate, a short-chain fatty acid, acutely lowers heart rate and cardiac contractility along with blood pressure. J Pharmacol Exp Ther 2021; 377(1): 39–50
https://doi.org/10.1124/jpet.120.000187
15 BJH Verhaar, D Collard, A Prodan, JHM Levels, AH Zwinderman, F Bäckhed, L Vogt, MJL Peters, M Muller, M Nieuwdorp, den Born BH van. Associations between gut microbiota, faecal short-chain fatty acids, and blood pressure across ethnic groups: the HELIUS study. Eur Heart J 2020; 41(44): 4259–4267
https://doi.org/10.1093/eurheartj/ehaa704
16 I Nemet, PP Saha, N Gupta, W Zhu, KA Romano, SM Skye, T Cajka, ML Mohan, L Li, Y Wu, M Funabashi, AE Ramer-Tait, SV Naga Prasad, O Fiehn, FE Rey, WHW Tang, MA Fischbach, JA DiDonato, SL Hazen. A cardiovascular disease-linked gut microbial metabolite acts via adrenergic receptors. Cell 2020; 180(5): 862–877.e22
https://doi.org/10.1016/j.cell.2020.02.016
17 JW Seakins. The determination of urinary phenylacetylglutamine as phenylacetic acid. Studies on its origin in normal subjects and children with cystic fibrosis. Clin Chim Acta 1971; 35(1): 121–131
https://doi.org/10.1016/0009-8981(71)90302-0
18 J Agergaard, TEH Justesen, SE Jespersen, T Tagmose Thomsen, L Holm, G van Hall. Even or skewed dietary protein distribution is reflected in the whole-body protein net-balance in healthy older adults: a randomized controlled trial. Clin Nutr 2023; 42(6): 899–908
https://doi.org/10.1016/j.clnu.2023.04.004
19 D Murashige, C Jang, M Neinast, JJ Edwards, A Cowan, MC Hyman, JD Rabinowitz, DS Frankel, Z Arany. Comprehensive quantification of fuel use by the failing and nonfailing human heart. Science 2020; 370(6514): 364–368
https://doi.org/10.1126/science.abc8861
20 Y Liu, Y Hou, G Wang, X Zheng, H Hao. Gut microbial metabolites of aromatic amino acids as signals in host-microbe interplay. Trends Endocrinol Metab 2020; 31(11): 818–834
https://doi.org/10.1016/j.tem.2020.02.012
21 C Barrios, M Beaumont, T Pallister, J Villar, JK Goodrich, A Clark, J Pascual, RE Ley, TD Spector, JT Bell, C Menni. Gut-microbiota-metabolite axis in early renal function decline. PLoS One 2015; 10(8): e0134311
https://doi.org/10.1371/journal.pone.0134311
22 Y Zhu, M Dwidar, I Nemet, JA Buffa, N Sangwan, XS Li, JT Anderson, KA Romano, X Fu, M Funabashi, Z Wang, P Keranahalli, S Battle, AN Tittle, AM Hajjar, V Gogonea, MA Fischbach, JA DiDonato, SL Hazen. Two distinct gut microbial pathways contribute to meta-organismal production of phenylacetylglutamine with links to cardiovascular disease. Cell Host Microbe 2023; 31(1): 18–32.e9
https://doi.org/10.1016/j.chom.2022.11.015
23 S Bouatra, F Aziat, R Mandal, AC Guo, MR Wilson, C Knox, TC Bjorndahl, R Krishnamurthy, F Saleem, P Liu, ZT Dame, J Poelzer, J Huynh, FS Yallou, N Psychogios, E Dong, R Bogumil, C Roehring, DS Wishart. The human urine metabolome. PLoS One 2013; 8(9): e73076
https://doi.org/10.1371/journal.pone.0073076
24 RD Mair, S Lee, NS Plummer, TL Sirich, TW Meyer. Impaired tubular secretion of organic solutes in advanced chronic kidney disease. J Am Soc Nephrol 2021; 32(11): 2877–2884
https://doi.org/10.1681/ASN.2021030336
25 R Poesen, K Claes, P Evenepoel, H de Loor, P Augustijns, D Kuypers, B Meijers. Microbiota-derived phenylacetylglutamine associates with overall mortality and cardiovascular disease in patients with CKD. J Am Soc Nephrol 2016; 27(11): 3479–3487
https://doi.org/10.1681/ASN.2015121302
26 RD Mair, TL Sirich, TW Meyer. Uremic toxin clearance and cardiovascular toxicities. Toxins (Basel) 2018; 10(6): 226
https://doi.org/10.3390/toxins10060226
27 SW Brusilow. Phenylacetylglutamine may replace urea as a vehicle for waste nitrogen excretion. Pediatr Res 1991; 29(2): 147–150
https://doi.org/10.1203/00006450-199102000-00009
28 TL Sirich, BA Funk, NS Plummer, TH Hostetter, TW Meyer. Prominent accumulation in hemodialysis patients of solutes normally cleared by tubular secretion. J Am Soc Nephrol 2014; 25(3): 615–622
https://doi.org/10.1681/ASN.2013060597
29 M Posada-Ayala, I Zubiri, M Martin-Lorenzo, A Sanz-Maroto, D Molero, L Gonzalez-Calero, B Fernandez-Fernandez, F de la Cuesta, CM Laborde, MG Barderas, A Ortiz, F Vivanco, G Alvarez-Llamas. Identification of a urine metabolomic signature in patients with advanced-stage chronic kidney disease. Kidney Int 2014; 85(1): 103–111
https://doi.org/10.1038/ki.2013.328
30 R Safadi, RS Rahimi, D Thabut, JS Bajaj, K Ram Bhamidimarri, N Pyrsopoulos, A Potthoff, S Bukofzer, L Wang, K Jamil, KR Devarakonda. Pharmacokinetics/pharmacodynamics of L-ornithine phenylacetate in overt hepatic encephalopathy and the effect of plasma ammonia concentration reduction on clinical outcomes. Clin Transl Sci 2022; 15(6): 1449–1459
https://doi.org/10.1111/cts.13257
31 X Wang, J Tseng, C Mak, N Poola, RA Vilchez. Exposures of phenylacetic acid and phenylacetylglutamine across different subpopulations and correlation with adverse events. Clin Pharmacokinet 2021; 60(12): 1557–1567
https://doi.org/10.1007/s40262-021-01047-5
32 F Andrade, A Cano, Suarez M Unceta, A Arza, A Vinuesa, L Ceberio, N López-Oslé, Frutos G de, R López-Oceja, E Aznal, D González-Lamuño, Las Heras J de. Urine phenylacetylglutamine determination in patients with hyperphenylalaninemia. J Clin Med 2021; 10(16): 3674
https://doi.org/10.3390/jcm10163674
33 I Magnusson, WC Schumann, GE Bartsch, V Chandramouli, K Kumaran, J Wahren, BR Landau. Noninvasive tracing of Krebs cycle metabolism in liver. J Biol Chem 1991; 266(11): 6975–6984
https://doi.org/10.1016/S0021-9258(20)89598-2
34 E Esenmo, V Chandramouli, WC Schumann, K Kumaran, J Wahren, BR Landau. Use of 14CO2 in estimating rates of hepatic gluconeogenesis. Am J Physiol 1992; 263(1): E36–E41
35 JP Shockcor, SE Unger, ID Wilson, PJ Foxall, JK Nicholson, JC Lindon. Combined HPLC, NMR spectroscopy, and ion-trap mass spectrometry with application to the detection and characterization of xenobiotic and endogenous metabolites in human urine. Anal Chem 1996; 68(24): 4431–4435
https://doi.org/10.1021/ac9606463
36 Y Fukui, M Kato, Y Inoue, A Matsubara, K Itoh. A metabonomic approach identifies human urinary phenylacetylglutamine as a novel marker of interstitial cystitis. J Chromatogr B Analyt Technol Biomed Life Sci 2009; 877(30): 3806–3812
https://doi.org/10.1016/j.jchromb.2009.09.025
37 BJ Blaise, GDS Correia, GA Haggart, I Surowiec, C Sands, MR Lewis, JTM Pearce, J Trygg, JK Nicholson, E Holmes, TMD Ebbels. Statistical analysis in metabolic phenotyping. Nat Protoc 2021; 16(9): 4299–4326
https://doi.org/10.1038/s41596-021-00579-1
38 AS Marchev, LV Vasileva, KM Amirova, MS Savova, ZP Balcheva-Sivenova, MI Georgiev. Metabolomics and health: from nutritional crops and plant-based pharmaceuticals to profiling of human biofluids. Cell Mol Life Sci 2021; 78(19–20): 6487–6503
https://doi.org/10.1007/s00018-021-03918-3
39 J Piszcz, D Lemancewicz, D Dudzik, M Ciborowski. Differences and similarities between LC-MS derived serum fingerprints of patients with B-cell malignancies. Electrophoresis 2013; 34(19): 2857–2864
https://doi.org/10.1002/elps.201200606
40 H Wei, J Wu, H Wang, J Huang, C Li, Y Zhang, Y Song, Z Zhou, Y Sun, L Xiao, L Peng, C Chen, C Zhao, DW Wang. Increased circulating phenylacetylglutamine concentration elevates the predictive value of cardiovascular event risk in heart failure patients. J Intern Med 2023; 294(4): 515–530
https://doi.org/10.1111/joim.13653
41 Y Tang, Y Zou, J Cui, X Ma, L Zhang, S Yu, L Qiu. Analysis of two intestinal bacterial metabolites (trimethylamine N-oxide and phenylacetylglutamine) in human serum samples of patients with T2DM and AMI using a liquid chromatography tandem mass spectrometry method. Clin Chim Acta 2022; 536: 162–168
https://doi.org/10.1016/j.cca.2022.09.018
42 D Yang, M Beylot, KC Agarwal, MV Soloviev, H Brunengraber. Assay of the human liver citric acid cycle probe phenylacetylglutamine and of phenylacetate in plasma by gas chromatography-mass spectrometry. Anal Biochem 1993; 212(1): 277–282
https://doi.org/10.1006/abio.1993.1323
43 C Fang, K Zuo, Y Fu, J Li, H Wang, L Xu, X Yang. Dysbiosis of gut microbiota and metabolite phenylacetylglutamine in coronary artery disease patients with stent stenosis. Front Cardiovasc Med 2022; 9: 832092
https://doi.org/10.3389/fcvm.2022.832092
44 C Fang, K Zuo, K Jiao, X Zhu, Y Fu, J Zhong, L Xu, X Yang. PAGln, an atrial fibrillation-linked gut microbial metabolite, acts as a promoter of atrial myocyte injury. Biomolecules 2022; 12(8): 1120
https://doi.org/10.3390/biom12081120
45 KW Kahl, JZ Seither, LJ Reidy. LC-MS-MS vs ELISA: validation of a comprehensive urine toxicology screen by LC-MS-MS and a comparison of 100 forensic specimens. J Anal Toxicol 2019; 43(9): 734–745
https://doi.org/10.1093/jat/bkz066
46 N Fabresse, IA Larabi, E Abe, E Lamy, C Rigothier, ZA Massy, JC Alvarez. Correlation between saliva levels and serum levels of free uremic toxins in healthy volunteers. Toxins (Basel) 2023; 15(2): 150
https://doi.org/10.3390/toxins15020150
47 Kuc D, Rahnama M, Tomaszewski T, Rzeski W, Wejksza K, Urbanik-Sypniewska T, Parada-Turska J, Wielosz M, Turski WA. Kynurenic acid in human saliva—does it influence oral microflora? Pharmacol Rep 2006; 58(3): 393–398
pmid: 16845213
48 W Wu, KT Bush, SK Nigam. Key role for the organic anion transporters, OAT1 and OAT3, in the in vivo handling of uremic toxins and solutes. Sci Rep 2017; 7(1): 4939
https://doi.org/10.1038/s41598-017-04949-2
49 I Nemet, XS Li, A Haghikia, L Li, J Wilcox, KA Romano, JA Buffa, M Witkowski, I Demuth, M König, E Steinhagen-Thiessen, F Bäckhed, MA Fischbach, WHW Tang, U Landmesser, SL Hazen. Atlas of gut microbe-derived products from aromatic amino acids and risk of cardiovascular morbidity and mortality. Eur Heart J 2023; 44(32): 3085–3096
https://doi.org/10.1093/eurheartj/ehad333
50 A Damasceno, N Lunet. Comorbidities and heart failure: heterogeneity and challenges to fill in the gaps. Lancet Glob Health 2023; 11(12): e1830–e1831
https://doi.org/10.1016/S2214-109X(23)00449-7
51 J Niebauer, HD Volk, M Kemp, M Dominguez, RR Schumann, M Rauchhaus, PA Poole-Wilson, AJ Coats, SD Anker. Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet 1999; 353(9167): 1838–1842
https://doi.org/10.1016/S0140-6736(98)09286-1
52 WH Tang, Z Wang, Y Fan, B Levison, JE Hazen, LM Donahue, Y Wu, SL Hazen. Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: refining the gut hypothesis. J Am Coll Cardiol 2014; 64(18): 1908–1914
https://doi.org/10.1016/j.jacc.2014.02.617
53 E Braunwald. Heart failure: a 70 year Odyssey. Eur Heart J 2022; 43(18): 1697–1699
https://doi.org/10.1093/eurheartj/ehac058
54 Y Zheng, B Yu, D Alexander, TA Manolio, D Aguilar, J Coresh, G Heiss, E Boerwinkle, JA Nettleton. Associations between metabolomic compounds and incident heart failure among African Americans: the ARIC Study. Am J Epidemiol 2013; 178(4): 534–542
https://doi.org/10.1093/aje/kwt004
55 HY Tang, CH Wang, HY Ho, JF Lin, CJ Lo, CY Huang, ML Cheng. Characteristic of metabolic status in heart failure and its impact in outcome perspective. Metabolites 2020; 10(11): 437
https://doi.org/10.3390/metabo10110437
56 X Zong, Q Fan, Q Yang, R Pan, L Zhuang, R Tao. Phenylacetylglutamine as a risk factor and prognostic indicator of heart failure. ESC Heart Fail 2022; 9(4): 2645–2653
https://doi.org/10.1002/ehf2.13989
57 WHW TangI NemetXS LiY WuA Haghikia M WitkowskiRA KoethI DemuthM KönigE Steinhagen-ThiessenF BäckhedMA FischbachA Deb U LandmesserSL Hazen. Prognostic value of gut microbe-generated metabolite phenylacetylglutamine in patients with heart failure. Eur J Heart Fail 2023; [Epub ahead of print] doi: 10.1002/ejhf.3111
58 Y Liu, S Liu, Z Zhao, X Song, H Qu, H Liu. Phenylacetylglutamine is associated with the degree of coronary atherosclerotic severity assessed by coronary computed tomographic angiography in patients with suspected coronary artery disease. Atherosclerosis 2021; 333: 75–82
https://doi.org/10.1016/j.atherosclerosis.2021.08.029
59 IK Yap, IJ Brown, Q Chan, A Wijeyesekera, I Garcia-Perez, M Bictash, RL Loo, M Chadeau-Hyam, T Ebbels, M De Iorio, E Maibaum, L Zhao, H Kesteloot, ML Daviglus, J Stamler, JK Nicholson, P Elliott, E Holmes. Metabolome-wide association study identifies multiple biomarkers that discriminate north and south Chinese populations at differing risks of cardiovascular disease: INTERMAP study. J Proteome Res 2010; 9(12): 6647–6654
https://doi.org/10.1021/pr100798r
60 F Ottosson, L Brunkwall, E Smith, M Orho-Melander, PM Nilsson, C Fernandez, O Melander. The gut microbiota-related metabolite phenylacetylglutamine associates with increased risk of incident coronary artery disease. J Hypertens 2020; 38(12): 2427–2434
https://doi.org/10.1097/HJH.0000000000002569
61 C Menni, C Lin, M Cecelja, M Mangino, ML Matey-Hernandez, L Keehn, RP Mohney, CJ Steves, TD Spector, CF Kuo, P Chowienczyk, AM Valdes. Gut microbial diversity is associated with lower arterial stiffness in women. Eur Heart J 2018; 39(25): 2390–2397
https://doi.org/10.1093/eurheartj/ehy226
62 F Yu, X Li, X Feng, M Wei, Y Luo, T Zhao, B Xiao, J Xia. Phenylacetylglutamine, a novel biomarker in acute ischemic stroke. Front Cardiovasc Med 2021; 8: 798765
https://doi.org/10.3389/fcvm.2021.798765
63 F Yu, X Feng, X Li, Y Luo, M Wei, T Zhao, J Xia. Gut-derived metabolite phenylacetylglutamine and white matter hyperintensities in patients with acute ischemic stroke. Front Aging Neurosci 2021; 13: 675158
https://doi.org/10.3389/fnagi.2021.675158
64 SM Azab, A Zamzam, MH Syed, R Abdin, M Qadura, P Britz-McKibbin. Serum metabolic signatures of chronic limb-threatening ischemia in patients with peripheral artery disease. J Clin Med 2020; 9(6): 1877
https://doi.org/10.3390/jcm9061877
65 Y Fu, Y Yang, C Fang, X Liu, Y Dong, L Xu, M Chen, K Zuo, L Wang. Prognostic value of plasma phenylalanine and gut microbiota-derived metabolite phenylacetylglutamine in coronary in-stent restenosis. Front Cardiovasc Med 2022; 9: 944155
https://doi.org/10.3389/fcvm.2022.944155
66 C Bogiatzi, G Gloor, E Allen-Vercoe, G Reid, RG Wong, BL Urquhart, V Dinculescu, KN Ruetz, TJ Velenosi, M Pignanelli, JD Spence. Metabolic products of the intestinal microbiome and extremes of atherosclerosis. Atherosclerosis 2018; 273: 91–97
https://doi.org/10.1016/j.atherosclerosis.2018.04.015
67 K Zuo, J Li, K Li, C Hu, Y Gao, M Chen, R Hu, Y Liu, H Chi, H Wang, Y Qin, X Liu, S Li, J Cai, J Zhong, X Yang. Disordered gut microbiota and alterations in metabolic patterns are associated with atrial fibrillation. Gigascience 2019; 8(6): giz058
https://doi.org/10.1093/gigascience/giz058
68 M Gawałko, TA Agbaedeng, A Saljic, DN Müller, N Wilck, R Schnabel, J Penders, M Rienstra, Gelder I van, T Jespersen, U Schotten, HJGM Crijns, JM Kalman, P Sanders, S Nattel, D Dobrev, D Linz. Gut microbiota, dysbiosis and atrial fibrillation. Arrhythmogenic mechanisms and potential clinical implications. Cardiovasc Res 2022; 118(11): 2415–2427
https://doi.org/10.1093/cvr/cvab292
69 H Fu, B Kong, J Zhu, H Huang, W Shuai. Phenylacetylglutamine increases the susceptibility of ventricular arrhythmias in heart failure mice by exacerbated activation of the TLR4/AKT/mTOR signaling pathway. Int Immunopharmacol 2023; 116: 109795
https://doi.org/10.1016/j.intimp.2023.109795
70 M Witkowski, TL Weeks, SL Hazen. Gut microbiota and cardiovascular disease. Circ Res 2020; 127(4): 553–570
https://doi.org/10.1161/CIRCRESAHA.120.316242
71 X Zhang, Y Li, P Yang, X Liu, L Lu, Y Chen, X Zhong, Z Li, H Liu, C Ou, J Yan, M Chen. Trimethylamine-N-oxide promotes vascular calcification through activation of NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome and NF-κB (nuclear factor κB) signals. Arterioscler Thromb Vasc Biol 2020; 40(3): 751–765
https://doi.org/10.1161/ATVBAHA.119.313414
72 J Zhao, Q Zhang, W Cheng, Q Dai, Z Wei, M Guo, F Chen, S Qiao, J Hu, J Wang, H Chen, X Bao, D Mu, X Sun, B Xu, J Xie. Heart-gut microbiota communication determines the severity of cardiac injury after myocardial ischaemia/reperfusion. Cardiovasc Res 2023; 119(6): 1390–1402
https://doi.org/10.1093/cvr/cvad023
73 X Li, J Geng, J Zhao, Q Ni, C Zhao, Y Zheng, X Chen, L Wang. Trimethylamine N-oxide exacerbates cardiac fibrosis via activating the NLRP3 inflammasome. Front Physiol 2019; 10: 866
https://doi.org/10.3389/fphys.2019.00866
74 K Aoki, Y Teshima, H Kondo, S Saito, A Fukui, N Fukunaga, T Nawata, T Shimada, N Takahashi, H Shibata. Role of indoxyl sulfate as a predisposing factor for atrial fibrillation in renal dysfunction. J Am Heart Assoc 2015; 4(10): e002023
https://doi.org/10.1161/JAHA.115.002023
75 L Adamo, C Rocha-Resende, SD Prabhu, DL Mann. Reappraising the role of inflammation in heart failure. Nat Rev Cardiol 2020; 17(5): 269–285
https://doi.org/10.1038/s41569-019-0315-x
76 X Xu, WJ Lu, JY Shi, YL Su, YC Liu, L Wang, CX Xiao, C Chen, Q Lu. The gut microbial metabolite phenylacetylglycine protects against cardiac injury caused by ischemia/reperfusion through activating β2AR. Arch Biochem Biophys 2021; 697: 108720
https://doi.org/10.1016/j.abb.2020.108720
77 M Hazekawa, K Ono, T Nishinakagawa, T Kawakubo-Yasukochi, M Nakashima. In vitro anti-inflammatory effects of the phenylbutyric acid metabolite phenylacetyl glutamine. Biol Pharm Bull 2018; 41(6): 961–966
https://doi.org/10.1248/bpb.b17-00799
78 C Fang, K Zuo, K Jiao, X Zhu, Y Fu, J Zhong, L Xu, X Yang. PAGln, an atrial fibrillation-linked gut microbial metabolite, acts as a promoter of atrial myocyte injury. Biomolecules 2022; 12(8): 1120
https://doi.org/10.3390/biom12081120
79 Glassock RJ, Massry SG. Chapter 6 — Uremic toxins: an integrated overview of classification and pathobiology. In: Kopple JD, Massry SG, Kalantar-Zadeh K, Fouque D. Nutritional Management of Renal Disease (Fourth Edition). Academic Press, 2022: 77–89
80 J Zhong, A Kirabo, HC Yang, AB Fogo, EL Shelton, V Kon. Intestinal lymphatic dysfunction in kidney disease. Circ Res 2023; 132(9): 1226–1245
https://doi.org/10.1161/CIRCRESAHA.122.321671
81 G Glorieux, SK Nigam, R Vanholder, F Verbeke. Role of the microbiome in gut-heart-kidney cross talk. Circ Res 2023; 132(8): 1064–1083
https://doi.org/10.1161/CIRCRESAHA.123.321763
82 SY Ahn, SK Nigam. Toward a systems level understanding of organic anion and other multispecific drug transporters: a remote sensing and signaling hypothesis. Mol Pharmacol 2009; 76(3): 481–490
https://doi.org/10.1124/mol.109.056564
83 SB Rosenthal, KT Bush, SK Nigam. A network of SLC and ABC transporter and DME genes involved in remote sensing and signaling in the gut-liver-kidney axis. Sci Rep 2019; 9(1): 11879
https://doi.org/10.1038/s41598-019-47798-x
84 S Lekawanvijit, AR Kompa, BH Wang, DJ Kelly, H Krum. Cardiorenal syndrome: the emerging role of protein-bound uremic toxins. Circ Res 2012; 111(11): 1470–1483
https://doi.org/10.1161/CIRCRESAHA.112.278457
85 V Sundaram, JC Fang. Gastrointestinal and liver issues in heart failure. Circulation 2016; 133(17): 1696–1703
https://doi.org/10.1161/CIRCULATIONAHA.115.020894
86 JD Spence, BL Urquhart. Cerebrovascular disease, cardiovascular disease, and chronic kidney disease: interplays and influences. Curr Neurol Neurosci Rep 2022; 22(11): 757–766
https://doi.org/10.1007/s11910-022-01230-6
87 T Tsutamoto, C Kawahara, K Nishiyama, M Yamaji, M Fujii, T Yamamoto, M Horie. Prognostic role of highly sensitive cardiac troponin I in patients with systolic heart failure. Am Heart J 2010; 159(1): 63–67
https://doi.org/10.1016/j.ahj.2009.10.022
88 Sandoval Y, Apple FS, Mahler SA, Body R, Collinson PO, Jaffe AS; International Federation of Clinical Chemistry and Laboratory Medicine Committee on the Clinical Application of Cardiac Biomarkers. High-sensitivity cardiac troponin and the 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guidelines for the evaluation and diagnosis of acute chest pain. Circulation 2022; 146(7): 569–581 doi:10.1161/CIRCULATIONAHA.122.059678
pmid: 35775423
89 TA McDonagh, M Metra, M Adamo, RS Gardner, A Baumbach, M Böhm, H Burri, J Butler, J Čelutkienė, O Chioncel, JGF Cleland, AJS Coats, MG Crespo-Leiro, D Farmakis, M Gilard, S Heymans, AW Hoes, T Jaarsma, EA Jankowska, M Lainscak, CSP Lam, AR Lyon, JJV McMurray, A Mebazaa, R Mindham, C Muneretto, Piepoli M Francesco, S Price, GMC Rosano, F Ruschitzka, Skibelund A; ESC Scientific Document Group Kathrine. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021; 42(36): 3599–3726
https://doi.org/10.1093/eurheartj/ehab368
90 PG Shiels. ‘Debugging’ heart failure. J Intern Med 2023; 294(4): 374–376
https://doi.org/10.1111/joim.13691
91 KA Romano, I Nemet, Saha P Prasad, A Haghikia, XS Li, ML Mohan, B Lovano, L Castel, M Witkowski, JA Buffa, Y Sun, L Li, CM Menge, I Demuth, M König, E Steinhagen-Thiessen, JA DiDonato, A Deb, F Bäckhed, WHW Tang, Prasad SV Naga, U Landmesser, Wagoner DR Van, SL Hazen. Gut microbiota-generated phenylacetylglutamine and heart failure. Circ Heart Fail 2023; 16(1): e009972
https://doi.org/10.1161/CIRCHEARTFAILURE.122.009972
92 P Elliott, JM Posma, Q Chan, I Garcia-Perez, A Wijeyesekera, M Bictash, TM Ebbels, H Ueshima, L Zhao, L van Horn, M Daviglus, J Stamler, E Holmes, JK Nicholson. Urinary metabolic signatures of human adiposity. Sci Transl Med 2015; 7(285): 285ra62
https://doi.org/10.1126/scitranslmed.aaa5680
93 AY Chang, SM Abdullah, T Jain, HG Stanek, SR Das, DK McGuire, RJ Auchus, JA de Lemos. Associations among androgens, estrogens, and natriuretic peptides in young women: observations from the Dallas Heart Study. J Am Coll Cardiol 2007; 49(1): 109–116
https://doi.org/10.1016/j.jacc.2006.10.040
94 C Mueller, K McDonald, Boer RA de, A Maisel, JGF Cleland, N Kozhuharov, AJS Coats, M Metra, A Mebazaa, F Ruschitzka, M Lainscak, G Filippatos, PM Seferovic, WC Meijers, A Bayes-Genis, T Mueller, M Richards, JL Jr; Heart Failure Association of the European Society of Cardiology Januzzi. Heart Failure Association of the European Society of Cardiology practical guidance on the use of natriuretic peptide concentrations. Eur J Heart Fail 2019; 21(6): 715–731
https://doi.org/10.1002/ejhf.1494
95 BR Landau, V Chandramouli, WC Schumann, K Ekberg, K Kumaran, SC Kalhan, J Wahren. Estimates of Krebs cycle activity and contributions of gluconeogenesis to hepatic glucose production in fasting healthy subjects and IDDM patients. Diabetologia 1995; 38(7): 831–838
https://doi.org/10.1007/s001250050360
96 S Hua, B Lv, Z Qiu, Z Li, Z Wang, Y Chen, Y Han, KL Tucker, H Wu, W Jin. Microbial metabolites in chronic heart failure and its common comorbidities. EMBO Mol Med 2023; 15(6): e16928
https://doi.org/10.15252/emmm.202216928
97 J Xu, M Cai, Z Wang, Q Chen, X Han, J Tian, S Jin, Z Yan, Y Li, B Lu, H Lu. Phenylacetylglutamine as a novel biomarker of type 2 diabetes with distal symmetric polyneuropathy by metabolomics. J Endocrinol Invest 2023; 46(5): 869–882
https://doi.org/10.1007/s40618-022-01929-w
98 J Zuo, Y Lan, H Hu, X Hou, J Li, T Wang, H Zhang, N Zhang, C Guo, F Peng, S Zhao, Y Wei, C Jia, C Zheng, G Mao. Metabolomics-based multidimensional network biomarkers for diabetic retinopathy identification in patients with type 2 diabetes mellitus. BMJ Open Diabetes Res Care 2021; 9(1): e001443
https://doi.org/10.1136/bmjdrc-2020-001443
99 YM Tan, Y Gao, G Teo, HWL Koh, ES Tai, CM Khoo, KP Choi, L Zhou, H Choi. Plasma metabolome and lipidome associations with type 2 diabetes and diabetic nephropathy. Metabolites 2021; 11(4): 228
https://doi.org/10.3390/metabo11040228
100 A Pan, Q Sun, AM Bernstein, MB Schulze, JE Manson, MJ Stampfer, WC Willett, FB Hu. Red meat consumption and mortality: results from 2 prospective cohort studies. Arch Intern Med 2012; 172(7): 555–563
https://doi.org/10.1001/archinternmed.2011.2287
101 D Mohan, A Mente, M Dehghan, S Rangarajan, M O’Donnell, W Hu, G Dagenais, A Wielgosz, S Lear, L Wei, R Diaz, A Avezum, P Lopez-Jaramillo, F Lanas, S Swaminathan, M Kaur, K Vijayakumar, V Mohan, R Gupta, A Szuba, R Iqbal, R Yusuf, N Mohammadifard, R Khatib, K Yusoff, S Gulec, A Rosengren, A Yusufali, E Wentzel-Viljoen, J Chifamba, A Dans, KF Alhabib, K Yeates, K Teo, HC Gerstein, S; PURE Yusuf, investigators ONTARGET. Associations of fish consumption with risk of cardiovascular disease and mortality among individuals with or without vascular disease from 58 countries. JAMA Intern Med 2021; 181(5): 631–649
https://doi.org/10.1001/jamainternmed.2021.0036
102 TCA Hitch, LJ Hall, SK Walsh, GE Leventhal, E Slack, T de Wouters, J Walter, T Clavel. Microbiome-based interventions to modulate gut ecology and the immune system. Mucosal Immunol 2022; 15(6): 1095–1113
https://doi.org/10.1038/s41385-022-00564-1
103 M Witkowski, M Witkowski, J Friebel, JA Buffa, XS Li, Z Wang, N Sangwan, L Li, JA DiDonato, C Tizian, A Haghikia, D Kirchhofer, F Mach, L Räber, CM Matter, WHW Tang, U Landmesser, TF Lüscher, U Rauch, SL Hazen. Vascular endothelial tissue factor contributes to trimethylamine N-oxide-enhanced arterial thrombosis. Cardiovasc Res 2022; 118(10): 2367–2384
https://doi.org/10.1093/cvr/cvab263
104 WJ Dahl, WL Hung, AL Ford, JH Suh, J Auger, V Nagulesapillai, Y Wang. In older women, a high-protein diet including animal-sourced foods did not impact serum levels and urinary excretion of trimethylamine-N-oxide. Nutr Res 2020; 78: 72–81
https://doi.org/10.1016/j.nutres.2020.05.004
105 Q Chan, GM Wren, CE Lau, TMD Ebbels, R Gibson, RL Loo, GS Aljuraiban, JM Posma, AR Dyer, LM Steffen, BL Rodriguez, LJ Appel, ML Daviglus, P Elliott, J Stamler, E Holmes, L Van Horn. Blood pressure interactions with the DASH dietary pattern, sodium, and potassium: the International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP). Am J Clin Nutr 2022; 116(1): 216–229
https://doi.org/10.1093/ajcn/nqac067
106 DM Kaye, WA Shihata, HA Jama, K Tsyganov, M Ziemann, H Kiriazis, D Horlock, A Vijay, B Giam, A Vinh, C Johnson, A Fiedler, D Donner, M Snelson, MT Coughlan, S Phillips, XJ Du, A El-Osta, G Drummond, GW Lambert, TD Spector, AM Valdes, CR Mackay, FZ Marques. Deficiency of prebiotic fiber and insufficient signaling through gut metabolite-sensing receptors leads to cardiovascular disease. Circulation 2020; 141(17): 1393–1403
https://doi.org/10.1161/CIRCULATIONAHA.119.043081
107 FZ Marques, E Nelson, PY Chu, D Horlock, A Fiedler, M Ziemann, JK Tan, S Kuruppu, NW Rajapakse, A El-Osta, CR Mackay, DM Kaye. High-fiber diet and acetate supplementation change the gut microbiota and prevent the development of hypertension and heart failure in hypertensive mice. Circulation 2017; 135(10): 964–977
https://doi.org/10.1161/CIRCULATIONAHA.116.024545
108 Y Zhou, N Zhang, AY Arikawa, C Chen. Inhibitory effects of green tea polyphenols on microbial metabolism of aromatic amino acids in humans revealed by metabolomic analysis. Metabolites 2019; 9(5): 96
https://doi.org/10.1016/j.metabol.2019.01.017
109 V Lam, J Su, A Hsu, GJ Gross, NH Salzman, JE Baker. Intestinal microbial metabolites are linked to severity of myocardial infarction in rats. PLoS One 2016; 11(8): e0160840
https://doi.org/10.1371/journal.pone.0160840
110 Z Li, Z Wu, J Yan, H Liu, Q Liu, Y Deng, C Ou, M Chen. Gut microbe-derived metabolite trimethylamine N-oxide induces cardiac hypertrophy and fibrosis. Lab Invest 2019; 99(3): 346–357
https://doi.org/10.1038/s41374-018-0091-y
111 A Riba, L Deres, K Eros, A Szabo, K Magyar, B Sumegi, K Toth, R Halmosi, E Szabados. Doxycycline protects against ROS-induced mitochondrial fragmentation and ISO-induced heart failure. PLoS One 2017; 12(4): e0175195
https://doi.org/10.1371/journal.pone.0175195
112 A Palleja, KH Mikkelsen, SK Forslund, A Kashani, KH Allin, T Nielsen, TH Hansen, S Liang, Q Feng, C Zhang, PT Pyl, LP Coelho, H Yang, J Wang, A Typas, MF Nielsen, HB Nielsen, P Bork, J Wang, T Vilsbøll, T Hansen, FK Knop, M Arumugam, O Pedersen. Recovery of gut microbiota of healthy adults following antibiotic exposure. Nat Microbiol 2018; 3(11): 1255–1265
https://doi.org/10.1038/s41564-018-0257-9
113 P Winkel, J Hilden, JF Hansen, J Kastrup, HJ Kolmos, E Kjøller, GB Jensen, M Skoog, J Lindschou, C; CLARICOR trial group Gluud. Clarithromycin for stable coronary heart disease increases all-cause and cardiovascular mortality and cerebrovascular morbidity over 10years in the CLARICOR randomised, blinded clinical trial. Int J Cardiol 2015; 182: 459–465
https://doi.org/10.1016/j.ijcard.2015.01.020
114 G Wang, B Kong, W Shuai, H Fu, X Jiang, H Huang. 3,3-Dimethyl-1-butanol attenuates cardiac remodeling in pressure-overload-induced heart failure mice. J Nutr Biochem 2020; 78: 108341
https://doi.org/10.1016/j.jnutbio.2020.108341
115 AMN Fatani, JH Suh, J Auger, KM Alabasi, Y Wang, MS Segal, WJ Dahl. Pea hull fiber supplementation does not modulate uremic metabolites in adults receiving hemodialysis: a randomized, double-blind, controlled trial. Front Nutr 2023; 10: 1179295
https://doi.org/10.3389/fnut.2023.1179295
116 WW Tang, SL Hazen. Dietary metabolism, gut microbiota and acute heart failure. Heart 2016; 102(11): 813–814
https://doi.org/10.1136/heartjnl-2016-309268
117 Z Zhang, B Cai, Y Sun, H Deng, H Wang, Z Qiao. Alteration of the gut microbiota and metabolite phenylacetylglutamine in patients with severe chronic heart failure. Front Cardiovasc Med 2023; 9: 1076806
https://doi.org/10.3389/fcvm.2022.1076806
118 X Zong, Q Fan, Q Yang, R Pan, L Zhuang, R Tao. Phenylacetylglutamine as a risk factor and prognostic indicator of heart failure. ESC Heart Fail 2022; 9(4): 2645–2653
https://doi.org/10.1002/ehf2.13989
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