KALP BAĞIRSAK EKSENİ

Yıl 2023, Cilt: 14 Sayı: 1, 49 - 58, 06.05.2023

Cansu Balıkçı , Gamze Gökçay , Songül Erdoğan , Hasan Erdoğan , Kerem Ural

https://doi.org/10.38137/vftd.1276374

Öz

Barsak-kalp ekseninde, intestinal epitelyal disfonksiyon, disbiyoz, butirat üreten bakteriler, safra asitleri ve bağırsak mikrobiyotundan türetilen metabolitler gibi çeşitli etkileşimler yer almaktadır. Kalp yetmezliği (KY) bulunan hastalarda, bağırsakta mikrosirkülasyon bozuklukları nedeniyle mukozal malabsorpsiyon, intestinal duvar ödemi ve bariyer disfonksiyonu meydana gelmektedir. Bu durum, perfüzyonun azalması, konjesyonun artması ve sempatik vazokonstriksiyon nedeniyle ortaya çıkmaktadır. İntestinal hasarlı sıkı bağlantı noktaları, intestinal geçirgenliğin artmasına neden olarak toksik, patojenik, immünogenik ve yangısal faktörlerin mukozadan geçerek lokal-sistemik inflamasyona neden olmasına yol açmaktadır. KY ile ilişkili disbiyoz, aşırı bakteriyel üreme, bakteriyel translokasyon ve lipopolisakkarit (LPS), trimetilamin N-oksid (TMAO), p-krezilsülfat (PCS) ve indoksil sülfat (IS) gibi birçok toksik madde oluşumuna neden olmaktadır. Artan intestinal geçirgenlik nedeniyle bu toksik maddeler sistemik dolaşıma ulaşarak, tromboz, trombosit invazyonu, köpük hücre formasyonu ve inflamasyon süreçlerinde rol oynayarak ateroskleroz riskini arttırmaktadır. Bağırsak bariyer bütünlüğünü korumak gibi birçok gastrointestinal etkiye sahip olan kısa zincirli yağ asitlerinden biri olan butirat seviyelerindeki azalma, disbiyozu kötüleştirir ve endotoksinlerin genel dolaşıma ulaşmasına neden olarak köpük hücre formasyonunu teşvik eder ve intestinal bariyer fonksiyonunu bozmaktadır. Bu derleme, mevcut literatür ışığında barsak-kalp eksenindeki fizyo-patolojik süreçler hakkında bilgi sağlamayı amaçlamaktadır.

Anahtar Kelimeler

Bağırsak geçirgenliği, Disbiyoz, IS, SCFA, TMAO

GUT-HEART AXIS

Öz

Many interactions play a role in the gut-heart axis. These include intestinal epithelial dysfunction, dysbiosis, butyrate-producing bacteria, bile acids, and intestinal microbe-derived metabolites. In patients with heart failure (HF), mucosal malabsorption, intestinal wall edema and barrier dysfunction develop as a result of microcirculation disorders in the gut due to decreased perfusion, increased congestion and sympathetically mediated vasoconstriction. Toxic, pathogenic, immunogenic and inflammatory factors, through the increase in intestinal permeability as a result of damaged tight junctions in the intestine, pass through the mucosa and reach the systemic circulation, causing local-systemic inflammation. Many factors that cause dysbiosis by changing the intestinal flora, which are frequently seen in HF, lead to bacterial overgrowth, bacterial translocation and formation of many toxic substances, including lipopolysaccharide (LPS), trimethylamine N-oxide (TMAO), p-cresylsulfate (PCS) and indoxyl sulfate (IS). Depending on the increase in intestinal permeability, these toxic substances reach the systemic circulation; it increases the risk of atherosclerosis by playing a role in thrombosis, platelet invasion, foam cell formation and inflammation processes. Decreased levels of butyrate, one of the short-chain fatty acids that have many effects on the gastrointestinal tract, including maintaining intestinal barrier integrity; It promotes foam cell formation, exacerbates dysbiosis, and plays a role in the disruption of intestinal barrier function, causing endotoxins to reach the general circulation. With this review, it is aimed to inform about the physiopathological processes in the gut-heart axis, in the light of the current literature.

Anahtar Kelimeler

Dysbiosis, IS, Intestinal permeability, SCFA, TMAO

Kaynakça

• Alverdy, J. C., Spitz, J., Hecht, G. & Ghandi, S. (1994). Causes and consequences of bacterial adherence to mucosal epithelia during critical illness. New horizons (Baltimore, Md.), 2 (2), 264-272.
• Andreesen, J. R. (1994). Glycine metabolism in anaerobes. Antonie Van Leeuwenhoek, 66 (1), 223-237.
• Anker, S. D., Egerer, K. R., Volk, H. D., Kox, W. J., Poole-Wilson, P. A. & Coats, A. J. (1997). Elevated soluble CD14 receptors and altered cytokines in chronic heart failure. The American Journal of Cardiology, 79 (10),1426-1430.
• Bäckhed, F. (2013). Meat-metabolizing bacteria in atherosclerosis. Nature Medicine, 19 (5), 533-534.
• Bastin, M. & Andreelli, F. (2020). The gut microbiota and diabetic cardiomyopathy in humans. Diabetes & Metabolism, 46 (3),197-202.
• Battson, M. L., Lee, D. M., Weir, T. L. & Gentile, C. L. (2018). The gut microbiota as a novel regulator of cardiovascular function and disease. The Journal of Nutritional Biochemistry, 56, 1-15.
• Bennett, B. J., de Aguiar Vallim, T. Q., Wang, Z., Shih, D. M., Meng, Y., Gregory, J., Allaye, H., Lee, R., Graham, M., Crooke, R., Edwards, P. A., Hazen, S. L. & Lusis, A. J. (2013). Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metabolism, 17 (1), 49-60.
• Bentzon, J. F., Otsuka, F., Virmani, R. & Falk, E. (2014). Mechanisms of plaque formation and rupture. Circulation Research, 114 (12), 1852-1866.
• Bischoff, S. C., Barbara, G., Buurman, W., Ockhuizen, T., Schulzke, J. D., Serino, M., Tilg, H., Watson, A. & Wells, J. M. (2014). Intestinal permeability–a new target for disease prevention and therapy. BMC Gastroenterology, 14 (1), 1-25.
• Boutagy, N. E., Neilson, A. P., Osterberg, K. L., Smithson, A. T., Englund, T. R., Davy, B. M., Hulver, M. W. & Davy, K. P. (2015). Probiotic supplementation and trimethylamine‐N‐oxide production following a high‐fat diet. Obesity, 23 (12), 2357-2363.
• Charo, I. F. & Taub, R. (2011). Anti-inflammatory therapeutics for the treatment of atherosclerosis. Nature reviews Drug Discovery, 10 (5), 365-376.
• Chen, W., Zhang, S., Wu, J., Ye, T., Wang, S., Wang, P. & Xing, D. (2020). Butyrate-producing bacteria and the gut-heart axis in atherosclerosis. Clinica Chimica Acta, 507, 236-241.
• Chiang, J. Y. (2009). Bile acids: regulation of synthesis: thematic review series: bile acids. Journal of Lipid Research, 50 (10), 1955-1966.
• Chistiakov, D. A., Bobryshev, Y. V., Kozarov, E., Sobenin, I. A. & Orekhov, A. N. (2015). Role of gut microbiota in the modulation of atherosclerosis-associated immune response. Frontiers in Microbiology, 6, 671.
• Conraads, V. M., Jorens, P. G., De Clerck, L. S., Van Saene, H. K., Ieven, M. M., Bosmans, J. M., Schuerwegh, A., Bridts, C. H., Wuyts, F., Stevens, W. J., Anker, S. D., Rauchhaus, M. & Vrints, C. J. (2004). Selective intestinal decontamination in advanced chronic heart failure: a pilot trial. European Journal of Heart Failure, 6 (4), 483-491.
• Cosola, C., Rocchetti, M. T., Cupisti, A. & Gesualdo, L. (2018). Microbiota metabolites: Pivotal players of cardiovascular damage in chronic kidney disease. Pharmacological Research, 130, 132-142.
• Craciun, S., Marks, J. A. & Balskus, E. P. (2014). Characterization of choline trimethylamine-lyase expands the chemistry of glycyl radical enzymes. ACS Chemical Biology, 9 (7), 1408-1413.
• Cui, L., Zhao, T., Hu, H., Zhang, W. & Hua, X. (2017). Association study of gut flora in coronary heart disease through high-throughput sequencing. BioMed Research International, 2017.
• Deitch, E. A. (2002). Bacterial translocation or lymphatic drainage of toxic products from the gut: what is important in human beings? Surgery, 131 (3), 241-244.
• Deshmukh, H. A., Maiti, A. K., Kim-Howard, X. R., Rojas-Villarraga, A., Guthridge, J. M., Anaya, J. M. & Nath, S. K. (2011). Evaluation of 19 autoimmune disease-associated loci with rheumatoid arthritis in a Colombian population: evidence for replication and gene-gene interaction. The Journal of Rheumatology, 38 (9), 1866-1870.
• Dinakaran, V., Rathinavel, A., Pushpanathan, M., Sivakumar, R., Gunasekaran, P. & Rajendhran, J. (2014). Elevated levels of circulating DNA in cardiovascular disease patients: metagenomic profiling of microbiome in the circulation. PloS one, 9 (8), e105221.
• Dregan, A., Charlton, J., Chowienczyk, P. & Gulliford, M. C. (2014). Chronic inflammatory disorders and risk of type 2 diabetes mellitus, coronary heart disease, and stroke: a population-based cohort study. Circulation, 130 (10), 837-844.
• Edwards, C. A., Havlik, J., Cong, W., Mullen, W., Preston, T., Morrison, D. J. & Combet, E. (2017). Polyphenols and health: Interactions between fibre, plant polyphenols and the gut microbiota.
• European Uremic Toxin Work Group (EUTox) (2009). Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clinical Journal of the American Society of Nephrology, 4 (10), 1551-1558.
• Falconi, C. A., Junho, C. V. D. C., Fogaça-Ruiz, F., Vernier, I. C. S., Da Cunha, R. S., Stinghen, A. E. M. & Carneiro-Ramos, M. S. (2021). Uremic toxins: an alarming danger concerning the cardiovascular system. Frontiers in Physiology, 667.
• Fluitman, K. S., Wijdeveld, M., Nieuwdorp, M. & IJzerman, R. G. (2018). Potential of butyrate to influence food intake in mice and men. Gut, 67 (7), 1203-1204.
• Forkosh, E. & Ilan, Y. (2019). The heart-gut axis: new target for atherosclerosis and congestive heart failure therapy. Open Heart, 6 (1), e000993.
• Frangogiannis, N. G. (2014). The inflammatory response in myocardial injury, repair, and remodelling. Nature Reviews Cardiology, 11 (5), 255-265.
• Fruhwald, S., Holzer, P. & Metzler, H. (2007). Intestinal motility disturbances in intensive care patients pathogenesis and clinical impact. Intensive Care Medicine, 33 (1), 36-44.
• Hayashi, T., Yamashita, T., Watanabe, H., Kami, K., Yoshida, N., Tabata, T., Emoto, T., Sasaki, N., Mizoguchi, T., Irino, Y., Toh, R., Shinohara, M., Okada, Y., Ogawa, W., Tamada, T. & Hirata, K. I. (2018). Gut microbiome and plasma microbiome-related metabolites in patients with decompensated and compensated heart failure. Circulation Journal, 83 (1), 182-192.
• Hori, M. & Yamaguchi, O. (2013). Is tumor necrosis factor-α friend or foe for chronic heart failure? Circulation Research, 113 (5), 492-494.
• Janeiro, M. H., Ramírez, M. J., Milagro, F. I., Martínez, J. A. & Solas, M. (2018). Implication of trimethylamine N-oxide (TMAO) in disease: potential biomarker or new therapeutic target. Nutrients, 10 (10), 1398.
• Jia, L., Li, D., Feng, N., Shamoon, M., Sun, Z., Ding, L., Zhang, Z., Chen, W., Sun, J. & Chen, Y. Q. (2017). Anti-diabetic effects of Clostridium butyricum CGMCC0313. 1 through promoting the growth of gut butyrate-producing bacteria in type 2 diabetic mice. Scientific Reports, 7 (1), 1-15.
• Jie, Z., Xia, H., Zhong, S. L., Feng, Q., Li, S., Liang, S., ... & Kristiansen, K. (2017). The gut microbiome in atherosclerotic cardiovascular disease. Nature Communications, 8 (1), 1-12.
• Kallio, K. A., Hätönen, K. A., Lehto, M., Salomaa, V., Männistö, S. & Pussinen, P. J. (2015). Endotoxemia, nutrition, and cardiometabolic disorders. Acta Diabetologica, 52 (2), 395-404.
• Kamo, T., Akazawa, H., Suzuki, J. I. & Komuro, I. (2017a). Novel concept of a heart-gut axis in the pathophysiology of heart failure. Korean Circulation Journal, 47(5):663-669.
• Kamo, T., Akazawa, H., Suda, W., Saga-Kamo, A., Shimizu, Y., Yagi, H., ... & Komuro, I. (2017b). Dysbiosis and compositional alterations with aging in the gut microbiota of patients with heart failure. PloS one, 12 (3), e0174099.
• Khan, T. J., Ahmed, Y. M., Zamzami, M. A., Siddiqui, A. M., Khan, I., Baothman, O. A., ... & Yasir, M. (2018). Atorvastatin treatment modulates the gut microbiota of the hypercholesterolemic patients. Omics: a Journal of Integrative Biology, 22 (2), 154-163.
• Khurana, S., Raufman, J. P. & Pallone, T. L. (2011). Bile acids regulate cardiovascular function. Clinical and Translational Science, 4 (3), 210-218.
• Koeth, R. A., Levison, B. S., Culley, M. K., Buffa, J. A., Wang, Z., Gregory, J. C., ... & Hazen, S. L. (2014). γ-Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO. Cell Metabolism, 205), 799-812.
• Koeth, R. A., Wang, Z., Levison, B. S., Buffa, J. A., Org, E., Sheehy, B. T., ... & Hazen, S. L. (2013). Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nature Medicine, 19 (5), 576-585.
• Lekawanvijit, S. (2015). Role of gut-derived protein-bound uremic toxins in cardiorenal syndrome and potential treatment modalities. Circulation Journal, 79 (10), 2088-2097.
• Lerner, A., Steigerwald, C. & Matthias, T. (2021). Feed your microbiome and your heart: The gut-heart axis. Front Biosci, 26, 468-477.
• Li, J., Lin, S., Vanhoutte, P. M., Woo, C. W. & Xu, A. (2016). Akkermansia muciniphila protects against atherosclerosis by preventing metabolic endotoxemia-induced inflammation in Apoe−/− mice. Circulation, 133 (24), 2434-2446.
• Lu, Y. C., Yeh, W. C. & Ohashi, P. S. (2008). LPS/TLR4 signal transduction pathway. Cytokine, 42 (2), 145-151.
• Mann, D. L. (2015). Innate immunity and the failing heart: the cytokine hypothesis revisited. Circulation Research, 116 (7), 1254-1268.
• Marshall, B. M. & Levy, S. B. (2011). Food animals and antimicrobials: impacts on human health. Clinical Microbiology Reviews, 24 (4), 718-733.
• Martin, F. P. J., Wang, Y., Sprenger, N., Yap, I. K., Lundstedt, T., Lek, P., ... & Nicholson, J. K. (2008). Probiotic modulation of symbiotic gut microbial–host metabolic interactions in a humanized microbiome mouse model. Molecular Systems Biology, 4 (1), 157.
• Milani, R. V., Mehra, M. R., Endres, S., Eigler, A., Cooper, E. S., Lavie Jr, C. J. & Ventura, H. O. (1996). The clinical relevance of circulating tumor necrosis factor-α in acute decompensated chronic heart failure without cachexia. Chest, 110 (4), 992-995.
• Mondo, E., Marliani, G., Accorsi, P. A., Cocchi, M. & Di Leone, A. (2019). Role of gut microbiota in dog and cat’s health and diseases. Open Veterinary Journal, 9 (3), 253-258.
• Morrison, D. J. & Preston, T. (2016). Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes, 7 (3), 189-200.
• Nagatomo, Y., & Tang, W. W. (2015). Intersections between microbiome and heart failure: revisiting the gut hypothesis. Journal of Cardiac Failure, 21 (12), 973-980.
• Nemet, I., Saha, P. P., Gupta, N., Zhu, W., Romano, K. A., Skye, S. M., ... & Hazen, S. L. (2020). A cardiovascular disease-linked gut microbial metabolite acts via adrenergic receptors. Cell, 180 (5), 862-877.
• Niebauer, J., Volk, H. D., Kemp, M., Dominguez, M., Schumann, R. R., Rauchhaus, M., ... & Anker, S. D. (1999). Endotoxin and immune activation in chronic heart failure: a prospective cohort study. The Lancet, 353 (9167), 1838-1842.
• Organ, C. L., Otsuka, H., Bhushan, S., Wang, Z., Bradley, J., Trivedi, R., ... & Lefer, D. J. (2016). Choline diet and its gut microbe–derived metabolite, trimethylamine N-oxide, exacerbate pressure overload–induced heart failure. Circulation: Heart Failure, 9 (1), e002314.
• Pasini, E., Aquilani, R., Testa, C., Baiardi, P., Angioletti, S., Boschi, F., ... & Dioguardi, F. (2016). Pathogenic gut flora in patients with chronic heart failure. JACC: Heart Failure, 4 (3), 220-227.
• Peschel, T., Schönauer, M., Thiele, H., Anker, S., Schuler, G. & Niebauer, J. (2003). Invasive assessment of bacterial endotoxin and inflammatory cytokines in patients with acute heart failure. European Journal of Heart Failure, 5 (5), 609-614.
• Ralls, M. W., Miyasaka, E. & Teitelbaum, D. H. (2014). Intestinal microbial diversity and perioperative complications. Journal of Parenteral and Enteral Nutrition, 38 (3), 392-399.
• Reif, S. & Lerner, A. (2004). Tissue transglutaminase—the key player in celiac disease: a review. Autoimmunity Reviews, 3 (1), 40-45.
• Rogler, G. & Rosano, G. (2014). The heart and the gut. European Heart Journal, 35 (7), 426-430.
• Romano, K. A., Vivas, E. I., Amador-Noguez, D. & Rey, F. E. (2015). Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide. MBio, 6 (2), e02481-14.
• Salzano, A., Cassambai, S., Yazaki, Y., Israr, M. Z., Bernieh, D., Wong, M. & Suzuki, T. (2020a). The gut axis involvement in heart failure: focus on trimethylamine N-oxide. Heart Failure Clinics, 16 (1), 23-31.
• Salzano, A., Israr, M. Z., Yazaki, Y., Heaney, L. M., Kanagala, P., Singh, A., ... & Suzuki, T. (2020b). Combined use of trimethylamine N-oxide with BNP for risk stratification in heart failure with preserved ejection fraction: findings from the DIAMONDHFpEF study. European Journal of Preventive Cardiology, 27 (19), 2159-2162.
• Sandek, A., Bauditz, J., Swidsinski, A., Buhner, S., Weber-Eibel, J., von Haehling, S., ... & Anker, S. D. (2007). Altered intestinal function in patients with chronic heart failure. Journal of the American College of Cardiology, 50 (16), 1561-1569.
• Sandek, A., Swidsinski, A., Schroedl, W., Watson, A., Valentova, M., Herrmann, R., ... & Bauditz, J. (2014). Intestinal blood flow in patients with chronic heart failure: a link with bacterial growth, gastrointestinal symptoms, and cachexia. Journal of the American College of Cardiology, 64 (11), 1092-1102.
• Savi, M., Bocchi, L., Bresciani, L., Falco, A., Quaini, F., Mena, P., ... & Del Rio, D. (2018). Trimethylamine-N-oxide (TMAO)-induced impairment of cardiomyocyte function and the protective role of urolithin B-glucuronide. Molecules, 23 (3), 549.
• Schroeder, B. O., & Bäckhed, F. (2016). Signals from the gut microbiota to distant organs in physiology and disease. Nature Medicine, 22 (10), 1079-1089.
• Schuett, K., Kleber, M. E., Scharnagl, H., Lorkowski, S., März, W., Niessner, A., ... & Meinitzer, A. (2017). Trimethylamine-N-oxide and heart failure with reduced versus preserved ejection fraction. Journal of the American College of Cardiology, 70 (25), 3202-3204.
• Sekirov, I., Russell, S. L., Antunes, L. C. M. & Finlay, B. B. (2010). Gut microbiota in health and disease. Physiological Reviews.
• Seo, J., Matthewman, L., Xia, D., Wilshaw, J., Chang, Y. M. & Connolly, D. J. (2020). The gut microbiome in dogs with congestive heart failure: a pilot study. Scientific Reports, 10 (1), 1-9.
• Staels, B. & Fonseca, V. A. (2009). Bile acids and metabolic regulation: mechanisms and clinical responses to bile acid sequestration. Diabetes Care, 32 (2), S237-S245.
• Stepankova, R., Tonar, Z., Bartova, J., Nedorost, L., Rossman, P., Poledne, R., ... & Tlaskalova-Hogenova, H. (2010). Absence of microbiota (germ-free conditions) accelerates the atherosclerosis in ApoE-deficient mice fed standard low cholesterol diet. Journal of Atherosclerosis and Thrombosis, 17 (8), 796-804.
• Suzuki, T., Heaney, L. M., Bhandari, S. S., Jones, D. J. & Ng, L. L. (2016). Trimethylamine N-oxide and prognosis in acute heart failure. Heart, 102 (11), 841-848.
• Suzuki, T., Heaney, L. M., Jones, D. J. & Ng, L. L. (2017). Trimethylamine N-oxide and risk stratification after acute myocardial infarction. Clinical Chemistry, 63 (1), 420-428.
• Swann, J. R., Want, E. J., Geier, F. M., Spagou, K., Wilson, I. D., Sidaway, J. E., ... & Holmes, E. (2011). Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proceedings of the National Academy of Sciences, 108 (Supplement 1), 4523-4530.
• Tang, W. W., & Hazen, S. L. (2014). The contributory role of gut microbiota in cardiovascular disease. The Journal of Clinical Investigation, 124 (10), 4204-4211.
• Tang, W. W., Wang, Z., Levison, B. S., Koeth, R. A., Britt, E. B., Fu, X., ... & Hazen, S. L. (2013). Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. New England Journal of Medicine, 368 (17), 1575-1584.
• Tang, W. W., Wang, Z., Shrestha, K., Borowski, A. G., Wu, Y., Troughton, R. W., ... & Hazen, S. L. (2015). Intestinal microbiota-dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure. Journal of Cardiac Failure, 21 (2), 91-96.
• Trøseid, M., Andersen, G. Ø., Broch, K. & Hov, J. R. (2020). The gut microbiome in coronary artery disease and heart failure: Current knowledge and future directions. EBioMedicine, 52, 102649.
• Von Haehling, S., Schefold, J. C., Jankowska, E. A., Springer, J., Vazir, A., Kalra, P. R., ... & Anker, S. D. (2012). Ursodeoxycholic acid in patients with chronic heart failure: a double-blind, randomized, placebo-controlled, crossover trial. Journal of the American College of Cardiology, 59 (6), 585-592.
• Wang, F., Li, Q., Wang, C., Tang, C. & Li, J. (2012). Dynamic alteration of the colonic microbiota in intestinal ischemia-reperfusion injury. PloS one, 7 (7), e42027.
• Wang, Z., Klipfell, E., Bennett, B. J., Koeth, R., Levison, B. S., DuGar, B., ... & Hazen, S. L. (2011). Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature, 472 (7341), 57-63.
• Wang, Z., Roberts, A. B., Buffa, J. A., Levison, B. S., Zhu, W., Org, E., ... & Hazen, S. L. (2015). Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell, 163 (7), 1585-1595.
• Watanabe, M., Houten, S. M., Mataki, C., Christoffolete, M. A., Kim, B. W., Sato, H., ... & Auwerx, J. (2006). Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature, 439 (7075), 484-489.
• Wikoff, W. R., Anfora, A. T., Liu, J., Schultz, P. G., Lesley, S. A., Peters, E. C. & Siuzdak, G. (2009). Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proceedings of the National Academy of Sciences, 106 (10), 3698-3703.
• Zeisel, S. H. & Warrier, M. (2017). Trimethylamine N-oxide, the microbiome, and heart and kidney disease. Annual Review of Nutrition, 37, 157-181.
• Zhang, Y., Wang, Y., Ke, B. & Du, J. (2021). TMAO: how gut microbiota contributes to heart failure. Translational Research, 228, 109-125.
• Zhu, Y., Jameson, E., Crosatti, M., Schäfer, H., Rajakumar, K., Bugg, T. D. & Chen, Y. (2014). Carnitine metabolism to trimethylamine by an unusual Rieske-type oxygenase from human microbiota. Proceedings of the National Academy of Sciences, 111 (11), 4268-4273.