573
Views
8
CrossRef citations to date
0
Altmetric
Review

The human gut microbiome – a new and exciting avenue in cardiovascular drug discovery

, , , , &
Pages 1037-1052 | Received 20 Apr 2019, Accepted 28 Jun 2019, Published online: 18 Jul 2019

References

  • Jones DS, Podolsky SH, Greene JA. The burden of disease and the changing task of medicine. N Engl J Med. 2012;366:2333–2338.
  • Chen WW, Gao RL, Liu LS, et al. [China cardiovascular disease report 2017: a summary]. Chin Circ J. 2018;33:1–8. Chinese.
  • Yang Y, Wang L, Si S, et al. How can high-throughput screening deliver drugs to treat atherosclerosis? Expert Opin Drug Discov. 2010;5:1175–1188.
  • Du Y, Wang L, Hong B. High-density lipoprotein-based drug discovery for treatment of atherosclerosis. Expert Opin Drug Discov. 2015;10:841–855.
  • Sender R, Fuchs S, Milo R. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell. 2016;164:337–340.
  • Qin J, Li R, Raes J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464:59–65.
  • Goodrich JK, Waters JL, Poole AC, et al. Human genetics shape the gut microbiome. Cell. 2014;159:789–799.
  • Lederberg J. Infectious history. Science. 2000;288:287–293.
  • Koren O, Spor A, Felin J, et al. Human oral, gut, and plaque microbiota in patients with atherosclerosis. Proc Natl Acad Sci USA. 2011;108(Suppl 1):S4592–4598.
  • Ott SJ, El Mokhtari NE, Musfeldt M, et al. Detection of diverse bacterial signatures in atherosclerotic lesions of patients with coronary heart disease. Circulation. 2006;113(7):929–937.
  • Turnbaugh PJ, Ley RE, Mahowald MA, et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–1031.
  • Karlsson FH, Fak F, Nookaew I, et al. Symptomatic atherosclerosis is associated with an altered gut metagenome. Nat Commun. 2012;3:1245.
  • Emoto T, Yamashita T, Kobayashi T, et al. Characterization of gut microbiota profiles in coronary artery disease patients using data mining analysis of terminal restriction fragment length polymorphism: gut microbiota could be a diagnostic marker of coronary artery disease. Heart Vessels. 2017;32:39–46.
  • Li J, Lin S, Vanhoutte PM, et al. Akkermansia muciniphila protects against atherosclerosis by preventing metabolic endotoxemia-induced inflammation in Apoe-/- mice. Circulation. 2016;133(24):2434–2446.
  • Plovier H, Everard A, Druart C, et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat Med. 2017;23(1):107–113.
  • Stepankova R, Tonar Z, Bartova J, et al. Absence of microbiota (germ-free conditions) accelerates the atherosclerosis in ApoE-deficient mice fed standard low cholesterol diet. J Atheroscler Thromb. 2010;17:796–804.
  • Lindskog Jonsson A, Caesar R, Akrami R, et al. Impact of gut microbiota and diet on the development of atherosclerosis in Apoe-/- mice. Arterioscler Thromb Vasc Biol. 2018;38:2318–2326.
  • Kasahara K, Tanoue T, Yamashita T, et al. Commensal bacteria at the cross-road between cholesterol homeostasis and chronic inflammation in atherosclerosis. J Lipid Res. 2017;58:519–528.
  • Gregory JC, Buffa JA, Org E, et al. Transmission of atherosclerosis susceptibility with gut microbial transplantation. J Biol Chem. 2015;290:5647–5660.
  • Zhu W, Gregory JC, Org E, et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell. 2016;165:111–124.
  • Cani PD. Human gut microbiome: hopes, threats and promises. Gut. 2018;67(9):1716–1725.
  • Donia MS, Fischbach MA. Small molecules from the human microbiota. Science. 2015;349:1254766.
  • Canfora EE, Meex RCR, Venema K, et al. Gut microbial metabolites in obesity, NAFLD and T2DM. Nat Rev Endocrinol. 2019;15(5):261–273.
  • Bennett BJ, de Aguiar Vallim TQ, Wang Z, et al. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 2013;17:49–60.
  • Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472:57–63.
  • Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19(5):576–585.
  • Tang WH, Wang Z, Levison BS, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013;368:1575–1584.
  • Collins HL, Drazul-Schrader D, Sulpizio AC, et al. L-Carnitine intake and high trimethylamine N-oxide plasma levels correlate with low aortic lesions in ApoE-/- transgenic mice expressing CETP. Atherosclerosis. 2016;244:29–37.
  • Nagata C, Wada K, Tamura T, et al. Choline and betaine intakes are not associated with cardiovascular disease mortality risk in Japanese men and women. J Nutr. 2015;145:1787–1792.
  • Geng J, Yang C, Wang B, et al. Trimethylamine N-oxide promotes atherosclerosis via CD36-dependent MAPK/JNK pathway. Biomed Pharmacother. 2018;97:941–947.
  • Ma G, Pan B, Chen Y, et al. Trimethylamine N-oxide in atherogenesis: impairing endothelial self-repair capacity and enhancing monocyte adhesion. Biosci Rep. 2017;37:BSR20160244.
  • Seldin MM, Meng Y, Qi H, et al. Trimethylamine N‐oxide promotes vascular inflammation through signaling of mitogen‐activated protein kinase and nuclear factor‐κB. J Am Heart Assoc. 2016;5:e002767.
  • Royall D, Wolever T, Jeejeebhoy KN. Clinical significance of colonic fermentation. Am J Gastroenterol. 1990;85:1307–1312.
  • Samuel BS, Shaito A, Motoike T, et al. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc Natl Acad Sci USA. 2008;105:16767–16772.
  • Vrieze A, Van Nood E, Holleman F, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012;143:913–916.
  • Den Besten G, Bleeker A, Gerding A, et al. Short-chain fatty acids protect against high-fat diet-induced obesity via a PPARγ-dependent switch from lipogenesis to fat oxidation. Diabetes. 2015;64:2398–2408.
  • Wang L, Zhu Q, Lu A, et al. Sodium butyrate suppresses angiotensin II-induced hypertension by inhibition of renal (pro)renin receptor and intrarenal renin-angiotensin system. J Hypertens. 2017;35:1899–1908.
  • Aguilar EC, Leonel AJ, Teixeira LG, et al. Butyrate impairs atherogenesis by reducing plaque inflammation and vulnerability and decreasing NFκB activation. Nutr Metab Cardiovasc Dis. 2014;24:606–613.
  • Aguilar EC, Santos LC, Leonel AJ, et al. Oral butyrate reduces oxidative stress in atherosclerotic lesion sites by a mechanism involving NADPH oxidase down-regulation in endothelial cells. J Nutr Biochem. 2016;34:99–105.
  • Kasahara K, Krautkramer KA, Org E, et al. Interactions between Roseburia intestinalis and diet modulate atherogenesis in a murine model. Nat Microbiol. 2018;3:1461–1471.
  • Brown AJ, Goldsworthy SM, Barnes AA, et al. The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem. 2003;278:11312–11319.
  • Tolhurst G, Heffron H, Lam YS, et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein–coupled receptor FFAR2. Diabetes. 2012;61:364–371.
  • Pluznick J. A novel SCFA receptor, the microbiota, and blood pressure regulation. Gut Microbes. 2014;5:202–207.
  • Li Z, Yi CX, Katiraei S, et al. Butyrate reduces appetite and activates brown adipose tissue via the gut-brain neural circuit. Gut. 2018;67:1269–1279.
  • Frost G, Sleeth ML, Sahuri-Arisoylu M, et al. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat Commun. 2014;5:3611.
  • Jonsson AL, Bäckhed F. Role of gut microbiota in atherosclerosis. Nat Rev Cardiol. 2017;14:79–87.
  • Sayin SI, Wahlström A, Felin J, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 2013;17:225–235.
  • Zimmermann M, Zimmermann-Kogadeeva M, Wegmann R, et al. Mapping human microbiome drug metabolism by gut bacteria and their genes. Nature. 2019;1. DOI:10.1038/s41586-019-1291-3.
  • Enright EF, Griffin BT, Gahan CGM, et al. Microbiome-mediated bile acid modification: role in intestinal drug absorption and metabolism. Pharmacol Res. 2018;133:170–186.
  • Islam KBMS, Fukiya S, Hagio M, et al. Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology. 2011;141(5):1773–1781.
  • Wahlström A, Sayin SI, Marschall HU, et al. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 2016;24:41–50.
  • Makishima M, Okamoto AY, Repa JJ, et al. Identification of a nuclear receptor for bile acids. Science. 1999;284:1362–1365.
  • Watanabe M, Houten SM, Mataki C, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006;439:484–489.
  • Inagaki T, Choi M, Moschetta A, et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2005;2:217–225.
  • Sun L, Xie C, Wang G, et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nat Med. 2018;24:1919–1929.
  • Watanabe M, Houten SM, Wang L, et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest. 2004;113:1408–1418.
  • Hartman HB, Gardell SJ, Petucci CJ, et al. Activation of farnesoid X receptor prevents atherosclerotic lesion formation in LDLR-/- and apoE-/- mice. J Lipid Res. 2009;50:1090–1100.
  • Mencarelli A, Renga B, Distrutti E, et al. Antiatherosclerotic effect of farnesoid X receptor. Am J Physiol Heart Circ Physiol. 2009;296:H272–H281.
  • Pols TWH, Nomura M, Harach T, et al. TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab. 2011;14:747–757.
  • Miyazaki-Anzai S, Masuda M, Levi M, et al. Dual activation of the bile acid nuclear receptor FXR and G-protein-coupled receptor TGR5 protects mice against atherosclerosis. PLoS One. 2014;9:e108270.
  • Jadhav K, Xu Y, Xu Y, et al. Reversal of metabolic disorders by pharmacological activation of bile acid receptors TGR5 and FXR. Mol Metab. 2018;9:131–140.
  • Miyazaki-Anzai S, Masuda M, Kohno S, et al. Simultaneous inhibition of FXR and TGR5 exacerbates atherosclerotic formation. J Lipid Res. 2018;59:1709–1713.
  • Agus A, Planchais J, Sokol H. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe. 2018;23:716–724.
  • Venkatesh M, Mukherjee S, Wang H, et al. Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. Immunity. 2014;41:296–310.
  • Beaumont M, Neyrinck AM, Olivares M, et al. The gut microbiota metabolite indole alleviates liver inflammation in mice. Faseb J. 2018;32:6681–6693.
  • Krishnan S, Ding Y, Saedi N, et al. Gut microbiota-derived tryptophan metabolites modulate inflammatory response in hepatocytes and macrophages. Cell Rep. 2018;23:1099–1111.
  • Federici M. Gut microbiome and microbial metabolites: a new system affecting metabolic disorders. J Endocrinol Invest. 2019;1–8. DOI:10.1007/s40618-019-01022-9
  • Pedersen HK, Gudmundsdottir V, Nielsen HB, et al. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature. 2016;535:376–381.
  • Lynch CJ, Adams SH. Branched-chain amino acids in metabolic signaling and insulin resistance. Nat Rev Endocrinol. 2014;10:723–736.
  • Pichette J, Fynn-Sackey N, Gagnon J. Hydrogen sulfide and sulfate prebiotic stimulates the secretion of GLP-1 and improves glycemia in male mice. Endocrinology. 2017;158:3416–3425.
  • Grasset E, Puel A, Charpentier J, et al. A specific gut microbiota dysbiosis of type 2 diabetic mice induces GLP-1 resistance through an enteric NO-dependent and gut-brain axis mechanism. Cell Metab. 2017;25:1075–1090. e5.
  • Maier L, Pruteanu M, Kuhn M, et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018;555:623–628.
  • Shin NR, Lee JC, Lee HY, et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut. 2014;63:727–735.
  • Forslund K, Hildebrand F, Nielsen T, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015;528:262–266.
  • de la Cuesta-Zuluaga J, Mueller NT, Corrales-Agudelo V, et al. Metformin is associated with higher relative abundance of mucin-degrading akkermansia muciniphila and several short-chain fatty acid-producing microbiota in the gut. Diabetes Care. 2017;40:54–62.
  • Wu H, Esteve E, Tremaroli V, et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med. 2017;23:850–858.
  • Ma W, Chen J, Meng Y, et al. Metformin alters gut microbiota of healthy mice: implication for its potential role in gut microbiota homeostasis. Front Microbiol. 2018;9:1336.
  • Nolan JA, Skuse PH, Govindarajan K, et al. The influence of rosuvastatin upon the gastrointestinal microbiota and host gene expression profiles. Am J Physiol Gastrointest Liver Physiol. 2017;312:G488–G497.
  • Khan TJ, Ahmed YM, Zamzami MA, et al. Atorvastatin treatment modulates the gut microbiota of the hypercholesterolemic patients. Omics. 2018;22:154–163.
  • Khan TJ, Ahmed YM, Zamzami MA, et al. Effect of atorvastatin on the gut microbiota of high fat diet-induced hypercholesterolemic rats. Sci Rep. 2018;8:662.
  • Milks M, He X, Sharkey-Toppen T, et al. Statin use is associated with lower trimethylamine-n-oxide (TMAO) level in adults at risk of atherosclerotic cardiovascular disease, independent of serum cholesterol and renal function. J Clin Lipidol. 2018;12:567–568.
  • Li DY, Wang Z, Li XS, et al. Relationship between statin use and trimethylamine n-oxide in cardiovascular risk assessment. J Am Coll Cardiol. 2018;71:A115.
  • Caparrós-Martín JA, Lareu RR, Ramsay JP, et al. Statin therapy causes gut dysbiosis in mice through a PXR-dependent mechanism. Microbiome. 2017;5:95.
  • Kaddurah-Daouk R, Baillie RA, Zhu H, et al. Enteric microbiome metabolites correlate with response to simvastatin treatment. PLoS One. 2011;6:e25482.
  • Liu Y, Song X, Zhou H, et al. Gut microbiome associates with lipid-lowering effect of rosuvastatin in vivo. Front Microbiol. 2018;9:530.
  • Han J, Lin H, Huang W. Modulating gut microbiota as an anti-diabetic mechanism of berberine. Med Sci Monit. 2011;17:RA164–167.
  • Zhang H, Wei J, Xue R, et al. Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression. Metabolism. 2010;59:285–292.
  • Kong W, Wei J, Abidi P, et al. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med. 2004;10:1344–1351.
  • Zhang Y, Li X, Zou D, et al. Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. J Clin Endocrinol Metab. 2008;93:2559–2565.
  • Dong SF, Hong Y, Liu M, et al. Berberine attenuates cardiac dysfunction in hyperglycemic and hypercholesterolemic rats. Eur J Pharmacol. 2011;660:368–374.
  • Yao J, W J K, Jiang JD. Learning from berberine: treating chronic diseases through multiple targets. Sci China Life Sci. 2015;58(9):854–859.
  • Zuo F, Nakamura N, Akao T, et al. Pharmacokinetics of berberine and its main metabolites in conventional and pseudo germ-free rats determined by liquid chromatography/ion trap mass spectrometry. Drug Metab Dispos. 2006;34:2064–2072.
  • Feng R, Shou JW, Zhao ZX, et al. Transforming berberine into its intestine-absorbable form by the gut microbiota. Sci Rep. 2015;5:12155.
  • Wang Y, Tong Q, Shou JW, et al. Gut microbiota-mediated personalized treatment of hyperlipidemia using berberine. Theranostics. 2017;7:2443.
  • Zhang X, Zhao Y, Zhang M, et al. Structural changes of gut microbiota during berberine-mediated prevention of obesity and insulin resistance in high-fat diet-fed rats. PLoS One. 2012;7:e42529.
  • Wang Y, Shou JW, Li XY, et al. Berberine-induced bioactive metabolites of the gut microbiota improve energy metabolism. Metabolism. 2017;70:72–84.
  • Zhu L, Zhang D, Zhu H, et al. Berberine treatment increases Akkermansia in the gut and improves high-fat diet-induced atherosclerosis in Apoe-/- mice. Atherosclerosis. 2018;268:117–126.
  • Gu S, Cao B, Sun R, et al. A metabolomic and pharmacokinetic study on the mechanism underlying the lipid-lowering effect of orally administered berberine. Mol Biosyst. 2015;11:463–474.
  • Sun R, Yang N, Kong B, et al. Orally administered berberine modulates hepatic lipid metabolism by altering microbial bile acid metabolism and the intestinal FXR signaling pathway. Mol Pharmacol. 2017;91:110–122.
  • Tian Y, Cai J, Gui W, et al. Berberine directly affects the gut microbiota to promote intestinal farnesoid X receptor activation. Drug Metab Dispos. 2019;47:86–93.
  • Craciun S, Balskus EP. Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme. Proc Natl Acad Sci USA. 2012;109:21307–21312.
  • Bodea S, Funk MA, Balskus EP, et al. Molecular basis of C-N bond cleavage by the glycyl radical enzyme choline trimethylamine-lyase. Cell Chem Biol. 2016;23:1206–1216.
  • Rath S, Heidrich B, Pieper DH, et al. Uncovering the Trimethylamine-producing bacteria of the human gut microbiota. Microbiome. 2017;5:54.
  • Zhu Y, Jameson E, Crosatti M, et al. Carnitine metabolism to trimethylamine by an unusual Rieske-type oxygenase from human microbiota. Proc Natl Acad Sci USA. 2014;111:4268–4273.
  • Andreesen JR. Glycine metabolism in anaerobes. Antonie Van Leeuwenhoek. 1994;66:223–237.
  • Koeth RA, Levison BS, Culley MK, et al. γ-Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO. Cell Metab. 2014;20:799–812.
  • Pascal MC, Burini JF, Chippaux M. Regulation of the trimethylamine N-oxide (TMAO) reductase in Escherichia coli: analysis of tor:: mud1operon fusion. Mol Gen Genet. 1984;195(1–2):351–355.
  • Wang Z, Roberts AB, Buffa JA, et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell. 2015;163:1585–1595.
  • Roberts AB, Gu X, Buffa JA, et al. Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential. Nat Med. 2018;24:1407–1417.
  • Orman M, Bodea S, Funk MA, et al. Structure-guided identification of a small molecule that inhibits anaerobic choline metabolism by human gut bacteria. J Am Chem Soc. 2018;141:33–37.
  • Chittim CL, Del Campo A, Balskus EP. Gut bacterial phospholipase Ds support disease-associated metabolism by generating choline. Nat Microbiol. 2019;4:155–163.
  • Ridlon JM, Kang DJ, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. J Lipid Res. 2006;47:241–259.
  • Ridlon JM, Hylemon PB. Identification and characterization of two bile acid coenzyme A transferases from Clostridium scindens, a bile acid 7α-dehydroxylating intestinal bacterium. J Lipid Res. 2012;53:66–76.
  • Long SL, Gahan CGM, Joyce SA. Interactions between gut bacteria and bile in health and disease. Mol Aspects Med. 2017;56:54–65.
  • 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;111:7421–7426.
  • Korpela K, Salonen A, Virta LJ, et al. Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children. Nat Commun. 2016;7:10410.
  • Williams BB, Van Benschoten AH, Cimermancic P, et al. Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. Cell Host Microbe. 2014;16:495–503.
  • London J, Goldberg ME. The tryptophanase from Escherichia coli K-12. I. Purification, physical properties, and quaternary structure. J Biol Chem. 1972;247:1566–1570.
  • Pott AS, Dahl C. Sirohaem sulfite reductase and other proteins encoded by genes at the dsr locus of Chromatium vinosum are involved in the oxidation of intracellular sulfur. Microbiology. 1998;144:1881–1894.
  • X21 Peck SC, Denger K, Burrichter A, et al. A glycyl radical enzyme enables hydrogen sulfide production by the human intestinal bacterium Bilophila wadsworthia. Proc Natl Acad Sci USA. 2019;116:3171–3176.
  • Drew L. Microbiota: reseeding the gut. Nature. 2016;540:S109–S112.
  • Chen YS, Liu HM, Lee TY. Ursodeoxycholic acid regulates hepatic energy homeostasis and white adipose tissue macrophages polarization in leptin-deficiency obese mice. Cells. 2019;8:253.
  • Pellicciari R, Costantino G, Camaioni E, et al. Bile acid derivatives as ligands of the farnesoid X receptor. Synthesis, evaluation, and structure-activity relationship of a series of body and side chain modified analogues of chenodeoxycholic acid. J Med Chem. 2004;47:4559–4569.
  • GlobeNewswire. Intercept announces positive topline results from pivotal Phase 3 REGENERATE study of obeticholic acid in patients with liver fibrosis fue to NASH; 2019 Feb 19 [cited 2019 Apr 2]. [about 2 screens]. Available from: https://www.globenewswire.com/news-release/2019/02/19/1734111/0/en/Intercept-Announces-Positive-Topline-Results-from-Pivotal-Phase-3-REGENERATE-Study-of-Obeticholic-Acid-in-Patients-with-Liver-Fibrosis-Due-to-NASH.html
  • Ohira H, Tsutsui W, Fujioka Y. Are short chain fatty acids in gut microbiota defensive players for inflammation and atherosclerosis? J Atheroscler Thromb. 2017;24:660–672.
  • Vinolo MAR, Rodrigues HG, Festuccia WT, et al. Tributyrin attenuates obesity-associated inflammation and insulin resistance in high-fat-fed mice. Am J Physiol Endocrinol Metab. 2012;303:E272–E282.
  • Cresci GA, Bush K, Nagy LE. Tributyrin supplementation protects mice from acute ethanol-induced gut injury. Alcohol Clin Exp Res. 2014;38:1489–1501.
  • Cohen LJ, Kang HS, Chu J, et al. Functional metagenomic discovery of bacterial effectors in the human microbiome and isolation of commendamide, a GPCR G2A/132 agonist. Proc Natl Acad Sci USA.2015;112:E4825–4834.•
  • Lynch A, Crowley E, Casey E, et al. The Bacteroidales produce an N-acylated derivative of glycine with both cholesterol-solubilising and hemolytic activity. Sci Rep. 2017;7(1):13270.
  • Cohen LJ, Esterhazy D, Kim SH, et al. Commensal bacteria make GPCR ligands that mimic human signalling molecules. Nature. 2017;549:48–53.
  • Donia MS, Cimermancic P, Schulze CJ, et al. A systematic analysis of biosynthetic gene clusters in the human microbiome reveals a common family of antibiotics. Cell. 2014;158:1402–1414.
  • Guo CJ, Chang FY, Wyche TP, et al. Discovery of reactive microbiota-derived metabolites that inhibit host proteases. Cell. 2017;168:517–526. e18.
  • Hill C, Guarner F, Reid G, et al. Expert consensus document: the international scientific association for probiotics and prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. 2014;11:506–514.
  • Yadav H, Jain S, Sinha PR. Antidiabetic effect of probiotic dahi containing Lactobacillus acidophilus and Lactobacillus casei in high fructose fed rats. Nutrition. 2007;23:62–68.
  • Tahri K, Grille JP, Schneider F. Bifidobacteria strain behavior toward cholesterol: coprecipitation with bile salts and assimilation. Curr Microbiol. 1996;33:187–193.
  • Nguyen TDT, Kang JH, Lee MS. Characterization of Lactobacillus plantarum PH04, a potential probiotic bacterium with cholesterol-lowering effects. Int J Food Microbiol. 2007;113:358–361.
  • Asemi Z, Zare Z, Shakeri H, et al. Effect of multispecies probiotic supplements on metabolic profiles, hs-CRP, and oxidative stress in patients with type 2 diabetes. Ann Nutr Metab. 2013;63:1–9.
  • Huang Y, Wang J, Quan G, et al. Lactobacillus acidophilus ATCC 4356 prevents atherosclerosis via inhibition of intestinal cholesterol absorption in apolipoprotein E-knockout mice. Appl Environ Microbiol. 2014;80:7496–7504.
  • Costabile A, Buttarazzi I, Kolida S, et al. An in vivo assessment of the cholesterol-lowering efficacy of Lactobacillus plantarum ECGC 13110402 in normal to mildly hypercholesterolaemic adults. PloS One. 2017;12:e0187964.
  • Karlsson C, Ahrné S, Molin G, et al. Probiotic therapy to men with incipient arteriosclerosis initiates increased bacterial diversity in colon: a randomized controlled trial. Atherosclerosis. 2010;208:228–233.
  • van Baarlen P, Troost F, van der Meer C, et al. Human mucosal in vivo transcriptome responses to three lactobacilli indicate how probiotics may modulate human cellular pathways. Proc Natl Acad Sci USA. 2011;108:4562–4569.
  • Cani PD, de Vos WM. Next-generation beneficial microbes: the case of Akkermansia muciniphila. Front Microbiol. 2017;8:1765.
  • Anonye BO. Commentary: dietary polyphenols promote growth of the gut bacterium Akkermansia muciniphila and attenuate high-fat diet-induced metabolic syndrome. Front Microbiol. 2017;8:850.
  • Tang WHW, Kitai T, Hazen SL. Gut microbiota in cardiovascular health and disease. Circ Res. 2017;120:1183–1196.
  • Dieterle MG, Rao K, Young VB. Novel therapies and preventative strategies for primary and recurrent Clostridium difficile infections. Ann NY Acad Sci. 2019;1435:110–138.
  • O’Toole PW, Marchesi JR, Hill C. Next-generation probiotics: the spectrum from probiotics to live biotherapeutics. Nat Microbiol. 2017;2:17057.
  • Chen Z, Guo L, Zhang Y, et al. Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity. J Clin Invest. 2014;124:3391–3406.
  • Duan FF, Liu JH, March JC. Engineered commensal bacteria reprogram intestinal cells into glucose-responsive insulin-secreting cells for the treatment of diabetes. Diabetes. 2015;64:1794–1803.
  • Lagier JC, Dubourg G, Million M, et al. Culturing the human microbiota and culturomics. Nat Rev Microbiol. 2018;16(9):540–550.
  • Knight R, Vrbanac A, Taylor BC, et al. Best practices for analysing microbiomes. Nat Rev Microbiol. 2018;16(7):410–422.
  • van der Helm E, Genee HJ, Sommer MOA. The evolving interface between synthetic biology and functional metagenomics. Nat Chem Biol. 2018;14:752–759.
  • Genee HJ, Bali AP, Petersen SD, et al. Functional mining of transporters using synthetic selections. Nat Chem Biol. 2016;12:1015–1022.
  • Koh A, Molinaro A, Ståhlman M, et al. Microbially produced imidazole propionate impairs insulin signaling through mTORC1. Cell. 2018;175:947–961. e17.
  • Franzosa EA, Sirota-Madi A, Avila-Pacheco J, et al. Gut microbiome structure and metabolic activity in inflammatory bowel disease. Nat Microbiol. 2019;4:293–305.
  • Wang M, Carver JJ, Phelan VV, et al. Sharing and community curation of mass spectrometry data with global natural products social molecular networking. Nat Biotechnol. 2016;34:828–837.
  • Mohimani H, Gurevich A, Shlemov A, et al. Dereplication of microbial metabolites through database search of mass spectra. Nat Commun. 2018;9:4035.
  • Pirhaji L, Milani P, Leidl M, et al. Revealing disease-associated pathways by network integration of untargeted metabolomics. Nat Methods. 2016;13:770–776.
  • Mohimani H, Gurevich A, Mikheenko A, et al. Dereplication of peptidic natural products through database search of mass spectra. Nat Chem Biol. 2016;13:30–37.
  • Covington BC, McLean JA, Bachmann BO. Comparative mass spectrometry-based metabolomics strategies for the investigation of microbial secondary metabolites. Nat Prod Rep. 2017;34:6–24.
  • Quinn RA, Phelan VV, Whiteson KL, et al. Microbial, host and xenobiotic diversity in the cystic fibrosis sputum metabolome. ISME J. 2016;10:1483–1498.
  • Zou Y, Xue W, Luo G, et al. 1,520 reference genomes from cultivated human gut bacteria enable functional microbiome analyses. Nat Biotechnol. 2019;37:179–185.
  • Almeida A, A L M, Boland M, et al. A new genomic blueprint of the human gut microbiota. Nature. 2019;568(7753):499–504.
  • Blin K, Wolf T, Chevrette MG, et al. antiSMASH 4.0-improvements in chemistry prediction and gene cluster boundary identification. Nucleic Acids Res. 2017;45(W1):W36–W41.
  • Faïs T, Delmas J, Barnich N, et al. Colibactin: more than a new bacterial toxin. Toxins (Basel). 2018;10:151.
  • Brotherton CA, Balskus EP. A prodrug resistance mechanism is involved in colibactin biosynthesis and cytotoxicity. J Am Chem Soc. 2013;135:3359–3362.
  • Vizcaino MI, Engel P, Trautman E, et al. Comparative metabolomics and structural characterizations illuminate colibactin pathway-dependent small molecules. J Am Chem Soc. 2014;136:9244–9247.
  • Li ZR, Li J, Gu JP, et al. Divergent biosynthesis yields a cytotoxic aminomalonate-containing precolibactin. Nat Chem Biol. 2016;12:773–775.
  • Healy AR, Vizcaino MI, Crawford JM, et al. Convergent and modular synthesis of candidate precolibactins. Structural revision of precolibactin A. J Am Chem Soc. 2016;138:5426–5432.
  • Healy AR, Nikolayevskiy H, Patel JR, et al. A mechanistic model for colibactin-induced genotoxicity. J Am Chem Soc. 2016;138:15563–15570.
  • Levin BJ, Huang YY, Peck SC, et al. A prominent glycyl radical enzyme in human gut microbiomes metabolizes trans-4-hydroxy-l-proline. Science. 2017;355:eaai8386.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.