REVIEW

Pharmacomicrobiomics: a novel route towards personalized medicine?

  • Marwah Doestzada 1,2 ,
  • Arnau Vich Vila 1,3 ,
  • Alexandra Zhernakova 1 ,
  • Debby P. Y. Koonen 2 ,
  • Rinse K. Weersma 3 ,
  • Daan J. Touw 4 ,
  • Folkert Kuipers 2,5 ,
  • Cisca Wijmenga 1,6 ,
  • Jingyuan Fu , 1,2
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  • 1. Departments of Genetics, University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands
  • 2. Departments of Paediatrics, University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands
  • 3. Departments of Gastroenterology & Hepatology, University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands
  • 4. Departments of Clinical Pharmacy & Pharmacology, University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands
  • 5. Departments of Laboratory Medicine, University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands
  • 6. K.G. Jebsen Coeliac Disease Research Centre, Department of Immunology, University of Oslo, P.O. Box 1072, Blindern, 0316 Oslo, Norway

Received date: 05 Mar 2018

Accepted date: 16 Apr 2018

Published date: 08 Jun 2018

Copyright

2018 The Author(s) 2018

Abstract

Inter-individual heterogeneity in drug response is a serious problem that affects the patient’s wellbeing and poses enormous clinical and financial burdens on a societal level. Pharmacogenomics has been at the forefront of research into the impact of individual genetic background on drug response variability or drug toxicity, and recently the gut microbiome, which has also been called the second genome, has been recognized as an important player in this respect. Moreover, the microbiome is a very attractive target for improving drug efficacy and safety due to the opportunities to manipulate its composition. Pharmacomicrobiomics is an emerging field that investigates the interplay of microbiome variation and drugs response and disposition (absorption, distribution, metabolism and excretion). In this review, we provide a historical overview and examine current state-of-the-art knowledge on the complex interactions between gut microbiome, host and drugs. We argue that combining pharmacogenomics and pharmacomicrobiomics will provide an important foundation for making major advances in personalized medicine.

Cite this article

Marwah Doestzada , Arnau Vich Vila , Alexandra Zhernakova , Debby P. Y. Koonen , Rinse K. Weersma , Daan J. Touw , Folkert Kuipers , Cisca Wijmenga , Jingyuan Fu . Pharmacomicrobiomics: a novel route towards personalized medicine?[J]. Protein & Cell, 2018 , 9(5) : 432 -445 . DOI: 10.1007/s13238-018-0547-2

1
Alexander JL, Wilson ID, Teare J, Marchesi JR, Nicholson JK, Kinross JM (2017) Gut microbiota modulation of chemotherapy efficacy and toxicity. Nat Rev Gastroenterol Hepatol 14:356–365

DOI

2
Ananthakrishnan AN, Luo C, Yajnik V, Khalili H, Garber JJ, Stevens BW, Cleland T, Xavier RJ (2017) Gut microbiome function predicts response to anti-integrin biologic therapy in inflammatory bowel diseases. Cell Host Microbe 21:603.e3–610.e3

DOI

3
Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, Nishikawa H, Fukuda S, Saito T, Narushima S, Hase K (2013) Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500:232–236

DOI

4
Basit AW, Lacey LF (2001) Colonic metabolism of ranitidine: implications for its delivery and absorption. Int J Pharm 227:157–165

DOI

5
Benson AK, Kelly SA, Legge R, Ma F, Low SJ, Kim J, Zhang M, Oh PL,Nehrenberg D , Hua K (2010) Individuality in gut microbiota composition is a complex polygenic trait shaped by multiple environmental and host genetic factors. Proc Natl Acad Sci USA 107:18933–18938

DOI

6
Bhatia SN, Ingber DE (2014) Microfluidic organs-on-chips. Nat Biotechnol 32:760–772

DOI

7
Boelsterli UA, Redinbo MR, Saitta KS (2013) Multiple NSAIDinduced hits injure the small intestine: underlying mechanisms and novel strategies. Toxicol Sci 131:654–667

DOI

8
Bonder MJ, Kurilshikov A, Tigchelaar EF, Mujagic Z, Imhann F, Vila AV, Deelen P, Vatanen T, Schirmer M, Smeekens SP (2016) The effect of host genetics on the gut microbiome. Nat Genet 48:1407–1412

DOI

9
Bouvy JC, De Bruin ML, Koopmanschap MA (2015) Epidemiology of adverse drug reactions in Europe: a review of recent observational studies. Drug Saf 38:437–453

DOI

10
Campbell TC, Hayes JR (1976) The effect of quantity and quality of dietary protein on drug metabolism. Fed Proc 35:2470–2474

11
Dabek M, McCrae SI, Stevens VJ, Duncan SH, Louis P (2008) Distribution of beta-glucosidase and beta-glucuronidase activity and of beta-glucuronidase gene gus in human colonic bacteria. FEMS Microbiol Ecol 66:487–495

DOI

12
Dao MC, Everard A, Aron-Wisnewsky J, Sokolovska N, Prifti E, Verger EO, Kayser BD, Levenez F, Chilloux J, Hoyles L (2016) Akkermansia muciniphilaand improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut 65:426–436

DOI

13
David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, Ling AV, Devlin AS, Varma Y, Fischbach MA (2013) Diet rapidly and reproducibly alters the human gut microbiome. Nature 505:559–563

DOI

14
Derrien M, Vaughan EE, Plugge CM, de Vos WM (2004) Akkermansia muciniphilagen. nov., sp. nov., a human intestinal mucindegrading bacterium. Int J Syst Evol Microbiol 54:1469–1476

DOI

15
Dial S, Alrasadi K, Manoukian C, Huang A, Menzies D (2004) Risk of Clostridium difficilediarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case–control studies. CMAJ 171:33–38

DOI

16
European surveillance of Clostridium difficile infections.Surveillance protocol version 2.2 (2015) European Centre for Disease Prevention and Control. https://doi.org/10.2900/44795

17
Everard A, Lazarevic V, Derrien M, Girard M, Muccioli GG, Muccioli GM, Neyrinck AM, Possemiers S, Van Holle A, François P (2011) Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice. Diabetes 60:2775–2786

DOI

18
Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, Guiot Y, Derrien M, Muccioli GG, Delzenne NM (2013) Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci USA 110:9066–9071

DOI

19
Falcony G, Joossens M, Vieira-Silva S, Wang J, Darzi Y, Faust K, Kurilshikov A, Bonder MJ, Valles-Colomer M, Vandeputte D (2016) Population-level analysis of gut microbiome variation. Science 352:560–564

DOI

20
Forslund K, Hildebrand F, Nielsen T, Falony G, Le Chatelier E, Sunagawa S, Prifti E, Vieira-Silva S, Gudmundsdottir V, Krogh Pedersen H (2015) Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528:262–266

DOI

21
Francino MP (2016) Antibiotics and the human gut microbiome: dysbioses and accumulation of resistances. Front Microbiol.https://doi.org/10.3389/fmicb.2015.01543

DOI

22
Freedberg DE, Lebwohl B, Abrams JA (2014) The impact of proton pump inhibitors on the human gastrointestinal microbiome—clinical key. Clin Lab Med 34:771–785

DOI

23
Freedberg DE, Toussaint NC, Chen SP, Ratner AJ, Whittier S, Wang TC, Wang HH, Abrams JA (2015) Proton pump inhibitors alter specific taxa in the human gastrointestinal microbiome: a crossover trial. Gastroenterology 149:883–885

DOI

24
Fu J, Bonder MJ, Cenit MC, Tigchelaar EF, Maatman A, Dekens JAM, Brandsma E, Marczynska J, Imhann F, Weersma RK (2015) The gut microbiome contributes to a substantial proportion of the variation in blood lipids. Circ Res 117:817–824

DOI

25
Fuller AT (1937) Is p-aminobenzenesulphonamide the active agent in protonsil therapy? Lancet (Lond) 229:194–198

DOI

26
Goodrich JK, Waters JL, Poole AC, Sutter JL, Koren O, Blekhman R, Beaumont M, Van Treuren W, Knight R, Bell JT (2014) Human genetics shape the gut microbiome. Cell 159:789–799

DOI

27
Goodrich JK, Davenport ER, Beaumont M, Jackson MA, Knight R, Ober C, Spector TD, Bell JT, Clark AG, Ley RE (2016) Genetic determinants of the gut microbiome in UK twins. Cell Host Microbe 19:731–743

DOI

28
Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC(2017) Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 4236:1–15

29
Haiser HJ, Gootenberg DB, Chatman K, Sirasani G, Balskus EP, Turnbaugh PJ (2013) Predicting and manipulating cardiac drug inactivation by the human gut bacterium Eggerthella lenta. Science 341:295–298

DOI

30
Harris RZ, Jang GR, Tsunoda S (2003) Dietary effects on drug metabolism and transport. Clin Pharmacokinet 42:1071–1088

DOI

31
Higuchi K, Umegaki E, Watanabe T, Yoda Y, Morita E, Murano M, Tokioka S, Arakawa T (2009) Present status and strategy of NSAIDs-induced small bowel injury. J Gastroenterol 44:879–888

DOI

32
Huh D, Hamilton GA, Ingber DE (2011) From 3D cell culture to organs-on-chips. Trends Cell Biol 21:745–754

DOI

33
Huttenhower C, Human Microbiome Project Consortium (2012) Structure, function and diversity of the healthy human microbiome. Nature 486:207–214

DOI

34
Imhann F, Bonder MJ, Vila AV, Fu J, Mujagic Z, Vork L,Tigchelaar EF, Jankipersadsing SA, Cenit MC, Harmsen HJM (2016) Proton pump inhibitors affect the gut microbiome. Gut 65:740–748

DOI

35
Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch L, Ramírez J, Rudin CM (2004) Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 22:1382–1388

DOI

36
Jackson MA, Goodrich JK, Maxan M-E, Freedberg DE, Abrams JA, Poole AC, Sutter JL, Welter D, Ley RE, Bell JT (2016) Proton pump inhibitors alter the composition of the gut microbiota. Gut 65:749–756

DOI

37
Jourova L, Anzenbacher P, Anzenbacherova E (2016) Human gut microbiota plays a role in the metabolism of drugs. Biomed Pap 160:317–326

DOI

38
Kaddurah-Daouk R, Baillie RA, Zhu H, Zeng ZB, Wiest MM, Nguyen UT, Wojnoonski K, Watkins SM, Trupp M, Krauss RM (2011) Enteric microbiome metabolites correlate with response to simvastatin treatment. PLoS ONE. https://doi.org/10.1371/ journal.pone.0025482

DOI

39
Kalow W, Tang B-K, Endrenyi L (1998) Hypothesis: comparisons of inter- and intra-individual variations can substitute for twin studies in drug research. Pharmacogenetics 8:283–289

DOI

40
Kim HJ, Huh D, Hamilton G, Ingber DE (2012) Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsislike motions and flow. Lab Chip 12:2165

DOI

41
Koppel N, Rekdal VM, Balskus EP (2017) Chemical transformation of xenobiotics by the human gut microbiota. Science 356:1246–1257

DOI

42
Kumar K, Jaiswal SK, Dhoke GV, Srivastava GN, Sharma AK, Sharma VK (2017) Mechanistic and structural insight into promiscuity based metabolism of cardiac drug digoxin by gut microbial enzyme. J Cell Biochem. https://doi.org/10.1002/jcb. 26638

43
Kurilshikov A, Wijmenga C, Fu J, Zhernakova A(2017) Host genetics and gut microbiome: challenges and perspectives. Trends Immunol 38:633–647

DOI

44
Lagier J-C, Khelaifia S, Alou MT, Ndongo S, Dione N, Hugon P, Caputo A, Cadoret F, Traore SI, Seck EH (2016) Culture of previously uncultured members of the human gut microbiota by culturomics. Nat Microbiol 1:16203

DOI

45
Lindenbaum J, Rund DG, Butler VPJ, Tse-Eng D, Saha JR (1981) Inactivation of digoxin by the gut flora: reversal by antibiotic therapy. N Engl J Med 305:789–794

DOI

46
Madian AG, Wheeler HE, Jones RB, Dolan ME (2012) Relating human genetic variation to variation in drug responses. Trends Genet 28:487–495

DOI

47
Markowitz JS, Donovan JL, DeVane CL, Taylor RM, Wort TJOHNS, Per HY, Ruan Y, Wang J-S, Chavin KD (2003) Effect of St John’s wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. JAMA 290:1500–1504

DOI

48
Omenetti S, Pizarro TT (2015) The Treg/Th17 axis: a dynamic balance regulated by the gut microbiome. Front Immunol. https://doi.org/10.3389/fimmu.2015.00639

DOI

49
Peppercorn MA, Goldman P (1972) The role of intestinal bacteria in the metabolism of salicylazosulfapyridine. J Pharmacol Exp Ther 181:555–562

50
Peters SA, Jones CR, Ungell AL, Hatley OJD (2016) Predicting drug extraction in the human gut wall: assessing contributions from drug metabolizing enzymes and transporter proteins using preclinical models. Clin Pharmacokinet 55:673–696

DOI

51
Plovier H,Everard A , Druart C, Depommier C, Van Hul M, Geurts L, Chilloux J, Ottman N, Duparc T, Lichtenstein L (2017) A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat Med 23:107–113

DOI

52
Raju TN (1999) The nobel chronicles. Lancet 353:681

DOI

53
Roopchand DE, Carmody RN, Kuhn P, Moskal K, Rojas-Silva P, Turnbaugh PJ, Raskin I (2015) Dietary polyphenols promote growth of the gut bacterium Akkermansia muciniphila and attenuate high-fat diet-induced metabolic syndrome. Diabetes 64:2847–2858

DOI

54
Rothschild D, Weissbrod O, Barkan E, Korem T, Zeevi D, Costea PI, Godneva A, Kalka IN, Bar N, Zmora N (2017) Environmental factors dominate over host genetics in shaping human gut microbiota composition. bioRxiv.https://doi.org/10.1101/150540

DOI

55
Routy B, Le Chatelier E, Derosa L,Duong CPM, Alou MT, Daillère R, Fluckiger A, Messaoudene M, Rauber C,Roberti MP (2018) Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359:91–97

DOI

56
Saad R, Rizkallah MR, Aziz RK (2012) Gut pharmacomicrobiomics: the tip of an iceberg of complex interactions between drugs and gut-associated microbes. Gut Pathog 4:16

DOI

57
Saha JR, Butler VP, Neu HC, Lindenbaum J (1983) Digoxininactivating bacteria: identification in human gut flora. Science 220:325–327

DOI

58
Schirmer M, Smeekens SP, Vlamakis H, Jaeger M, Oosting M, Franzosa EA, Jansen T, Jacobs L, Bonder MJ, Kurilshikov A (2016) Linking the human gut microbiome to inflammatory cytokine production capacity. Cell 167:1125.e8–1136.e8

DOI

59
Scholtens S, Smidt N, Swertz MA, Bakker SJL, Dotinga A, Vonk JM, Van Dijk F, Van Zon SKR, Wijmenga C, Wolffenbuttel BHR (2015) Cohort profile: LifeLines, a three-generation cohort study and biobank. Int J Epidemiol 44:1172–1180

DOI

60
Sheehan NA, Didelez V, Burton PR, Tobin MD (2008) Mendelian randomisation and causal inference in observational epidemiology. PLoS Med 5:e177

DOI

61
Shin NR, Lee JC, Lee HY, Kim MS, Whon TW, Lee MS, Bae JW (2014) An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in dietinduced obese mice. Gut 63:727–735

DOI

62
Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, Benyamin FW, Man Lei Y, Jabri B, Alegre M-L (2015) Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350:1084–1089

DOI

63
Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly-Y M, Glickman JN, Garrett WS (2013) The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341:569–573

DOI

64
Spanogiannopoulos P, Bess EN, Carmody RN, Turnbaugh PJ (2016) The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism. Nat Rev Microbiol 14:273–287

DOI

65
Spear BB, Heath-Chiozzi M, Huff J (2001) Clinical application of pharmacogenetics. Trends Mol Med 7:201–204

DOI

66
Sperry J, Wilkins T (1976) Arginine, a growth-limiting factor for Eubacterium lentum. J Bacteriol 127:780–784

67
Stefka AT, Feehley T, Tripathi P,Qiu J, McCoy K, Mazmanian SK, Tjota MY, Seo G-Y, Cao S, Theriault BR (2014) Commensal bacteria protect against food allergen sensitization. Proc Natl Acad Sci USA 111:13145–13150

DOI

68
Stein A, Voigt W, Jordan K (2010) Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management. Ther Adv Med Oncol 2:51–63

DOI

69
Sudlow C, Gallacher J, Allen N, Beral V, Burton P,Danesh J, Downey P, Elliott P, Green J, Landray M (2015) UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med.https://doi.org/10.1371/journal.pmed.1001779

DOI

70
Sultana J, Cutroneo P, Trifirò G (2013) Clinical and economic burden of adverse drug reactions. J Pharmacol Pharmacother 4:S73–S77

DOI

71
Sylvetsky AC, Edelstein SL, Walford G, Boyko EJ, Horton ES, Ibebuogu UN, Knowler WC, Montez MG, Temprosa M, Hoskin M (2017) A high-carbohydrate, high-fiber, low-fat diet results in weight loss among adults at high risk of type 2 diabetes. J Nutr.https://doi.org/10.3945/jn.117.252395

DOI

72
Takayama K, Inamura M, Kawabata K, Katayama K, Higuchi M, Tashiro K, Nonaka A, Sakurai F, Hayakawa T, Furue MK (2012) Efficient generation of functional hepatocytes from human embryonic stem cells and induced pluripotent stem cells by HNF4α transduction. Mol Ther 20:127–137

DOI

73
Takebe T, Zhang RR, Koike H,, Kimura M, Yoshizawa E, Enomura M, Koike N, Sekine K, Taniguchi H (2014) Generation of a vascularized and functional human liver from an iPSC-derived organ bud transplant. Nat Protoc 9:396–409

DOI

74
Tigchelaar EF, Zhernakova A, Dekens JAM, Hermes G, Baranska A, Mujagic Z, Swertz MA, Muñoz AM, Deelen P,Cénit MC (2015) Cohort profile: LifeLines DEEP, a prospective, general population cohort study in the northern Netherlands: study design and baseline characteristics. BMJ Open 5:e006772

DOI

75
Tigchelaar EF, Bonder MJ, Jankipersadsing SA, Fu J, Wijmenga C, Zhernakova A (2016) Gut microbiota composition associated with stool consistency. Gut 65:540–542

DOI

76
Touw DJ (1997) Clinical implications of genetic polymorphisms and drug interactions mediated by cytochrome P-450 enzymes. Drug Metab Drug Interact 14:55–82

77
Trietsch SJ, Naumovska E, Kurek D, Setyawati MC, Vormann MK, Wilschut KJ, Lanz HL, Nicolas A, Ng CP, Joore J (2017) Membrane-free culture and real-time barrier integrity assessment of perfused intestinal epithelium tubes. Nat Commun.https://doi. org/10.1038/s41467-017-00259-3

DOI

78
Wallace BD, Hongwei W, Lane KT, Scott JE, Orans J, Koo JS, Venkatesh M, Jobin C, Yeh L-A, Mani S (2010) Alleviating cancer drug toxicity by inhibiting a bacterial enzyme. Science 330:831–835

DOI

79
Wang J, Thingholm LB, Skiecevičienė J, Rausch P, Kummen M, Hov JR, Degenhardt F, Heinsen F-A, Rühlemann MC, Szymczak S (2016) Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota. Nat Genet 48:1396–1406

DOI

80
Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R, Mannerås-Holm L, Ståhlman M, Olsson LM, Serino M, Planas-Fèlix M (2017) Metformin alters the gut microbiome of individuals with treatmentnaive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med 23:850–858

DOI

81
Yadav V,Gaisford S, Merchant HA, Basit AW (2013) Colonic bacterial metabolism of corticosteroids. Int J Pharm 457:268–274

DOI

82
Yepuri G, Sukhovershin R, Nazari-Shafti TZ, Petrascheck M, Ghebre YT, Cooke JP (2016) Proton pump inhibitors accelerate endothelial senescence. Circ Res 118:e36–e42

DOI

83
Zeevi D, Korem T, Zmora N, Israeli D, Rothschild D, Weinberger A, Ben-Yacov O, Lador D, Avnit-Sagi T, Lotan-Pompan M (2015) Personalized nutrition by prediction of glycemic responses. Cell 163:1079–1095

DOI

84
Zhernakova A, Kurilshikov A, Bonder MJ, Tigchelaar EF, Schirmer M, Vatanen T, Mujagic Z,, Vila AV, Falony G, Vieira-Silva S (2016) Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science 352:565–569

DOI

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