#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Fecal microbiota transplantation for the improvement of metabolism in obesity: The FMT-TRIM double-blind placebo-controlled pilot trial


Autoři: Elaine W. Yu aff001;  Liu Gao aff001;  Petr Stastka aff001;  Michael C. Cheney aff001;  Jasmin Mahabamunuge aff003;  Mariam Torres Soto aff003;  Christopher B. Ford aff004;  Jessica A. Bryant aff004;  Matthew R. Henn aff004;  Elizabeth L. Hohmann aff002
Působiště autorů: Endocrine Unit, Division of Endocrinology and Metabolism, Massachusetts General Hospital, Boston, Massachusetts, United States of America aff001;  Harvard Medical School, Boston, Massachusetts, United States of America aff002;  Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America aff003;  Seres Therapeutics, Cambridge, Massachusetts, United States of America aff004
Vyšlo v časopise: Fecal microbiota transplantation for the improvement of metabolism in obesity: The FMT-TRIM double-blind placebo-controlled pilot trial. PLoS Med 17(3): e1003051. doi:10.1371/journal.pmed.1003051
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pmed.1003051

Souhrn

Background

There is intense interest about whether modulating gut microbiota can impact systemic metabolism. We investigated the safety of weekly oral fecal microbiota transplantation (FMT) capsules from healthy lean donors and their ability to alter gut microbiota and improve metabolic outcomes in patients with obesity.

Methods and findings

FMT-TRIM was a 12-week double-blind randomized placebo-controlled pilot trial of oral FMT capsules performed at a single US academic medical center. Between August 2016 and April 2018, we randomized 24 adults with obesity and mild–moderate insulin resistance (homeostatic model assessment of insulin resistance [HOMA-IR] between 2.0 and 8.0) to weekly healthy lean donor FMT versus placebo capsules for 6 weeks. The primary outcome, assessed by intention to treat, was change in insulin sensitivity between 0 and 6 weeks as measured by hyperinsulinemic euglycemic clamps. Additional metabolic parameters were evaluated at 0, 6, and 12 weeks, including HbA1c, body weight, body composition by dual-energy X-ray absorptiometry, and resting energy expenditure by indirect calorimetry. Fecal samples were serially collected and evaluated via 16S V4 rRNA sequencing. Our study population was 71% female, with an average baseline BMI of 38.8 ± 6.7 kg/m2 and 41.3 ± 5.1 kg/m2 in the FMT and placebo groups, respectively. There were no statistically significant improvements in insulin sensitivity in the FMT group compared to the placebo group (+5% ± 12% in FMT group versus −3% ± 32% in placebo group, mean difference 9%, 95% CI −5% to 28%, p = 0.16). There were no statistically significant differences between groups for most of the other secondary metabolic outcomes, including HOMA-IR (mean difference 0.2, 95% CI −0.9 to 0.9, p = 0.96) and body composition (lean mass mean difference −0.1 kg, 95% CI −1.9 to 1.6 kg, p = 0.87; fat mass mean difference 1.2 kg, 95% CI −0.6 to 3.0 kg, p = 0.18), over the 12-week study. We observed variable engraftment of donor bacterial groups among FMT recipients, which persisted throughout the 12-week study. There were no significant differences in adverse events (AEs) (10 versus 5, p = 0.09), and no serious AEs related to FMT. Limitations of this pilot study are the small sample size, inclusion of participants with relatively mild insulin resistance, and lack of concurrent dietary intervention.

Conclusions

Weekly administration of FMT capsules in adults with obesity results in gut microbiota engraftment in most recipients for at least 12 weeks. Despite engraftment, we did not observe clinically significant metabolic effects during the study.

Trial registration

ClinicalTrials.gov NCT02530385.

Klíčová slova:

Antibiotics – Drug metabolism – Glucose metabolism – Insulin – Insulin resistance – Microbiome – Obesity – Shotgun sequencing


Zdroje

1. Tilg H, Kaser A. Gut microbiome, obesity, and metabolic dysfunction. J Clin Invest. 2011;121(6):2126–32. doi: 10.1172/JCI58109 21633181

2. Maruvada P, Leone V, Kaplan LM, Chang EB. The human microbiome and obesity: moving beyond associations. Cell Host Microbe. 2017;22(5):589–99. doi: 10.1016/j.chom.2017.10.005 29120742

3. Ridaura VK, Faith JJ, Rey FE, Cheng J, Duncan AE, Kau AL, et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science. 2013;341(6150):1241214. doi: 10.1126/science.1241214 24009397

4. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444(7122):1027–31. doi: 10.1038/nature05414 17183312

5. Thaiss CA, Zeevi D, Levy M, Zilberman-Schapira G, Suez J, Tengeler AC, et al. Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell. 2014;159(3):514–29. doi: 10.1016/j.cell.2014.09.048 25417104

6. Cox LM, Yamanishi S, Sohn J, Alekseyenko AV, Leung JM, Cho I, et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell. 2014;158(4):705–21. doi: 10.1016/j.cell.2014.05.052 25126780

7. Bahr SM, Weidemann BJ, Castro AN, Walsh JW, deLeon O, Burnett CML, et al. Risperidone-induced weight gain is mediated through shifts in the gut microbiome and suppression of energy expenditure. EBioMedicine. 2015;2(11):1725–34. doi: 10.1016/j.ebiom.2015.10.018 26870798

8. Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A. 2004;101(44):15718–23. doi: 10.1073/pnas.0407076101 15505215

9. Le Roy T, Llopis M, Lepage P, Bruneau A, Rabot S, Bevilacqua C, et al. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut. 2013;62(12):1787–94. doi: 10.1136/gutjnl-2012-303816 23197411

10. Liou AP, Paziuk M, Luevano JM, Machineni S, Turnbaugh PJ, Kaplan LM. Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci Transl Med. 2013;5(178):178ra41. doi: 10.1126/scitranslmed.3005687 23536013

11. Smith MI, Yatsunenko T, Manary MJ, Trehan I, Mkakosya R, Cheng J, et al. Gut microbiomes of Malawian twin pairs discordant for kwashiorkor. Science. 2013;339(6119):548–54. doi: 10.1126/science.1229000 23363771

12. Nguyen TL, Vieira-Silva S, Liston A, Raes J. How informative is the mouse for human gut microbiota research? Dis Model Mech. 2015;8(1):1–16. doi: 10.1242/dmm.017400 25561744

13. Bailey LC, Forrest CB, Zhang P, Richards TM, Livshits A, DeRusso PA. Association of antibiotics in infancy with early childhood obesity. JAMA Pediatr. 2014;168(11):1063–9. doi: 10.1001/jamapediatrics.2014.1539 25265089

14. Stark CM, Susi A, Emerick J, Nylund CM. Antibiotic and acid-suppression medications during early childhood are associated with obesity. Gut. 2019;68(1):62–9. doi: 10.1136/gutjnl-2017-314971 30377188

15. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature. 2006;444(7122):1022–3. doi: 10.1038/4441022a 17183309

16. Le Chatelier E, Nielsen T, Qin J, Prifti E, Hildebrand F, Falony G, et al. Richness of human gut microbiome correlates with metabolic markers. Nature. 2013;500(7464):541–6. doi: 10.1038/nature12506 23985870

17. Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, et al. A core gut microbiome in obese and lean twins. Nature. 2009;457(7228):480–4. doi: 10.1038/nature07540 19043404

18. Karlsson FH, Tremaroli V, Nookaew I, Bergstrom G, Behre CJ, Fagerberg B, et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature. 2013;498(7452):99–103. doi: 10.1038/nature12198 23719380

19. Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490(7418):55–60. doi: 10.1038/nature11450 23023125

20. Finucane MM, Sharpton TJ, Laurent TJ, Pollard KS. A taxonomic signature of obesity in the microbiome? Getting to the guts of the matter. PLoS ONE. 2014;9(1):e84689. doi: 10.1371/journal.pone.0084689 24416266

21. Zhernakova A, Kurilshikov A, Bonder MJ, Tigchelaar EF, Schirmer M, Vatanen T, et al. Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science. 2016;352(6285):565–9. doi: 10.1126/science.aad3369 27126040

22. Beaumont M, Goodrich JK, Jackson MA, Yet I, Davenport ER, Vieira-Silva S, et al. Heritable components of the human fecal microbiome are associated with visceral fat. Genome Biol. 2016;17(1):189. doi: 10.1186/s13059-016-1052-7 27666579

23. Vrieze A, Van Nood E, Holleman F, Salojarvi J, Kootte RS, Bartelsman JF, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012;143(4):913–6.e7. doi: 10.1053/j.gastro.2012.06.031 22728514

24. Kootte RS, Levin E, Salojarvi J, Smits LP, Hartstra AV, Udayappan SD, et al. Improvement of insulin sensitivity after lean donor feces in metabolic syndrome is driven by baseline intestinal microbiota composition. Cell Metab. 2017;26(4):611–9.e6. doi: 10.1016/j.cmet.2017.09.008 28978426

25. Gupta S, Allen-Vercoe E, Petrof EO. Fecal microbiota transplantation: in perspective. Therap Adv Gastroenterol. 2016;9(2):229–39. doi: 10.1177/1756283X15607414 26929784

26. Youngster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J, Hohmann EL. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA. 2014;312(17):1772–8. doi: 10.1001/jama.2014.13875 25322359

27. Kao D, Roach B, Silva M, Beck P, Rioux K, Kaplan GG, et al. Effect of oral capsule- vs colonoscopy-delivered fecal microbiota transplantation on recurrent Clostridium difficile infection: a randomized clinical trial. JAMA. 2017;318(20):1985–93. doi: 10.1001/jama.2017.17077 29183074

28. Youngster I, Mahabamunuge J, Systrom HK, Sauk J, Khalili H, Levin J, et al. Oral, frozen fecal microbiota transplant (FMT) capsules for recurrent Clostridium difficile infection. BMC Med. 2016;14(1):134. doi: 10.1186/s12916-016-0680-9 27609178

29. Quast C, Pruesse E, Yilmaz P, Gerken J, Schweer T, Yarza P, et al. The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res. 2013;41(Database issue):D590–6. doi: 10.1093/nar/gks1219 23193283

30. Lozupone C, Knight R. UniFrac: a new phylogenetic method for comparing microbial communities. Appl Environ Microbiol. 2005;71(12):8228–35. doi: 10.1128/AEM.71.12.8228-8235.2005 16332807

31. Gu Z, Eils R, Schlesner M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics. 2016;32(18):2847–9. doi: 10.1093/bioinformatics/btw313 27207943

32. Legendre P, Legendre L. Numerical ecology. 3rd edition. Amsterdam: Elsevier; 2012. 1006 p.

33. Li SS, Zhu A, Benes V, Costea PI, Hercog R, Hildebrand F, et al. Durable coexistence of donor and recipient strains after fecal microbiota transplantation. Science. 2016;352(6285):586–9. doi: 10.1126/science.aad8852 27126044

34. Simmons S, Diao L, O’Brien E, Chafee M, Zhao J, Bernardo P, et al. Engraftment of Ser-287, an investigational microbiome therapeutic, is related to clinical remission in a placebo-controlled, double-blind randomized trial (Seres-101) in patients with active mild to moderate ulcerative colitis (UC). Gastroenterology. 2018;154(6):S1371–2.

35. Fukuyama J, Rumker L, Sankaran K, Jeganathan P, Dethlefsen L, Relman DA, et al. Multidomain analyses of a longitudinal human microbiome intestinal cleanout perturbation experiment. PLoS Comput Biol. 2017;13(8):e1005706. doi: 10.1371/journal.pcbi.1005706 28821012

36. Deschasaux M, Bouter KE, Prodan A, Levin E, Groen AK, Herrema H, et al. Depicting the composition of gut microbiota in a population with varied ethnic origins but shared geography. Nat Med. 2018;24(10):1526–31. doi: 10.1038/s41591-018-0160-1 30150717

37. Vangay P, Johnson AJ, Ward TL, Al-Ghalith GA, Shields-Cutler RR, Hillmann BM, et al. US immigration westernizes the human gut microbiome. Cell. 2018;175(4):962–72.e10. doi: 10.1016/j.cell.2018.10.029 30388453

38. Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, et al. Human gut microbiome viewed across age and geography. Nature. 2012;486(7402):222–7. doi: 10.1038/nature11053 22699611

39. Dominianni C, Sinha R, Goedert JJ, Pei Z, Yang L, Hayes RB, et al. Sex, body mass index, and dietary fiber intake influence the human gut microbiome. PLoS ONE. 2015;10(4):e0124599. doi: 10.1371/journal.pone.0124599 25874569

40. Youngster I, Sauk J, Pindar C, Wilson RG, Kaplan JL, Smith MB, et al. Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study. Clin Infect Dis. 2014;58(11):1515–22. doi: 10.1093/cid/ciu135 24762631

41. Zeevi D, Korem T, Zmora N, Israeli D, Rothschild D, Weinberger A, et al. Personalized nutrition by prediction of glycemic responses. Cell. 2015;163(5):1079–94. doi: 10.1016/j.cell.2015.11.001 26590418

42. Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende DR, et al. Enterotypes of the human gut microbiome. Nature. 2011;473(7346):174–80. doi: 10.1038/nature09944 21508958

43. Kovatcheva-Datchary P, Nilsson A, Akrami R, Lee YS, De Vadder F, Arora T, et al. Dietary fiber-induced improvement in glucose metabolism is associated with increased abundance of Prevotella. Cell Metab. 2015;22(6):971–82. doi: 10.1016/j.cmet.2015.10.001 26552345

44. Hjorth MF, Roager HM, Larsen TM, Poulsen SK, Licht TR, Bahl MI, et al. Pre-treatment microbial Prevotella-to-Bacteroides ratio, determines body fat loss success during a 6-month randomized controlled diet intervention. Int J Obes (Lond). 2018;42(3):580–3. doi: 10.1038/ijo.2017.220 28883543


Článek vyšel v časopise

PLOS Medicine


2020 Číslo 3
Nejčtenější tento týden
Nejčtenější v tomto čísle
Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

Hypertenze a hypercholesterolémie – synergický efekt léčby
nový kurz
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Multidisciplinární zkušenosti u pacientů s diabetem
Autoři: Prof. MUDr. Martin Haluzík, DrSc., prof. MUDr. Vojtěch Melenovský, CSc., prof. MUDr. Vladimír Tesař, DrSc.

Úloha kombinovaných preparátů v léčbě arteriální hypertenze
Autoři: prof. MUDr. Martin Haluzík, DrSc.

Halitóza
Autoři: MUDr. Ladislav Korábek, CSc., MBA

Terapie roztroušené sklerózy v kostce
Autoři: MUDr. Dominika Šťastná, Ph.D.

Všechny kurzy
Přihlášení
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se

#ADS_BOTTOM_SCRIPTS#