Metagenomic and Bile Acid Metabolomic Analysis of Fecal Microbiota Transplantation for Recurrent Clostridiodes Difficile and/or Inflammatory Bowel Diseases
Main Article Content
Abstract
Background. Fecal microbiota transplantation (FMT) is an effective treatment of recurrent Clostridioides difficile infections (rCDI), but has more limited efficacy in treating either ulcerative colitis (UC) or Crohn’s disease (CD), two major forms of inflammatory bowel diseases (IBD). We hypothesize that FMT recipients with rCDI and/or IBD have baseline fecal bile acid (BA) compositions that differ significantly from that of their healthy donors and that FMT will normalize the BA compositions.
Aim. To study the effect of single colonoscopic FMT on microbial composition and function in four recipient groups: 1.) rCDI patients without IBD (rCDI-IBD); 2.) rCDI with IBD (rCDI+IBD); 3.) UC patients without rCDI (UC-rCDI); 4.) CD patients without rCDI (CD-rCDI).
Methods. We performed 16S rRNA gene sequence, shotgun DNA sequence and quantitative bile acid metabolomic analyses on stools collected from 55 pairs of subjects and donors enrolled in two prospective single arm FMT clinical trials (Clinical Trials.gov ID NCT03268213, 479696, UC no rCDI ≥ 2x IND 1564 and NCT03267238, IND 16795). Fitted linear mixed models were used to examine the effects of four recipient groups, FMT status (Donor, pre-FMT, 1-week post-FMT, 3-months post-FMT) and first order Group*FMT interactions on microbial diversity and composition, bile acid metabolites and bile acid metabolizing enzyme gene abundance.
Results. The pre-FMT stools collected from rCDI ± IBD recipients had reduced α-diversity compared to the healthy donor stools and was restored post-FMT. The α-diversity in the pre-FMT stools collected from UC-rCDI or CD-rCDI recipients did not differ significantly from donor stools. FMT normalized some recipient/donor ratios of genus level taxa abundance in the four groups. Fecal secondary BA levels, including some of the secondary BA epimers that exhibit in vitro immunomodulatory activities, were lower in rCDI±IBD and CD–rCDI but not UC-rCDI recipients compared to donors. FMT restored secondary BA levels. Metagenomic baiE gene and some of the eight bile salt hydrolase (BSH) phylotype abundances were significantly correlated with fecal BA levels.
Conclusion. Restoration of multiple secondary BA levels, including BA epimers implicated in immunoregulation, are associated with restoration of fecal baiE gene counts, suggesting that the 7-α-dehydroxylation step is rate-limiting.
Article Details
How to Cite
RAMOS, Ruben JF et al.
Metagenomic and Bile Acid Metabolomic Analysis of Fecal Microbiota Transplantation for Recurrent Clostridiodes Difficile and/or Inflammatory Bowel Diseases.
Medical Research Archives, [S.l.], v. 10, n. 10, oct. 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3318>. Date accessed: 22 dec. 2024.
doi: https://doi.org/10.18103/mra.v10i10.3318.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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4. Cammarota G, Ianiro G, Tilg H, Rajilić-Stojanović M, Kump P, Satokari R, et al. European consensus conference on faecal microbiota transplantation in clinical practice. Gut. 2017;66(4):569-580. doi: 10.1136/gutjnl-2016-313017.
5. Rodemann JF, Dubberke ER, Reske KA, Seo DH, Stone CD. Incidence of Clostridium difficile infection in inflammatory bowel disease. Clin Gastroenterol Hepatol. 2007;5(3):339-44. doi: 10.1016/j.cgh.2006.12.027.
6. Ananthakrishnan AN, Binion DG. Impact of Clostridium difficile on inflammatory bowel disease. Expert Rev Gastroenterol Hepatol. 2010;4(5):589-600. doi: 10.1586/egh.10.55.
7. Pascarella F, Martinelli M, Miele E, Del Pezzo M, Roscetto E, Staiano A. Impact of Clostridium difficile infection on pediatric inflammatory bowel disease. J Pediatr. 2009;154(6):854-8. doi: 10.1016/j.jpeds.2008.12.039.
8. Martinelli M, Strisciuglio C, Veres G, Paerregaard A, Pavic AM, Aloi M, Martín-de-Carpi J, et al. Clostridium difficile and pediatric inflammatory bowel disease: a prospective, comparative, multicenter, ESPGHAN study. Inflamm Bowel Dis. 2014;20(12):2219-25. doi: 10.1097/MIB.0000000000000219.
9. Saffouri G, Gupta A, Loftus EV Jr, Baddour LM, Pardi DS, Khanna S. The incidence and outcomes from Clostridium difficile infection in hospitalized adults with inflammatory bowel disease. Scand J Gastroenterol. 2017;52(11):1240-1247. doi: 10.1080/00365521.2017.1362466.
10. Hourigan SK, Chen LA, Grigoryan Z, Laroche G, Weidner M, Sears CL, et al. Microbiome changes associated with sustained eradication of Clostridium difficile after single faecal microbiota transplantation in children with and without inflammatory bowel disease. Aliment Pharmacol Ther. 2015;42(6):741-52. doi: 10.1111/apt.13326.
11. Fischer M, Kao D, Kelly C, Kuchipudi A, Jafri SM, Blumenkehl M, et al. Fecal microbiota transplantation is safe and efficacious for recurrent or refractory Clostridium difficile infection in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2016;22(10):2402-9. doi: 10.1097/MIB.0000000000000908.
12. Khoruts A, Rank KM, Newman KM, Viskocil K, Vaughn BP, Hamilton MJ, et al. MJ. Inflammatory Bowel Disease Affects the Outcome of Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection. Clin Gastroenterol Hepatol. 2016;14(10):1433-8. doi: 10.1016/j.cgh.2016.02.018.
13. Khanna S, Vazquez-Baeza Y, González A, Weiss S, Schmidt B, Muñiz-Pedrogo DA, et al. Changes in microbial ecology after fecal microbiota transplantation for recurrent C. difficile infection affected by underlying inflammatory bowel disease. Microbiome. 2017;5(1):55. doi: 10.1186/s40168-017-0269-3.
14. Tabbaa OM, Aboelsoud MM, Mattar MC. Long-term safety and efficacy of fecal microbiota transplantation in the treatment of Clostridium difficile infection in patients with and without inflammatory bowel disease: A tertiary care center's experience. Gastroenterology Res. 2018;11(6):397-403. doi: 10.14740/gr1091.
15. Chin SM, Sauk J, Mahabamunuge J, Kaplan JL, Hohmann EL, Khalili H. Fecal microbiota transplantation for recurrent Clostridium difficile infection in patients with inflammatory bowel disease: A single-center experience. Clin Gastroenterol Hepatol. 2017 Apr;15(4):597-599. doi: 10.1016/j.cgh.2016.11.028.
16. Kump PK, Gröchenig HP, Lackner S, Trajanoski S, Reicht G, Hoffmann KM, et al. Alteration of intestinal dysbiosis by fecal microbiota transplantation does not induce remission in patients with chronic active ulcerative colitis. Inflamm Bowel Dis. 2013;19(10):2155-65. doi: 10.1097/MIB.0b013e31829ea325.
17. Kump P, Wurm P, Gröchenig HP, Wenzl H, Petritsch W, Halwachs B, et al. The taxonomic composition of the donor intestinal microbiota is a major factor influencing the efficacy of faecal microbiota transplantation in therapy refractory ulcerative colitis. Aliment Pharmacol Ther. 2018;47(1):67-77. doi: 10.1111/apt.14387.
18. Kunde S, Pham A, Bonczyk S, Crumb T, Duba M, Conrad H Jr, et al. Safety, tolerability, and clinical response after fecal transplantation in children and young adults with ulcerative colitis. J Pediatr Gastroenterol Nutr. 2013;56(6):597-601. doi: 10.1097/MPG.0b013e318292fa0d.
19. Moayyedi P, Surette MG, Kim PT, Libertucci J, Wolfe M, Onischi C, et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology. 2015;149(1):102-109.e6. doi: 10.1053/j.gastro.2015.04.001.
20. Mizuno S, Nanki K, Matsuoka K, Saigusa K, Ono K, Arai M, et al. Single fecal microbiota transplantation failed to change intestinal microbiota and had limited effectiveness against ulcerative colitis in Japanese patients. Intest Res. 2017;15(1):68-74. doi: 10.5217/ir.2017.15.1.68.
21. Nishida A, Imaeda H, Ohno M, Inatomi O, Bamba S, Sugimoto M, et al. Efficacy and safety of single fecal microbiota transplantation for Japanese patients with mild to moderately active ulcerative colitis. J Gastroenterol. 2017;52(4):476-482. doi: 10.1007/s00535-016-1271-4.
22. Paramsothy S, Kamm MA, Kaakoush NO, Walsh AJ, van den Bogaerde J, Samuel D, Leong RWL, et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet. 2017;389(10075):1218-1228. doi: 10.1016/S0140-6736(17)30182-4.
23. Costello SP, Hughes PA, Waters O, Bryant RV, Vincent AD, Blatchford P, et al. Effect of fecal microbiota transplantation on 8-week remission in patients with ulcerative colitis: A randomized clinical trial. JAMA. 2019;321(2):156-164. doi: 10.1001/jama.2018.20046.
24. Fuentes S, Rossen NG, van der Spek MJ, Hartman JH, Huuskonen L, Korpela K, et al. Microbial shifts and signatures of long-term remission in ulcerative colitis after faecal microbiota transplantation. ISME J. 2017;11(8):1877-1889. doi: 10.1038/ismej.2017.44.
25. Vermeire S, Joossens M, Verbeke K, Wang J, Machiels K, Sabino J, et al. Donor species richness determines faecal microbiota transplantation success in inflammatory bowel disease. J Crohns Colitis. 2016;10(4):387-94. doi: 10.1093/ecco-jcc/jjv203.
26. Gutin L, Piceno Y, Fadrosh D, Lynch K, Zydek M, Kassam Z, et al. Fecal microbiota transplant for Crohn disease: A study evaluating safety, efficacy, and microbiome profile. United European Gastroenterol J. 2019;7(6):807-814. doi: 10.1177/2050640619845986.
27. Sokol H, Landman C, Seksik P, Berard L, Montil M, Nion-Larmurier I, et al. Fecal microbiota transplantation to maintain remission in Crohn's disease: a pilot randomized controlled study. Microbiome. 2020;8(1):12. doi: 10.1186/s40168-020-0792-5.
28. Buffie CG, Bucci V, Stein RR, McKenney PT, Ling L, Gobourne A, et al. Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nature. 2015;517(7533):205-8. doi: 10.1038/nature13828.
29. Ridlon JM, Harris SC, Bhowmik S, Kang DJ, Hylemon PB. Consequences of bile salt biotransformations by intestinal bacteria. Gut Microbes. 2016;7(1):22-39. doi: 10.1080/19490976.2015.1127483.
30. Hang S, Paik D, Yao L, Kim E, Trinath J, Lu J, et al. Bile acid metabolites control TH17 and Treg cell differentiation. Nature. 2019;576(7785):143-148. doi: 10.1038/s41586-019-1785-z.
31. Campbell C, McKenney PT, Konstantinovsky D, Isaeva OI, Schizas M, Verter J, et al. Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells. Nature. 2020;581(7809):475-479. doi: 10.1038/s41586-020-2193-0.
32. Li W, Hang S, Fang Y, Bae S, Zhang Y, Zhang M, et al. A bacterial bile acid metabolite modulates Treg activity through the nuclear hormone receptor NR4A1. Cell Host Microbe. 2021;29(9):1366-1377.e9. doi: 10.1016/j.chom.2021.07.013.
33. Franzosa EA, Sirota-Madi A, Avila-Pacheco J, Fornelos N, Haiser HJ, Reinker S, et al. Gut microbiome structure and metabolic activity in inflammatory bowel disease. Nat Microbiol. 2019;4(2):293-305. doi: 10.1038/s41564-018-0306-4.
34. Paik D, Yao L, Zhang Y, Bae S, D'Agostino GD, Zhang M, et al. Human gut bacteria produce ΤΗ17-modulating bile acid metabolites. Nature. 2022;603(7903):907-912. doi: 10.1038/s41586-022-04480-z.
35. Connors J, Dunn KA, Allott J, Bandsma R, Rashid M, Otley AR, et al. The relationship between fecal bile acids and microbiome community structure in pediatric Crohn's disease. ISME J. 2020;14(3):702-713. doi: 10.1038/s41396-019-0560-3.
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