Can Fecal Microbiota Transplantation Become a Standard of Care for Ulcerative Colitis?

Can Fecal Microbiota Transplantation Become a Standard of Care for Ulcerative Colitis?

Growing evidence indicates that alterations in the gut microbiome, known as “dysbiosis,” is one of the most influential environmental factors that may promote the development of ulcerative colitis (UC).1 Patients with UC have specific gut microbiota changes linked to the impairment of various functions, including short-chain fatty acid metabolism, amino acid biosynthesis, oxidative stress control, and toxin production.1 As a result, both patients and clinicians have expressed interest in using therapeutic manipulation of gut microbiota, via fecal microbiota transplantation (FMT), as a potential treatment for UC. Before FMT can become a standard treatment for UC, there are several challenges to address, and this concept is yet to be fully translated into clinical practice.

How Is FMT Performed?

The aim of FMT is to correct dysbiosis caused due to impaired gut microbiota. Feces from healthy donors is infused into the gut of a recipient, and it can be performed in many ways, with colonoscopy being the most common. Currently, it is recommended as an effective treatment strategy for recurrent Clostridium difficile (C difficile) infection.2

FMT for Ulcerative Colitis


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FMT for UC was first reported in 1989 when Justin Bennet, a physician with severe active UC, used an enema to self-administer a fecal infusion from a healthy donor and achieved a 6-month symptom-free remission.3 Since then, FMT has been rarely used in UC and mostly in patients with C difficile superinfection. According to a systemic review, only 27 patients with UC were treated with FMT in 2011.4 In recent years, there has been a growing interest in FMT for UC, and several randomized controlled trials (RCTs) and cohort studies have been published. It is an evolving therapy, still in its earliest stage, with significant gaps in understanding the mechanisms involved and logistics of practical application.

Controlled Trials of FMT for Ulcerative Colitis

Two randomized trials evaluating FMT for the induction of remission in UC were published with conflicting results in 2015.5,6 In a double-blind, placebo-controlled, randomized trial named TURN (Transplantation of Feces in UC: Returning Nature’s Homeostasis) trial, Rossen et al. reported no significant difference in clinical remission at 12 weeks between patients with UC who received fecal transplantation from donors and patients with UC who received their own fecal microbiota (30.4% [7/23] vs 20% [5/25]).5 Moreover, both recipients had increased microbial diversity scores (increased Clostridium clusters IV, XIVa and XVIII and decreased Bacteroidetes) at 12 weeks than at baseline.5 The study reported no serious adverse events. In a study by Moayyedi et al., the remission rate at week 7 was significantly higher among patients receiving donor FMT compared with those receiving placebo (24% [9/38] vs 5% [2/37]).6 No significant difference in adverse events was observed between the 2 groups. The FMT group had a significant increase in microbial diversity compared with the placebo. Both these studies used feces from a single donor in each transplantation.

In another study by Paramsothy et al., feces from multiple donors were used with intensively repeated FMT for 8 weeks. The number of patients achieving remission at 8 weeks was significantly higher in the FMT group compared with placebo (27% [11/41] vs 8% [3/40]).7 Similar to the previous studies, microbial diversity was significantly higher among FMT recipients than at baseline. Furthermore, microbial diversity was higher in donor batches compared with samples from individual donors. Barnesiella, Parabacteroides, Clostridium cluster IV, and Ruminococcus species all correlated with clinical remission, whereas Fusobacterium  and Sutterella species correlated with nonremission.7

Costello et al. in their study evaluated the efficacy of anaerobically prepared feces from multiple donors and compared it with self-fecal transplantation. Remission was achieved in 32% (12/38) of patients receiving feces from donors and was significantly higher than in those receiving their own feces 9% (3/35).8 Microbial diversity was higher among patients receiving donor FMT compared with those receiving their own FMT.

Another study evaluating the therapeutic benefits of a combination of FMT with pretreatment of an antibiotic cocktail (amoxicillin, fosfomycin, and metronidazole) reported increased rates of clinical response at 4 weeks in patients receiving the combination therapy compared with those receiving only the antibiotic cocktail (82.4% [14/17] vs 68.4% [13/19]).9 Bacteroidetes were completely eradicated by antibiotics but were recovered in patients receiving FMT, thereby suggesting a beneficial role of Bacteroidetes in the management of UC.9

Challenges of FMT

Patient and donor selection

Most of the participants in the randomized trials so far were middle-aged patients with mild to moderately active UC who were taking stable doses of concomitant medications.5-8 The results of these trials cannot be compared due to variability in the route and dose of administration, the number of treatment sessions, choice of placebo, and the exact indication for FMT.

In addition to screening for infectious agents and multi-drug resistant organisms, microbial diversity profiling and functionality are key to optimal donor selection. Currently, both recipient and donor genetics and their dietary patterns are not routinely analyzed, which could impact ideal donor selection. Based on the findings of Moayyedi et al., microbial diversity of the donor was the most important predictor of FMT outcome.6 However, Paramsothy et al. did not find a significant increase in clinical response despite using multi-donor intensive FMT.7 Furthermore, a multi-omics approach to characterize recipient and donor metagenomics, metatranscriptomics, and metabolomics, in order to correct functional inadequacies through suitable matching, may improve the efficacy of FMT.10

Route of administration

So far, there is no consensus on the perfect route of administration of FMT. Studies showed better response rates with colonic transplantation compared with upper GI route.5-8 For upper and lower GI tract administration, the pooled proportion of clinical remission rates were 8% and 31%, respectively.11 The response rates when delivered via enema varied from 24% to 32% in RCTs.6-8 However, by using a multisession colonoscopic approach, steroid-free clinical remission was achieved in 46.3% of patients.12

Regulation of FMT

FMT is still in its early stages of development for patients with UC and is not currently recommended as a standard of care for UC and is applied only in clinical trials. Even in the case of recurrent C difficile, the FDA exercises discretion and categorizes it as an investigational new drug. The exact composition of fecal samples, even from the same donor, varies on different days.12 Therefore, it is extremely challenging for regulatory authorities to assess the safety of this approach, and it is unlike any other therapeutics approved for clinical use. This is further complicated by drug-resistant Escherichia coli transmission in immunocompromised patients.13 To date, no consensus exists on how FMT must be classified or regulated. In the US and Canada, FMT is regulated as a drug and in Australia as a biologic but remains unregulated in many countries.

Conclusion

Based on randomized controlled trial results, FMT has the potential to become an effective therapy for UC. However, standardization of administration method, frequency of application, optimization of donors, and patient selection are required to implement it in clinical practice, which is challenging and complicated and warrants more research to standardize the procedure. Furthermore, studies are inconsistent in terms of microbial populations that can predict the therapeutic effect of FMT. Further research is required to identify appropriate recipients for whom FMT is beneficial, including long-term efficacy and safety.

References

  1. Cammarota G, Ianiro G, Cianci R, Bibbò S, Gasbarrini A, Currò D. The involvement of gut microbiota in inflammatory bowel disease pathogenesis: potential for therapy. Pharmacol Ther. 2015;149:191-212. doi:10.1016/j.pharmthera.2014.12.006
  2. McDonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):987-994. doi:10.1093/cid/ciy149
  3. Bennet JD, Brinkman M. Treatment of ulcerative colitis by implantation of normal colonic flora. Lancet. 1989;333(8630):164. doi:10.1016/s0140-6736(89)91183-5
  4. Anderson JL, Edney RJ, Whelan K. Systematic review: faecal microbiota transplantation in the management of inflammatory bowel disease. Aliment Pharmacol Ther. 2012;36(6):503-516. doi:10.1111/j.1365-2036.2012.05220.x
  5. Rossen NG, Fuentes S, van der Spek MJ, et al. Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis. Gastroenterology. 2015;149(1):110-118.e4. doi:10.1053/j.gastro.2015.03.045
  6. Moayyedi P, Surette MG, Kim PT, 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
  7. Paramsothy S, Kamm MA, Kaakoush NO, 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
  8. Costello SP, Hughes PA, Waters O, 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
  9. Ishikawa D, Sasaki T, Osada T, et al. Changes in intestinal microbiota following combination therapy with fecal microbial transplantation and antibiotics for ulcerative colitis. Inflamm Bowel Dis. 2017;23(1):116-125. doi:10.1097/MIB.0000000000000975
  10. Duvallet C, Zellmer C, Panchal P, Budree S, Osman M, Alm EJ. Framework for rational donor selection in fecal microbiota transplant clinical trials. PLoS One. 2019;14(10):e0222881. doi:10.1371/journal.pone.0222881
  11. Fang H, Fu L, Wang J. Protocol for fecal microbiota transplantation in inflammatory bowel disease: A systematic review and meta-analysis. Biomed Res Int. 2018;2018:8941340. doi:10.1155/2018/8941340
  12. Sood A, Mahajan R, Juyal G, et al. Efficacy of fecal microbiota therapy in steroid dependent ulcerative colitis: a real world intention-to-treat analysis. Intest Res. 2019;17(1):78-86. doi:10.5217/ir.2018.00089
  13. DeFilipp Z, Bloom PP, Torres Soto M, et al. Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant. N Engl J Med. 2019;381(21):2043-2050. doi:10.1056/NEJMoa1910437

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General Inflammatory Bowel Diseases (IBD) Ulcerative Colitis