Fecal Microbiota

Transplantation
POSSIBLE TREATMENT OF INFLAMMATORY BOWEL
DISEASE?
CHARLEY SOMSANGUANSIT
S O D E XO I N T E R N FA L L 2 0 1 5

Fun Fact
STRAUB WILL BE STARTING FECAL MICROBIOTA
TRANSPL ANTATION IN OCTOBER 2016

Abbreviations
FMT Fecal Microbiota Transplant
CDI C. diff Infection
IBD Inflammatory Bowel Disease
UC Ulcerative Colitis
IND Investigational New Drug

Why are there high hopes for FMT in

treatment for GI diseases?

History

4thth Century
China Yellow Soup
by
by Dr. Ge
Ge Hong
Hong

1958
US First
use of
FMT

1989
UK - First
use
use of
FMT in UC

2011
The
The American
Gastroenterologica
l Association
develop guidelines
for
for FMT in CDI

2013
FDA classifies
fecal matter
matter as
an
investigational
new drug
drug

Currently FMT is used to treat

CDI

Since 1958, FMT has been used without regulation in the United States
In 2013, the FDA came out with regulations
An approved IND application is recommended but not required for FMT with CDI
All other applications of FMT require an approved IND application

FMT for CDI

Works by altering the colonic microbiome and introducing new diverse

microorganisms
Highly effective success rates of more than 90% of patients with recurrent CDI
Other treatments for recurrent CDI are not as effective
FMT is relatively low-cost, low-risk, and highly effective treatment for recurrent CDI
Not always covered by insurance

2013 FDA Regulations

Signed consent from the patients
Extensively test the donor (serology and health questionnaire)
Extensively test the donor stool
Donor must be known to the patient or the physician

2011 AGA Guidelines

Note that these are general guidelines and many protocols vary widely
1. Educate patient on FMT procedure, risks, and side effects
2. Obtain signed consent
Patients may be advised to stop taking antibiotics or probiotics 24-48 hours before
procedure
Patients may also be advised to avoid unnecessary antibiotic treatment in the future
Before the procedure patients may clear the colon (generally by taking polyethylene
glycol the night before)

3. Donors undergo blood tests and extensive interview to assess lifestyle and
health history*
4. Test donor stool for transmissible pathogens*
*costs of these screening tests average $500 and may not be covered by insurance

2011 AGA Guidelines Cont.

5. Donors must not eat food that the patient is allergic to (usually 5-7 days
before stool collection)
6. Minimum of 50g of stool collected in a sterile container
Fresh vs. Frozen

7. Mix donor stool with preservative-free sterile saline solution

Manually or with a blender

8. Filter to ensure that all particles are no larger than 1-2 mm

Usually done by pouring through gauze

9. Deliver mixture
Via colonoscopy, retention enema, naso-tube, or pill
Must be administered within 6 hours of donor voiding (if using fresh)

IBD Review
Umbrella term for two chronic inflammatory diseases of
the intestines
Crohns Disease affects anywhere along the GI tract
(usually the ileum)
UC affects only the colon

Etiology unknown
Interaction between the GI immunologic system, genetic,
and environmental factors

Current treatments focus on suppressing the immune

system
Effective, but does not always lead to remission
Can be costly and have bad side effects

Current IBD Research

Mostly focuses on drug development to alter immune response
Other research includes personalized medicine and antibiotic therapy
These do not focus on finding and addressing the root causes of IBD
Difficult to pinpoint what is driving the immune response associated with IBD
Unlikely that food may be causing the immune response

FMT for IBD?

o Currently being explored
o Studies revealed gut microbiome differences between healthy vs. those with
IBD
Microbiota dysbiosis may play a role in IBD
FMT?

o 2 randomized controlled trials (RCTs) for UC

o None for Crohns Disease

o 1 systematic review and meta-analysis

o Many observational studies for IBD
o Many studies in general about microbiome

Moayyedi et al
75 subjects with active UC
Weekly FMT or water (placebo) via retention enema for 6 weeks
retain for at least 20 minutes

Subjects permitted to be on treatments for UC (given stable dose for at least 12

weeks)
Discontinued at interim analysis by the Data Monitoring and Safety Committee
(DMSC) due to futility
Primary outcome was remission at week 7
Results: significant benefit of FMT induced remission of those treated with FMT
(9 of 38, 24%) vs. those treated with placebo (2 of 37, 5%)
Subgroup analysis suggested donor dependence and success if FMT given earlier
in the course of UC

Rossen et al
48 subjects with active UC
FMT using donor stool or their own stool (placebo) via nasoduodenal tube once at
baseline and once at week 3
Subjects were excluded if using anti-TNF or methotrexate treatment and cyclosporine
Subjects pretreated with bowel lavage night before and morning of treatment
Discontinued at interim analysis by the DMSC due to futility
Primary outcome was remission at week 12
37 patients completed the primary end point assessment.
Results: insignificant benefit of FMT induced remission of those treated with FMT (7
of 23, 30.4%) vs. those treated with placebo (5 of 25, 20%)
Subgroup analysis showed FMT group to have similar microbiomes to their donors

Major Differences = Different

Results?
MOAYYEDI ET AL

ROSSEN ET AL

6 FMT infusions

2 FMT infusions

Via retention enema/lower GI route

Via ND tube/upper GI route

Permitted UC treatments

Did not permit UC treatments

No pretreatment

Pretreated with bowel lavage

Water as placebo

Own stool as placebo

Downfalls of the RCTs

Both studies had small population sizes due to termination by their DSMC
Small population size makes it hard to determine significant results of both primary
analysis and subgroup analysis

Both overestimated the treatment effect of FMT for UC

However, both studies are significant in terms of planning future RCTs

Crohns Disease
Systematic Review and Meta-Analysis of 18 studies of FMT for treatment of
IBD
4 studies evaluating 38 patients with Crohns Disease

Pooled response rate of 60.5%

Suggests FMT may be effective in Crohns Disease

Primary outcome was clinical response, rather than remission or mucosal

healing
More RCTs are needed to compare measurable outcomes of FMT vs.
placebo
Challenge: administration method

Terminal ileum
Colonoscopy delivery not recommended for frequency of FMT infusions needed
Retention enemas are likely to be ineffective
Possibility of oral capsules?

Conclusion
Research for FMT as treatment for IBD is still in its early stages
More RCTs are needed for both UC and Crohns Disease
More research is needed to find the most effective way to administer FMT in
regards to IBD
Even with C. diff, there is still yet to be a definitive protocol

Much more research must be done before we are

able to use FMT to treat IBD

Questions?

Thank you!

References
From fourth-century soup to 21st-century procedure, fecal transplantation proves its worth against stubborn bacteria. (2016, January 28). Retrieved July 28,
2016, from http://www.research.va.gov/currents/winter2015/winter2015-11.cfm

Marinski, Amy. Fecal Microbiota Transplantation. Am Nurs Today. 2013;8(6)

Eiseman B, Silen W, Bascom GS, Kauvar AJ. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery. 1958;44:8549.

United States Government DoHaHS, Food and Drug Administration, Center for Biologics Evaluation and Research. Guidance for Industry: Enforcement Policy
Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium Difficile Infection Not Responsive to
Standard Therapies. July 2013.

Brandt LJ, Aroniadis OC, Mellow M, et al. Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am J
Gastroenterol. 2012;107:1079-1087.

David A. Johnson. Fecal Transplantation for C difficile: A How-To Guide. Medscape. Feb 15, 2013.

Tauxe WM, Dhere T, Ward A, Racsa LD, Varkey JB, Kraft CS. Fecal Microbiota Transplant Protocol for Clostridium Difficle Infection. Lab Med.2015;46(1):e1923.

Bakken JS, Borody T, Brandt LJ, et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol. 2011;9:10441049.

Lee CH, Steiner T, Petrof EO, et al. Frozen vs fresh fecal microbiota transplantation and clinical resolution of diarrhea in patients with recurrent Clostridium
difficile infection: a randomized clinical trial. JAMA 2016; 315:142149.

References Cont.
Moayyedi, P., Surette, M. G., Kim, P. T., Libertucci, J., Wolfe, M., Onischi, C., ... & Lee, C. H. (2015). Fecal microbiota transplantation induces remission in patients with active ulcerative colitis
in a randomized controlled trial. Gastroenterology, 149(1), 102-109.

Rossen, N. G., Fuentes, S., van der Spek, M. J., Tijssen, J. G., Hartman, J. H., Duflou, A., & Zoetendal, E. G. (2015). Findings from a randomized controlled trial of fecal transplantation for
patients with ulcerative colitis. Gastroenterology, 149(1), 110-118.

Colman, R. J., & Rubin, D. T. (2014). Fecal microbiota transplantation as therapy for inflammatory bowel disease: a systematic review and meta-analysis. Journal of Crohn's and Colitis, 8(12),
1569-1581.

Rowe, W. A., & Gary, L. R. (2016, June 17). Inflammatory Bowel Disease. Retrieved July 29, 2016, from http://emedicine.medscape.com/article/179037-overview

Mosll MH, Sandborn WJ, Kim RB, et al. Toward a personalized medicine approach to the management of inflammatory bowel disease. Am J Gastroenterol 2014; 109:9941004.

Khan KJ, Ullman TA, Ford AC, et al. Antibiotic therapy in inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol 2011; 106:661673.

Rajca S, Grondin V, Louis E, et al. Alterations in the intestinal microbiome (dysbiosis) as a predictor of relapse after infliximab withdrawal in Crohn's disease. Inflamm Bowel Dis 2014; 20:978
986.

Machiels K, Joossens M, Sabino J, et al. A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis.
Gut 2014; 63:12751283.

Wang W, Chen L, Zhou R, et al. Increased proportions of Bifidobacterium and the Lactobacillus group and the loss of butyrate-producing bacteria in inflammatory bowel disease. J Clin
Microbiol 2014; 52:398406

Moayyedi, P. Fecal Transplantation: Any Real Hope for Inflammatory Bowel Disease?. Curr Opin Gastroenterol.2016;32(4):282-286

Youngster I, Russell GH, Pindar C, et al. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA 2014; 312:17721