Fecal Microbiota Transplant

Fecal Microbiota Transplant
Transfusion Medicine Final Presentation March 1, 2013 Meghan E. Kapp, MD, MS Resident Physician, PGY1 Department of Pathology, Microbiology, Immunology Vanderbilt University

Gut Microbiome The Human Microbiome Project, NIH 2007 Goal Sequenced
Catalogue microbial genes and species found within and on the human body Sequenced 60 million predicted genes 600 microbial reference genomes 700 metagenomes Microbiome 10 trillion to 100 trillion cells 10 times the number of eukaryotic cells in the human body Most of which reside in our GI tract

Gut Microbiome Gut Microbiota
Complex, diverse and vast microbial community 10 conserved bacterial phyla Firmicutes and Bacteroidetes comprise more than 90% Actinobacteria and proteobacteria Fusobacteria, Verrucomicrobia, Cyanobacteria Species vary widely between individuals Populated starting at birth Affected by mode of delivery Fostered by method of feeding Breast milk vs formula Protein and animal fat vs carbohydrate predominant diets Modified by Age

Gut Microbiome In the absence of major dietary changes or antibiotics, the microbiota is remarkably stable Significant role in health and disease Eubiotic State Energy harvest from otherwise inaccessible starches Regulation of metabolism Production of micronutrients and vitamins Metabolism of xenobiotics Gut epithelial-cell renewal Immune system development Protection from pathogenic organisms

Gut Microbiome In the absence of major dietary changes or antibiotics, the microbiota is remarkably stable Significant role in health and disease Eubiotic State Dysbiotic State Asthma and atopic diseases Obesity and metabolic syndrome Colorectal cancer Enteric infections Irritable bowel syndrome Inflammatory bowel disease

Clostridium difficile infection (CDI)
Acquired after antibiotic treatment and ingestion of environmental spores Public health problem Prevalence of 13.1 per 1,000 patients 100,000 people dying annually Strains with increased virulence Resistance to fluoroquinolones Increased toxin production

Clostridium difficile infection (CDI)
Standard treatment is currently based on antibiotics Metronidazole Vancomycin Perpetuates recurrence of CDI after discontinuation Broad activity against the dominant colonic microbiota phyla Spores able to repopulate Relapse after initial treatment is approximately 20-25%

Randomized controlled study comparing three therapies
500 mg vancomycin PO four times daily for14 days (std vancomycin regimen) 4/13 (31%) cured 2. Standard vancomycin regimen + bowel lavage 3/13 (23%) cured 3. Standard vancomycin regimen + bowel lavage + infusion of donor feces solution /16 pts cured after first infusion; 2/3 pts cured with second infusion p<0.01 for both comparisons after first infusion and p<0.001 for overall cure rates

Fecal Microbiota Transplantation Historical Perspective
Dong-jin dynasty in the 4th century in China, Ge Hong described the use of human fecal suspension by mouth for patients who had poisoning or severe diarrhea Yielded positive results and considered miraculous as it reportedly brought patients back from the brink of death. “Zhou Hou Bei Ji Fang” “Handy Therapy for Emergencies”

Ming dynasty of the 16th century, Li Shizhen described a series of prescriptions using fermented fecal solutions, fresh, dry, or infant for effective treatment of abdominal diseases with severe diarrhea, fever, pain, vomiting, and constipation “Ben Cao Gang Mu” “Compendium of Materia Medica”

Zoobiquitous Approach
Fabricius Aquapendente in the 17th century Transfaunation has been used for centuries to treat ruminants with severe ruminal acidosis and other gastrointestinal disorders and for treatment of equine diarrhea

Eiseman et el Colorado, 1954 Case series of 4 patients with pseudomembranous enterocolitis ¾ were in critical state with fulminant pseudomembranous colitis, which at the time had a 75% mortality rate Treated with antibiotics, hydration, vasopressors, hydrocortisone and Lactobacillus acidophilus probiotic No response Fecal retention enemas All symptoms resolved within hours of FMT Discharged within days of treatment

Recipient Screening Indications for Recipient
Recurrent or relapsing CDI 3+ episodes of mild to moderate CDI and failure of a 6 to 8 week taper with vancomycin with or without an alternative antibiotic 2+ episodes of severe CDI resulting in hospitalization and associated with significant morbidity. Moderate CDI not responding to standard therapy for at least a week Severe (fulminant) C difficile colitis with no response to standard therapy after 48 hours. 3rd or greater episode of C. difficile infection Proven by a positive C.difficile stool assay Previous treatment with 1st line therapies for C. difficile infection Previous receipt of at least 1 course of a 6-8 week vancomycin taper or vancomycin treatment followed by rifaximin chaser for 2 weeks Refractory moderate to severe C. difficile diarrhea, failing vancomycin therapy after >1 week “Treating Clostridium difficile infection with fecal microbiota transplantation”. Clinical Gastroenterology and Hepatology 2011;9:

Recipient Screening Inclusion Criteria for Recipient
Able to safely undergo and consent to colonoscopy Able to identify potential donor Family member Household contact Able to stop gastric acid suppression and antibiotics 15

Recipient Screening Exclusion Criteria for Recipient
Patients on immunosuppressive agents High-dose corticosteroids Calcineurin and mTOR inhitors Lymphocyte-depleting agents Anti-tumor necrosis factor agents Chemotherapeutic agents Patients with Decompensated liver cirrhosis Advanced HIV/AIDS Recent bone marrow transplant Severe bowel disease precluding colonoscopy Severe underlying immune suppression Decompensated liver cirrhosis

Recipient Screening Laboratory Testing for Recipients
Human immunodeficiency virus (HIV antibody) Syphilis enzyme immunoassay or RPR Hepatitis HAV IgM HBV surface antigen HBV surface and core antibody HCV antibody Optional Human T-lymphotropic virus I/II

Recipient Preparation
Large volume bowel prep regardless of route of FMT Loperamide if FMT via enema or colonoscopy PPI if FMT via nasogastric tube Order colonoscopy Prescribe colon preparation Moviprep Golytely Ask patient to stop treatment the day before the procedure

Donor Screening Little data to suggest any factors other than specific exclusion criteria based on medical history and laboratory testing that would endorse a particular donor to be optimal. Advantageous donors Intimate contacts as they share infectious risk factors Maternal-line first degree relatives theoretically share greatest number of microbial species in their intestinal microbiota Unrelated, healthy, but rigorously screened young donors

Donor Screening Exclusion Criteria
Exclude: Active communicable illness Metabolic syndrome Autoimmune disorder Recent or chronic diarrheal disorder Known colonic malignancy/polyps High risk sexual behavior Illicit drug use/tattoos/incarceration Exposure risk for hepatitis >1 year Travel to high risk areas for infectious diarrhea in past 6 months High risk for CJD History of C. difficile infection Hospitalization within the past 3 months Absolute: Consider using American Association of Blood Banks Donor History Questionnaire Gastrointestinal comorbidities Antibiotics within the preceding 3 months Recent ingestion of potential allergen Relative Major GI surgery Metabolic syndrome Systemic autoimmunity Atopic diseases Chronic pain syndromes

Donor Screening Serologic Testing
Human immunodeficiency virus Syphilis enzyme immunoassay or RPR Hepatitis Hepatitis A IgM Hepatitis B surface antigen, Hepatitis B surface and core antibody Hepatitis C antibody Optional Human T-lymphotropic virus I/II antibody HIV, type 1 and 2 Hepatitis A IgM B surface antigen, core antibody, surface antibody C antibody RPR and FTA

Donor Screening Stool Studies
All Donors Bacterial/enteric pathogen culture or PCR Clostridium difficile stool assay Immunocompromised recipients Ova and parasite exam Cryptosporidial stool antigen Microsporidia stool test C. difficile PCR Routine bacterial culture for enteric pathogens Fecal giardia antigen Fecal cryptosporidium antigen Acid fast stain for cyclospora, isospora and cryptospora Ova and parasites Helicobacter pylori fecal antigen if ND administration

Donor Preparation Provide donor with extra stool collection container and stool “hat” 30 mL of Milk of Magnesia orally the night prior to collection Collect as much stool as possible in the container at home or on site Sealed refrigerated container to the Endoscopy suite with the recipient at the time of colonoscopy Consider a gentle osmotic laxative the night before procedure Avoidance of any foods to which recipient might be allergic for 5 days before the procedure

Stool Processing Donor will deposit stool sample in an airtight stool collection hat Carried on an ice bath/packs to the laboratory Airtight container Chilled; never frozen Sample prepared using hood and universal precautions; used within 6 hours

Stool Preparation Diluent Stool Sample
Preservative- free normal saline 4% milk “Conventional household blender (dedicated to this purpose)” to create liquid slurry Filtered to remove particulate matter Ideal volume has not been established 25-50 mL above mL below Stool Sample Weighed Diluted in preservative free normal saline 50 g of stool:250 mL of normal saline Placed into Fisher blender bag Mixed in stomacher for 60 seconds Filtrate placed into five 50 mL conical tubes and placed on ice Sent to endoscopy suite

Route of Administration
Nasoduodenal tube Fulminant C. difficile infections Spore forming bacteria (Firmicutes) require germination factors in the upper GI tract in order to be viable Colonoscopy Direct implantation along colon Acidic environment of stomach may damage bacteria (Bacteroidetes)

FMT and Inflammatory Bowel Disease
Chronic relapsing inflammatory disorder of the intestine affecting ~0.5% of the adult US population IBD includes both ulcerative colitis and Crohn’s disease Etiology unknown Dominant hypothesis: inflammation results from altered or pathogenic microbiota in genetically susceptible host Nearly every mouse model of IBD requires the presence of the intestinal microbiota for colitis to develop Diversion of the fecal stream often leads to improvement of downstream inflammation UC: probiotics have demonstrated efficacy in induction and maintenance of remission

16S rRNA sequencing of the microbiota in IBD Is different from the microbiota of healthy people Lower representation of Bacteroidetes and Firmicutes Higher representation of Actinobacteria and Enterobacteria Mycobacterium and Escherichia coli, respectively Diversity and bacterial load are decreased, especially in regions of active inflammation

Bacteroides fragilis Symbiosis factor polysaccharide A Induce regulatory T cells and cytokines that are protective against colitis Firmicutes Induce regulatory T cells Reduce inflammation in dextran sodium sulfate-induced colitis Faecalibacterium prausnitizii Reduced risk of recurrent ileitis aftery surgery in CD Reduce 2,4,6-trinitrobenzene sulphonic acid-induced colitis in mice

Studies demonstrate the therapeutic potential for replenishing depleted Bacteroidetes and Firmicutes Mixtures of probiotic species, including food-derived and in vitro-passaged bacteria such as Lactobacillus and Bifidobacterium have shown some efficacy in treating IBD Not adapted for intestinal homeostasis Transiently populate the intestine Few case reports of successful treatment of IBD with FMT First report in 1989 by the author (Bennet) who treated himself with large- volume donor stool retention enemas Serial infusions No standardized trial have been published Study of patient preference demonstrated that most UC patients would consider FMT and wish that it were already available

FMT and Metabolic Syndrome
Accumulating data suggest that intestinal microbiota contributes to host metabolism. Animal models Obesity is associated with substantial changes in the composition and metabolic function of the gut microbiota Colonic microbiota in obese mice shows lower microbial diversity enriched in carbohydrate and lipid users Humans Consensus is lacking Most studies focus on colonic microbiota, whereas proximal intestine is crucial for carbohydrate and fat uptake

FMT and Metabolic Syndrome
Vrienze et al 2012 Double-blind randomized controlled trial Treatment-naïve male subjects with metabolic syndrome underwent small-intestine biopsies subseqent bowel lavage via duodenal tube Either allogenic (lean male donor BMI <23kg/m2) or autologous gut microbiota infusion Six weeks post infusion Insulin sensitivity of allogenic recipients increased Median rate of glucose disappearance changed from 26.2 to micromoles/kg/min; p<0.05 Improvement of fasting triglycerides

Other Potential Clinical Indications
Systemic autoimmunity Food allergies Eosinophilic disorders of the gastrointestinal tract Neurodegenerative and neurodevelopmental disorders

Other Potential Clinical Indications
Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort Gut microbiota of healthy infants at 4 months Profiles by mode of delivery and infant diet Formula-fed infants had increased richness of species with overrepresentation of Clostridium difficile. Infants born via c-section had underrepresentation of Bacteroides spp and overal low bacterial richness and diversity

Transfusion Medicine Taking cells from one individual and infusing them in to another Red blood cells or bacterial cells from GI flora Donor Screening Donor Collection Storage

Standardized Frozen Preparation for FMT
University of Minnesota Moved from patient-identified individual donors to standardized volunteer donors Material preparation shifted from the endoscopy suite to a standardized process in the laboratory Banking of frozen processed fecal material that is ready to use when needed.

University of Minnesota Moved from patient-identified individual donors to standardized volunteer donors Removed the burden of donor identification from the patient Improved efficiency and costs related to donor screening Consistent supply of donor fecal microbiota Ability to impose extensive and stringent exclusion criteria on donor selection Medical history was reviewed before every donation Complete laboratory screening every 6 months

University of Minnesota Material preparation shifted from the endoscopy suite to a standardized process in the laboratory Material from “universal” donors transported on ice into the laboratory Processed within 2 hours of collection Weighed Homogenized under N2 gas Filtered through increasingly fine sieves Centrifuged at 6,000xg for 15 mins Resuspended to one-half the original volume in non-bacteriostatic normal saline Administered to the patient immediately Amended and stored

University of Minnesota Banking of frozen processed fecal material that is ready to use when needed Concentrated fecal bacteria suspension Amended with sterile pharmaceutical grade glycerol to final concentration of 10% Stored frozen an -80C for 1-8 weeks until used Material requested Thawed over 2-4 hours in an ice bath Diluted to 250 ml with non-bacteriostatic normal saline Sent to endoscopy suite Frozen donor preparations are as effective as fresh in treating recurrent C. difficile infection

Transfusion Medicine: Home for FMT?

References Agito MD, Atreja A, Rizk M. Fecal microbiota transplantation for recurrent C difficile infection: Ready for prime time? Azad MB, Konya T, et al. Gut microbiota of healthy Canadian infants: profiles by mode of delivery and infant diet at 4 months. CMAJ Brandt L, Reddy S. Fecal microbiota transplantation for recurrent Clostridium difficile infection. J Clin Gastroenterol 2011; 45(suppl):S159-S167. Borody TH, Khoruts A. Fecal microbiota transplantation and emerging applications. Nat Rev Gastroenterol Hepatol 2011; 9:88-96 Damman CJ, Miller SI, Surawicz CM, Zisman TL. The microbiome and inflammatory bowel disease: is there a therapeutic role for fecal microbiota transplantation? Am J Gastroenterol 2012;107: Hamilton MJ, Weingarden AR, Sadowsky MJ, Khoruts A. Standardized Frozen Preparation for transplantation of Fecal Microbiota for Recurrent Clostridium difficile Infection. Am J Gastroenterol 2012; 107: Tilg H, Kaser A. Gut microbiome, obesity, and metabolic dysfunction. J Clin Invest. 2011; 121(6): Vrieze A, Van Nood E, Holleman F, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology Oct; 143(4):913-6.e7

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