Fecal Microbiota Transplantation FMT Bret Lashner MD Cleveland

Fecal Microbiota Transplantation (FMT) Bret Lashner, MD Cleveland Clinic

Early History of FMT • • 4 th Century (Ge Hong): - Oral human fecal suspension (“yellow soup”) for severe diarrheal illnesses, food poisoning 16 th Century (Li Shinzen): fermented fecal solution, dry feces - treated fever, severe diarrhea, vomiting and constipation 17 th Century: Veterinary medicine - Fecal transfer for horses with diarrhea 1958: FMT enema - Eismann, et al. 4 patients with pseudomembranous colitis - “Dramatic” response within 48 hours

Yellow Soup or Cappuccino? Cleveland Plain Dealer, October 21, 2015

Fecal transplantation in veterinary medicine since the 17 th century • Transfaunation • Horses with diarrhea- infuse stool from healthy horse per rectum • Cattle - per os as rumen

Human Intestinal Microbiome • Includes bacteria, archea (singlecelled prokaryotes), viruses, fungi and parasites - Only 10 of more than 50 known bacterial phyla - Bacteroidites, Firmicutes ~ 90% gut microbiota - 1014 bacterial cells 10 times greater than number of human cells in our body - Diversity within phyla, vary widely between individuals Eckburg, PB et al. Science 2005: 308; 1635 -8

Different ages and geographic populations have very different microbiomes Age Population Yatsunenko et al. 2012 Nature

The mammalian gut microbiota (Ley et al) Divisions % sequences Firmicutes 69 Bacteroidetes 17 Actinobacteria 6 Proteobacteria 5 Gemmatimonadetes 0. 02 Defferibacteres 0. 1 Verrucomicrobia 2. 1 Lentisphaerae 0. 08 Planctomycetes 0. 08 *@CD Gut 1 0. 2 *@CD Gut 2 0. 01 Fusobacteria 0. 9 Spirochaeates 0. 7 Fibrobacteres 0. 08 *Cyano Sister 0. 15 Synergistes 0. 12 Chloroflexi 0. 01 *TM 7 0. 04 *: no cultured representatives @: novel candidate division • Firmicutes and Bacteroidetes dominate across all mammals. • Dietary influence: – Carnivores have the fewest divisions and are most enriched in Firmicutes. – Humans are typical omnivores; cluster with omnivorous primates; leaf-eating primates cluster with herbivores

Kostic, et al. Gastro. 2014; 146(5): 1489 -1499

Fecal Microbiota Transplantation (FMT) · Definition: Instillation of stool from a healthy person into a sick person to treat a certain disease · Rationale: A perturbed imbalance in our intestinal microbiota (dysbiosis) is associated with or causes disease and can be corrected with re-introduction of donor feces

Conditions Potentially Treatable By FMT Smits LP, et al. Gastroenterology 2013; 145: 946 -53

C. difficile Infection (CDI) • • Spore-forming, anaerobic, gram positive Leading cause of healthcare-associated infectious diarrhea in US - - 3 million cases per year-1996 – 2009 in U. S. , rates of CDI doubled Unadjusted fatality rate - 1. 2 % (2000) 2. 3% (2004) - Majority > 65 y/o ~ 3. 2 billion dollars excess cost of care Gastroenterology 2012 Nov; 143(5): 1179 -11

C. difficile Manifestations · Carrier state · C. difficile - associated diarrhea (CDAD) · C. difficile colitis · Pseudomembranous colitis · Fulminant Colitis / Toxic megacolon · Atypical (e. g. , sepsis, ascites) · Recurrent disease Khanna AJG 2012

Recurrent CDI · 15 -20% of patients · Relapse · Re-infection · Post-CDI irritable bowel syndrome · 2 nd recurrence: 40%; 3 rd recurrence 60% · Rx failure before 2003 < 10%; after 2003 ~ 20% · Relapses can continue for years · No universal Rx algorithm

Why Do We Get Recurrent CDI ? • Virulence of infection • Impaired host-response • Altered intestinal microbiome - “Dysbiosis” = decreased microbiota diversity

Host factors for recurrent CDI • Age ≥ 65 years • Immunosuppression - recipients of organ transplants (3 -11%), chemotherapy, corticosteroids, HIV, IBD, ESRD, ESLD • PPI use ≥ 3 -fold • Hospitalization, long-term care facilities - After 1 week 13%, after 4 weeks > 50% colonization rate 1. Hookman P, Barkin, JS. World J Gastroenterol. 2009; 15: 1554 -1580. • Previous CDI 2. APIC. Guide to the Elimination of Clostridium difficile in Healthcare Settings. 2008. 3. Makris AT, Gelone S. J Am Med Dir Assoc. 2007; 8: 290 -299. 4. Cohen SH, et al. Infection Control and Hospital Epidemiology. 2010; 31(5): 431 -455. 5. Goodhand JR, et al. Ailment Pharmacol Ther. 2011; 33: 428 -441. 6. Aseeri M, et al. Am J Gastroenterol. 2008; 103: 2308 -2313. 7. Schaier M, et al. Nephrol Dial Transplant. 2004; 19: 2432 -2436.

How Does FMT Work? Borody, T. J. & Khoruts, A. (2011) Nat. Rev. Gastroenterol. Hepatol.

FMT for CDAD · 20 full-text case series, 15 case reports, 1 randomized controlled study through Feb 2013 · Total 536 pts with symptomatic CDAD · 467 (87%) experienced resolution of diarrhea after FMT · Diarrhea resolution rates varied according to the site of infusion: · 81% in the stomach; 86% in the duodenum/jejunum; 93% in the cecum/ascending colon; 84% in the distal colon. · No severe adverse events were reported with the procedure. Cammarota, J Clin Gastro 2014; 48: 693 -702

Included patients: • Median number of recurrences 3 (1 -9) • Cure rate donor feces 94% • Cure rate vancomycin 23 -31% 13 15 Trial stopped early - unethical to continue Van Nood N et. al. NEJM 2013; 368: 2145

Protocol for FMT in Recurrent CDI · Insurance Approval: $4, 300. · IRB-Approved informed consent · Choose donor · · · Spouse/partner 1 st degree relative Household contact · Donor exclusions · · Antibiotic use within 3 months Diarrhea, constipation, IBS, IBD, colorectal cancer, immunocompromised, anti-neoplastic drugs, high-risk behaviors · Testing · · Donor Stool: culture for enteric pathogens, O&P, C. difficile Donor and Recipient Blood: Hepatitis remote panel, syphilis, HIV, HTLV Brandt LJ ACG Meeting Oct. 2012

Protocol for FMT in Recurrent CDI · Donor · Gentle laxative (e. g. MOM) evening before FMT · Freshly passed stool · Mixed with 500 m. L non-bacteriostatic water/saline · Filtered · Used within 6 -8 hours · Recipient · D/C antibiotics 5 days prior to procedure · Large volume bowel prep evening before FMT · Loperamide before procedure · Instill up to 500 m. L in the right colon Brandt LJ ACG Meeting Oct. 2012

Protocol for FMT in Recurrent CDI • Stool Transplant - Donor stool suspension with nonbacteriostatic water - Filtered - 60 cc catheter tip syringe - Volume of ~ 300 m. L instilled into ascending colon - Patient to hold stool for 4 -6 hours Brandt LJ AJG 2012

Cleveland Clinic Outcomes · · · N > 150 Average age: 63 Indication: C difficile 96% success in eradicating C difficile 1 repeat FMT successful · 16 with repeat C difficile testing - neg

Follow-up Survey · 77 patients > 3 months after FMT · Duration of illness: 11 months · Symptomatic response after FMT · < 3 days in 74% · Primary cure rate: 91% · Secondary cure rate: 98. 7% · 97% of patients would have another FMT for recurrent CDI · 58% would chose FMT as their preferred Rx Brandt LJ, et al. Am J Gastroenterol 2012: 108: 177 -85

Cost-Effectivenes FMT · Decision analytic model comparing 4 strategies for 1 st episode recurrent CDI · Metronidazole · Vancomycin · Fidaxomicin · FMT-colonoscopy · FMT most cost-effective strategy with incremental costeffectiveness ratio of $17, 016 vs Vancomycin · More cost effective than Fidaxomicin and metronidazole because of higher cost and/or lower efficacy of medications · FMT colonoscopy most cost-effective strategy with cure rate 96. 4% Konijeti GG, et al. Clin Infect Dis 2014; 58: 1507 -14 ACG 2013

Conditions Potentially Treatable By FMT Smits LP, et al. Gastroenterology 2013; 145: 946 -53

IBD: Etiologic Hypothesis Defective mucosa integrity Persistent Infection - Mycoplasma - Helicobacter - Measles-mumps - Toxigenic E. coli -Increased permeability -- Cellular starvation -Impaired restitution IBD Dysbiosis - ↓Protective bacteria - ↑Aggressive commensals Dysregulated -Immune System - Loss of Tolerance -Aggressive cellular activation --Defective apoptosis

Why don’t we all develop IBD when exposed to aggressive gut bacteria? Normal colon Ulcerative colitis

Fut 2 Sartor RB Gastroenterology 2010 Sartor, Gastroenterology 2010

Microbiome in prevention of inflammation · · · Microbiota altered in IBD: · Decreased diversity and bacterial load: Bacteroides · Induce T-regs and cytokines Firmicutes · Induce T-regs and reduce inflammation in DSS induced colitis in mice · SCFA production: Butyrateimmunoregulatory properties Mann EA, Saeed SA. Curr Opin Gastroenterol 2011; 28: 24– 9 Kamada Nature Reviews 2013

FMT in patients with active Ulcerative Colitis • • • UC pts, randomized to 50 m. L retention enema, anonymous donor, 1 x/wk for 6 weeks vs placebo enema Pancolitis - more common in transplant group Outcome Transplant Group n=38 Placebo Group N=37 P value Remission 9 (24%) 2 (5%) 0. 05 Mayo Score 6. 0 6. 3 0. 80 IBDQ score 61. 0 66. 2 0. 34 • Primary outcome - remission with Mayo score of < 2; and an endoscopic Mayo score of 0, week 7. • Secondary outcome - change in QOL, assessed with the IBDQ • Trial stopped early for futility. • Stool from patients receiving FMT had greater microbial diversity than at baseline Moayyedi, P, Gastroenterology 2015: 149: 102 -9

Taxonomic profiles of donors used in the trial . **Donor microflora matters ** Moayyedi. P. et al. Gastroenterology, 2015.

FMT for IBD • Altered microbiome in IBD, so FMT could be useful • FMT in IBD patients with recurrent C difficile is likely to be beneficial, especially if the C difficile is associated with disease flare • FMT in IBD patients without C difficile has not been shown to be helpful, possibly related to diversity of donor microflora

Atherosclerosis and Fecal Dysbiosis • • Mechanistic link between atherosclerosis and intestinal microbial metabolism of dietary nutrients to produce trimethylamine Noxide (TMAO) Specific dietary nutrients – choline, phosphatidyl choline, and carnitine – eggs, liver, meat Atherosclerosis-prone strain of mice were given FMT from low TMAO producing strain Choline-rich diet led to lower atherosclerotic plaques and lower TMAO Gregory JC, et al. J Biol Chem 2015; 290: 5647 -60

Gut microbiota-dependent metabolism of dietary phosphatidylcholine in atherosclerosis ZN Wang et al. Nature 472, 57 -63 (2011)

Dietary/ microbial interactions impact intestinal, hepatic and vascular inflammation J Goldsmith and RB Sartor J. Gastroenterology 2014

Perfect Donor • • Lean No chronic diseases No infectious disease No predisposion to diabetes, or other chronic diseases like NAFLD, MS, IBD, or chronic fatigue syndrome • Low TMAO-producing foods

FMT and the FDA: Existing Regulatory Framework Drug and Biologic • IND requirement • “Enforcement discretion” • C difficile only Source: U. S. Food & Drug Administration, www. fda. gov/About. FDA/Transparency/Basics/ucm 361441. htm

Dilemmas For regulatory agencies For patients For clinicians and clinical researchers For healthcare organizations Source: Wikipedia, https: //en. wikipedia. org/wiki/List_of_The_Thinker_sculptures#/media /File: Cleveland_Museum_of_Art_-_damaged_Thinker. jpg

Capsules for FMT • • 20 patients, open-label, relapsing C difficile *****Healthy donor volunteers***** 15 capsules on 2 consecutive days Resolution of diarrhea – 70% 4/6 non-responders responded to second FMT Overall response rate 90% No adverse events Youngster I, et al. JAMA 2014; 312: 1772 -8

Open. Biome • • No IND Donor testing: 3% of prospective donors pass testing, retested every 60 days www. openbiome. org

Open. Biome • • Recommendations: - PPI - Informed Consent - Direct observation of capsules Cost - $385 – 30 m. L upper GI or 250 m. L lower GI - $535 – 30 capsules www. openbiome. org

• FMT is being conducted under an enforcement discretion from FDA—as described in a Guidance issued in 2013, followed by two Draft Guidances issued in 2014 and 2016, respectively. • The draft guidances are not enforceable, but they do reflect FDA’s current opinion on the topic, and in this case it is pretty clear they would want an IND for using capsules from Open. Biome. • The changes from 2013 to 2016 have added progressively more language circumscribing third-party specimen use without an IND, while encouraging providers to obtain and bank specimens obtained and screened under their (or their colleagues’) supervision without an IND. • Open. Biome has made it clear that since the draft guidances are not enforceable, they will not obtain an IND. • You can see that this puts us in a difficult position from a regulatory standpoint. position, from a regulatory standpoint.

The Do-It-Yourself Approach Source: “Fecal Transplant at Home — DIY Instructions, ” The Power of Poop, http: //thepowerofpoop. com/epatients/fecal-transplant-instructions/

and Fecal Microbiota Transplantation