10/4/2014. The Microbiome vs. the Gastroenterologist. Human Microbiome. Microbiome and Host Physiology: A Delicate Balance

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1 The Microbiome vs. the Gastroenterologist John K. Marshall MD MSc FRCPC AGAF Division of Gastroenterology McMaster University Human Microbiome Mouth Finlay BB. Scientific American 2010;302:56-63 Microbiome and Host Physiology: A Delicate Balance Brandt LJ. Am J Gastroenterol 2013;108:

2 Effects of an Altered Microbiome Smits LP. Gastroenterology 2013;145: How An Altered Microbiome Contributes to Disease A B C Smits LP. Gastroenterology 2013;145: Characterizing the Microbiome Owyang C, Wu GD. Gastroenterology 2014;146:

3 % with Rome I IBS 10/4/2014 Irritable Bowel Syndrome Chronically altered bowel habit and abdominal discomfort Common in general population (10%-20%) Diagnosis of exclusion (no biomarkers) No cure Treatment unsatisfactory JKM 2011 Incidence of IBS 2 Years After Acute Gastroenteritis in Walkerton Ontario OR 4.8 (95% CI 3.4,6.8); p<0.001 p< % p< % 10.1% N=701 N=904 N=464 Acute Gastroenteritis During Outbreak Marshall JK. Gastroenterology 2006;131:

4 Post-Infectious Irritable Bowel Syndrome Altered bowel habit and abdominal discomfort that persist after acute enteric infection despite clearance of the inciting pathogen and recovery from the acute illness? Global and Deep Molecular Analysis of Microbiota in IBS Rajilic-Stojanovic M. Gastroenterology 2011; Species-Specific Changes in Micobiota Define IBS Subtypes Jeffery IB. Gut 2012;61:

5 RCT of Bifidobacterium infantis for Treatment of IBS (Align TM ) 362 primary care patients with IBS (any subtype) Whorwell PJ. Am J Gastroenterol 2006;101: Definitions Probiotics are live microorganisms which, when administered in adequate amounts, confer a health benefit to the host. Prebiotics are non-digestible food ingredients that stimulate the growth and/or activity of bacteria in the digestive system that are beneficial to the host Synbiotics are nutritional supplements combining probiotics and prebiotics in a form of synergism JKM 2013 Pseudomembranous Colitis 5

6 Pseudomembranous Colitis Clostridium Difficile Gram-positive spore-forming bacterium Non-invasive, toxin-producing (A and B) Fecal oral transmission Environmental surface contamination in healthcare facilities Asymptomatic carriage in 5-15% of healthy adults Up to 84% of infants Up to 57% of long-term care residents Risk factors for acquisition: Exposure to antibiotics Comorbid conditions Gastrointestinal surgery Proton pump inhibitors Surawicz CM. Am J Gastroenterol 2013;108: C. Difficile Pathogenesis Peniche AG. Current Opinion Infect Dis 2013;26:

7 Reduced Microbial Diversity in CDI N=39 CDI, N=36 CD-negative nosocomial diarrhea, N=40 HC Culture-independent high-density Roche 454 pyrosequencing 526,071 partial 16S rrna sequence reads of V1-V3 regions aligned with 16S databases to identify 3,531 bacterial phylotypes Antharam VC. J Clin Microbiol 2013;51: Probiotics for Prevention of C. Difficile-Associated Diarrhea JKM 2013 Johnston BC. Ann Intern Med 2012;157: Lactobacillus acidophilus Lbc80r and Lactobacillus casei CI 1285 (Bio-K+ TM ) Randomized double-blind placebo-controlled doseresponse trial in 255 adult inpatients starting antibiotic therapy at a single centre in Shanghai Gao XW. Am J Gastroenterol 2010;105:

8 JKM 2011 Probiotics: Who What Where When? Reasonable clinical evidence: VSL#3 or Mutaflor for ulcerative colitis VSL#3 for pouchitis BioGaia for H. pylori Align or TuZen for IBS Bio-K+ or Florastor for AAD or CDAD JKM 2011 Genetically Modified Probiotics JKM

9 Clinical Guide to Probiotics Available in Canada Fecal Transplantation First reported use for C. difficile in 1958 Eiseman B. Surgery 1958;44:854-9 Why I Donated My Stool This spring I saved a friend from a terrible illness, maybe even death. No, I didn t donate a kidney or a piece of my lung. I did it with my stool Lee MMO. New York Times. July

10 Early FMT Dong-jin dynasty (4 th century): Ge Hong resports using an oral human fecal suspension for food poisoning or severe diarrhea. Medical miracle returned patients from brink of death Ming dynasty (16 th century): Li Shizhen reports using fermented fecal solution, fresh fecal suspension, dry feces, or infant feces for abdominal diseases with severe diarrhea, fever, pain, vomiting, or constipation Zhang F. Am J Gastroenterol 2012;107:1755 Home Fecal Transplantation Duodenal Infusion of Donor Feces for Recurrent C. difficile Van Nood E. N Engl J Med 2013;368:

11 Pathogenesis of IBD Luminal Antigens IBD Genetic Susceptibility Environmental Triggers Treatment of UC by Implantation of Normal Colonic Flora 1 st author (Bennet) had endoscopically and histologically confirmed UC for 7 years, refractory to sulfasalazine and steroids Received FMT using large-volume retention enemas from healthy volunteer donor Histologic remission at 3 months Clinical remission at 6 months Bennet JD. Lancet 1989;333:164 Fecal Transplantation for UC in Children and Young Adults (N=10) Kunde S. J Ped Gastroenterol Nutr 2013;56:

12 RCT of FMT for UC Moayyedi (PI), Marshall, Armstrong, Surette, Lee Funding: CCFC Subjects: active ulcerative colitis (N=130) Mayo >3 with endoscopy sub-score 1 Intervention: weekly FMT vs. placebo for 6 weeks Unrelated healthy donor 6 additional weeks open label available to non-responders Primary outcome: remission (Mayo<3) with endoscopic subscore 0 Endoscopy at weeks 3 and 6 Roche 454 pyrosequencing and Illumina sequencing to characterize microbiome RCT of FMT for UC Healthy unrelated donors No medications for 3d prior to collection Detailed health questionnaire Negative tests for: HIV, HAV, HBV, HCV, syphilis, HTLV I/II, VRE, MRSA, Stool specimen analyzed No visible blood, mucus, urine Negative tests for: O&P, C. difficile, Salmonella, Shigella, E. coli 0157:H7, Yersinia, Campylobacter, norovirus, adenovirus, rotavirus RCT of FMT for UC Stool processed within 5h of collection 50g of stool mixed with 300ml water Emulsified with spatula and allowed to settle Supernatant (150ml) decanted and filtered Refrigerated at 2-8 o C for up to 24 hours Delivered as retention enema 12

13 RCT of FMT for UC Interim analysis: 63 randomized, 53 completed 45% pancolitis 42% on steroids, 19% on IMM, 9% on biologics Partial responders on HBT offered additional 6 weeks of open-label therapy with overall remission rate of 9/27 (33%) Conclusion: no evidence from this RCT that FMT effective DSMB advised that recruitment be halted! Moayyedi P et al. DDW 2014 RCT of FMT for UC Primary Endpoint: Week 7 Remission (Mayo 2 with Endoscopic Subscore 0) TOP SECRET P= FMT Control Moayyedi P et al. [submitted] 13

14 Schwartz M. Am J Gastroenterology 2013;108:1367 Effects of an Altered Microbiome Smits LP. Gastroenterology 2013;145: Chronic Gut Inflammation Induces Anxiety and Alters CNS Biochemistry in Mice JKM 2013 Bercik P. Gastroenterology 2010;139:

15 Gut Microbiota from Twins Discordant for Obesity Affect Metabolism in Mice Germ-free mice colonized with fecal microbiota from twins discordant for obesity Changes in body composition monitored by MRI Ridaura VK. Science 2013;341: Effects of Intestinal Microbiota on Human Metabolism Nieuwdorp M. Gastroenterology 2014;146: Ideal Fecal Donors? 15

16 Summary We are vastly outnumbered Technology to profile structure and function of the microbiome is advancing Bioinformatic challenges remain Manipulation of the microbiome can utilize diet, antibiotics, probiotics, and fecal transplantation Potential efficacy across spectrum of human disease Your colon is the next frontier Thank You 16