Pro biotics or Amateurbiotics?

Pro biotics or Amateurbiotics? Probiotics for gastrointestinal illness Faculty/Presenter Disclosure Presenter: Tony Nickonchuk Relationships that may introduce potential bias and/or conflict of interest: Grants/Research Support: None Speakers Bureau/Honoraria: Tony has received a speaker fee and expense support from the Alberta College of Family Physicians Consulting Fees: None 1

Disclosure of Commercial Support This program is presented by the Alberta College of Family Physicians (ACFP) without any commercial or in kind support: The ACFP provides a speaker fee and expense support for presenting at the Practical Evidence for Informed Practice Conference Abbreviations L.=Lactobacillus B.=Bifidobacterium E.=Escherichia 2

What is a Probiotic? Live microorganisms which when administered in adequate amounts confer a health benefit on the host Expert Panel of the Food and Agriculture Organization of the United Nations 1 Caveat: Barely a paper is published without the use of a different definition, or challenging the most used one, or proposing a different nuance of it. 1. Best Pract Res Clin Gastroenterol 2016;30(1) How do they Work? There are MULTIPLE answers to this question Simple answer? They work by creating a more favourable gut environment, and supporting a healthy digestive tract and a healthy immune system 1 1. Best Pract Res Clin Gastroenterol 2016;30(1) 3

GI Products on Canadian Market Brand Name Strain Align B. longum infantis 35624 BioGaia L. reuteri protectis DSM 17938 Bio K+ CL 1285 L. Acidophilus CL 1285 L. casei LBC80R L. Rhamnosus CLR2 Culturelle L. rhamnosus GG Florastor Saccharomyces boulardii lyo Mutaflor E. coli Nissle 1917 Proxiflor L. rhamnosus R0011 L. helveticus R0052 TuZen L. plantarum 299v VSL#3 4 Lactobacillus strains, 3 Bifidobacterium strains and 1 Streptococcus strain 2. Clinical Guide to Probiotic Supplements Available in Canada, 2015. History of Probiotics 2000s present: explosion in research, including controlled clinical trials 3 Human Microbiome Project has now identified >40 000 species in the colon 3. Clin Infect Dis 2015;60(suppl 2) 4

Do Patients Use Probiotics? Small Canadian survey 4 35% taken probiotics for overall or digestive health Global retail market value $41 billion USD in 2015 5 Only 9% of that is probiotic supplements All cost roughly $1/day, except VSL#3, ~$4/day 4. Swiss Naturals. Canadians Puzzled by Probiotic Health Benefits Available online. 5. Natural Products Insider. The New Market Profile of Probiotics Consumption Available online. Most Common Indications 6 **Evidence is strongest for conditions in bold NEC=necrotizing enterocolitis AAD=antibiotic associated diarrhea RR=reduces risk IBS=irritable bowel syndrome T=treatment CID=common infectious diseases URTI=upper respiratory tract infection 6. Gut 2013;62(5) 5

Strain Really Matters All of the following potentially influence differences in effect between probiotic studies 7 Genus, species and strain studied Tolerance to acid, growth requirements and fecal recovery rates Method of delivery, i.e. yogourt vs capsule Disease state Age group of subjects Combined vs single strains Treatment duration Number of colony forming units (CFU) 7. Therap Adv Gastroenterol 2010;3(5) Are Probiotics Safe? Lack of systematic reporting 8 Poorly documented interventions For RCTs where adverse events were reported, no statistically significant increase (RR 1.00; 95% CI 0.93 1.07) Despite the substantial number of publications, the current literature is not well equipped to answer questions on the safety of probiotic interventions with confidence 8. Safety of Probiotics to Reduce Risk and Prevent or Treat Disease. AHRQ. April 2011. 6

CDAD Clostridium difficile associated diarrhea (CDAD) Cochrane Review of 23 RCTs, 4303 patients looked at probiotics for prevention of CDAD Incidence of CDAD: 2% in probiotic group vs 5.5% in placebo/no treatment arm (NNT 29) Problems 10 different strain combinations Only 4 showed difference in subgroup analysis 9. Cochrane Systematic Reviews. CD006095. 2013. CDAD: Impact of Funding 24 studies separated by public funding or industry/unclear funding 11 Industry supported/unclear funded studies were more than twice as likely as publicly funded studies to report benefit of probiotics in preventing CDAD 11. Am J Gastro 2014;109(7) 7

Antibiotic Associated Diarrhea (AAD) JAMA 2012 13 82 RCTs, multiple strains, capsules, liquids, powders, yogurts, etc. 63 RCTs meta analyzed NNT 13; effect still significant for numerous subgroup analyses and specific strains 13. JAMA 2012;307(18) Hold the Phone New large multi centre RCT, 2981 patients, government funded 10 Lactobacilli and Bifidobacteria At 12 weeks, no significant difference in CDAD or AAD incidence: CDAD: 0.8% probiotic, 1.2% placebo AAD: 10.8% probiotic, 10.4% placebo 10. Lancet 2013;382(9900) 8

Irritable Bowel Syndrome (IBS) Problem with outcomes Abdominal pain improvement, pain score by VAS, IBS severity score, global improvement, adequate general symptom improvement 2010 meta analysis of 10 RCTs with 918 patients, reporting dichotomous outcomes 14 NNT 4 to report symptom improvement or cure Sub analysis of only higher quality trials: not statistically significant 14. Gut 2010;59:e325 e332 Inflammatory Bowel Disease (IBD) Crohn s: few very small studies, no benefit 15 Ulcerative colitis Maintaining remission 16 : statistically similar to 5 ASA Inducing remission 17 : only VSL#3 shows benefit; 5 studies of 438 patients; NNT ~6 15. Cochrane Systematic Reviews. CD006634. 16. Cochrane Systematic Reviews. CD007443. 17. Inflamm Bowel Dis. 2014;20(1). 9

Specific Products Florastor: S. boulardii Dose: 1 2 capsules per day Prevention of AAD 13 : NNT 10 Prevention of CDAD 9 : NNT ~55 Treatment of acute pediatric diarrhea 18 : Meta analysis of 17 studies with 2102 patients Reduced duration of diarrhea on average ~20 hours, 1 less loose stool per day Only 2 studies (230 subjects) done in advanced economies 18. Pediatrics. 2014;134:e176 e191 Specific Products:Florastor Caveat on CDAD & AAD findings LV McFarland, listed as author on one in six metaanalyses, guidelines, and systematic reviews regarding Saccharomyces boulardii on PubMed Discloses paid speaker for manufacturer but not that from 1988 to 2001, scientific director for patent holder 19 Two of her RCTs published during that time included in CDAD and AAD reviews 19. LinkedIn profile job history of Lynne V McFarland. 10

Specific Products Align: B. bacterium longum Infantis 35624 Dose: 1 capsule per day Marketed for IBS symptom improvement Two RCTs with specific strain 20,21 Both funded, partly conducted by manufacturer Statistically significant improvement, but not likely clinically significant; 0.9 1 point improvement on 7 point symptom scale Neither had same dose as current product and one was in a liquid vehicle 20. Gastroenterology 2005;128(3) 21. Am J Gastroenterol 2006;101(7) Specific Products Culturelle: L. rhamnosus GG Dose: 1 capsule per day Management of acute infectious diarrhea in children 22 Prevention of nosocomial diarrhea and rotavirus gastroenteritis Meta analysis, only 3 studies (1043 subjects), two by metaanalysis author Only one not done by author and done in advanced economy showed no effect Prevention of CDAD/AAD No statistically significant difference from placebo 9 22. Aliment Pharmacol Ther 2011;34(9) 11

Specific Products TuZen: L. plantarum 299v Dose: 1 2 capsules per day Marketed for improvement of IBS symptoms 3 small RCTs done, all by manufacturer 23 25 Small benefit;questionable clinical significance Independent meta analysis 26 concluded no benefit based on data 23. World J Gastroenterol 2012;18(30) 24. Eur J Gastroenterol Hepatol 2001;13(10) 25. Am J Gastroenterol 2000;95(5) 26. PLoS ONE 2012;7(4) Specific Products Biogaia: L. reuteri protectis Dose: 5 drops Treatment of infantile colic Meta analysis of 6 RCTs including 423 infants with colic 27 Decreased crying time at 2 weeks by 43 minutes per day Treatment effect gone by 4 weeks 27. PLoS ONE 2015;10(10) 12

Other Uses Meta analysis of multiple GI uses found no evidence for traveler s diarrhea 26 Likely benefit Necrotizing enterocolitis in <34 week infants of very low birth weight (<1500g) 28 Unlikely Benefit Prevention of URTIs 29 No benefit Weight loss 30 28. Cochrane Systematic Reviews. CD005496 29. Cochrane Systematic Reviews. CD006895 30. Nutr Res 2015;35(7) Bottom Line Multiple problems with CDAD/AAD findings Small sample sizes, industry funding, selection bias Frequent detection of publication bias in meta analyses Hodgepodge of study populations, strains, doses, vehicles, and study outcomes 13

Bottom Line Best evidence currently exists for: Treatment of acute diarrhea in children Small effect; if limit analysis to high income countries, reduce duration of diarrhea by <20 hours Prevention of AAD Only 10% of RCTs adequately powered to find result Frequency of AAD in placebo abnormally high; ~35% compared to general population ~10% 35 35. BMC Infect Dis. 2015;15(129) Bottom Line Most reviews urge caution in interpreting results due to significant methodological limitations Small sample sizes, industry funding, selection bias Frequent detection of publication Hodgepodge of study populations, strains, doses, vehicles, and study outcomes 14

Conclusion Probiotics need to up their game in spring training before they re ready for the big leagues References 1. Reid G. Probiotics: definition, scope and mechanisms of action. Best Practice & Research Clinical Gastroenterology. 2016;30(1):17 25. doi:10.1016/j.bpg.2015.12.001. 2. Skokovic Sunjic D. Clinical Guide to Probiotic Supplements Available in Canada. The Science of Probiotics. http://www.scienceofprobiotics.ca/wpcontent/uploads/2015/03/clinical guide to probiotic supplements 2015.pdf. Published March 2015. Accessed October 4, 2016. 3. Mcfarland LV. From Yaks to Yogurt: The History, Development, and Current Use of Probiotics. Clinical Infectious Diseases. 2015;60(suppl 2):S85 S90. doi:10.1093/cid/civ054. 4. New study says: Canadians Puzzled by Probiotic Health Benefits Swiss Natural English. http://www.swissnatural.com/en/media/releases/new study sayscanadians puzzled by probiotic health benefits/. Published February 2012. Accessed October 4, 2016. 5. Feldman M. The New Market Profile of Probiotics Consumption. The New Market Profile of Probiotics Consumption. http://www.naturalproductsinsider.com/articles/2016/09/the new market profile of probiotics consumption.aspx. Published September 22, 2016. Accessed October 4, 2016. 6. Sanders ME, Guarner F, Guerrant R, et al. An update on the use and investigation of probiotics in health and disease. Gut. 2013;62(5):787 796. doi:10.1136/gutjnl 2012 302504. 7. Verna EC, Lucak S. Use of probiotics in gastrointestinal disorders: what to recommend? Therapeutic Advances in Gastroenterology. 2010;3(5):307 319. doi:10.1177/1756283x10373814. 8. Hempel S, Newberry S, Ruelaz A, et al. Safety of probiotics to reduce risk and prevent or treat disease. Evidence report/technology Assessment No. 200. AHRQ Publication No. 11 E007. Rockville, MD: Agency for Healthcare Research and Quality. April 2011. Available at: http://www.ahrq.gov/clinic/tp/probiotictp.htm Accessed: October 4, 2016 15

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