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FMT: Can we cure obesity and insulin resistance?

Max Nieuwdorp MD PhD Internist-endocrinologist Dept of Vascular Medicine Amsterdam Wallenberg Laboratory, Gothenberg, Sweden session Panacea or Pandora’s Box 17th august 2014: 0840-0905am. FMT: Can we cure obesity and insulin resistance?. Disclosure slide.

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FMT: Can we cure obesity and insulin resistance?

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  1. Max Nieuwdorp MD PhD Internist-endocrinologist Dept of Vascular Medicine Amsterdam Wallenberg Laboratory, Gothenberg, Sweden session Panacea or Pandora’s Box 17th august 2014: 0840-0905am FMT: Can we cure obesity and insulin resistance?

  2. Disclosure slide • Scientific advisory board Seres Health • Founder Caelus pharmaceuticals

  3. Take home message Decreased butyrate producing bacteria in obesity associated with malign obesity and insulin resistance FMT incudes changes in (small) iIntestinal microbiota and affects insulin resistance (but it is not a panancea) Using FMT as a working model can derive novel probiotics on top of current treatment for insulin resistance

  4. Intestinal microbiota in obesity and MetSyn

  5. Benign vs malign obesity • 66% metabolically healthy obese • 34% insulin resitance and DM2 • Low grade inflammation involved Samocha-bonet et al, obesity Reviwws 2014.

  6. Gut microbiota and obesity/type 2 diabetes mellitus Qin, Nature 2012 Le Chatelier, Nature 2013 Karlsson, Nature 2013 Ridaura, Science 2013

  7. Diagnostic and clinical value of gut microbiota composition in Dm2 • Reduced short-chain fatty acid butyrate producers (Roseburia species and Faecalibacterium prausnitzii) in DM2 • Enrichment of Lactobacillus gasseri and Streptococcus mutans in fecal sample has predictive value for developing insulin resistance Karlsson, Nature 2013

  8. Results of these cohort based studies using fecal samples F prausznitzii lower Ruminococcus lower Smits/Nieuwdorp, Gastroenterology 2013 [in press]

  9. Major disadvantages of current fecal sample centered approach • 1. Small intestine is more involved in metabolism than the colon • 2. Association is not causality! • 3. Sequencing vs culturing bacteria

  10. pH dictates bacterial survival and gutmicrobiota composition Hartstra/nieuwdorp, Diabetes Care 2014.

  11. Koch’s postulatesfor causality • The microorganism must be identified/isolated from a diseased organ(ism). • The microorganism should be associated with disease (association/intervention). • The cultured microorganism should induce beneficial or adverse effects when introduced into an organism (inoculation).

  12. Manipulating gut microbiota by fecal transplant

  13. Effects of fecal transplantations in clostridium difficile diarroea Van Nood, NEJM 2013

  14. Gutmicrobiota Diversity in Cdiff After FMT Correction of Low Diversity of Patients by Transplantation Diverse Community Stably Maintained for Over 2 Months

  15. FMT Randomized controlled trials performed at AMC • Since 1958 casereport by Eiseman, at least 4500 patients treated worldwide with donor feces (since 2007 at AMC), • RCT superiority of fecal Tx in clostridium difficile diarrhea and MetSyn • At AMC ongoing/finished RCT’s for: -IBD (Colitis ulcerosa, TURN trial) - insulin resistance -NAFLD/NASH • Long term side effects not seen yet Smits/Nieuwdorp, Gastroenterology 2013 [in press]; van Nood/Nieuwdorp, NEJM 2013

  16. No adverse effects! • No effect on weight 6 weeks after lean donor FMT A.Vrieze, Gastroenterology 2012

  17. Effect donor faeces on periferal insulin sensitivity A.Vrieze, Gastroenterology 2012

  18. Fecal gut microbiota composition Gutmicrobiota diversity increased F prausznitzii higher Ruminococcus higher A.Vrieze, Gastroenterology 2012

  19. Small intestinal gut microbiota composition A.Vrieze, Gastroenterology 2012

  20. Koch’s postulates • Fecal transplant doesn’t induce a definate cure! • The cultured microorganism should induce beneficial or adverse effects when introduced into a healthy organism (3rd postulate) • Concentrations of Eubacterium hallii in small intestinal biopsies correlated significantly with improved insulin sensitivity upon lean donor Fecal Tx Eiseman (Surgery 1958)

  21. Manipulating gutmicrobiota by Eubacterium hallii : effect on insulin resistance

  22. Eubacterium hallii • belongs to Firmicutes phylum (spore former) • Anaerobic gram positive lactate-utilizing SCFA butyrate- producing bacterial strain • Can produce butyrate at pH 5-6 (small intestine) as well as at pH 6-7 (colon) • Sensitive to vancomycine

  23. Studyprotocol I Db/db male mice (8 weeks old), n=8 per group Daily gavage (100ul/mouse) with E. Hallii (stored in 10% glycerol at -80C), gavage within 1 hour after thawing for 4 weeks with: -10^6 CFU/ml - 10^8 CFU/ml - 10^10 CFU/ml - placebo (dissolvens = 10% glycerol)

  24. Insulin tolerance test (insulin sensitivity) E. Hallii normalises insulin sensitivity (ITT) compared to placebo Udayappan/Manneras, submitted

  25. Gutmicrobiota analyses: Ehallii treatment significantly increases Ehallii in cecum Mean ±SEM

  26. Studyprotocol II Db/db male mice (8 weeks old), n=7-9 per group (Gothenborg university, Sweden) Daily gavage (100ul/mouse) with alive or heat inactivated E. Hallii 10x6CFU/ (stored in 10% glycerol at -80C), gavage within 1 hour after thawing for 4 weeks followed by: -48h in Metabolic cages (Somedic cages) - hyperinsulinemic normoglycemic clamp

  27. Effect E. Halli on food intake and bodyweight Udayappan/Manneras, submitted

  28. 10^8 E.hallii treatment significantly increases E.halli in cecum P<0.05 Udayappan/Manneras, submitted

  29. Active E. Hallii treatment significantly increases verruco bacteria, cyanobacteria, deferribacteres and fusobacteria * Significant p<0.05 Mann Whitney U Cyanobacteria: p=0.015(2-tailed), .007 (1-tailed) Deferribacteres: p=0.028 (2-tailed), .0014 (1-tailed) Fusobacteria: p=0.028 (2-tailed), .0014 (1-tailed) Verrucomicrobia: p=0.028 (2-tailed), .0014 (1-tailed) Red: E hallii 10x8CUF Green: plaecbo

  30. Resting energy increased upon E. hallii Udayappan/Manneras, submitted Mean ±SEM

  31. Insulin sensitivity (clamp) increased upon E. hallii * Peripheral insulin sensitivity Udayappan/Manneras, submitted

  32. E. hallii increases fecal secondary bile acids Mean ±SEM

  33. Ehallii treatment: effect on fecal SCFA P<0.05 Mean ±SEM

  34. E.Halli as novel therapeutic in in insulin resistance? • Has beneficial effects on insulin sensitivity • Potential mechanism via bileacids and brown fat (Increased Energy Expenditure) • Human intervention phase 1 dosefinding trial with E.hallii curently ongoing at AMC Eubacterium hallii De Vos WM and Nieuwdorp M. Nature 2013; 498(7452):48-9

  35. Take home message Decreased butyrate producing bacteria in obesity associated with malign obesity and insulin resistance FMT incudes changes in (small) iIntestinal microbiota and affects insulin resistance (but it is not a panancea) Using FMT as a working model can derive novel probiotics on top of current treatment for insulin resistance

  36. Acknowledgments Erik Stroes AMC Willem de Vos WUR/Helsinki Fredrik backhed Gothenborg Hans Romijn AMC Ruud Kootte MD Fleur van der Valk, MD Pim Gilijamse, MD Loek Smits, MD Sophie Bernelot Moens, MD Mara Sandberg, MD Kristien Bouter, MSc Pieter de Groot, MD Annick Hartstra MD Han Levels PhD Geesje Dallinga, PhD Alinda Schimmel, Bsc Anne Vrieze MD PhD AMC Shanti Udayappan Mireille Serlie MD PhD AMC Louise Manneras

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