Effect van boterzuur op insulineresistentie. Voeding, inflammatie en insulinerestentie Utrecht

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1 Effect van boterzuur op insulineresistentie Voeding, inflammatie en insulinerestentie Utrecht Max Nieuwdorp MD PhD Internist-endocrinologist Professor Diabetes, Chair Diabetes Center AMC Visiting Professor Wallenberg Laboratorium, Gothenborg University

2 Disclosure slide Lecture fees: Danone, Astrazeneca, EliLilly, Sanofi Scientific advisory board: Seres health and Caelus therapeutics AMC hospital owns several patents in the field

3 Take home message Short chain fatty acids (butyrate) from intestinal microbiota play a driving role in insulin resistance Therapy butyate producing bacteria in insulin sensitivity Therapy: metabolites (butyrate) in insulin sensitivity Future challenges

4 Short chain fatty acids (butyrate) from intestinal microbiota play a driving role in insulin resistance

5 Background Gut microbiota Total bowel surface (tennis court); kilogram feces in a human life produced! The gut microbiota (60% of the dry mass of feces) content consists of (!) bacteria 99% anaerobic 90% belong to 2 phyla:firmicutes & Bacteroidetes Microbiome 100 times larger than the human genome Large fraction gut microbiota is difficult to culture, therefore only estimations of total amount of about 400 different bacterial species could be made by microbiologists throughout the last decades 1 Ley et al, Nature 2006, 444: Bäckhed et al, PNAS 2004, 101:

6 Background Gut microbiota Total bowel surface (tennis court); kilogram feces in a human life produced! The gut microbiota (60% of the dry mass of feces) content consists of (!) bacteria 99% anaerobic 90% belong to 2 phyla:firmicutes & Bacteroidetes Microbiome 100 times larger than the human genome Large fraction gut microbiota is difficult to culture, therefore only estimations of total amount of about 400 different bacterial species could be made by microbiologists throughout the last decades 1 Ley et al, Nature 2006, 444: Bäckhed et al, PNAS 2004, 101:

7 Function of bacteriae Intestinal Bacteriae: Fermenting unused energy substrates into ScFA (butyrate) training the immune system preventing growth of harmful, pathogenic bacteria (clostridium difficile) producing vitamins (such as biotin, B12 and vitamin K) and facilitate electrolye absorption (Magnesium, Calcium and Iron) hormone production (adiponectin) to direct the host to store fats Wikoff, PNAS 2009

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

9 Estimated prevalence of insulin resistance and diabetes mellitus in 2025

10 Dog owners share 50% microbiome with dogs Real Dogs Real People MAIN MENU In feces, palm of the hand and the tongue. Song SJ, Elife Apr 16;2:e STUDIES SHOW FLU AND DENTAL DISE TRANSMITTED BETWEEN PEOPLE AND P transmitted-people-pets/ While it s widely known that animals can transmit dis the swine flu (H1N1) and bird flu, for example recen that people can also transmit disease to their pets, and Veterinarians and scientists are trying to understand w

11 Rapid effect dietchange on microbiome Within 24 hours 1.High fat based diet : bacterial generes enriched in the metabolism of fatty acids and gluconeogenesis. (Bacteroides); less ScFA butyrate 2.Plant based diet 2 bacterial generes enriched in the metabolism of catabolism of sugars and amino acids. (Prevotella) more ScFA butyrate 3. fructose diet : more gram negative proteobacteriae (E.coli) and less ScFA butyrate Wu, Science 2011; David, Nature 2014

12 Short chain fatty acids in metabolism SCFA -acetate (50%) -butyrate (30%) -propionate (20%): Intestinal integrity Backhed, Nature 2012

13 Gut microbiota and type 2 diabetes mellitus; less Scfa producing bacteria Qin, Nature 2012 Le Chatelier, Nature 2013 Karlsson, Nature 2013 Ridaura, Science 2013

14 ph dictates bacterial survival and gutmicrobiota composition Hartstra/nieuwdorp, Diabetes Care 2014.

15 Therapy: altering butyate producing bacteria in insulin sensitivity

16 2. Fecal transplant Past Fecal transplant - History 4 th Century BC: Chinese medicine, food poisoning and diarrhea 1,3 16th Century AD: Li Shizhen yellow soup, gastro-intestinal illness 2,3 Present 1958: Eiseman, antibiotics-induced chronic diarrhea 1. Ge Hong (Dongjin Dynasty) (2000) Zhou Hou Bei Ji Fang. Tianjijn Science & Technology Press: Tianjin, 2. Li S (Ming Dynasty) (2011) Ben Cao Gang Mu. Huaxia Press: Beijin 3. Faming Zhang et al,, American College of Gastroenterology 2012: 1755

17 De Vrieze, Science 2013

18 Not all (autoimmune) disease benefit from fecal Tx Since 1958 casereport by Eiseman, at least 4500 patients treated worldwide with donor feces, effective for: - recurrent C. difficile infection, - Inflammatory Bowel Disease/IBS - Multiple Sclerosis RCT superiority of fecal Tx in clostridium difficile diarrhea Long term side effects have not been reported yet Smits/Nieuwdorp, Gastroenterology 2013 [in press]; van Nood/Nieuwdorp, NEJM 2013

19 Increased wais Metabolic syndrome (overweight/pre diabetes with no medication yet) Dyslipidemia Hypertension Insulin resistance Hyperglycemia

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

21 Fecal gut microbiota composition F prausznitzii higher Ruminococcus higher A.Vrieze, Gastroenterology 2012

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

23 Koch s postulates Fecal transplant doesn t induce a definate cure! Eiseman (Surgery 1958) 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

24 Therapy: bacterial metabolites (butyrate) supplementation in insulin sensitivity

25 Butyrate improves insulin sensitivity and brown fat activation in db/db mice Gao et al, Diabetes, 2009

26 Short chain fatty acids in metabolism SCFA -acetate (50%) -butyrate (30%) approximately 8 gram per day produced in intestine -propionate (20%): Intestinal integrity Backhed, Nature 2012

27 Oral 4 gram/day Sodium Butyrate daily during 1 month on insulin sensitivity Bouter K, Manuscript in preparation

28 Oral Sodium Butyrate daily during 1 month Brown fat and FGF21 Bouter K, Manuscript in preparation

29 Future challenges: butyrate tip of the iceberg o gutmicrobiota derived metabolites Metabolites side effect ( glycemic index/ side effects) SCFA Bacteria or SCFA butyrate itself: Compliance (daily intake?) Human phase 1-2 dosefinding trial with GMP produced E.hallii in MetSyn started in 2014 v2 Eubacterium hallii De Vos WM and Nieuwdorp M. Nature 2013; 498(7452):48-9

30 Take home message Short chain fatty acids (butyrate) from intestinal microbiota play a driving role Therapy butyate producing bacteria in insulin sensitivity Therapy: metabolites (butyrate) in insulin sensitivity Future challenges

31 Willem de Vos WUR/Helsinki Acknowledgements Fredrik backhed Gothenborg Anne Vrieze MD PhD AMC Nieuwdorp Diabetes research center PhD students Ruud Kootte MD Fleur van der Valk, MD Pim Gilijamse, MD Kasper ter Horst, MD Loek Smits, MD Sophie Bernelot Moens, MD Kristien Bouter, MSc Pieter de Groot, MD Annick Hartstra MD Guido Bakker, MD Mark Smits, MD Marcel Muskiet MD Lennaert Tonneijk, MD Shanti Udayappan, Msc Postdocs Han Levels PhD Daniel van Raalte, MD PhD Hilde Herrema PhD Jing Zhao PhD Geesje Dallinga, PhD Hans Romijn AMC Bert Groen Erik Stroes AMC Louise Manneras