Effect van boterzuur op insulineresistentie Voeding, inflammatie en insulinerestentie Utrecht 9-03-2015 16.20-16.40 Max Nieuwdorp MD PhD Internist-endocrinologist Professor Diabetes, Chair Diabetes Center AMC Visiting Professor Wallenberg Laboratorium, Gothenborg University
Disclosure slide Lecture fees: Danone, Astrazeneca, EliLilly, Sanofi Scientific advisory board: Seres health and Caelus therapeutics AMC hospital owns several patents in the field
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
Short chain fatty acids (butyrate) from intestinal microbiota play a driving role in insulin resistance
Background Gut microbiota Total bowel surface (tennis court); 6000-7000 kilogram feces in a human life produced! The gut microbiota (60% of the dry mass of feces) content consists of 10 14 (!) 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, 444:1022-1023 2 Bäckhed et al, PNAS 2004, 101:15718-15723
Background Gut microbiota Total bowel surface (tennis court); 6000-7000 kilogram feces in a human life produced! The gut microbiota (60% of the dry mass of feces) content consists of 10 14 (!) 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, 444:1022-1023 2 Bäckhed et al, PNAS 2004, 101:15718-15723
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
Results of these cohort based studies using fecal samples F prausznitzii lower Ruminococcus lower Smits/Nieuwdorp, Gastroenterology 2013 [in press]
Estimated prevalence of insulin resistance and diabetes mellitus in 2025
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. 2013 Apr 16;2:e00458. STUDIES SHOW FLU AND DENTAL DISE TRANSMITTED BETWEEN PEOPLE AND P http://www.findavet.us/2012/10/studies-show-flu-de 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
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
Short chain fatty acids in metabolism SCFA -acetate (50%) -butyrate (30%) -propionate (20%): Intestinal integrity Backhed, Nature 2012
Gut microbiota and type 2 diabetes mellitus; less Scfa producing bacteria Qin, Nature 2012 Le Chatelier, Nature 2013 Karlsson, Nature 2013 Ridaura, Science 2013
ph dictates bacterial survival and gutmicrobiota composition Hartstra/nieuwdorp, Diabetes Care 2014.
Therapy: altering butyate producing bacteria in insulin sensitivity
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
De Vrieze, Science 2013
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
Increased wais Metabolic syndrome (overweight/pre diabetes with no medication yet) Dyslipidemia Hypertension Insulin resistance Hyperglycemia
Effect donor faeces on periferal insulin sensitivity A.Vrieze, Gastroenterology 2012
Fecal gut microbiota composition F prausznitzii higher Ruminococcus higher A.Vrieze, Gastroenterology 2012
Small intestinal gut microbiota composition A.Vrieze, Gastroenterology 2012
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
Therapy: bacterial metabolites (butyrate) supplementation in insulin sensitivity
Butyrate improves insulin sensitivity and brown fat activation in db/db mice Gao et al, Diabetes, 2009
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
Oral 4 gram/day Sodium Butyrate daily during 1 month on insulin sensitivity Bouter K, Manuscript in preparation
Oral Sodium Butyrate daily during 1 month Brown fat and FGF21 Bouter K, Manuscript in preparation
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
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
Willem de Vos WUR/Helsinki Acknowledgements Fredrik backhed Gothenborg Anne Vrieze MD PhD AMC Nieuwdorp group @ 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