Welke rol speelt het microbioom bij malaborptie? - Microbiome and malabsorption -

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1 Welke rol speelt het microbioom bij malaborptie? - Microbiome and malabsorption - Daisy Jonkers Division Gastroenterology-Hepatology Maastricht University Medical Center+ 20 april 2017 d.jonkers@maastrichtuniversity.nl

2 Alcoholic liver disease Anxiety Diabetes GI infections Graft-versus-host disease Allergy Cirrhosis Autism Depression Non-alcoholic fatty liver disease (NAFLD) NEC Obesity MICROBIOME Metabolic syndrome Inflammatory bowel diseases (IBD) Irritable bowel syndrome (IBS) Diverticulosis Colorectal cancer 2

3 Gastrointestinal microbiota

4 Most abudant bacterial taxa 4

5 Functions intestinal microbiota Colonisation resistance Metabolic activity Growth / function epithelium Barrier function Immune system 5

6 Intestinal microbial metabolic activity Highly active organ Synthesis vitamins (B/K) Conversion bile acids Conversion xenobiotics Saccharolytic / proteolytic fermentation Large intestine Small intestine fermentation Feces carbohydrates digestion absorption SCFA production SCFA ( 5%) proximal distal SCFAs + lactate + gases acetate (C2), propionate (C3), butyrate (C3), valerate (C4), caproate (C5) Energy generation: 2kcal/g Hamer et al. Alim Pharm Ther 2008;27(2): Byrne et al. Int J Obesity 2015; 39: Reigstad et al. Faseb J 2015; 29:

7 Effects of butyrate Energy source for epithelial cell Affect several pathophysiological processes Regulation gene expression ( via inhibition histone deacetylation) Signaling molecule (via G-protein coupled receptors) Lipid and glucose metabolism Brain-gut interaction (serotonin) Hamer et al. Alim Pharm Ther 2008;27(2): Byrne et al. Int J Obesity 2015; 39: Reigstad et al. Faseb J 2015; 29:

8 Protein fermentation branched chain fatty acids gas -> H 2 S ammonia, amines, indoles and phenols Damaging effects saccharolytic fermentation proteolytic fermentation Inhibition butyrate oxidation Impaired barrier function Cytotoxic effects Pro-inflammatory response 8

9 Hormone-like metabolites produced or regulated by the microbiota GABA Noradrenalin Dopamine Serotonin Clarke, Mol Endocirnol

10 Small intestine duodenum Villi (microvilli) Paneth / Goblet Immune system Nutrients ph O 2 Digestion Absorption ileum Paneth cells Bacterial numbers, diversity and function differs along the GI tract No Paneth cells Carbohydrate fermentation SCFAs Goblet cells >> Thick mucus layer Protein fermentation Mowat, Nat Rev Immunol

11 Factors affecting gut microbiome variation Bristol stool form: largest effect size Medication: largest total variance explained Falony et al, Science

12 Do differences in food intake affect your microbiome? Daily variation? Differences in dietary patterns? 12

13 Impact of diet on microbiota composition 3 enterotypes: driven by Bacteroides Prevotella Ruminococcus Independent of geographic origin, age, gender, BMI Arumugam, Nature 2011; 473:

14 Association between diet and enterotypes Enterotypes associated with long-term dietary habits Bacteroides-enterotype - Animal fat, saturated fat, proteins Prevotella-enterotype - Carbohydrates / simple sugars Wu et al. Science 2011; 334:

15 Short term dietary intervention I Controlled feeding trial (Wu 2011) High-fat/low-fiber or low-fat/high fiber n=10, 10 days, daily fecal sampling Change in microbiota within 24 hours Subject dependent effects No enterotype-switch Effect of diet < inter-individual variation Wu et al. Science 2011; 334:

16 Short term dietary intervention II Plant versus animal-based dietary intervention (n=10, 5 days) Plant-based diet Grains, legumes, fruits, vegetables Animal-based diet Meat, eggs, cheese Intake fiber fat and protein Microbiota 3 bacterial clusters 22 bacterial cluster β-diversity Animal diet: metabolites protein fermentation metabolites carbohydrate fermentation Altered gene expression of several metabolic pathways David et al. Nature 2014; 505;

17 Establishment of the intestinal microbiota Acquisition of microbial genes depends on life cycle and setting: Vitamin biosynthesis (folate, cobalamin, thiamine, biotin) Amino acid metabolism Processing of complex polysaccharides Development of microbiome parallels maturation GI tract and CNS (Subramanina 2012, Yatsunenko Nature 2012, Subramanina Cell 2015) Van Best et al., Birth Defects Res C Embryo Today

18 Impact of diet shaping the gut microbiota Bacteroidetes Firmicutes More SCFAs Microbiota in children (1-6 yrs) Rural area Burkino Faso (n=14) low in fat, animal protein, rich in starch, fiber, plant polysaccharides Urban area Europe (N=15) high in animal protein, sugar, starch, fat low in fiber De Filippo, PNAS

19 Microbiota in malnourished children Altered composition and activity >> less mature More Proteobacteria, less diverse, more inflammogenic (Subramanian 2104, Monira 2011, Smith 2013) Animal studies of protein malnutrition richness/diversity, saccharolytic fermentation capacity (Preidis 2015) 19

20 Malnourished microbiota induces features of environmental enteropathy in children Low protein and low fat diet in mice (Brown, Nature Comm 2015) microbiota / metabolites, growth, intestinal permeability More prone to Salmonella infection Bacteroides / E. coli cocktail >> replicated features of environmental enteropathy Microbiota of malnourished children transplanted in mice: >>> weight loss and enteropathy features (Smith, Science 2013) 20

21 Altered food intake and altered microbiota diet microbiota frailty Impaired nutritional status in 30-40% of outpatients 21

22 Short bowel syndrome Loss of intestinal absorptive capacity (by e.g. surgery, congenital defect, disease) Heterogenous underlying pathology, length / function of remaining intestine Diarrhea, fatty stools, abdominal pain, malnutrition, dehydration Often require PN / IV fluid support 22

23 Short bowel syndrome (Fermentable) fibre supplementation (Atia, JPEN 2011) Increased energy supply by colonic microbiota (up to kcal) SCFAs: trophic effects (intestinal adaptation), Na +, Cl - absorption microbiota (Mayeur Plos One 2013 / Boccia, Clin Nutrition 2016) Reduced bacterial diversity More lactobacilli / leuconostoc group Less diversity within Clostridium / Bacteroides A subgroup accumulates lactate D/L-lactate ratio associated with encephalopathy 23

24 Parenteral nutrition and microbiota Altered gut-lymphoid tissue function Altered barrier function cell proliferation,differentiation, tight juntion proteins, mucus layer Altered microbiota composition diversity, Firmicutes bacteroidetes, proteobacteria, opportunistic pathogens SCFAs?? Pierre, Am J Physiol Gastrointes Liver Physiol

25 Microbiota and bariatric surgery Obesity: microbiota composition and activity Firmicutes/ Bacterodetes ratio Mouse:mouse and human:mouse feces transplantation >> obese phenotype Roux-en-Y gastric bypass (Zhang 2009, Furet 2010) microbiota, but not lean phenotype 25

26 Microbiota, malnutrition and malabsorption malabsorption antibiotics Risk of enteropathogens Microbial perturbations Host physiology Gut/immune maturation and functioning Cognitive functioning Nutritional value (micro)nutrient availability Malnutrition Impaired nutritional status malabsorption 26

27 Probiotics / prebiotics Targeting the microbiota Limited /inconsistent evidence in probiotics SBS, bariatric surgery Benificial potential prebiotics but no/limited studies Fecal microbiota transplantation Enema, colonoscopy, capsules, catheters Beneficial effect in treatment Clostridium difficile infection overall success rate 80-98% (Dodin, In J Clin Pract 2014;368: 363) safety 27

28 Summary and conclusion Diet, malnutrition and reduced absorption affect the microbiota composition and activity Effects can differ between subjects Diet-microbiota interactions can impact host physiology, contributing to a vicious circle Systems medicine approach to unravel the diet-microbiota-host interaction to identify target for theurapeutic / preventive strategies host health Microbiota disease composition and activity diet 28

29 Thanks you for your attention 29