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

Colorectal cancer

MICROBIOME

Dia

bet

es

Alc

oh

olic

live

r d

ise

ase

An

xiet

y Autism Obesity

Cirrhosis

Non-alcoholic fatty liver disease (NAFLD)

Irritable bowel syndrome (IBS)

Diverticulosis

Inflammatory bowel diseases (IBD)

Metabolic syndrome Depression

Allergy

Graft-versus-host disease GI i

nfe

ctio

ns

NEC

Gastrointestinal microbiota

4

Most abudant bacterial taxa

Functions intestinal microbiota

Colonisation resistance

Growth / function epithelium

Barrier function

Immune system

Metabolic activity

5

Small intestine

Large intestine

Feces

SCFAs + lactate + gases

acetate (C2), propionate (C3), butyrate (C3), valerate (C4), caproate (C5)

digestion

absorption

proximal distal

carbohydrates

fermentation

SCFA production SCFA

(≈5%)

Energy generation: 2kcal/g

6

Intestinal microbial metabolic activity

Hamer et al. Alim Pharm Ther 2008;27(2):104-19 Byrne et al. Int J Obesity 2015; 39: 1331-1338

Reigstad et al. Faseb J 2015; 29: 1395-1403

Highly active ‘organ’

•Synthesis vitamins (B/K)

•Conversion bile acids

•Conversion xenobiotics

•Saccharolytic / proteolytic fermentation

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)

Hamer et al. Alim Pharm Ther 2008;27(2):104-19

Byrne et al. Int J Obesity 2015; 39: 1331-1338

Brain-gut interaction (serotonin)

Lipid and glucose metabolism

Reigstad et al. Faseb J 2015; 29: 1395-1403 7

Protein fermentation

• branched chain fatty acids

• gas -> H2S

• ammonia, amines, indoles and phenols

Damaging effects • Inhibition butyrate oxidation

• Impaired barrier function • Cytotoxic effects • Pro-inflammatory response

saccharolytic fermentation

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proteolytic fermentation

Hormone-like metabolites produced or regulated by the microbiota

9 Clarke, Mol Endocirnol 2014

• GABA • Noradrenalin • Dopamine • Serotonin

10

Smal

l in

test

ine

Villi (microvilli)

Immune system

Nutrients pH O2

Digestion Absorption

No Paneth cells

Goblet cells >> Thick mucus layer

Paneth cells

ileum

duodenum Paneth / Goblet

SCFAs Carbohydrate fermentation

Protein fermentation

Mowat, Nat Rev Immunol 2014

Bacterial numbers, diversity and function

differs along the GI tract

Factors affecting gut microbiome variation

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• Bristol stool form: largest effect size • Medication: largest total variance explained

Falony et al, Science 2016

Do differences in food intake affect your microbiome?

Daily variation? Differences in dietary patterns?

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Impact of diet on microbiota composition

3 enterotypes: • driven by

• Bacteroides • Prevotella • Ruminococcus

• Independent of geographic

origin, age, gender, BMI

Arumugam, Nature 2011; 473: 174-180 13

Association between diet and enterotypes

Wu et al. Science 2011; 334: 105-108

Enterotypes associated with long-term dietary habits • Bacteroides-enterotype

- Animal fat, saturated fat, proteins • Prevotella-enterotype

- Carbohydrates / simple sugars

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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: 105-108 15

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

David et al. Nature 2014; 505; 559-563

• Animal diet: • metabolites protein fermentation • metabolites carbohydrate fermentation

• Altered gene expression of several

metabolic pathways

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Establishment of the intestinal microbiota

17 Van Best et al., Birth Defects Res C Embryo Today 2015

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)

Impact of diet shaping the gut microbiota

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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

Bacteroidetes Firmicutes More SCFAs

De Filippo, PNAS 2010

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)

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‘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)

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Altered food intake and altered microbiota

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Impaired nutritional status in 30-40% of outpatients

diet

microbiota frailty

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

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Short bowel syndrome

• 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

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• (Fermentable) fibre supplementation (Atia, JPEN 2011)

– Increased energy supply by colonic microbiota (up to 700-1000 kcal)

– SCFAs: trophic effects (intestinal adaptation), Na+ , Cl- absorption

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??

24 Pierre, Am J Physiol Gastrointes Liver Physiol 2017

Microbiota and bariatric surgery

• Obesity: microbiota composition and activity

– Firmicutes/ Bacterodetes ratio

• Mouse:mouse and human:mouse feces transplantation

– >> obese phenotype

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Roux-en-Y gastric bypass (Zhang 2009, Furet 2010)

microbiota, but not ‘lean’ phenotype

Microbiota, malnutrition and malabsorption

Host physiology

Malnutrition

Impaired nutritional status

Microbial perturbations

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Risk of enteropathogens

• Gut/immune maturation and functioning

• Cognitive functioning

antibiotics

Nutritional value (micro)nutrient availability

malabsorption

malabsorption

Targeting the microbiota

• Probiotics / prebiotics – 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)

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safety

Summary and conclusion

Systems medicine approach • to unravel the diet-microbiota-host interaction • to identify target for theurapeutic / preventive

strategies

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

host

diet Microbiota composition and activity

health

disease

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Thanks you for your attention

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