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Welke rol speelt het microbioom
bij malaborptie?
- Microbiome and malabsorption -
Daisy Jonkers
Division Gastroenterology-Hepatology
Maastricht University Medical Center+
20 april 2017
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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
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Gastrointestinal microbiota
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Most abudant bacterial taxa
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Functions intestinal microbiota
Colonisation resistance
Growth / function epithelium
Barrier function
Immune system
Metabolic activity
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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
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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
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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
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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
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Hormone-like metabolites produced or regulated by the microbiota
9 Clarke, Mol Endocirnol 2014
• GABA • Noradrenalin • Dopamine • Serotonin
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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
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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
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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
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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
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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)
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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
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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
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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
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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
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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
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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
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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
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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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