ESPEN Congress Copenhagen 2016

ESPEN Congress Copenhagen 2016 THE DIVERSITY OF OBESITY OBESITY AND THE GI TRACT N. Delzenne (BE)

Metabolism and Nutrition Research Group The Diversity of Obesity (educational session) Obesity and the GI tract N.M. Delzenne I declare no conflict of interest related to this presentation

Energy, metabolism Digestion, motility microbiota «Barrier» Fermentation energy sparing Metabolic dialogue with host tissues Key gut functions (neuroendocrine, immune, vascular functions) Energy metabolism, behavior

Energy, metabolism Digestion, motility microbiota «Barrier» Fermentation (energy sparing) Metabolic dialogue with host tissues Key gut functions (neuroendocrine, immune, vascular functions) Energy metabolism, behavior

Intestinal cell diversity and functions Gut hormones i.e. CCK, GLP-1, 2, PYY Mucus* Immuno-modulatory Peptides* Antimicrobial Peptides* Medena and Vermeulen 2011 *Control of the gut microbiota

A key role for gut peptides (i.e. GLP-1) in the control of metabolic disorders associated with obesity endotheliumdependent relaxation Myat A., Heart, 2014

Gut immunity and obesity : novel perspectives Access to «absorptive» intestinal tissue in 185 obese patients with or without co-morbidity and diabetes; obesity surgery From Monteiro-Sepulveda et al Cell Metab 2015

Therapeutic approaches Energy, metabolism Lipase inhibitor Bariatric surgery Digestion, motility? microbiota «Barrier» Fermentation (energy sparing) Metabolic dialogue with host tissues LP-1 analogues DPPIV inhibitors Key gut functions (neuroendocrine, immune, vascular functions) Energy metabolism, behavior

The Gut Microbiota: an internal organ we feed everyday for the maintenance and/or recovery of health 1. Human cells : 30000 genes (genome) 2. Bacterial cells: 1600 genes (microbiome) 3. The gut microbiota contains up to 1000 species (10 14 cells) dominated by 3 (of 70) divisions: 10 14 bacterial cells in the gut - Firmicutes (E. rectale-cl. Coccoides, Cl. leptum) - Bacteroidetes (Bacteroides, Prevotella) - Actinobacteria (Bifidobacterium) 100 fold more gene in the microbiome than in the human genome Production of hundreds of metabolites, mostly from nutrients escaping the digestion in the upper part of the gut 4. Bacteries are classified as gram negative (LPS) or gram positive A fragile equilibrium..

Nutrients- gut microbiome-host interactions 1.Dysbiosis related to obesity, diabetes and metabolic diseases 2.Tools available to modulate the gut microbiota and host health in obesity : a place for nutrition?

Dysbiosis associated with obesity and type 2 diabetes (T2D) in humans (Karlsonn et al Nature 2013,Delzenne et al Diabetologia 2015 Shoaie et al Cell Metab. 2016)). Prediction of obesity and related metabolic diseases through microbiota analysis? Characteristics of a «moderate»dysbiosis - Decrease in bacterial diversity - Shift in major phyla (increased Firmicutes/Bacteroidetes) - Decrease in «beneficial» bacteria Bifidobacteria (immune system), F. Prausnitzii (anti-inflammatory), Roseburia intestinalis or Clostridium (butyrate producers), Akkermansia muciniphila (gut barrier) - Increase in potentially harmful bacteria bacteria (i.e. Desulfovibrio spp., betaproteobacteria, Bacteroides-Prevotella) - changes in bacterial functions (drug and oxidative stress resistance) James Ensor

Dysbiosis allows to distinguish obese individuals as «responder» and «non responder» to diet-induced weight loss Dao et al, Clin. Nutr. Exp. Dec 2015

Complex carbohydrates Microbial metabolites as modulators of key gut function Saccharolytic bacteria + Akkermansia Butyrate Acetate Propionate Butyrate GPR43/41 Short chain fatty acids as modulators of glycemia? Bile acids? TGR5 Propionate GNG Goblet cell Mucus production GLP-2 L cell Portal glucose Portal propionate Gut barrier Endotoxaemia Intestinal transit Glucose homeostasis PYY Appetite Insulin secretion/ response GLP-1 Neuron GPR41 Substrate for GNG Inhibitor of GNG from lactate Indicates Gut microbial activity GNG : gluconeogenesis Systemic glucose? Delzenne et al modified from Diabetologia 2015

Complex carbohydrates Butyrate Acetate Propionate Butyrate Tau/Gly-1 BA GPR43/41 2 BA Decrease in butyrate/propionate producers Decrease in BSH H 2 S TGR5 Sulfide Increase in sulfate reducers Indole Tryptophan Propionate Butyrate Propionate *Increased ACETATE Goblet cell Mucus production Gut barrier Endotoxaemia GLP-2 Intestinal transit Glucose homeostasis PYY Appetite L cell Insulin secretion/ response GLP-1 Neuron GPR41 Gut microbial activity Portal glucose Increased glucose stimulated insulin secretion, and ghreliin* Negative impact of diabetes-related dysbiosis *Perry Schulman Nature 6th may 2016 «acetate mediates a microbiome-brain beta cells axis to promote metabolic syndrome»

Nutrients- gut microbiome-host interactions 1.Dysbiosis related to obesity, diabetes and metabolic diseases 2.Tools available to modulate the gut microbiota and host health in obesity : a place for nutrition?

Tools to modulate dysbiosis associated with metabolic disorders Antibiotics Health Modified from Lozupone et al, Nature 2012

Short term antibiotic treatment changes bacterial metabolites without significantly modulating the host metabolism Reijnders et al Cell Metab 2016 57 obese-prediabetic men

Tools to modulate dysbiosis associated with metabolic disorders Health Mostly proposed for severe infection (C difficile) Antipoison in China (400 a.c.) Modified from Lozupone et al, Nature 2012

Fecal Material transplantation (FMT) in diabetic/obese individuals : improvement of h insulin resistance for 6 wks De Vrieze et al 2013

Tools to modulate dysbiosis associated with metabolic disorders Probiotic approach= Spread «missing» bacteria with key functions Health Modified from Lozupone et al, Nature 2012

Probiotic intervention in obese individuals BW: body weight; BWG: body weight gain; BMI: body mass index; NEFA: non-esterified fatty acid Druart et al. Advances in Nutrition 2014

Dysbiosis is a driver of metabolic alterations linked to the disease, namely by disrupting the gut barrier (translocation of LPS =, 16S rdna, lipoteichoic acid) Dysbiosis Akkermansia muciniphila LPS Disturbed Mucus production Endotoxin (EU/ml) 6 * 5 4 3 2 1 0 ND T2DM Serum LPS increases In diabetic patients Cani et al Gut Microbes, 2012, Geurts et al 2013

Obesity & metabolic syndrome Akkermansia muciniphila as a probiotic to improve the gut barrier function and metabolic disorders in obesity? CT or HF Akkermansia muciniphila 4 weeks Decreases serum LPS, glycemia, systemic inflammation Everard et al, PNAS 2013

Investigation of the physiological effects of Akkermansia on diabetes and cardiometabolic risk factors BMI 25, insulin resistance and metabolic syndrome Randomized, single-blind, parallel, placebo-controlled 100 subjects NCT02637115 Randomization Informed consent 15days Safety check 3 months of treatment Placebo Live A. muciniphila 10 9 /day Live A. muciniphila 10 10 /day ERC-PoC-2016 Pasteurized Heat treated A.muciniphila 10 10 /day Key Outcomes : insulin-resistance, inflammation, dyslipidemia, body-weight, type-2 diabetes, gut microbiota, gut barrier function First Spin Off project 39 ClinicalTrials.gov Protocol Record 2015/02JUL/369 Prof. Jean-Paul Thissen Prof. Michel Hermans Prof. Dominique Maiter Dr. Audrey Loumaye Dr. Amandine Everard Dr. Céline Druart Clara Depommier Marie de Barsy Prof. Willem de Vos

Tools to modulate dysbiosis associated with metabolic disorders «Feeding» the ecosystem properly PREBIOTIC APPROACH TO COUNTERACT DYSBIOSIS LINKED TO MALNUTRITION Modified from Lozupone et al, Nature 2012 Health Concept : nutrients escape the digestion in the upper part of the gut and, through their metabolization by microorganisms in the gut, modulate the composition and/or activity of the gut microbiota, thus conferring a physiological effect on the host (Gibson and Roberfroid, J. Nutr, 125, 1401, 1995; Br J Nutr 2010; www.isapp.net), Bindels et al Nature Rev Gastroenterol.Hepatol. 2015

Prebiotic approach: use of inulin type fructans (ITF) as modulators of the gut microbiota Gas Prebiotic effect Short Chain Fatty Acids Acetate Propionate Butyrate Lactate ITF are also present in cereals, onions, garlic, leek, jerusalem artichoke Roberfroid and Gibson Br J Nutr 1995: Bindels et al Nature Reviews Gastroenterology and Hepatology online 2015 «Opportunistic» increase In Bacteria expressing b- fructosidase,such as Bifidobacteria

Microbiome analysis :changes in gut microbiota upon prebiotics reveals bacteria correlated to intestinal L cells in ob/ob mice GL Increase in L cell differentiation! (mrna Everard et al Neurogenin3, Diabetes 2011 NeuroD) GLP-2 GLP-1 + Intestinal barrier Everard et al Diabetes 2011, Cani et al Gut 2010 Decreased LPS, and inflammation glycemia satiety

Food4Gut project (walloon region) https://www.uclouvain.be/467674.html Hypothesis : local vegetables rich in inulin-type fructans can be promoted in the control of obesity Includes : a multicentric single-blind placebo-controlled parallel study with both dietary and supplement (inulin) supplementation for 3 months (recruitment of 150 patients) Outcomes : body weight, behaviour (food preference), fat/lean mass, NAFLD (Fibroscan), glucose homeostasis, inflammation, gut microbiota

InyInKey intervention studies In obese patients to modulate the gut microbiota

Take Home Messages and Future Prospects Obesity and related metabolic diseases are linked to gut dysfunctions (endocrine, immune, barrier ), including gut microbial dysbiosis. Several tools are proposed to modulate gut dysbiosis to improve health, including a prebiotic approach. A need to revisit the concept of dietary fibers? Mechanistic studies point out the modulation of gut endocrine functions (GLP-1, GLP-2 ), gut barrier, gut vascular function by prebiotics, which are able to modulate host gene expression in the intestine and the liver. Extrapolation to human? Adequate intervention studies in humans are required to evaluate the relevance of such nutritional approaches in human nutrition (prevention treatment of the metabolic diseases)

Thanks to our collaborators : In Belgium Y. Guiot, G. Muccioli, JP Thissen, Ph.de Timary, Y. Larondelle, JB Demoulin, C Dessy, K. Verbeke (KUL), T. VanDeWiele (UGent) Abroad : F. Backhed (Göteborg, Sweden), D. Langin (Toulouse, F), S. Claus (Reading, UK), J. Schrenzel (Geneva, CH), K. Scott (Aberdeen, UK), W. DeVos( Wageningen, Netherlands), B. Pot, B. Staels, A. Muhr and S. Lestavel (Lille, F). Metabolism and Nutrition Research Group FOOD4GUT project