Exploring the Role of Gut Microbiome in Energy Balance: the MyNewGut Project

Transcription

1 Exploring the Role of Gut Microbiome in Energy Balance: the MyNewGut Project Yolanda Sanz Institute of Agrochemistry and Food Technology (IATA) National Research Council (CSIC) Valencia, Spain 2nd Microbiome Forum, 7-8 May, London

2 No country has reversed its obesity epidemic to date

3 Gut microbiota causes obesity: energy harvest theory Germ-free mice versus colonized mice A 45-60% increased adiposity and Insulin resistance B Bäckhed et al., PNAS. 101, 15718; Proc Natl Acad Sci U S A 2007, 104 :979e84.

4 Gut microbiota influences energy metabolism Increase host ability for extracting and storing energy Dietary complex carbohydrates Adipose tissue Lipid storage Fiaf Gut lumen Bile Blood stream Na/Glu Lipogenesis AMP-PK Oxidation FFA Digestion L-FABP SCFA Glucose uptake Energy metabolites Insulin Bäckhed et al., Proc Natl. Sci.; PNAS. 101, Stappenbeck et al., PNAS. 2002, 99, ; Hooper et al., Angiogenesis

5 Gut microbiota provides energy digesting complex CH DIET Insoluble complex polysaccharides (cellulose, mucin, etc) Soluble polysaccharides / Oligosaccharides (starch / fructooligosaccharides) Firmicutes / Bacteroidetes Ruminococcus flavifaciens Fibrobacter succinogenes Bacteroides cellulosilyticus Intermediate products (lactate, succinate, etc.) Bacteroides spp Bifidobacterium Ruminococcus bromii Roseburia spp Butyrivibrio ssp Roseburia spp Bacteroides Energy supply Butyrate Propionate Short chain fatty acids Acetate CO 2 H 2 Fermentation Enterocytes Portal vein Acetogens Methanogens (Archaea) Sulfatoreducers Acetate CH 4 SH 2 Energy Lipid metabolism 10% energy supply Sanz Y et al. Interdiscip Perspect Infect Dis. 2008;2008:

6 Key bacteria involved in human obesity?

7 Bacteroidetes, butyrate-producers and lean-phenotype Gram-positve High G+C 8-17% Frimicutes Gram-positve low G+C 46-58% C. coccoides C. histolyticum C. lituseburense Butyrate producers F. praustnitzii Akkermansia E. halli Bacteroidetes Gram-negative 10-30% Bacteroides sub-groups Sanz Y, et al. Pharmacol Res. 2013;69: Ley et al PNAS.102: Verdam et al. Obesity (Silver Spring). 2013, 21; Remely et al., Beneficial Microbes.

8 Short-chain fatty acids may exert beneficial effects in obesity Butyrate Propionate GPR41 GPR109A PPAR- PPAR- GPR41/43 Satiety GLP-1 GLP-2 TNFα, IL-6 ROS Anti-inflammatory Histone H3 acetylation Tregs NF-κB LI-10 ANGPTL4/FIAF PYY GLP-1 Energy Intake TNF-α adipogenesis thermogenesis lipid oxidation Chambers et al., Gut 2014; Alex S et al. Mol. Cell. Biol. 2013;33: ; Dewulf Nutr Metab (Lond) Jan 17;10(1):11) GaoDiabetes Jul;58(7):

9 Obesogenic human microbiota causes obesity in mice Ridaura et al. Science ;341(6150):

10 Lean human microbiota rescue mice from obesity Ridaura et al. Science ;341(6150):

11 Lean human microbiota integrated by Bacteroides spp. Ridaura et al. Science ;341(6150):

12 Which Bacteroides species could help? B. uniformis? IL10 TNFα Gauffin et al. PLoS One. 2012;7(7):e41079; O'Sullivan J Proteome Res Jun 7;12(6):

13 % weight gain in the 7th week B. uniformis CECT 7771 reduces weight gain in obese mice 10% reduction compared to 5% by a classical probiotic HFD+B HFD+Bif HFD Gauffin et al. PLoS One. 2012;7(7):e41079.

14 T rig lyceride (m g/dl) L eptin ( n g /m l) G luco se (m g/d l) C h o lesterol (m g/d l) B. uniformis CECT 7771 normalises metabolic markers p = p = p = p < p = p = S D H F D S D + B H F D + B 0 S D H F D S D + B H F D + B p = p = p = p = p < p = S D H F D S D + B H F D + B 0 S D H F D S D + B H F D + B Gauffin et al. PLoS One. 2012;7(7):e41079.

15 G lu c o s e A U C (m g /L * m in ) G lu c o s e A U C (m g /L * m in ) B. uniformis CECT 7771 improves glucose tolerance ** ** ** ** SD HFD p < Plasma glucose (mg/dl) * ** ** S D H F D Plasama glucose (mg/dl) * * ** Time (min) ** ** HFD+B HFD ** p < H F D Time (min) Gauffin et al. PLoS One. 2012;7(7):e H F D + B

16 Lack of consistency lack of control for confounders Low (L) and high (H) bacterial gene count (GC) subjects LGC-Metabolic dysfunction Bacteroidetes/Proteobacteria Bacteroides, Parabacteroides, Ruminococcus Anaerostipes, etc. HGC-Healthy Faecalibacterium, Bifidobacterium, Lactobacillus, Butyrivibrio, Alistipes, Akkermansia, Coprococcus and Methanobrevibacter. E Le Chatelier et al. Nature 500, (2013)

17 Obesogenic diets induce pathobiont expansion Obesogenic diets favour dominance of Gram-negative bacteria GF, CV and Myd88 / mouse models under a high-fat, high-sugar Western diet Reigstad et al. PLoS One Jun 9;4(6):e5842

18 Obesogenic diet, leaky gut and bacterial translocation LPS translocate via leaky gut resulting from high-fat diets Dietary lipids LPS LPS PGN DNA Delzenne et al Nat Rev Endocrinol. 2011;7: Caesaret al. Gut. 2012;61(12):

19 Obesogenic diets induce pathobiont expansion PUFAS Bacteroidetes Frimicutes SF Bacteroidetes Frimicutes D-Proteobacteria H 2 S TC- BA Bilophila wadsworthia Devkota et al. Nature ;487:104; David et al., Nature. 2014, 23;505:559.

20 Protein effects: the result of co-metabolic process LARGE INTESTINE BLOOD UREA ALIMENTARY AND ENDOGENOUS PROTEINS PANCREATIC PROTEASES RESIDUAL PROTEINS PEPTIDES OLIGOPEPTIDES AMINO ACIDS enterocytes RESIDUAL PROTEINS MICROBIOTA Lys, Leu RESIDUAL PANCREATIC PROTEASES MICROBIOTA AMINO ACIDS BACTERIAL UREASES FECES PORTAL BLOOD SCFA BCFA H 2 S POLYAMINES PHENOLS INDOLES NH 4 + etc. SMALL INTESTINE colonocytes Satiety BACTERIAL METABOLITES Davila, Sanz et al. Pharm. Res PORTAL BLOOD

21 Microbiota mediates secondary effects of dietary lipids Secondary messengers Secondary BA (lithocholic acid) TGR5 MICROBIOTA Bile camp Dietary Lipids GLP1 Satiety, Gastric emptying Insulin sensitivity TGR5 Energy expenditure Martin et al., Mol Systems Biol, 3, 112. Greiner & Bäckhed Trends End Metag, 4, 117

22 Short-term dietary changes explain 10% microbiota variance Long-term stability studies: 30-40% variation OBSERVATIONAL studies Vegetarian diet Western diet SINGLE POINT DATA-CONFOUNDERS INTERVENTION with foods Whole-grain products Fruits and nuts Vegetables and legumes INTERVENTION with food constituents Fiber: RS, non-starch polysaccharides, inulin, XO, FOS/GOS, polidextrose, AXOS, R-MaltoDex FAT-at expenses of carbohydrates Proteins-at expenses of carbohydrates VARIABILITY OF FOOD COMPOSITION Influences on the host response and health effects unknown Flint et al., ; Salonen et al. 2014; Faith et al Bifidobacterium Bacteroides Butyrate produces: F. prausnizzi Roseburia E. rectale Ruminococcus-RS Lachnospiraceae-WG

23 Funded by the European Union s 7FP under grant agreement no

24 MyNewGut objectives related to obesity and behaviour 1. Identify the role of specific components of the gut microbiome in nutrient metabolism and in the host response to dietary intervention and energy balance. 2. Identify microbiome-related features that predict obesity. 3. Identify the role of the gut microbiota and their metabolites in motivation to eat, regulation of reward mechanisms and eating behaviour. 4. Developing new food and food ingredients, which targeting the gut ecosystem, could reduce the risk of metabolic and behavioural disorders

25 Obesity viewed as a multifactorial disorder in life-span Human epidemiological and intervention studies CONFOUNDERS Type of birth Antibiotics Milk-feeding Physical Activity Diet, etc. SUBJECTS: GENOTYPE PHENOTYPES Human microbiota/strains transplants Mouse models

26 Obesity and overeating: cause or consequence Energy-dense foods Sedentary life High energy intake OBESITY Highly palatable foods with specific macronutrient composition Stress, sleep pattern OVEREATING HUNGER

27 Translating microbiome data into human physiology Functional -omics and Systems Biology + + Environment 16S rrna gene seq Metagenomics Metatrascirptomics Lipidomics Metabolomics

28 MyNewGut : 30 partners 15 EU and non-eu countries Yolanda Sanz CSIC - Spain Coordinator WP leaders Patrizia Brigidi UNIBO - Italy Co-coordinator Max Nieuwdorp AMC- Netherlands Nathalie Delzenne UCL - Belgium Ted Dinnan UCC - Ireland Douwina Bosscher CARGILL- Belgium Lesli Hingstrup UCPH - Denmark Guus Roeselers TNO - Netherlands Laura Fernández EUFIC - Belgium Domingo Terroba CAPSA - Spain Stoffer Loman LFC - Netherlands

29 Thanks for your attention! Yolanda Sanz IATA-CSIC