consequences on microbiota composition and metabolic health of adult - PowerPoint PPT Presentation

Early prebiotic supplementation induces long-lasting consequences on microbiota composition and metabolic health of adult pigs consuming an unbalanced diet. C. Le Bourgot 1 *, B. Taminiau 2 , S. Ferret-Bernard 3 , A. Cahu 3 , L. Le Normand 3 , F. Respondek 1 , E. Apper 1 , I. Le Huërou-Luron 3 , S. Blat 3 1 Tereos, France 2 University of Liège, Belgium; 3 Numecan, INRA, INSERM, Univ Rennes 1, France *Cindy.lebourgot@tereos.com

Food transition and evolution of non-communicable chronic diseases Quantity, quality and Family Lack of exercise structure of food environment Carbohydrates International Lipids Diabetes Federation Proteins Perinatal nutrition Combris (FAO Stat) Increased prevalence of obesity and associated metabolic disorders Overweight and obesity Diabetes (% world population ; INSEE & OMS)

Developmental origins of health and disease (DOHaD): Barker’s hypothesis Importance of the early nutritional Adult environnent health Critical developmental window Conception – Gestation – Birth – 2 years = 1000 days % adult population with 45 intolerance to glucose or diabete 40 35 Hales et al. , 1991 30 25 20 15 10 5 0 < 2,5 - 2,94 - 3,40 - 3,85 - 4,30 > 4,31 Birth weight

The gut microbiota: an actor of metabolic programming  Complex interactions with host Non digestible Microbiota food SCFA Mucus Gut GPR Entero-insular axis Pancreas GLP-1 SCFA Insulin Glucose metabolism Liver Muscle Adipose tissue

The gut microbiota: an actor of metabolic programming  Establishment during early life and consequences later in life Cox et al ., 2014 Control Antibiotic Diet rich in lipids Gestation Lactation Post-weaning Weaning Conception D0 Adult (D21-28) Hallam et al ., 2013 & 2014 Control High-protein 22% Prebiotic Prebiotics : A beneficial nutritional strategy for adult health ?

Prebiotics – scFOS « The selective stimulation of growth and/or activity of one or a limited number of bacteria in the gut microbiota that confers health benefits to the host » (Roberfroid et al. 2010) Short-chain fructo-oligosaccharides Sucrose (scFOS) Beet Direct effects of scFOS :  ↑ Beneficial bacteria Bifidobacteria & Lactobacilli, and SCFA production (Saulnier et al., 2008; Le Blay et al., 2003)  ↓ A diposity and inflammatory markers (Shinoki et al., 2011)  ↑ GLP-1 secretion (Kaji et al., 2011) and insulin sensitivity (Respondek et al., 2008 and 2010) scFOS: Long-term effects when consuming during early life ?

Objective ? scFOS Glucose metabolism Microbiota

Experimental design HF Control diet = CTRL CTRL scFOS-supplemented diet = scFOS HF scFOS 0,33% = 10g/j 0,15% = 1,2g/j Age Gestation Lactation Post-weaning (days) +56/77 -28 0 +28 +190 +274 Diets Control High-Fat (HF) Digestible energy, MJ 13,43 14,99 * Microbiota * Microbiota % digestible energy : analysis analysis  Proteins 23,5 17,9 * Blood, intestinal 7 22,6  Lipids contents, tissues  Carbohydrates 59,5 69,5 and organs

D+253 Microbiota – Bacterial composition 16S rRNA sequencing Phylum Genus 100  D+190: Standard diet 90 ↑ Firmicutes 80 ↑ scFOS Bacteroidetes Abondance relative (%) 70 Bacteria_unclassified ↑ Spirochaetae 60 Tenericutes ↑ ↑ 50 ↓ Cyanobacteria 40 Proteobacteria ↑ Lentisphaerae 30 SHA-109 ↑ 20 scFOS Verrucomicrobia CTRL ↓ ↑ Actinobacteria n=6 10 n=6 ↑ ↓ 0 CTRL scFOS 100  D+253: HF diet 90 Firmicutes 80 scFOS ↑ Bacteroidetes Abondance relative (%) Bacteria_unclassified 70 Spirochaetae 60 Tenericutes Cyanobacteria ↑ 50 ↓ Proteobacteria ↑ Lentisphaerae 40 SHA-109 ↑ Verrucomicrobia 30 scFOS Actinobacteria CTRL ↑ 20 Fibrobacteres n=6 n=6 ↑ ↓ Planctomycetes 10 ↑ Candidate_division_TM7 ↓ Elusimicrobia 0 Synergistetes CTRL-HF CTRL scFOS FOS-HF Perinatal scFOS: ↑ Prevotella Fusobacteria Deferribacteres

D+253 Microbiota – Metabolic activity 130 * CTRL-HF CTRL n=7 Faecal SCFA 120 scFOS n=7 FOS-HF ↑ Acetate : + 28,6% 110 mmol/kg ↑ Propionate : + 21,7% Gaz chromatography 100 90 * P < 0,05 80 70 J190 J211 J253 Faecal metabolome Liquid chromatography coupled to mass spectrometry (LC/MS) CTRL scFOS vs CTRL scFOS n=7 n=7 Isobutyric acid ↑ Fermentative metabolites Hydroxy-methyl butyric acid ↑ Taurocholic acid ↑ Bile acid L-Threonine ↑ Amino acid Glycerol ↑↓ Energy metabolism Perinatal scFOS: ↑ Fermentative metabolites and bile acids

D+253 Microbiota ↑ Bacteroidetes Perinatal (Prevotella) scFOS R = 0,64 ↑ SCFA and other ↑ Taurocholic fermentative metabolites acid Gut What are the consequences for adult metabolic health? Pancreas Adipose tissue Muscle

D+274 Entero-insular axis and glucose homeostasis Nb GLP-1 secreting L cells (caecum) 5 * Nb/mm 2 mucosa 4 3 2 1 0 CTRL scFOS HF HF-FOS L cell 0.47 GLP-1 Plasma GLP-1 40 + 30 Pmol/L 20 10 0 HF HF-FOS CTRL scFOS n=11 CTRL n=13 scFOS * P < 0,05 + P < 0,10

D+274 Entero-insular axis and glucose homeostasis Nb GLP-1 secreting L cells (caecum) 5 * Nb/mm 2 mucosa 4 3 Insulin content 2 Endocrine tissue 0.65 1 0 CTRL scFOS HF HF-FOS L cell Pancreas GLP-1 Plasma GLP-1 40 + 30 Pmol/L 20 10 0 HF HF-FOS CTRL scFOS n=11 CTRL n=13 scFOS * P < 0,05 + P < 0,10

D+274 Entero-insular axis and glucose homeostasis Nb GLP-1 secreting L cells (caecum) 5 * Nb/mm 2 mucosa 4 3 Insulin content 2 Endocrine tissue 1 0 CTRL scFOS HF HF-FOS L cell Adipose tissue Pancreas GLP-1 Genes : GLUT4, Chan et al ., 2011 Plasma GLP-1 Insulin (IVGTT) INSR, SREBP1-C 250 40 Glucose + + * * injection 30 * 200 + Muscle Pmol/L * 20 150 µUI/ml 10 100 0 HF HF-FOS Diet p=0,09 CTRL scFOS 50 Time p<0,001 Diet*t p=0,01 0 n=11 CTRL -30 -20 -10 0 10 20 30 40 50 60 70 n=13 scFOS Perinatal scFOS: Stimulation of capacity to secrete GLP-1 and improvement of * P < 0,05 pancreas sensitivity to glucose (Le Bourgot et al ., in preparation) + P < 0,10

D+253 Plasmatic metabolome  PLS-DA discriminating both groups (LC/MS) Lysophosphatidylcholine (18:0) L y s o P C p la s m a (LysoPC) 1 0 8 CTRL 6 X 1 0 8 scFOS 4 2 0 C T R L s c F O S  LysoPC : identified as a potential plasma Glucose intolerant Glucose tolerant Glucose tolerant and marker of obesity and metabolic disorders ( ↓ ) glycemia <6,4 mmol/l (Zhao et al. , 2010; Barber et al., 2012; Yea et al. , 2009) Perinatal scFOS: ↑ LysoPC (18:0) = improvement of glucose control

Conclusion scFOS : 0.15 to 0.33% of the diet = physiological dose Metabolic adaptation Microbiota Sustained effect on microbiota Stimulation of entero-insular axis (GLP-1)

Thank you for your attention QUESTIONS ?