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Costa rica 2_lecture 8 Oct 2012 "Nutrigenomics of the gut"
 

Costa rica 2_lecture 8 Oct 2012 "Nutrigenomics of the gut"

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Nutrigenomics to explore metabolic plasticity and health of the intestine

Nutrigenomics to explore metabolic plasticity and health of the intestine

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    Costa rica 2_lecture 8 Oct 2012 "Nutrigenomics of the gut" Costa rica 2_lecture 8 Oct 2012 "Nutrigenomics of the gut" Presentation Transcript

    • Nutrigenomics to explore the impact of the intestine for metabolic homeostasis Michael Müller Netherlands Nutrigenomics Centre & Nutrition, Metabolism and Genomics Group Division of Human Nutrition, Wageningen University @nutrigenomics
    • Organ and systemic responses to dietary lipids Lipids FFA Remnant VLDL LPL Chylomicrons
    • A major role for PPARain intestinal fatty acid sensing Physiol Genomics. 2007 ;30(2):192-204
    • Intestinal PPAR target genes are largely regulated by dietary PUFAS/MUFAs6h after oral gavage OA 18:1 EPA 20:5 DHA 22:6 WY14643 Genes 508 874 894 1218 Fatty acid Intestinal lipases & transport & phospholipases binding Pnliprp2 , Pnliprp1, Mgll, Fat/Cd36, Slc27a2, Lipe, Lipa, Pla2g6, Slc27a4, Acsl1, Acsl3, Pnpla2, Pnpla8, Daglb, Acsl5, Fabp2, Fabp1, Ces1, Ces3 Scarb2, Scarb1 TAG (re)-synthesis Mitochondrial, microsomal, peroxisomal P Gpat1, Mogat2, Dgat1, Dgat2, Gpat3, Agpat3 f atty acid oxidation P Chylomicron assembly Acaa2, Acad10, Acad8, Acad9, Acadl, Acadm, Acads, Acadsb, A & secretion Mttp, Stx5a, Vti1a, Bet1, Sar1a Acadvl, Acot10, Acot2, Acot9, Aldh9a1, Cpt1a, Cpt2, Crat, Dci, R α Decr1, Hadha, Hadhb, Hibch, Slc22a5, Slc25a20, Aldh3a2, Cyp4a10, Abcd3, Acaa1a, Acaa1b, Acot3, Acot4, Acot5, Acot8, Acox1, Acox2, Crot, Decr2, Ech1, Ehhadh, Hsd17b4, Peci, Pecr, Apolipoproteins & related Ppara Apob, Apoa1 , Apoa2, Angptl4, Ketone body synthesis Apoa4, Apoc2, Vldlr, Apoc3, Apoe, Apol3, Apool Acat1, Hmgcl, Hmgcs2
    • Longitudinal distribution of genes involved in dietary lipid metabolism in wild-type mice on PPARα activation by WY14643 A Intestinal lipases and phospholipases B Fatty acid transport and binding C TAG (re-) synthesis D Chylomicron formation MGLL PNPLA2 MOGAT2 MTTP Microarray FABP2 ACSL1 Microarray Microarray 12 4 4 16 3.0 4 * * * Rel. expression * Rel. expression *Rel. expression Rel. expression Rel. expression Rel. expression 2.5 9 * 3 * * * * * * 3 12 * 3 * * * * * * 2.0 * * * * * * * * * * * * * * * 6 2 * * 2 * 8 1.5 2 * * * * * * * 1.0 3 1 * 1 4 1 0.5 * 0 0 0 0 0.0 0 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 LIPA PLA2G6 SLC27A2 ACSL3 DGAT1 BET1 3 3 12 12 3.0 4 Rel. expression * * * Rel. expression * Rel. expressionRel. expression Rel. expression 2.5 Rel. expression * 9 9 * 3 * * 2 2 * * 2.0 * * * * * * * * * * * * * * 6 * 6 * * 1.5 2 * * * * * * * 1 * * 1 * * 1.0 3 * * 3 * 1 * 0.5 * 0 0 0 0 0.0 0 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 PLCB1 PNPLA8 SLC27A4 ACSL5 DGAT2 FABP1 5 3 6 6 3.0 16 * Rel. expression Microarray * Microarray * Rel. expression Rel. expressionRel. expression Rel. expression 4 * Rel. expression 2.5 * * * * * 12 * 2 * * * 4 4 * 3 * * * * * * * 2.0 * * * * * * 8 * * * * * 1.5 * * 2 * * 2 2 * * * 1 * * 1.0 1 4 0.5 * 0 0 0 0 0.0 0 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 W TControl W TWY14643 W TControl W TWY14643 W TControl W TWY14643 W TControl W TWY14643
    • Response to the intestine to different doses of dietary fat De Wit PLOS one 2011
    • Dose-dependent effects of dietary fat on development of obesity inrelation to intestinal differential gene expression in C57BL/6J mice De Wit PLOS one 2011
    • Robust & concentration dependent effects in small intestine Differentially regulated intestinal genes by high fat diet C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 De Wit PLOS one 2011
    • Heat map diagrams of fat-dose dependently regulated genes,categorized according to their biological function De Wit PLOS one 2011
    • Cellular localization and specific lipid metabolism-related function of fat-dose dependently regulated genes De Wit PLOS one 2011
    • Conclusion: Do not overload the gut 40 cm4 cmC1 C2 C3 C4 C5 C6 C7 C8 C9 C10 10% FAT 45% FAT
    • Diet-independent and -dependent microbial effects on host metabolism
    • Saturated fat affects obesity and gut microbiota composition De Wit et al AJPhysiol 2012
    • Intake, fecal loss and absorption of total energy and dietary fat De Wit et al AJPhysiol 2012
    • HF-PO diet reduced microbial diversity andincreased the Firmicutes-to-Bacteroidetes ratio De Wit et al AJPhysiol 2012
    • Lipid metabolism-related gene expression in the distal small intestine after 8 weeks of diet intervention De Wit et al AJPhysiol 2012
    • Conclusions• Saturated fat stimulates obesity and hepatic steatosis and affects gut microbiota composition by an enhanced overflow of dietary fat to the distal intestine.
    • Influence of aging on intestinal functions• Young (4 M) & old (21 M) male C57BL/6 J mice on a control low-fat (10E%) or a high-fat diet (45E%) for 2 weeks.• Small and large intestine were isolated and the small intestine was divided in three equal parts.• Mucosal scrapings from each segment to determine differential gene expression by microarray analysis and global DNA methylation by pyrosequencing.
    • Aging related changes in distal villi lengths
    • Aging-induced differential gene expression in the small intestine and the colon
    • Differential gene expression induced by a high- fat diet in the 4 segments of the intestine.
    • Immune response andinflammatory genes in oldmice fed a low- or high-fat diet
    • Aging-induced global hypomethylation
    • Conclusions• No significant aging-induced morphological changes in the small intestine or the colon of 21-month-old mice. No decrease in macronutrient metabolic functions of the intestine of old mice.• Micronutrient metabolism might be affected in old mice which might contribute to some of the micronutrient deficiencies frequently occurring in the elderly.• Decrease in global DNA methylation and the altered status of the immune system of the colon might have play a causal role in the decreased health status of this organ at old age.• => Ageing changes metabolic plasticity by epigenetic mechanisms. Structural, functional and molecular analysis of the effects of aging in the small intestine and colon of C57BL/6 J mice BMC Medical Genomics 2012, 5:38
    • If the gut stays flexible it is staying healthy
    • Guido HooiveldMark BoekschotenNicole de WitWilma SteegengaNoortje IJssennagger+ many more