Nutrigenomics to explore metabolic plasticity and health of the intestine

1. 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

2. Organ and systemic responses to dietary lipids
Lipids
FFA
Remnant
VLDL LPL
Chylomicrons

3. A major role for PPARa
in intestinal fatty acid sensing
Physiol Genomics. 2007 ;30(2):192-204

4. Intestinal PPAR target genes are largely
regulated by dietary PUFAS/MUFAs
6h 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

5. 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. expression
Rel. 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. expression
Rel. 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

6. Response to the intestine to different
doses of dietary fat
De Wit PLOS one 2011

7. Dose-dependent effects of dietary fat on development of obesity in
relation to intestinal differential gene expression in C57BL/6J mice
De Wit PLOS one 2011

8. 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

9. Heat map diagrams of fat-dose
dependently regulated genes,
categorized according to their
biological function
De Wit PLOS one 2011

10. Cellular localization and specific lipid metabolism-related
function of fat-dose dependently regulated genes
De Wit PLOS one 2011

11. Conclusion: Do not overload the gut
40 cm
4 cm
C1 C2 C3 C4 C5 C6 C7 C8 C9 C10
10% FAT
45% FAT

12. Diet-independent and -dependent microbial
effects on host metabolism

13. Saturated fat affects obesity and gut
microbiota composition
De Wit et al AJPhysiol 2012

14. Intake, fecal loss and absorption of total
energy and dietary fat
De Wit et al AJPhysiol 2012

15. HF-PO diet reduced microbial diversity and
increased the Firmicutes-to-Bacteroidetes
ratio
De Wit et al AJPhysiol 2012

16. Lipid metabolism-related gene expression in the distal small
intestine after 8 weeks of diet intervention
De Wit et al AJPhysiol 2012

17. Conclusions
• Saturated fat stimulates obesity and hepatic steatosis
and affects gut microbiota composition by an enhanced
overflow of dietary fat to the distal intestine.

18. 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.

19. Aging related changes in distal villi lengths

20. Aging-induced differential gene expression
in the small intestine and the colon

21. Differential gene expression induced by a high-
fat diet in the 4 segments of the intestine.

22. Immune response and
inflammatory genes in old
mice fed a low- or high-fat
diet

23. Aging-induced global hypomethylation

24. 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

25. If the gut stays flexible it is staying healthy

26. Guido Hooiveld
Mark Boekschoten
Nicole de Wit
Wilma Steegenga
Noortje IJssennagger
+ many more