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Effect of gut microbiota on host metabolism in humans and mice

Effect of gut microbiota on host metabolism in humans and mice. 3 rd NuGO workshop “Nutritional Metabolomics”. Doris Jacobs Unilever R&D. 02 July 2010. Gut-mediated metabolites from non-digestible food ingredients Kati Hanhineva

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Effect of gut microbiota on host metabolism in humans and mice

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  1. Effect of gut microbiota on host metabolism in humans and mice 3rd NuGO workshop “Nutritional Metabolomics” Doris Jacobs Unilever R&D 02 July 2010

  2. Gut-mediated metabolites from non-digestible food ingredients • Kati Hanhineva • Metabolomics to characterize gastrointestinal disorders / diseases • Daryl Rowan • Effect of gut microbiota on host metabolism in humans and mice • Doris Jacobs

  3. Retrieved from ‘’Development of functional ingredients for gut health’’, R. Puupponen, Trends in Food Science & Technology 13 (2002) 3–11 Understanding what’s happening... Effect of gut microbiota on host metabolism

  4. Gut microbiota and immune system • Evidence for the potential role of gut microbiota in the development of • Colon cancer and inflammatory bowel disease • (Mazmanina, S.K. et al. Nature 2008, 453, 620-625.) • Type 1 diabetes • (Wen L. Nature, 2008, 455, 1109-1113.) • obesity and related metabolic disorders • Alteration in the gut microbiota that occur with obesity may enhance energy extraction from the diet. (Turnbaugh, P.J. et al. Nature 2006, 444, 1027-1031.) • Increased blood levels of lipopolysaccharides, due to impairment of the barrier function of the gut by altered gut microbiota, might trigger obesity-associated inflammation. (Cani, P.D. et al. Diabetes 2007, 56, 1761-1772.)

  5. Host-microbe communication in systemic inflammation Microbiota intestinal lumen intestinal epithelium circulation microbial particles/ metabolites? immune / non-immune cells Inflammation Li, P. & Hotmaisligil, G., Nature 2010, 464, 1287-1288. Metabolic disorders such as obesity are characterized by long-term, low-grade inflammation. Under certain conditions, the resident microorganisms of the gut might contribute to this inflammation, resulting in disease.

  6. Effect of gut microflora on mammalian blood metabolites cinamoylglycine hippuric acid phenylalanine phenylpropionyl glycine indole-3-propionic acid tryptophan N-acetyl tryptophan serotonin indoxyl sulfate phenylacetylglycine Wikoff, W.R. et al. PNAS 2009, 106(10), 3698-703 . • Plasma extracts from germ-free mice compared to conventional animals: • Amino acids, in particular indole-containing compounds derived from tryptophan • Organic acids containing phenyl groups

  7. Modulation of host energy and lipid metabolism by gut microbiota in mice Velagapudi, V. R. et al. J. Lipid Res. 2010, 106(10), 3698-703 . • Comparison between conv. and germ-free mice • in serum metabolome: • Increased levels of energy metabolites e.g. pyruvic acid, citric acid, glumaric acid, • and malic acid • Reduced levels of cholesterol and fatty acids • in lipidome of serum, adipose tissue and liver • Increased lipid clearance (lower levels of triglyceride and higher levels in adipose • tissue and liver) • increased levels of phosphatidylcholine (34:1) in serum and liver

  8. Effect of Antibiotics Romick-Rosendale, L. E. et al. Magn Reson Chem. 2009;47 Suppl 1:S36-46. NMR-based metabonomics analysis of 15 mouse urine and fecal extracts following oral treatment with the broad-spectrum antibiotic enrofloxacin (Baytril). • In urine: • decreased acetate due to loss of microbial catabolism of sugars • and polysaccharides, • decreased trimethylamine-N-oxide due to loss of microbial • catabolism of choline, • increased creatine and creatinine due to loss of microbial enzyme • degradation. • in fecal extracts: • depletion of amino acids produced by microbial proteases, • reduction in metabolites generated by lactate-utilizing bacteria, • increased urea caused by loss of microbial ureases.

  9. Multicompartmental effects of gut microbiome on mouse metabolic phenotype Claus, S. P.. et al. Mol. Sys. Biol. 2008, 4, 219 . • Comparison between conv. (n=5) and germ-free mice (n=5) • Gut microbiota modulate expression at both loacl (gut) and global (biofluid, • kidney, liver) system levels • Reduced levels of hippurate in GF urine • 5-aminovalerate in GF colon epithelium • Raffinose in GF mice • Elevated levels of betaine, choline, myo-inositol in GF kidney

  10. 24h-Urine 24h-Urine Plasma t=0h Plasma t=0h Plasma t=3h Plasma t=3h Short-term intervention study:Design 2 days 5 days 5 days Wine/grape PP Placebo 21 Males Placebo Wine/grape PP Run-in Intervention Wash-out Intervention Wash-out Population: 21 healthy males (18-69 years; non-smokers ) Treatment: wine / grape extract: mix of 870 mg Provinols red wine extract and 540 mg Mega-NaturalTM Rubired grape juice extract corresponding to 800 mg GAE per day placebo: microcrystalline cellulose Diet control: low polyphenol diet during treatment period same dietary intake during 36 hours before day 5 of each treatment period; Sample collection: 24-hour urine after four days of polyphenol / placebo intake plasma in fasted state (t=0h) on 5th treatment day plasma 3 hours after polyphenol / placebo intake on 5th treatment day

  11. Short-term intervention study: Analysis Metabolite profiling • Plasma/Urine: n = 251/256: • 161/159 known metabolites, including • 11/15 catecholamines and other monoamines, • 8/7 steroids • - 90/97 "known unknown" analytes

  12. Short-term intervention study: Effects in plasma Phenolic metabolites Metabolites from amino acid / proteins

  13. Short-term intervention study: Effects in urine Phenolic metabolites Metabolites from amino acid / proteins

  14. Short-term intervention study: Association

  15. Questions • How to generate causal relationships between the gut microbiome and the host metabolic response? • How to find evidence in humans? • How to correlate the metabolome with the microbiome? • How to deal with inter-individual variability caused by the diverse gut microbial composition and the host endogenous metabolism?

  16. Expected outcome • To compile a list of experimental factors that are crucial when investigating microbiome-metabolome relationships • To propose strategies / concepts for systematic approaches to assess the effect of the gut microbiome on the host metabolome

  17. Questions • Can metabolomics help to deconvolute the networks between gut microbiota or their products and the host immune response? • Models of metabolic syndrome that arises as a result of altered communication between the host immune system and the gut microbiota (Vijay-Kumar, M. et al. Science (2010), 328, 228-231

  18. Response and recovery in the plasma metabolome tracks the acute LCMV-induced immune response • Wikoff et al. J Proteome Res. 2009 8(7):3578-87. • Affected pathways during acute lymphocytic choriomeningitis virus (LCMV) infection of mice at days 1, 3, 7, and 14 post infection: • TCA cycle intermediates (citrate, cis-aconitate, α-ketoglutarate) • γ-glutamyl dipeptides, • lysophosphatidyl cholines, • fatty acids, • kynurenine pathway (surprising because it is stimulated by IFN-γ, which LCMV suppresses)

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