- PDF Free Download

Size: px

Start display at page:

Download ""

Roderick Butler
5 years ago
Views:

1 A real life example

In human studies, we quantify ~120 plasma related proteins Monocytes MMP9 Macrophages TNFα IL1ß platelet derived growth factor IFNγ MMP1 MMP8 MMP13 Myeloid Related Protein14 CD40 CD40L tissue factor

8 In human studies, we quantify ~120 plasma related proteins Monocytes MMP9 Macrophages TNFα IL1ß platelet derived growth factor IFNγ MMP1 MMP8 MMP13 Myeloid Related Protein14 CD40 CD40L tissue factor Foam cells IL18 IL18Rα/ß Endothelial cells P-selectin VCAM1 ICAM1 MCP1/CCL2 platelet derived growth factor CSF1 NO CD40 CD40L tissue factor PAI1 NFκB adenine dinucleotide phosphate oxidase Cathepsin S Smooth muscle cells collagen IFNγ IL6 CD40 CD40L tissue factor MCP1/CCL2 Platelets CD40L Myeloid Related Protein8 Myeloid Related Protein14 platelet derived growth factor CD40 T helper 1 cells IL1 scd40l INFγ RANTES MIF CD40 Adipose tissue adiponectin IL18 PAI1 HDL LDL oxldl Thrombin Factor VII paraoxonase 1 Angiotensin II Lipoprotein lipase Hepatic lipase MPO Lipoprotein associated phospholipase A2 Liver CRP PAI1 fibrinogen

9 Changes in proteins and metabolites in human plasma and gene expressions (in PBMC) related to inflammatory modulation by diclofenac Van Erk et al BMC Medicine 2010

10 The concept of nutrigenomics biomarkers Level 1 - functional or endpoint related biomarker (often not available) Level 2 biochemical reporters of processes (often non changed / not accepted) (CRP, IL1, adiponectin, ) Level 3 biological networks that support the evidence of level 2 (both statistically and mechanistically)

11 Anti-inflammatory effect of supplement mix 36 overweight males (BMI 25-35) with low-grade (CRP 1-10 mg/l) Consumption of supplement mix for 5 weeks in a randomized cross-over trial Supplement mix: based on mediterranean diet, contains resveratrol, vitamin E, vitamin C, tomato extract, green tea extract, fish oil Designed to exert effect on different inflammatory pathways (based on literature)

12 Extensive phenotyping proteome 110 cytokines 78 lipids omics analysis allows quantification of enormous # of parameters lipidome metabolome 198 metabolites ~ 30 parameters clinical chemistry genes transcriptome

13 Eicosanoid related (but no effect PGE2) fish oil endothelial inflammatory factors plaque formation / coagulation increased expr prostaglandin metabolism genes in adipose tissue anti-inflammatory effects in adipose tissue: adiponectin, IL10RA, SOCS3 Bakker, AJCN 2010

14 Effect on : part of the Inflammatory profile in plasma inflammatory markers adiponectin IL-18 Beta-2 Microglobulin Ferritin ICAM-1 VCAM-1 8-iso prostaglandin F2-alpha % change

15 Anti-inflammatory effects of supplement mix Postprandial challenge Oral Lipid Tolerance Test: Plasma measurements over time (up to 6 hours) after consumption of lipid-rich dairy product 120 Inflammatory proteins 246 Metabolites (GC-MS) lipid challenge minutes

16 Concentration inflammatory markers Homeostasis versus perturbation Inflammation markers at baseline and during an oral lipid tolerance test adiponectin IL-18 Beta-2 Microglobulin Ferritin ICAM-1 VCAM-1 8-iso prostaglandin F2-alpha % change Time (min)

17 Concentration Homeostasis versus perturbation adiponectin IL-18 inflammatory markers Inflammation markers at baseline and during an oral lipid tolerance test Beta-2 Microglobulin Ferritin ICAM-1 VCAM-1 8-iso prostaglandin F2-alpha % change Time (min)

18 Concentration inflammatory markers Homeostasis versus perturbation Inflammation markers at baseline and during an oral lipid tolerance test adiponectin IL-18 Beta-2 Microglobulin Ferritin ICAM-1 VCAM-1 8-iso prostaglandin F2-alpha % change Time (min)

19 Concentration inflammatory markers Homeostasis versus perturbation Inflammation markers at baseline and during an oral lipid tolerance test adiponectin IL-18 Beta-2 Microglobulin Ferritin ICAM-1 VCAM-1 8-iso prostaglandin F2-alpha % change Time (min)

20 Concentration inflammatory markers Homeostasis versus perturbation Inflammation markers at baseline and during an oral lipid tolerance test adiponectin IL-18 Beta-2 Microglobulin Ferritin ICAM-1 VCAM-1 8-iso prostaglandin F2-alpha % change Time (min)

21 Plasma concentration Time (h)

22 CRP ug/ml Same anti- food cocktail in transgenic CRP mice 25 basal CRP at various doses food mix Placebo Low dose Medium dose High dose mix does not influence inflammatory homeostasis in mice

23 CRP (ug/ml) CRP-mice (expressing human CRP) Challenge with interleukin-1 (IL-1) Supplement mix attenuates IL-1 induced CRP response 30,00 placebo food mix 25,00 20,00 Challenge tests as more powerful way to quantify modulation of? 15,00 * * * 10,00 5,00 0,00 low med high low med high Bas. IL-1 IL-1 IL-1

with food mix inhibits atherosclerosis development HC: plaque

24 Effect of anti inflammatory diet on in mice ApoE3L mice on high cholesterol diet develop atherosclerosis Supplementation with food mix inhibits atherosclerosis development HC: plaque in aorta HC + food mix: no plaque in aorta Verschuren, J Nutr 2011

25 Atherosclerotic lesion area (µm2) Atherosclerotic lesion number HC-placebo HC-AIDM 0.0 HC-placebo HC-AIDM Verschuren, J Nutr 2011

26 Metabolically healthy Chronic Stress Autonomic imbalance Dysruption circadian rhythm parasympathetic tone systemic adipose Vioxx Hepatic Salicylate fibrosis endothelial ectopic lipid overload Visceral adiposity Fatty liver Caloric excess Fenofibrate High cholesterol LXR agonist dyslipidemia LDL elevated Physical inactivity Hepatic IR Atorvastatin Rosiglitazone Pioglitazone Metformin High glucose Glucose toxicity Adipose IR Sitagliptin Glibenclamide Muscle metabolic inflexibility systemic Insulin resistance β-cell failure Sympathetic overactivation Atherosclerosis Microvascular damage Hypertension gut IBD Retinopathy Nephropathy Brain disorders Stroke Cardiac dysfunction Heart failure Myocardial infactions

27 Systems flexibility is the key! gut IBD adipose systemic Hepatic fibrosis endothelial ectopic lipid overload Cardiac dysfunction Visceral adiposity Fatty liver Caloric excess High cholesterol Heart failure Metabolically healthy dyslipidemia LDL elevated Atherosclerosis Myocardial infactions Hepatic IR Retinopathy Nephropathy Brain disorders High glucose Glucose toxicity Microvascular damage β-cell gluc Adipose IR Ìrreversible process Reversible process Pathology Risk factor Muscle metabolic inflexibility systemic Insulin resistance β-cell failure Hypertension Stroke reversible irreversible

Overall scheme of metabolic health & disease related processes Caloric excess Metabolically Ìrreversible process healthy Reversible process β-cell Pathology gluc Risk factor Visceral adiposity

28 Overall scheme of metabolic health & disease related processes Caloric excess Metabolically Ìrreversible process healthy Reversible process β-cell Pathology gluc Risk factor Visceral adiposity dyslipidemia Muscle metabolic inflexibility adipose ectopic lipid overload Adipose IR systemic Fatty liver Hepatic IR gut Hepatic fibrosis High cholesterol LDL elevated High glucose systemic Insulin resistance IBD endothelial Glucose toxicity β-cell failure Atherosclerosis Microvascular damage Hypertension Retinopathy Nephropathy Stroke Brain disorders Atherosclerosis Cardiac dysfunction Heart failure Myocardial infactions Retinopathy Nephropathy Brain disorders Stroke Nakatsuji, Metabolism 2009

29 Overall scheme of metabolic health & disease related processes RA Caloric excess Metabolically Ìrreversible process healthy Reversible process β-cell Pathology gluc Risk factor Alzheimer joint Visceral adiposity dyslipidemia Muscle metabolic inflexibility brain adipose ectopic lipid overload Adipose IR systemic Fatty liver Hepatic IR `lung COPD gut Hepatic fibrosis High cholesterol LDL elevated High glucose systemic Insulin resistance IBD endothelial Atherosclerosis Glucose toxicity Microvascular damage β-cell failure Hypertension - What does optimal inflammatory flexibility indicate? - Are there organ specific messages? Retinopathy Nephropathy Brain disorders Atherosclerosis Cardiac dysfunction Heart failure Myocardial infactions Retinopathy Nephropathy Stroke Brain disorders

30 Nutrition and maintaining robustness? The energy pulse and the control mechanisms Oxidative stress Inflammatory stress metabolic stress energy Decreased flexibility - linked to metabolic syndrome - may result in damage time

flexibility depends on - optimal damage control phenotype

31 Nutrition and maintaining robustness? The energy pulse and the control mechanisms energy Optimal flexibility depends on - optimal damage control phenotype - micronutrient levels - antioxidant status - anti inflammatory elasticity time

32 Kidney (re)absorptionn urea cycle Tissue injury Gut Host-microbe interaction Absorption, intestinal integrity, barrier function Gut-mediated control Chylomicron production Brain Gut-Brain axis Endocrine responses HPA axis Liver Adaptation carb/lipid switch Oxidative stress ER stress Tissue injury Fibrosis Toxicity Insulin sensitivity Muscle Protein metabolism Oxidative stress ER stress Tissue injury Energy metabolism Insulin sensitivity Diagnosis assay: organ flexibility Vasculature NO metabolism chronic low-grade Endothelial flexibility/integrity Reversibility of Microvascular damage Lipid droplet formation Arterial stiffness Adipose tissue Lipoprotein metabolism Lipid metabolism Energy metabolism Macrophage infiltration NEFA Expandibility Lipokine/Adipokine production Insulin sensitivity Pancreas Systemic insulin sensitivity b-cell failure

33 Kidney (re)absorption urea cycle Tissue injury Gut Host-microbe interaction Absorption, intestinal integrity, barrier function Gut-mediated control Chylomicron production Gut hormones (Ghrelin, GIP, etc) Brain Gut-Brain axis Endocrine responses HPA axis Liver Adaptation carb/lipid switch Oxidative stress ER stress Tissue injury Fibrosis Toxicity Insulin sensitivity Lipoprotein metabolism Lipid metabolism (MG, TG) Bile production Muscle Protein metabolism Oxidative stress ER stress Tissue injury Energy metabolism Insulin sensitivity OGTT (plasma) Vasculature NO metabolism chronic low-grade Endothelial flexibility/integrity Resolving of Microvascular damage Lipid droplet formation Arterial stiffness Systolic/Diastolic BP Heart rate (BPM) Lipotoxicity Adipose tissue Macrophage infiltration NEFA Expandibility Lipokine/Adipokine production Insulin sensitivity Pancreas Systemic insulin sensitivity b-cell integrety

34 Kidney (re)absorption urea cycle Tissue injury Gut Host-microbe interaction Absorption, intestinal integrity, barrier function Gut-mediated control Chylomicron production Gut hormones (Ghrelin, GIP, etc) Brain Gut-Brain axis Endocrine responses HPA axis Liver Adaptation carb/lipid switch Oxidative stress ER stress Tissue injury Fibrosis Toxicity Insulin sensitivity Lipoprotein metabolism Lipid metabolism (MG, TG) Bile production Muscle Protein metabolism Oxidative stress ER stress Tissue injury Energy metabolism Insulin sensitivity OLTT (plasma): dairy, incl. carbs and proteins Vasculature NO metabolism chronic low-grade Endothelial flexibility/integrity Resolving of Microvascular damage Lipid droplet formation Arterial stiffness Systolic/Diastolic BP Heart rate (BPM) lipotoxicity Adipose tissue Macrophage infiltration NEFA Expandibility Lipokine/Adipokine production Insulin sensitivity Pancreas Systemic insulin sensitivity b-cell integrety

hormones (Ghrelin, GIP, etc) Brain Gut-Brain axis Endocrine responses HPA axis Liver

Insulin sensitivity Lipoprotein metabolism Lipid metabolism (MG, TG) Bile production Muscle

sensitivity OLTT (plasma): sunflower oil Vasculature NO metabolism chronic low-grade

Arterial stiffness Systolic/Diastolic BP Heart rate (BPM) lipotoxicity Adipose tissue

35 Kidney (re)absorption urea cycle Tissue injury Gut Host-microbe interaction Absorption, intestinal integrity, barrier function Gut-mediated control Chylomicron production Gut hormones (Ghrelin, GIP, etc) Brain Gut-Brain axis Endocrine responses HPA axis Liver Adaptation carb/lipid switch Oxidative stress ER stress Tissue injury Fibrosis Toxicity Insulin sensitivity Lipoprotein metabolism Lipid metabolism (MG, TG) Bile production Muscle Protein metabolism Oxidative stress ER stress Tissue injury Energy metabolism Insulin sensitivity OLTT (plasma): sunflower oil Vasculature NO metabolism chronic low-grade Endothelial flexibility/integrity Resolving of Microvascular damage Lipid droplet formation Arterial stiffness Systolic/Diastolic BP Heart rate (BPM) lipotoxicity Adipose tissue Macrophage infiltration NEFA Expandibility Lipokine/Adipokine production Insulin sensitivity Pancreas Systemic insulin sensitivity b-cell integrety

36 role of local and systemic inflammatory control in metabolic health

37 The challenge concept: Stress response curve of glucose

38 Health is maintained by a complex interaction of processes, each maintaining homeostasis, elasticity and robustness.

39 healthy 4 weeks kcal Comparable response? High-fat challenge Blood sampling metabolic syndrome Figure 1a. Study design - fat challenges in healthy (10) and metabolic syndrome (10) subjects

40 High-fat challenge 500 ml shake consisting of 53% whipping cream, 3% sugar and 44% water 500 ml contains: Energy Protein Fat Saturated fat Carbohydrates 775 kcal 8 g 80 g 45 g 16 g

41 day1 day8 day15 day22 day29 High-fat high-caloric diet (+1300 kcal) HF challenge Body composition Blood sampling Body composition Dietitian consult Dispensing study substances Compliance check HF challenge Body composition Blood sampling HF challenge minutes Pre-study: food intake diary (3-day) Figure 1b. Study design High-fat high-caloric diet

The concept of nutrigenomics biomarkers Level 1 - functional or endpoint related biomarker (often not available) Level 2 biochemical reporters of processes

42 The concept of nutrigenomics biomarkers Level 1 - functional or endpoint related biomarker (often not available) Level 2 biochemical reporters of processes (often non changed / not accepted) (CRP, IL1, adiponectin, ) Level 3 biological networks that support the evidence of level 2 (both statistically and mechanistically)

State of the Science and Technology in Personalized Nutrition The nutritional systems biology

State of the Science and Technology in Personalized Nutrition The nutritional Ben van systems Ommen biology solution in Type 2 Diabetes and Cardiovascular Desease prevention and therapy". Ben van Ommen