LOW GRADE INFLAMMATION. Anne-Marie Minihane Prof of Nutrigenetics, Dept of Nutrition, Norwich Medical School, 1

Transcription

1 * LOW GRADE INFLAMMATION Anne-Marie Minihane Prof of Nutrigenetics, Dept of Nutrition, Norwich Medical School, 1

2 Inflammation is a essential metabolic response Inflammatory status analysis Low grade inflammation and chronic disease Dietary modulation of inflammation

3

4 LOW-GRADE INFLAMMATION, DIET COMPOSITION AND HEALTH: CURRENT RESEARCH EVIDENCE AND ITS TRANSLATION P.C. Calder, S. Vinoy, W. Russell, A. Baka, H. Roche, K. Tuohy, J. Teeling, E. Blaak, M. Fenech, D. Vauzour, H. McCardle, B. Kremer, L. Sterkman, K, Vafeiadou, M. Benedetti, C.M. Williams, A.M. Minihane

5 What is inflammation?? (Latin, īnflammō, "I ignite, set alight") An essential metabolic process A component of innate (non-specific) immunity A local response to cellular insults that is marked by increased blood flow, capillary dilatation, leukocyte infiltration, and the localised production of a host of chemical inflammatory mediators. It serves to return to homeostasis following injury mediated by an infectious agent, physical damage or metabolic stress Department of Nutrition Norwich Medical School

6 Innate vs. adaptive immunity Department of Nutrition Norwich Medical School

7 What is inflammation?? (Latin, inflammo, I ignite, set alight") An essential metabolic process A component of innate (non-specific) immunity A local response to cellular insults that is marked by increased blood flow, capillary dilatation, leukocyte infiltration, and the localised production of a host of chemical inflammatory mediators. It serves to return to homeostasis following injury mediated by an infectious agent, physical damage or metabolic stress Department of Nutrition Norwich Medical School

8

9

10 Inflammation is a complex metabolic process involving the interaction of numerous organs, cell types and a wide array of chemical inflammatory mediators Calder PC et al., BJN 2013, 109:S1, commissioned by ILSI Europe Nutrition & Immunity Task Force Department of Nutrition Norwich Medical School

11 Resolution of inflammation is an active process not simply a turning off of proinflammatory pathways

12 Chronic low grade inflammation is a pathological feature of a host of chronic diseases Department of Nutrition Norwich Medical School

13 Inflammation & atherosclerosis, CVD Libby P, 2002 Glass & Witzum, 2001 Department of Nutrition Norwich Medical School

14 Inflammation is a driver of the metabolic dysregulation associated with obesity and excess adipose tissue. Inflammatory status in part differentiates the metabolically healthy but obese (MHO) and the typical metabolically unhealthy obese phenotype In EU27, ~60% adults and 20% children are overweight or obese Obese adipose tissue Adipocyte hypertrophy Macrophage infiltration Production of inflammatory mediators Local and systemic inflammation & adipocyte dysfunction Metabolic syndrome, insulin resistance, non alcoholic fatty liver disease, type II diabetes, cardiovascular diseases Tilg, H. and A. R. Moschen (2006).

15 30% metabolically healthy obese (MHO) High fat mass High insulin sensitivity Low inflammation Normal lipids Low ectopic fat High adiponectin High Fat mass Low insulin sensitivity High inflammation Dyslipidaemia High ectopic fat Low adiponectin NHANES: Wildman P et al., % inflammation?? 50% 70% 50% Department of Nutrition Norwich Medical School

16 Inflammation is a driver the pathology of non-alcoholic fatty liver disease (NAFLD) Now the most prevalent form of liver disease in Western Countries. Co-morbidity of obesity & insulin insensitivity 25% UK population, 2% non-alcoholic steatohepatitis Two hit hypotesis

17 Although inflammation is an important pathological feature of numerous age-related chronic disease, causality remains to be established Lack of sensitive, tissue specific biomarkers of an early pro-inflammatory state Inflammation typically measured in fasting plasma/serum

18 Typical plasma/serum markers of inflammation Biochemical cytokines- TNFα, IL-6, IL-1β, IFN-γ chemokines- MCP-1, MIP-1α, acute phase proteins- CRP, SAA, fibrinogen adhesion molecules- VCAM-1, ICAM-1, P-selectin, E-selectin adipokines- leptin, adiponectin Cellular total leukocytes total neutrophils total eosinophils total monocytes

19 Major dietary patterns are related to plasma concentrations of markers of inflammation and endothelial dysfunction, Lopez-Garcia, AJCN 2004, n=732

20 Plasma biochemical and cellular inflammatory markers are highly variable Slide: Philip Calder

21 The inflammatory response is dynamic and responsive to challenges Slide: Philip Calder

22 Can challenge models be used to provide a more sensitive and physiological relevant model of inflammatory status? In vivo Oral glucose load Oral fat load Exercise LPS, TNF-α, IL-6 (IV or IM) UVB exposure Vaccination Ex vivo Whole blood culture

23

24 Fish oils shown to positively impact on almost all CVD risk factors- including inflammation Dyslipidaemia LDL-C HDL-C LDL3 TG blood pressure ANTI-INFLAMMATORY STATUS thrombosis plaque stability Improved vascular function and tone anti-arrhythmic

25

26 Do you need 3+g EPA+DHA/d to bring about positive changes? FINGEN Study (n=312) 1.Examine the responsiveness of ~ 40 CVD risk indicators to low(er) dose fish oil intervention 2.Examine impact of age/gender/apoe genotype on response to treatment CO- control oil 0.7FO- 0.7g EPA+DHA per day 1.8FO- 1.8g EPA+DHA per day CO/0.7FO/1.8FO CO/0.7FO/1.8FO CO/0.7FO/1.8FO 8 wks 12 wks 8 wks 12 wks 8 wks Reading, Southampton, Newcastle, Glasgow 50% males and female 33% APOE2, APOE3, APOE4 20% in each of 20-29y, 30-39y, 40-49y 50 59y, 60-70y 26

27 (n=312) CO- 0wk CO- 8wk 0.7FO- 0wk 0.7FO- 8wk 1.8FO- 0wk 1.8FO- 8wk P treatment VCAM (ng/ml) SE ICAM (ng/ml) SE Esel (ng/ml) SE PSel (ng/ml) SE TNF-α (pg/ml) SE IL6 (pg/ml) SE IL10 (pg/ml) SE CRP (mg/l) SE CRP (<6mg/l) SE

28 Fish oils, inflammation and plaque morphology 7-189d intervention, median 42d 1.4g EPA+DHA/d AHA classification Type III (%) Type IV (%) Type V (%) Type VI (%) Control oil (CO) Sunflower oil (SO) Fish oil (FO) P SO vs CO NS NS NS P FO vs. CO NS Intimal thickening (%) NS NS Fibrous cap atheroma (%) NS NS Thin fibrous cap atheroma (%) NS Plaque rupture (%) NS NS Macrophages Staining intensity 0 Staining intensity 1 Staining intensity NS NS Thies, F et al., Lancet, 2003 Cawood, AL et al., Atherosclerosis, 2010

29 5 slides of unpublished data

30 Take home messages Inflammation is an essential physiological process Low grade, chronic, and unresolved inflammation is a feature of numerous age-related chronic condition Causality is unknown Need to measure tissue inflammatory status or use more sensitive approaches to characterise circulating biomarkers of inflammatory status in human RCTs Numerous dietary components thought to be anti-inflammatory with establishment of efficacy in human RCTs often lacking

31