Biomarkers of inflammation in human nutrition studies

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Maximilian Sharp
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NIHR Southampton Biomedical Research Centre in nutrition Biomarkers of inflammation in human nutrition studies Philip Calder Professor of Nutritional Immunology University of Southampton The NIHR

1 NIHR Southampton Biomedical Research Centre in nutrition Biomarkers of inflammation in human nutrition studies Philip Calder Professor of Nutritional Immunology University of Southampton The NIHR Southampton Biomedical Research Centre in nutrition is funded by the National Institute for Health Research (NIHR) and is a partnership between University Hospital Southampton NHS Foundation Trust and the University of Southampton

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6 The five cardinal signs of inflammation 6

7 Where inflammation is uncontrolled or excessive or continues unabated tissue damage and metabolic changes occur

8 Diseases or conditions that involve inflammation Rheumatoid arthritis Crohn s disease Ulcerative colitis Cystic fibrosis Psoriasis Lupus Type-1 diabetes Childhood asthma Adult asthma Allergic diseases Atopic diseases COPD Atherosclerosis Acute cardiovascular events Response to surgery Major injury and trauma Sepsis Neurodegenerative diseases Some cancers Body wasting sarcopenia, cachexia Fatty liver disease Obesity.

9 Common features of inflammatory conditions A normal inflammatory response but in the wrong context Loss of barrier function, inappropriate triggering (e.g. loss of tolerance), lack of down regulation/resolution Tissue damage with loss of function Common mediators: cytokines (TNF-a, IL-1b, IL-6, IFN-g), chemokines (IL-8, MCP-1), eicosanoids (PGE 2, LTB 4 ), MMPs, ROS Common signaling pathways: NFkB, PPAR-g

10 Soluble markers Cytokines/chemokines TNF, TNFR, IL-6, IL-1b, IL-8, IFN-g, CCL2, CCL3, CCL5 Acute phase proteins CRP, SAA, Fibrinogen, vwf, anti-chymotrypsin, C3, IL-1ra, PAI-1, spla2 Adhesion molecules VCAM-1, ICAM-1, E-selectin, P-selectin Adipokines Leptin, Adiponectin

11 Blood cellular markers Total leukocytes Total neutrophils Total T cells Total eosinophils Total monocytes

12 There is wide variation in any of the soluble or blood cellular markers of inflammation even amongst normal, fairly healthy individuals

14 Chrysohoou et al. (2004) J. Am. Coll. Cardiol. 44, (n = 3000) Dai et al. (2008) Circulation 117,

15 Lopez-Garcia et al. (2004) Am. J. Clin. Nutr. 80, (n = 732)

16 Estruch et al. (2006) Ann. Intern. Med. 145, 1-11 Intervention; 3 months; n = 275/group; 90% overweight or obese; 50% diabetic

17 The inflammatory response is dynamic

18 Challenge models Can provide information about an individual s ability to respond to an inflammatory challenge -> may be a meaningful measure

19 Challenge models that have been used to study inflammatory responses in healthy humans Oral glucose load Oral fat load Acute exercise iv or im administration of LPS, TNF or IL-6 UVB exposure Vaccination

20 Am. J. Clin. Nutr. (2008) 87,

22 High fat challenge Subjects (n = 10) in fasted state Breakfast of toast and marmalade and a milkshake 117 g CHO, 15 g protein, 55 g fat, 4300 kj Blood samples collected at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours Repeated five times (two weeks apart)

24 IL-18 IL-18 High fat vs. High CHO/Lo fibre vs. High CHO/Hi fibre IL-18 at 0, 2 and 4 hours IL-18 Diabetics Time IL-18 Non-diabetics Time

26 Healthy men -> placebo or fish oil for 3 to 4 weeks in cross-over design Endotoxin (2 ng/kg body weight) each subject was studied twice LPS caused cytokine release, fever, increases in heart rate, resting EE and substrate oxidation, plasma glucagon and glucose concentrations, plasma stress hormones Fish oil significantly blunted fever, ACTH, cortisol plasma release, peak norepinephrine

28 UV challenge Healthy adult volunteers Skin exposed to UVR (UV6; nm; 23% UVB : 77% UVA) 3-4 minimal erythema doses (MED) Suction blisters and skin sections (0-72 h post UVR)

29 erythema index PGE 2 PGF 2a PGE 3 11-HETE 8-HETE 12-HETE 15-HETE 0 neutrophils CD time (h) early: inflammation vasodilatation, chemotaxis late: resolution repair Rhodes et al. (2009) FASEB J. 23,

32 Clusters or patterns of markers Omics technologies Identification of new markers Clusters or patterns as markers

38 Summary 1 Acute inflammation is a normal physiological response crucial for maintaining homeostasis but when it becomes chronic, inflammation contributes to pathology Common soluble and blood cellular markers can be identified The same markers are involved in acute and chronic inflammatory processes and so cannot be used to distinguish these processes There are a number of exogenous and endogenous modifiers that influence the levels of inflammatory markers

39 Summary 2 Inflammatory responsiveness or resilience to challenges may provide a more sensitive and meaningful indication of inflammatory state than the assessment of markers during the steady state There is a need to standardise challenges and subsequent assessments It is likely that a combination of multiple inflammatory markers and integrated readouts based on kinetic analysis following challenge will be the most informative biomarker of inflammation

Biomarkers of immunity and inflammation for use in nutrition interventions: ILSI Europe work on selection criteria and interpretation

NIHR Southampton Biomedical Research Centre in nutrition Biomarkers of immunity and inflammation for use in nutrition interventions: ILSI Europe work on selection criteria and interpretation Philip C.