Metabolomics and systems biology approaches to study health and disease. Matej Oreši

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1 Metabolomics and systems biology approaches to study health and disease Matej Oreši

2 1/19/ Biomarker concept in domain of human health [Wikipedia definition] A substance used as an indicator of a biological state [ FDA definition] A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention

1/19/2012 3 Metabolome NMR Mass Spectrometry CUSTOM mg/ml µg/ml ng/ml pg/ml Homeostasis Housekeeping Organic Acids Lipids

3 1/19/ Metabolome NMR Mass Spectrometry CUSTOM mg/ml µg/ml ng/ml pg/ml Homeostasis Housekeeping Organic Acids Lipids Amino Acids Nucleotides Steroids Eicosanoids Neurotransmitters Peptides Trace elements Biofluid metabolic profile = Phenotype

4 1/19/ Metabolomics in the clinic Piloting in Imperial College London, Dept. of Surgery and Cancer: MS, NMR, online GC ( electronic nose ) Kinross et al, Lancet (2011)

5 1/19/ Metabolome as intermediate phenotype The metabolic phenotype is sensitive to subtle but pathogenically relevant factors such as age, lifestyle, nutrition and the microbe environment of the gut. Changes in the concentrations of metabolites may thus reflect both genetic and environmental factors influencing later susceptibility to chronic diseases.

1/19/2012 6 Who we are Personnel 30 persons Competences: Metabolite analytics Biochemistry

6 1/19/ Who we are Personnel 30 persons Competences: Metabolite analytics Biochemistry Microbiology (gut microbiota) Computational biology Bioinformatics Statistics and data mining

7 1/19/ Diagnosis of psychosis [Schizophrenia vs. Other psychoses (affective, non-affective)] Multivariate logistic regression applied, using random subset (67%/33%) cross validation without fixing the model. Proline and TG(18:1/18:0/18:1) selected as the best model. Serum diagnostic test may help in diagnosis and treatment recommendation as part of psychiatric assesment. True positive rate AUC = 0.67 (0.54, 0.79) OR = 7.25 (2.00, Inf) RR = (1.094, 1.815) Oreši et al, Genome Med. (2011) False positive rate

1/19/2012 8 Prediction of Alzheimer s disease (AD) based on concentrations of three metabolites in patients with mild cognitive impairment (MCI) at baseline (~5 year follow-up) AD (n=52) vs Stable

8 1/19/ Prediction of Alzheimer s disease (AD) based on concentrations of three metabolites in patients with mild cognitive impairment (MCI) at baseline (~5 year follow-up) AD (n=52) vs Stable MCI (n=91) at follow-up In a healthcare setting, the application of such an assay could complement the neurocognitive assessment by the medical doctor and could be applied to identify the at-risk patients in need of further comprehensive follow-up. Oreši et al, Transl. Psychiatry (2011)

9 Metabolic disease as cost of adipocyte adaptation to obesity 1/19/2012 9

10 1/19/ Fatty acid composition in adipose tissue Remodeling of fatty acid composition in obesity, with unexpected elevation of PUFAs Pietiläinen et al, PLoS Biol. (2011)

1/19/2012 11 Lipid bilayer simulations PC(16:0/20:4)

help maintain the membrane fluidity an adaptive mechanism

area with increasing membrane fluidity Increasing order (S

11 1/19/ Lipid bilayer simulations PC(16:0/20:4) Fluidity The observed membrane lipid changes in obese twins help maintain the membrane fluidity an adaptive mechanism PC(P-16:0/20:4) PC(16:1/18:0) PE(P-16:0/20:4) Increasing area with increasing membrane fluidity Increasing order (S mol ) with decreasing membrane fluidity Pietiläinen et al, PLoS Biol. (2011)

12 1/19/ in morbidly obese subjects the adaptive mechanism is broken down! A ** PC(34:2) B mol/ mol Tot. PL PE(P-16:0/20:4) p < 10-6 * PC(36:2) mol/ mol Tot. PL PE(P-18:1/20:4) p < 10-6 Data from morbidly obese subjects from Kotronen et al., Obesity (2009) Pietiläinen et al, PLoS Biol. (2011

13 1/19/ Alostatic load (or cost of adaptation) due to obesity Arachidonic-acid containing plasmalogens under oxidative stress become precursors of alipid mediators such as leukotrienes and hydroxyeicosatetraenoic acids These reactive lipids are important mediators of inflammatory response The lipid remodelling process occurring in the membranes may therefore make the adipocytes more vulnerable and prone to inflammatory responses and therefore to metabolic comorbidities of obesity

14 1/19/ Progression of adipocyte membrane lipid remodeling Metabolically compensated Activation of immune system Lipotoxicity [PE(P-16:0/20:4)]/[PC(34:2)] The transition point as dependent on BMI varies from individual to individual BMI

15 Can we modulate the membrane lipid remodeling? 1/19/

16 1/19/ Regulation of adipose tissue remodeling: combining gene expression, lipidomics, and clinical data Pietiläinen et al, PLoS Biol. (2011

1/19/2012 17 Lipidomic changes in Elovl6 KD (adipocyte cell line) mirror the changes observed in acquired obesity Control 50% Elovl6 KD 70% Elovl6 KD 25.0 20.0 15.0 10.0 5.0 PC(34:2) p group <0.

17 1/19/ Lipidomic changes in Elovl6 KD (adipocyte cell line) mirror the changes observed in acquired obesity Control 50% Elovl6 KD 70% Elovl6 KD PC(34:2) p group <0.05, p time < PC(40:7) p group <0.05, p time < days 8 days days 8 days PC(34:3) p group <0.05, p time < days 8 days PC(O-34:1) p group <0.05, p time < days 8 days PE(O-38:7) p group <0.05, p time < days 8 days PE(O-40:6) p group <0.05, p time < days 8 days The identified adipose lipid network is amenable to genetic or therapeutic manipulation New opportunity for prevention & treatment of obesity-associated metabolic comorbidities Pietiläinen et al, PLoS Biol. (2011)

1/19/2012 18 Adaptation in acquired obesity:

18 1/19/ Adaptation in acquired obesity: benefits & costs Pietiläinen et al, PLoS Biol. (2011)

19 Autoimmune disease as cost of immune system response to host biochemical variation 1/19/

1/19/2012 20 Finnish Type 1 Diabetes Prediction and Prevention Study (DIPP) DIPP Newborns screened N=104111* 1 antibody N= 1167 STRIP N=1062 Genetic risk N=14822 2 antibody N=430 T1D N= 122

20 1/19/ Finnish Type 1 Diabetes Prediction and Prevention Study (DIPP) DIPP Newborns screened N=104111* 1 antibody N= 1167 STRIP N=1062 Genetic risk N= antibody N=430 T1D N= 122 Progressors N= 50 (473 samples) Progressors N= 6 (42 samples) In follow-up N=8026 Nonprogressors N= 67 (636 samples) Nonprogressors N=6 (45 samples) *as of June 2006 P. Bougnères & A.-J. Valleron J. Exp. Med. (2008) Cases and controls matched by gender, HLA genotype, city and period of birth. M. Oreši et al., J Exp Med (2008)

21 1/19/ Case report: Girl who developed overt type 1 diabetes at age 9 years GADA IAA IAA GADA GADA+ IAA+ Diagnosis Age (years) M. Oreši et al., J Exp Med (2008)

22 1/19/ Case report (cont) lysopc ether PC Metabolic dysregulation in pre-autoimmune period! GADA peak IAA peak Diagnosis Normal level M. Oreši et al., J Exp Med (2008) Age (years)

23 1/19/ Metabolic profile prior to autoimmune (GADA) response (Progressors vs. Nonprogressors) Glucose Alanine Impaired branched chain amino acid catabolism Pyruvate Ketoleucine Leucine Elevated glutamate & GABA Diminished TCA cycle metabolites M. Oreši et al., J Exp Med (2008) Succinic acid Reducing equivalents TCA cycle -KG Glutamic acid Upregulated Unchanged Downregulated Not present Glutamine Oxidative stress Antioxidant lipids GABA GAD GAD antibodies From metabolic stress to restoration of metabolic homeostasis by autoantibodies targeting the dysregulated pathways

24 1/19/ Can we predict T1D at birth? cord serum metabolome in progressors to T1D (N=33), newborns who developed 3 or 4 (N=32), two (N=34), or one (N=50) islet autoantibody (Aab) during the follow-up, and controls (N=160) matched for gender, HLA genotype, city and period of birth. Metabolomics platforms: (1) global lipidomics using UPLC-MS, (2) global metabolomics using GCxGC-TOFMS, and (3) bile acid platform using UPLC-MS/MS.

25 1/19/ Main findings T1D and 3-4Ab groups are most similar and characterized by diminished phospholipids (ether phosphatidylcholines and sphingomyelins), confirming earlier data. A lipid signature of 3 lipids was derived based on T1D progressor cord blood profile and independently tested on other subgroups. The signature predicts T1D in the 3-4Ab group with odds ratio of 18! The metabolic signature is independent of HLA associated T1D risk.

1/19/2012 26 Finnish Centre of Excellence in Molecular Systems Immunology and Physiology Research (SyMMyS)

between the immune system and other physiological systems in health and disease to translate this knowledge into

26 1/19/ Finnish Centre of Excellence in Molecular Systems Immunology and Physiology Research (SyMMyS) to understand the molecular mechanisms that control the immune system as well as the interactions between the immune system and other physiological systems in health and disease to translate this knowledge into novel treatment and prevention strategies of inflammatory/ immune-mediated disorders, with specific focus on type 1 diabetes

Biomarkers for gut comfort

Priority Research Programme Foods for improving gut function and comfort Biomarkers for gut comfort Karl Fraser Senior Scientist, Metabolomics AgResearch Foods for gut function and comfort Irritable Bowel