Gut Microbes as Participants and Targets in Cardiometabolic Diseases

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Gut Microbes as Participants and Targets in Cardiometabolic Diseases Stanley L Hazen, MD, PhD Section Head, Preventive Cardiology, Cleveland

of Cellular & Molecular Medicine, Lerner Research Institute Men In Black 2 Gut microbes are essential to human health Gut Microbes - break down

in the gut; they make up 3-5% of feces (dry weight) An estimated 3.

This vastly outnumbers the 23, or so genes in the human genome Homo sapien DNA constitutes only ~1% of the total DNA in each of us Disclosures:

Hazen is named as a co-inventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and/or

Obese microbiome has an increased capacity for dietary energy harvest, and is a transmissible trait donors transplant of cecal microbes germ free

1 Gut Microbes as Participants and Targets in Cardiometabolic Diseases Stanley L Hazen, MD, PhD Section Head, Preventive Cardiology, Cleveland Clinic Chair, Dept. of Cellular & Molecular Medicine, Lerner Research Institute Men In Black 2 Gut microbes are essential to human health Gut Microbes - break down toxins - make vitamins and essential amino acids - promote intestinal health/immunity - create a barrier against invaders There are ~1 23 microbes in the gut; they make up 3-5% of feces (dry weight) An estimated 3.3 million different genes are present amongst the intestinal microbial community. This vastly outnumbers the 23, or so genes in the human genome Homo sapien DNA constitutes only ~1% of the total DNA in each of us Disclosures: all research presented was funded by the NIH and the Office of Dietary Supplements Dr. Hazen is named as a co-inventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and/or therapeutics. Dr. Hazen reports having been paid as a consultant for the following companies: Esperion, and Procter & Gamble. Dr. Hazen reports receiving research funds or support from Abbott, Astra Zeneca, Pfizer, Procter & Gamble, Roche, and Takeda. Obese microbiome has an increased capacity for dietary energy harvest, and is a transmissible trait donors transplant of cecal microbes germ free recipients Dr. Hazen reports having the right to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics and/or therapeutics from Cleveland Heart Laboratory, Esperion, Frantz Biomarkers, LLC and Siemens. Dr. Hazen was the scientific founder of Cleveland Heart Laboratory, and reports having equity in that company. PJ Turnbaugh et al. Nature (26) 444:

Diet and Intestinal Microbes are Mechanistically Linked to Atherosclerotic Heart Disease

design for identifying unbiased small molecule profiles predictive of incident ri risks for major

carnitine RA Koeth (213) Nature Medicine WHW Tang (213) New Engl J Med B Bennett (213) Cell Metab

M Warrier (215) Cell Reports J Gregory (215) J Biol Chem Z Wang (215) Cell 5 C Organ (216) Circ

Additional take home concepts: Z Wang et al, Nature (211) Choline, betaine and

as our largest endocrine organ () ƽ The microbiome is a drugable target ƽ m/z 14 Identities

2 Diet and Intestinal Microbes are Mechanistically Linked to Atherosclerotic Heart Disease Meta-organismal pathway: (i) gut microbe (ii) host hepatic : FMOs Strategy of metabolomics study design for identifying unbiased small molecule profiles predictive of incident ri risks for major adverse cardiovascular events GeneBank (N=1,) carnitine Trimethylamine (TMA) Z Wang (211) Nature carnitine RA Koeth (213) Nature Medicine WHW Tang (213) New Engl J Med B Bennett (213) Cell Metab () Z Wang (214) Eur Heart J WHW Tang (214) JACC RA Koeth (214) Cell Metab WHW Tang (215) Circ Res M Warrier (215) Cell Reports J Gregory (215) J Biol Chem Z Wang (215) Cell 5 C Organ (216) Circ Heart Fail The microbiome is a filter of our largest environmental exposure what we eat Additional take home concepts: Z Wang et al, Nature (211) Choline, betaine and trimethylamine-n-oxide are plasma analytes associated with CVD ƽ The microbiome can be considered as our largest endocrine organ () ƽ The microbiome is a drugable target ƽ m/z 14 Identities confirmed by: n LC-MS, 1H,13C,15N NMR GC/MS/MS, Isotope tracer studies Z Wang et al, Nature (211) () m/z 76 Betaine m/z 118 HOOC-CH2-CH2-N(CH3)3

Prospective Cohort: Sequential Cardiology Patients Plasma levels of three phosphatidylcholine metabolites, choline, and betaine, predict CVD risks (N=1865) Intestinal Microbial Organisms Play an

Nature (211) Plasma levels of the gut flora dependent metabolite predict incident (3 year) CVD risks New Independent Cohort: N=47 Sequential Subjects TMANO 1 Q1 9 8 7 Log-Rank p<.

3 Prospective Cohort: Sequential Cardiology Patients Plasma levels of three phosphatidylcholine metabolites, choline, and betaine, predict CVD risks (N=1865) Intestinal Microbial Organisms Play an Obligatory Role in Generation from Dietary Egg Yolk PC in Mice 2 weeks Odds ratio (95%CI) adjusted for age, sex, DM, HTN, smoking, LDL, HDL, TG, CRP, egfr Z Wang et al, Nature (211) Wang Z et al, Nature (211) Plasma levels of the gut flora dependent metabolite predict incident (3 year) CVD risks New Independent Cohort: N=47 Sequential Subjects TMANO 1 Q Log-Rank p<.1 Q2 Q3 Q Time (days) Adjusted for age, sex, DM, HTN, smoking, LDL, HDL, TG, CRP, egfr WHW Tang et al, NEJM (213) is a gut flora dependent metabolite in humans : Ion extracted LC chromatograms in positive MRM MS in human plasma and urine after oral taking d9-dppc and two hard eggs PC challenge - Oral d9-pc and 2 hard boiled eggs at each visit 6 h post PC challenge 24 h post PC challenge Tang, Wang et al, NEJM (213) Pre-antibiotics Antibiotics ics Post-antibiotics Acquisition iti (visit 1) Suppression Suspension of (visit 2) of gut flora gut flora Plasma a d Urine g j d d b 1 5 e 1 h k d d c i l f visit d d

4 Dietary choline induces atherosclerosis in the presence of intact gut flora ( formation) apoe-ko, C57Blk6/J mice Intact flora Vegetarians/Vegans have lower synthetic capacity than Omnivores to form from carnitine because of altered gut microbial composition d9-carnitine d9 carnitine challenge car e Abx diet: 1 11 : adapted from Z Wang et al, Nature (211) Carnitine, an abundant nutrient in red meat, is also pro-atherogenic R Koeth et al, Nature Medicine (213) alters macrophage phenotype, and sterol metabolism in multiple compartments ATHEROSCLEROSIS FORWARD TRANSPORT REVERSE TRANSPORT ' ' sterol/bile transporters R Koeth et al, Nature Medicine (213) ' Cholesterol storage ' macrophage phenotype ' bile acid composition, pool size and transporters ' LXR and FXR signaling adapted from: R Koeth et al, Nature Medicine (213), and Warrier et al, Cell Reports (215)

Adherence to Mediterranean Diet Lowers Urinary Levels Choline TMA Lyase (CutC/D)

The Gut Microbial Endocrine Organ: Bacterially-Derived Signals Driving

De Filippis et al, Gut 215 What are Dietary Sources of Choline/Phosphatidylcholine?

Carnitine TMA Lyase (Cnt A/B) Promiscuous TMA Lyase (yeax/w) Li & Vance, J Lipid

5 Adherence to Mediterranean Diet Lowers Urinary Levels Choline TMA Lyase (CutC/D) Carnitine TMA Lyase (Cnt A/B) Promiscuous TMA Lyase (yeax/w) Brown JM and Hazen SL. The Gut Microbial Endocrine Organ: Bacterially-Derived Signals Driving Cardiometabolic Diseases. (215) Annu Rev Med. De Filippis et al, Gut 215 What are Dietary Sources of Choline/Phosphatidylcholine? Lekithos (Greek) = Egg yolk Chole (Greek) = Bile Choline TMA Lyase (CutC/D) Carnitine TMA Lyase (Cnt A/B) Promiscuous TMA Lyase (yeax/w) Li & Vance, J Lipid Res 28 Brown JM and Hazen SL. The Gut Microbial Endocrine Organ: Bacterially-Derived Signals Driving Cardiometabolic Diseases. (215) Annu Rev Med.

6 Sources of DMB Olives/Cold-pressed extra virgin olive oil Grape seed oil Screens - primary - secondary Choline TMA Lyase (CutC/D) - tertiary Carnitine TMA Lyase (Cnt A/B) - human Promiscuous TMA Lyase (yeax/w) Promi commensals Guinness Lager Stout Brown JM and Hazen SL. The Gut Microbial Endocrine Organ: Bacterially-Derived Signals Driving Cardiometabolic Diseases. (215) Annu Rev Med. Development of inhibitors (and activators) of microbial TMA lyases Dimethylbutanol (DMB) inhibits TMA production from multiple nutrients in human fecal commensals choline Wang et al, Cell (215) Wang et al, Cell (215)

7 A DMB is a non-lethal microbial TMA lyase inhibitor in multiple human commensals P. mirabilis 3 intact cell p=.7 B P. penneri p=.9 C E. fergusonii p=.7 Microbial lyase inhibition attenuates dietary choline enhanced atherosclerosis C57BL/6J ApoE-/- mice, male a choline chow+dmb choline+dmb b p=.3 p=.27 p= Time (h) DMB Time (h). 4 8 Time (h) 12 1 Chow (n=32) choline (n=23) Chow +DMB (n=2) choline +DMB (n=2) Wang et al, Cell (215) Wang et al, Cell (215) Microbial TMA-lyase inhibition reduces levels in vivo C57Blk/6J, apoe-/- mice Drugging the Microbiome Its in Our Future for CVD Therapeutics Inhibitor diet: Wang et al, Cell (215) Z Wang et al, Cell, Dec 17, 215

Thank you The Cleveland Clinic Zeneng Wang

UCLA Jake Lusis Elin Org Diana Shih Hazen

8 Thank you The Cleveland Clinic Zeneng Wang Jennifer Buffa Robert Koeth Manya Warrier Bruce Levison Mark Brown Xinmin Li WeiFei Zhu Wilson Tang Joe DiDonato Jill Gregory UCLA Jake Lusis Elin Org Diana Shih Hazen Lab Drugs for Bugs Drugging the Microbiome

medicine nature Metabolomics Studies Reveal New Pathways in Cardiovascular Disease with Potential for Diagnostics and Therapeutic Targeting

medicine nature Metabolomics Studies Reveal New Pathways in Cardiovascular Disease with Potential for Diagnostics and Therapeutic Targeting Metabolomics Studies Reveal New Pathways in Cardiovascular Disease with Potential for Diagnostics and Therapeutic Targeting nature medicine VOLUME 19 NUMBER 5 MAY 213 www.nature.com/naturemedicine Stanley