Gut-Heart Axis: Potential Therapeutic Implications

W. H. Wilson Tang, MD Research Director (HF/Transplant), Heart & Vascular Institute, Cleveland Clinic

Disclosure: Consultant for Sequana Medical, ABIM Funding: P20HL113452, R01DK106000,

R01HL126827

“Gut Hypothesis” of Heart Failure: Changes in Bowel Wall

Sadnek et al, Int J Cardiol 2012; Sandek et al, JACC 2007; Kitai et al, ACC 2017 (abstract)

*Lactulose (5g) + Rhamnose (5g) + Sucrose (5g) in 100cc deionized water (~1,500 mOsm/l)

Urine lactulose/ rhamnose ratio (LR) * Structure Microbes Function/Integrity

Gut Microbiota: Composition and Functionality Microbial cells may out-number human cells 10 to 1; genes

by 100 to 1, and may vary up 50% between individuals

Cui et al, Sci Rep 2018; Califf et al, Microbes 2014

Dietary Nutrients and Host-Microbial Metabolism

Kohl & Carey, J Exp Biol 2016

The biggest environment “exposure” is represented by what we ingest as food and filtered by gut microbiota and their metabolites’ interactions with human host.

Tang et al, J Am Coll Cardiol 2019

Diet, Intestinal Microbiota & Cardio-Renal Risk

Short-Chain Fatty Acid (SCFA) from Dietary Fiber

David et al, Nature 2014

Tang et al, Nat Rev Cardiol 2019

Pluznick, Kidney Int 2016

Renal Sensory Nerve Activation

Wang et al, Nat Med 2011

Involvement of Gut Microbiota

Tang et al., N Engl J Med 2013

Impact of Diet & Microbes on TMAO in Humans Vegans/Vegetarians vs Omnivores

Koeth et al, Nat Med 2013; Koeth et al, JCI 2019

Carnitine sources

γ-Butyrobetaine (pre-carnitine)

Koeth et al JCI 2019

Dietary Red Meat Intake Alters Both TMA/TMAO Production & Renal Clearance

Wang et al, Eur Heart J 2019

Pathogenic Mechanisms Linking TMAO to Diseases

Modified from Tang & Hazen, Circulation 2017 Chen et al., Cell Metab 2019

Li et al, JCI Insight 2018

Model 1: adjusted for age, sex, HDL, LDL, smoking, diabetes, SBP, hsCRP Model 2: Model 1 + TMAO

Li et al, Eur Heart J 2019

Therapeutic Implications with TMAO-Lowering

Withdrawal (WD) of dietary TMAO (0.12%) at 6 weeks

Organ et al, AHA 2016 (manuscript submitted, under review) Wang et al, Eur Heart J 2018

↓Dietary Red Meat

Zhu et al, Circulation 2017

Aspirin Dietary Restriction

Seafood TMA/TMAO Content and Consumption Male ApoE-/- mice on Western Diet (200g/kg) for 16 wks

TMA (mg/kg)

24.5

529.0 (white turbot)

23

(Milk

)

TMAO and TMA Content in Various Seafood

Zeneng et al, 2019 (unpublished) Yazdekhasti Mol Nutr & Foods Res 2016

Summary: Dietary Changes and TMAO in Humans Intervention Effects on TMAO References

Caloric restriction ↓ Erikson ML et al, Nutrients 2019

Intermittent fasting ↓ Washburn RL et al, Nutrients 2019

↓Red meat consumption ↓ Wang Z et al, Eur Heart J 2019

Vitamin B+D ↓ Obeid R et al, Mol Nutr Food Res 2017

Mediterranean diet ↓↔ Pignanelli M et al, Nutrients 2018 Guasch‐Ferré M et al, JAHA 2018

Probiotics ↔↑ Boutagy NE et al, Obesity 2015

Increase protein allowance ↑ Mitchell et al, Nutrients 2019 Animal intervention studies showing TMAO‐lowering effects with garlic (allicin), fish oil, and resveratrol

Roberts et al, Nat Med 2018

MC = methylcholine

Wang et al, Cell 2015 DMB = 3,3-dimethyl-1-butanol

Take Home Messages • Understanding gut‐heart axis and pathways associated with

intestinal microbial metabolism may be more relevant than recognizing species’ composition in human health and disease

• Intestinal microbiota and their ability to metabolize our ingested food can impact on cardio‐renal disease progression, with insights into TMA/TMAO pathway demonstrating transmission of susceptibility of cardio‐renal disease risk

• Modifying long‐term dietary nutrient intake and unique microbial targeting strategies are proof‐of‐concept approaches for cardiovascular prevention

Acknowledgements Cleveland Clinic Tang Lab

• Vichai Senthong, MD • Jennifer Kirsop • Timothy Engelman, LPN

Hazen Lab

• Stanley Hazen, MD PhD • Zeneng Wang, PhD • Robert Koeth, MD PhD • Xinmin S. Li, PhD • Weifei Zhu, PhD • Nilaksh Gupta, PhD • Ina Nemet, PhD • Jennifer Buffa, MS

Cleveland State University • Yuping Wu, PhD

USC/UCLA • Hooman Allayee, PhD • Jaana Hartiala, PhD • Aldon J. Lusis, PhD

Lousiana State University • David Lefer, PhD • Chelsea Organ, PhD

Funding Support • NIH R01HL105993 • NIH P20HL113452 • NIH UL1TR000439 • NIH R01DK106000 • NIH R01HL126827