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Zeneng et al, 2019 (unpublished) Yazdekhasti Mol Nutr & Foods Res 2016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