Gut-Heart Axis: Potential Therapeutic Implications
Transcript of Gut-Heart Axis: Potential Therapeutic Implications
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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
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“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
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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
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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.
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Tang et al, J Am Coll Cardiol 2019
Diet, Intestinal Microbiota & Cardio-Renal Risk
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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
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Wang et al, Nat Med 2011
Involvement of Gut Microbiota
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Tang et al., N Engl J Med 2013
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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)
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Koeth et al JCI 2019
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Dietary Red Meat Intake Alters Both TMA/TMAO Production & Renal Clearance
Wang et al, Eur Heart J 2019
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Pathogenic Mechanisms Linking TMAO to Diseases
Modified from Tang & Hazen, Circulation 2017 Chen et al., Cell Metab 2019
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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
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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
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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
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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
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Roberts et al, Nat Med 2018
MC = methylcholine
Wang et al, Cell 2015 DMB = 3,3-dimethyl-1-butanol
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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
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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