Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease

By W. Tang, Zeneng Wang, David J. Kennedy, Yuping Wu, J. Buffa, Brendan Agatisa-Boyle, Xinmin S. Li, B. Levison, S. L. Hazen. Circulation Research, 2014

1,024 citations recorded by the source corpus.

Rationale: Trimethylamine-N-oxide (TMAO), a gut microbial-dependent metabolite of dietary choline, phosphatidylcholine (lecithin), and L-carnitine, is elevated in chronic kidney diseases (CKD) and associated with coronary artery disease pathogenesis. Objective: To both investigate the clinical prognostic value of TMAO in subjects with versus without CKD, and test the hypothesis that TMAO plays a direct contributory role in the development and progression of renal dysfunction. Methods and Results: We first examined the relationship between fasting plasma TMAO and all-cause mortality over 5-year follow-up in 521 stable subjects with CKD (estimated glomerular filtration rate, <60 mL/min per 1.73 m2). Median TMAO level among CKD subjects was 7.9 &mgr;mol/L (interquartile range, 5.2–12.4 &mgr;mol/L), which was markedly higher (P<0.001) than in non-CKD subjects (n=3166). Within CKD subjects, higher (fourth versus first quartile) plasma TMAO level was associated with a 2.8-fold increased mortality risk. After adjustments for traditional risk factors, high-sensitivity C-reactive protein, estimated glomerular filtration rate, elevated TMAO levels remained predictive of 5-year mortality risk (hazard ratio, 1.93; 95% confidence interval, 1.13–3.29; P<0.05). TMAO provided significant incremental prognostic value (net reclassification index, 17.26%; P<0.001 and differences in area under receiver operator characteristic curve, 63.26% versus 65.95%; P=0.036). Among non-CKD subjects, elevated TMAO levels portend poorer prognosis within cohorts of high and low cystatin C. In animal models, elevated dietary choline or TMAO directly led to progressive renal tubulointerstitial fibrosis and dysfunction. Conclusions: Plasma TMAO levels are both elevated in patients with CKD and portend poorer long-term survival. Chronic dietary exposures that increase TMAO directly contributes to progressive renal fibrosis and dysfunction in animal models.

Subfields: Clinical Biochemistry, Molecular Biology, Rheumatology

View Paper: https://www.semanticscholar.org/paper/955ab3968676d7f7ce31e003868fb4c91285b7a4

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

Citations in the corpus

Microbiota in health and diseases (2022, background): “Increased levels of TMAO are associated with increased risk prediction of CVD, systemic inflammation, and mortality in CKD patients.(313) A trial study using samples obtained from CKD patients displayed higher plasma levels of TMAO in CKD vs nonCKD patients.”
Trimethylamine N‐Oxide Promotes Vascular Inflammation Through Signaling of Mitogen‐Activated Protein Kinase and Nuclear Factor‐κB (2016, background): “in mice chronically exposed to the choline-supplemented diet (Figure 1C) and in some human clinical studies.(9,10,17) At Figure 1.”
Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide (2015, background): “Recent human studies have established that the levels of TMAO in serum are positively correlated with impaired renal function, colorectal cancer, and cardiovascular disease (CVD) (8, 10, 17, 18).”
Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk (2016, positive): “…distinct clinical studies and cohorts to be associated with CVD risks (Wang et al., 2011; Tang et al., 2013; Lever et al., 2014; Wang et al., 2014a; Tang et al., 2015 ; Trøseid et al., 2015), and targetted suppression of microbial TMA/TMAO production has recently been shown to inhibit diet induced…”
The role of short-chain fatty acids in the interplay between gut microbiota and diet in cardio-metabolic health (2021, background): “TMAO pathway has been associated with atherosclerosis and thrombosis promotion in mouse, and with CMD in humans such as obesity, chronic kidney disease, and T2D.(44,45,54) Detailed e1897212-2 A.”
Gut Microbiota in Cardiovascular Health and Disease (2017, background): “Moreover, the profibrotic TGF-B (transforming growth factor-B) phosphor-Smad3 pathway was shown to be enhanced in the choline diet–fed mice.(59) Whether manipulation of the gut microbial TMAO pathway such as through inhibition of microbial TMA production can attenuate heart failure like phenotype fr”