The DOI matches its Crossref record; 43 of the 43 references it cites were found in a registry or an index; 6 of the 29 sources its claims cite were checked for support.
Gut Microbiota-Dependent Trimethylamine N -Oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease
Open accessAbstract
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 m 2 ). Median TMAO level among CKD subjects was 7.9 μmol/L (interquartile range, 5.2–12.4 μmol/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.
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25 Own result · 13 Not checked yet · 7 Own interpretation · 2 Own method · 1 Partly supported · accuracy not yet measured
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In the paper
“Specifically, gut microbiota-mediated metabolism of phosphatidylcholine, choline or L-carnitine each have been shown to ultimately produced trimethylamine-N-oxide (TMAO), and in multiple clinical studies, TMAO levels have been shown to be associated with cardiovascular risks8–10, 13.”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > INTRODUCTION
What the sources say
- Supportedcites [8] Koeth RA Wang Z Levison BS Buffa JA Org E Sheehy BT Britt EB Fu X Wu Y Li L Smith JD DiDonato JA Chen J Li H Wu GD Lewis JD Warrier M Brown JM Krauss RM Tang WH Bushman FD Lusis AJ Hazen SL Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis Nat Med 2013 19 576 585 23563705 PMC3650111 source
The Introduction describes gut-microbiota metabolism of dietary choline/phosphatidylcholine to trimethylamine, which the liver then converts to TMAO. The Results section, “Human gut microbiota is required to form TMAO from L-carnitine,” reports TMAO formation after an L-carnitine challenge. Thus the paper supports the claimed gut-microbiota-mediated pathway for all three dietary sources, though the final conversion to TMAO occurs in the liver. (LLM, conf=0.93)
- Partly supportedcites [9] Tang WH Wang Z Levison BS Koeth RA Britt EB Fu X Wu Y Hazen SL Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk N Engl J Med 2013 368 1575 1584 23614584 PMC3701945 sourceExperimental — accuracy not yet measured
The Discussion says intestinal microbes convert the choline moiety of dietary phosphatidylcholine to trimethylamine, which the liver then converts to TMAO. The paper supports the phosphatidylcholine pathway and identifies choline as the relevant component, but the passages in our copy do not establish the claimed L-carnitine pathway or a separate dietary-choline pathway. (LLM, conf=0.86)
- Partly supportedcites [10] Wang Z Klipfell E Bennett BJ Koeth R Levison BS Dugar B Feldstein AE Britt EB Fu X Chung YM Wu Y Schauer P Smith JD Allayee H Tang WH DiDonato JA Lusis AJ Hazen SL Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease Nature 2011 472 57 63 21475195 PMC3086762 sourceExperimental — accuracy not yet measured
The Results section reports gut-microbiota-dependent TMAO formation from dietary phosphatidylcholine and choline. The Discussion also reports an association between TMAO levels and cardiovascular risk. Our copy does not establish L-carnitine as a precursor of TMAO, so that part of the attributed claim is unsupported. (LLM, conf=0.88)
- Supportedcites [11] Wang Z Tang WH Buffa JA Fu X Britt EB Koeth RA Levison BS Fan Y Wu Y Hazen SL Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-n-oxide Eur Heart J 2014 35 904 910 24497336 PMC3977137 source
The Introduction states that gut microbiota play an obligate role in TMAO formation from ingested choline, phosphatidylcholine, and carnitine. It also reports an association between elevated TMAO and cardiovascular risk. The source describes microbiota-dependent production, not direct conversion of these nutrients to TMAO by microbes alone. (LLM, conf=0.94)
- Supportedcites [12] Tang WH Hazen SL The contributory role of gut microbiota in cardiovascular disease J Clin Invest 2014 124 4204 4211 25271725 PMC4215189 source
The passages on TMAO formation state that gut microbiota are required for TMAO generation from dietary nutrients, including phosphatidylcholine, choline and L-carnitine. The review distinguishes the steps: microbes produce TMA, which host enzymes subsequently convert to TMAO. This supports the citing sentence’s wording that microbial metabolism ultimately produces TMAO. (LLM, conf=0.93)
- Supportedcites [13] Tang WH Wang Z Fan Y Levison BS Hazen JE Donahue L Wu Y Hazen SL Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-n-oxide in patients with heart failure: Refining the gut hypothesis J Am Coll Cardiol 2014 2014 1908 1914 25444145 PMC4254529 source
The introductory passage labeled Abstract > Conclusion describes microbe-dependent generation of TMAO through a pathway involving dietary phosphatidylcholine, choline, and carnitine. This supports the attributed paraphrase; the paper does not claim that microbes alone perform every step of TMAO production. (LLM, conf=0.90)
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“a dose-dependent relationship between plasma TMAO levels and mortality risk was observed (log[TMAO]: adjusted HR=1.41, 95%CI 1.23–1.61, p<0.001 for CKD cohort; adjusted HR=1.21, 95%CI 1.07–1.36, p<0.01 for non-CKD cohort).”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > DISCUSSION
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“as well as after adjusting for traditional risk factors, log-transformed hsCRP, and log-transformed eGFR (adjusted HR 1.47, 95%CI 1.02–2.12, p<0.05, Table 2B).”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > RESULTS > Increased TMAO levels in non-CKD patients with elevated Cystatin C
plaincorrelationaln = 3,166 ·- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Using median cohort cut-offs with low cystatin C (<1.4 mg/dL) and low TMAO (<7.9 μM) as reference, those with concomitant high cystatin C and high TMAO had a 3-fold increase in mortality risk (HR 3.01, 95%CI 1.97–4.59, p<0.001).”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > RESULTS > Elevated TMAO in patients with renal insufficiency portend poorer survival
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Compared to non-CKD subjects, TMAO levels were elevated in patients with CKD (median TMAO: 7.9 [IQR 5.2–12.4]μM versus 3.4 [IQR 2.3–5.3]μM, p<0.001; Figure 1A).”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > RESULTS > Elevated TMAO in patients with renal insufficiency portend poorer survival
plaincorrelationaln = 3,687- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“a dose-dependent relationship between plasma TMAO levels and mortality risk was observed (log[TMAO]: adjusted HR=1.41, 95%CI 1.23–1.61, p<0.001 for CKD cohort; adjusted HR=1.21, 95%CI 1.07–1.36, p<0.01 for non-CKD cohort).”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > DISCUSSION
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Importantly, elevated TMAO levels were associated with corresponding increases in tubulointerstitital fibrosis and collagen deposition (Figure 3B–C)”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > RESULTS > Dietary choline and dietary TMAO both promote renal fibrosis and dysfunction in animal models
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Median TMAO level among CKD subjects was 7.9 μM (interquartile range 5.2–12.4μM)”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > Abstract > Methods and Results
plainn = 521- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Elevated TMAO levels are associated with higher 5-year mortality risk among subjects with either normal or elevated cystatin C levels (Figure 2).”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > RESULTS > Increased TMAO levels in non-CKD patients with elevated Cystatin C
plaincorrelationaln = 3,166 ·- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Using median cohort cut-offs with low cystatin C (<0.9 mg/dL) and low TMAO (<3.4μM) as reference, those with concomitant high cystatin C and high TMAO had a 3.7-fold increase in mortality risk (HR 3.67, 95%CI 2.57–5.23, p<0.001).”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > RESULTS > Increased TMAO levels in non-CKD patients with elevated Cystatin C
plaincorrelationaln = 3,166 ·- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 7
- Probably not a substantial claim. 10
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Overall in the CKD cohort, TMAO modestly correlated with eGFR (r= −0.48, p<0.001) and cystatin C (r=0.46, p<0.001), but did not correlate with hsCRP (r=0.04, p=0.332).”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > RESULTS > Elevated TMAO in patients with renal insufficiency portend poorer survival
plaincorrelationaln = 521- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Overall in the CKD cohort, TMAO modestly correlated with eGFR (r= −0.48, p<0.001) and cystatin C (r=0.46, p<0.001), but did not correlate with hsCRP (r=0.04, p=0.332).”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > RESULTS > Elevated TMAO in patients with renal insufficiency portend poorer survival
plainn = 521- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“in multiple clinical studies, TMAO levels have been shown to be associated with cardiovascular risks8–10, 13.”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > INTRODUCTION
What the sources say
- Not checked yetcites [8] Koeth RA Wang Z Levison BS Buffa JA Org E Sheehy BT Britt EB Fu X Wu Y Li L Smith JD DiDonato JA Chen J Li H Wu GD Lewis JD Warrier M Brown JM Krauss RM Tang WH Bushman FD Lusis AJ Hazen SL Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis Nat Med 2013 19 576 585 23563705 PMC3650111 source
- Not checked yetcites [9] Tang WH Wang Z Levison BS Koeth RA Britt EB Fu X Wu Y Hazen SL Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk N Engl J Med 2013 368 1575 1584 23614584 PMC3701945 source
- Not checked yetcites [10] Wang Z Klipfell E Bennett BJ Koeth R Levison BS Dugar B Feldstein AE Britt EB Fu X Chung YM Wu Y Schauer P Smith JD Allayee H Tang WH DiDonato JA Lusis AJ Hazen SL Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease Nature 2011 472 57 63 21475195 PMC3086762 source
- Not checked yetcites [13] Tang WH Wang Z Fan Y Levison BS Hazen JE Donahue L Wu Y Hazen SL Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-n-oxide in patients with heart failure: Refining the gut hypothesis J Am Coll Cardiol 2014 2014 1908 1914 25444145 PMC4254529 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These studies thus suggest both a causal relationship and clinical relevance of dietary choline-induced, gut microbiota-mediated, TMAO formation in CKD development and progression.”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > DISCUSSION
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“phosphorylation of Smad3, an important regulator of the pro-fibrotic TGF-β/Smad3 signaling pathway during fibrotic kidney disease23”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > RESULTS > Dietary choline and dietary TMAO both promote renal fibrosis and dysfunction in animal models
What the sources say
- Not checked yetcites [23] Qu X Li X Zheng Y Ren Y Puelles VG Caruana G Nikolic-Paterson DJ Li J Regulation of renal fibrosis by smad3 thr388 phosphorylation Am J Pathol 2014 184 944 952 24485922 source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The gut microbiota-dependent product, TMAO, is associated with both higher risk of progressive renal fibrosis and functional impairment, and poorer long-term survival.”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > Conclusion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“a recent untargeted metabolomic study from the Framingham Heart Study among subjects with normal renal function identified elevated choline and TMAO levels at baseline were each associated with an increased future risk of developing CKD 33.”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > DISCUSSION
What the sources say
- Not checked yetcites [33] Rhee EP Clish CB Ghorbani A Larson MG Elmariah S McCabe E Yang Q Cheng S Pierce K Deik A Souza AL Farrell L Domos C Yeh RW Palacios I Rosenfield K Vasan RS Florez JC Wang TJ Fox CS Gerszten RE A combined epidemiologic and metabolomic approach improves ckd prediction J Am Soc Nephrol 2013 24 1330 1338 23687356 PMC3736702 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Net reclassification and area under Receiver Operator Characteristic curve were calculated according to mortality risk estimated using Cox models adjusted for above mentioned traditional risk factors with versus without TMAO as previously described22.”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > METHODS > Statistical analyses
What the sources say
- Not checked yetcites [22] Pencina MJ D'Agostino RB Sr D'Agostino RB Jr Vasan RS Evaluating the added predictive ability of a new marker: From area under the roc curve to reclassification and beyond Stat Med 2008 27 157 172 17569110 source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
In the paper
“even in the C57BL/6J mouse model that is known to be relatively resistant to renal injury31.”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > DISCUSSION
What the sources say
- Not checked yetcites [31] Walkin L Herrick SE Summers A Brenchley PE Hoff CM Korstanje R Margetts PJ The role of mouse strain differences in the susceptibility to fibrosis: A systematic review Fibrogenesis Tissue Repair 2013 6 18 24294831 PMC3849643 source
boosted- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Adjustments were made for individual traditional risk factors including age, sex, systolic blood pressure, low-density lipoprotein cholesterol (LDLc), high-density lipoprotein cholesterol (HDLc), smoking, diabetes mellitus, as well as log-transformed hsCRP to predict all-cause mortality risks. Additional adjustment for log-transformed eGFR was also performed.”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > METHODS > Statistical analyses
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Ascertainment of all-cause mortality at 5-years was performed by prospective telephone contact and chart review plus interrogation of the Social Security Death Index (up to 2011).”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > METHODS > Human studies
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“However, it is important to note that choline is an essential nutrient; therefore, its total elimination from the diet is ill advised, and could result in development of a deficiency state35.”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > DISCUSSION
What the sources say
- Not checked yetcites [35] Zeisel SH Choline: Clinical nutrigenetic/nutrigenomic approaches for identification of functions and dietary requirements J Nutrigenet Nutrigenomics 2010 3 209 219 21474952 PMC3085526 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Plasma TMAO levels are both elevated in patients with CKD and portend poorer long-term survival.”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > Abstract > Conclusion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Estimated glomerular filtration rate (eGFR) was calculated according to the CKD-EPI creatinine and cystatin C formula20, with CKD defined as eGFR <60 ml/min/1.73m2 (CKD stage 3 or beyond).”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > METHODS > Human studies
What the sources say
- Not checked yetcites [20] Inker LA Schmid CH Tighiouart H Eckfeldt JH Feldman HI Greene T Kusek JW Manzi J Van Lente F Zhang YL Coresh J Levey AS Estimating glomerular filtration rate from serum creatinine and cystatin c N Engl J Med 2012 367 20 29 22762315 PMC4398023 source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Trimethylamine-N-oxide (TMAO) levels were determined by stable isotope dilution high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry (LC/MS/MS) on an AB SCIEX 5500 triple quadrupole mass spectrometer (AB SCIEX, Framingham MA) using d9-(trimethyl)-labeled internal standards as previously described10, 21.”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > METHODS > Plasma analysis
What the sources say
- Not checked yetcites [10] Wang Z Klipfell E Bennett BJ Koeth R Levison BS Dugar B Feldstein AE Britt EB Fu X Chung YM Wu Y Schauer P Smith JD Allayee H Tang WH DiDonato JA Lusis AJ Hazen SL Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease Nature 2011 472 57 63 21475195 PMC3086762 source
- Not checked yetcites [21] Wang Z Levison BS Hazen JE Donahue L Li XM Hazen SL Measurement of trimethylamine-n-oxide by stable isotope dilution liquid chromatography tandem mass spectrometry Anal Biochem 2014 455 35 40 24704102 PMC4167037 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
No prior studies had directly examined long-term mortality risk from TMAO in CKD subjects.
“However, no studies to date have directly looked at the long-term mortality risk of TMAO among CKD subjects.”
The paper relies on this without support.
No prior study had reported a direct role for TMAO in renal functional impairment.
“A direct role for TMAO in impacting renal functional impairment has not been reported.”
The paper relies on this without support.
The mechanism linking CKD to atherosclerotic heart disease is not fully understood.
“Yet the mechanism(s) through which CKD is linked to enhanced atherosclerotic heart disease is not fully elucidated.”
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The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Numerous recent case–control and longitudinal studies have shown a striking association between trimethylamine N‐oxide (TMAO) levels and cardiovascular disease risks in a variety of cohorts.1, 2, 3, 4, 5, 6, 7, 8, 9, 10”
From Trimethylamine N‐Oxide Promotes Vascular Inflammation Through Signaling of Mitogen‐Activated Protein Kinase and Nuclear Factor‐κB (2016) · cites this paper as [9]
Experimental — accuracy not yet measuredIn the citing paper
“Of note, the peak plasma TMAO levels with this protocol were similar to levels observed in mice chronically exposed to the choline‐supplemented diet (Figure 1C) and in some human clinical studies.9, 10, 17”
From Trimethylamine N‐Oxide Promotes Vascular Inflammation Through Signaling of Mitogen‐Activated Protein Kinase and Nuclear Factor‐κB (2016) · cites this paper as [9]
In the citing paper
“Trimethylamine N-oxide (TMAO) is a biologically active molecule and is a putative promoter of chronic diseases including atherosclerosis in humans.”
From Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [109]
In the citing paper
“Plasma TMAO concentrations were strongly associated with long-term mortality in heart failure patients, with advanced left-ventricular diastolic dysfunction, and with atherosclerosis burden in patients with atherosclerotic coronary artery disease (100, 101, 109, 111, 120).”
From Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [109]
In the citing paper
“Elevated plasma TMAO concentrations were predictive of five-year mortality risk after adjusting for traditional risk factors, such as high-sensitivity C-reactive protein, glomerular filtration rate, etc.”
From Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [109]
In the citing paper
“In a study of stable patients with kidney disease (n = 521), there was an association between fasting plasma TMAO concentrations and all-cause mortality (109).”
From Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [109]
In the citing paper
“Patients with poor kidney function have elevated plasma TMAO concentrations (93,109).”
From Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [109]
In the citing paper
“Many of the studies that identified an association between TMAO and heart disease also found that people with higher TMAO had decreased renal function (61,109).”
From Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [109]
In the citing paper
“When C57BL/6J mice were fed either a high-choline diet or a diet supplemented with TMAO for six weeks, plasma concentrations of TMAO increased and were associated with corresponding increases in tubulointerstitial fibrosis and collagen deposition, as well as increases in kidney injury marker-1.”
From Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [109]
In the citing paper
“The data from the mouse study discussed in Section 5.2.2 (109) are the most compelling evidence that TMAO (and choline a precursor of TMAO) causes renal disease.”
From Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [109]
In the citing paper
“Even among patients who did not have severe kidney disease, elevated plasma TMAO concentrations indicated poor prognosis (109).”
From Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [109]
In the citing paper
“When mice were fed these diets for 16 weeks, serum cystatin C concentrations rose (a marker of kidney injury) (109).”
From Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [109]
In the citing paper
“multiple human and animal studies supporting both mechanistic and clinical prognostic associations between TMAO formation and cardiometabolic disease risks have been reported8–16.”
From Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential (2018) · cites this paper as [12]
In the citing paper
“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).”
From Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine- N -Oxide (2015) · cites this paper as [17]
In the citing paper
“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).”
From Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine- N -Oxide (2015) · cites this paper as [17]
In the citing paper
“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).”
From Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine- N -Oxide (2015) · cites this paper as [17]
In the citing paper
“Second, renal functional decline leads to less efficient excretion and thus heightened levels of TMA(O)95.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [95]
In the citing paper
“TMAO is formed from trimethylamine (TMA), which is generated by the action of gut microbiota from dietary choline and phosphatidylcholine (lecithin) [8,9].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [9]
In the citing paper
“TMAO is then either transported to the tissues for accumulation as an osmolyte or, more commonly, cleared by the kidney [3,9,13,14].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [9]
In the citing paper
“Trimethylamine N-oxide (TMAO) is a small colorless amine oxide generated from choline, betaine, and carnitine by gut microbial metabolism.”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [9]
In the citing paper
“TMAO levels increase with decreasing levels of kidney function and is associated with mortality in patients with chronic kidney disease.”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [9]
In the citing paper
“A prospective cohort study of 521 stable subjects with CKD found elevated plasma TMAO levels which were associated with a 2.8-fold increased mortality risk [9].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [9]
In the citing paper
“Tang et al. showed that C57BL/6J mice fed with choline or TMAO exhibited tubulointerstitital fibrosis, collagen deposition and phosphorylation of Smad3; an important regulator of the profibrotic transforming growth factor-β/Smad3 signaling pathway [9].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [9]
In the citing paper
“The blood TMAO level has been reported to be positively correlated with long‐term mortality risk in patients with atherosclerosis, heart failure, and chronic kidney disease.5, 6, 7”
From Dysbiosis of gut microbiota with reduced trimethylamine-N-oxide level in patients with large-artery atherosclerotic stroke or transient ischemic attack (2015) · cites this paper as [7]
In the citing paper
“The strong relationship between kidney function and TMAO has been recognized in multiple early studies on rat models showing primarily renal excretion greater than 95% after radiolabel ingestion192.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [192]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > METHODS > Animal study
“A separate study included C57BL6J mice with ApoE−/− background were fed with the same diet groups for comparing their cystatin C levels at 14 weeks of follow-up using a commercially available mouse enzyme-linked immunosorbent assay (R&D systems, Minneapolis MN).”
§ Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease > RESULTS > Dietary choline and dietary TMAO both promote renal fibrosis and dysfunction in animal models
“Extending the TMAO/choline feeding to 16 weeks was associated with increased serum cystatin C levels compared to chow-fed mice (Figure 4C).”
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Metadata
- Authors
- Tang, W. H. W., Wang, Z., Kennedy, D. J., Wu, Y., Buffa, J. A., Agatisa-Boyle, B., Li, X. S., Levison, B. S., & Hazen, S. L.
- Affiliations
- Cleveland State University (US)
- ORCID
- Venue
- Circulation Research
- Published
- 2015-01-30
- Volume
- 116
- Issue
- 3
- Pages
- 448-455
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC4312512
- OpenAlex
- W2150350691
- Cited by
- 1,223
- References
- 43
- Citations by year
- 2026: 92 · 2025: 140 · 2024: 101 · 2023: 128 · 2022: 135 · 2021: 130 · 2020: 125 · 2019: 84 · 2018: 94 · 2017: 80 · 2016: 80 · 2015: 32
- FWCI
- 26.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- EngagedScholarship @ Cleveland State University (Cleveland State University) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR000439)
- National Heart, Lung, and Blood Institute (R01HL103931, P20HL113452, P01HL076491, P01HL098055, R01HL103866)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK106000)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Nephrology › Dialysis and Renal Disease Management
- Keywords
- trimethylamine N-oxide, chronic kidney disease, renal failure, gut microbiota, dietary choline, phosphatidylcholine, L-carnitine, all-cause mortality, prognostic factors, renal fibrosis, cystatin C, cardiovascular risk
- MeSH terms
- Aged, Aged, 80 and over, Animals, Female, Humans, Intestines, Male, Methylamines, Mice, Inbred C57BL, Middle Aged, Prognosis, Risk Factors, Biomarkers, Case-Control Studies, Mice, Renal Insufficiency, Chronic, Renal Insufficiency, Microbiota
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-05, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
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Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
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