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Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine- N -Oxide
Open accessAbstract
Choline is a water-soluble nutrient essential for human life. Gut microbial metabolism of choline results in the production of trimethylamine (TMA), which upon absorption by the host is converted in the liver to trimethylamine- N -oxide (TMAO). Recent studies revealed that TMAO exacerbates atherosclerosis in mice and positively correlates with the severity of this disease in humans. However, which microbes contribute to TMA production in the human gut, the extent to which host factors (e.g., genotype) and diet affect TMA production and colonization of these microbes, and the effects TMA-producing microbes have on the bioavailability of dietary choline remain largely unknown. We screened a collection of 79 sequenced human intestinal isolates encompassing the major phyla found in the human gut and identified nine strains capable of producing TMA from choline in vitro . Gnotobiotic mouse studies showed that TMAO accumulates in the serum of animals colonized with TMA-producing species, but not in the serum of animals colonized with intestinal isolates that do not generate TMA from choline in vitro . Remarkably, low levels of colonization by TMA-producing bacteria significantly reduced choline levels available to the host. This effect was more pronounced as the abundance of TMA-producing bacteria increased. Our findings provide a framework for designing strategies aimed at changing the representation or activity of TMA-producing bacteria in the human gut and suggest that the TMA-producing status of the gut microbiota should be considered when making recommendations about choline intake requirements for humans. IMPORTANCE Cardiovascular disease (CVD) is the leading cause of death and disability worldwide, and increased trimethylamine N -oxide (TMAO) levels have been causally linked with CVD development. This work identifies members of the human gut microbiota responsible for both the accumulation of trimethylamine (TMA), the precursor of the proatherogenic compound TMAO, and subsequent decreased choline bioavailability to the host. Understanding how to manipulate the representation and function of choline-consuming, TMA-producing species in the intestinal microbiota could potentially lead to novel means for preventing or treating atherosclerosis and choline deficiency-associated diseases.
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Written from the paper’s full text.
TL;DR
Gut microbial conversion of dietary choline to trimethylamine (TMA) drives serum trimethylamine-N-oxide (TMAO) accumulation in gnotobiotic mice, and TMA-producing bacteria reduce host-available choline. Host gender, genotype, and community composition also modulate TMAO levels via hepatic flavin monooxygenase (FMO) activity.
Key findings
- Screening 79 sequenced human intestinal isolates across six phyla identified TMA-producing strains from choline; the Results list eight species, including *Anaerococcus hydrogenalis*, *Clostridium asparagiforme*, *Clostridium hathewayi*, *Clostridium sporogenes*, *Escherichia fergusonii*, *Proteus penneri*, *Providencia rettgeri*, and *Edwardsiella tarda*. These consumed more than 60% of provided choline, and none generated TMA from l-carnitine under the same conditions.
- In gnotobiotic mice, a five-species “core” community that did not produce TMA in vitro yielded no detectable cecal TMA or serum TMAO. Adding *C. sporogenes*, representing only 0.15% ± 0.01% of the cecal community, reduced fecal choline, increased cecal TMA, and produced serum TMAO.
- A “core plus all” community had >100-fold higher relative abundance of TMA-producing bacteria than “core plus *C. sporogenes*,” but cecal TMA, fecal choline, and serum TMAO were not significantly different between the two groups. Serum choline decreased significantly as TMA-producer abundance increased.
- Female mice accumulated significantly more serum TMAO than males despite similar cecal TMA, with higher hepatic FMO activity in females. NMRI females showed 2-fold higher serum TMAO than C57BL/6J females. Mice on a choline-deficient diet had no detectable serum TMAO, while total TMA-producing bacteria did not differ significantly (24.7% ± 2.2% vs. 24.1% ± 1.8%).
Methods
- In vitro screen: 79 human intestinal isolates representing Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria, Verrucomicrobia, and Lentisphaerae were grown anaerobically with 15 mM choline; supernatants were analyzed by uHPLC-MS/MS for choline, TMA, and TMAO.
- Gnotobiotic mouse experiments: germ-free C57BL/6J and NMRI mice were colonized with defined communities (“core,” “core plus *C. sporogenes*,” or “core plus all”) and fed a 1% (wt/wt) choline diet or choline-deficient diet; serum, feces, cecal contents, and liver were collected for metabolite, microbial community (COPRO-Seq), and FMO activity analyses.
- Main analysis: metabolite quantification by uHPLC-MS/MS, community profiling by COPRO-Seq, hepatic FMO activity assays, and unpaired two-tailed Student’s t tests.
Limitations
- Stated: further experimentation is required to determine whether the observed reduction in choline bioavailability recapitulates the biochemical and pathological manifestations of choline deficiency; the gnotobiotic mouse model is a simplified representation of the human gut ecosystem.
- Stated: future studies are needed to understand how to manipulate TMA-producing bacteria or identify species that modulate host TMA-to-TMAO conversion.
- Evident from the text: experiments used low-complexity defined communities and small group sizes (often 3–6 animals per group); *A. hydrogenalis* was not detected in cecal samples of “core plus all” mice; and in vitro TMA production may not fully predict in vivo activity.
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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
“We identified eight species representing two different phyla (Firmicutes and Proteobacteria) and six genera that showed significant choline consumption and TMA accumulation: Anaerococcus hydrogenalis, Clostridium asparagiforme, Clostridium hathewayi, Clostridium sporogenes, Escherichia fergusonii, Proteus penneri, Providencia rettgeri, and Edwardsiella tarda (Table S1 and Table 1).”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > RESULTS AND DISCUSSION > In vitro screening reveals human gut isolates able to generate TMA from choline.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“These organisms consumed more than 60% of the choline provided in the growth media, unlike strains that did not make TMA (Table S1).”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > RESULTS AND DISCUSSION > In vitro screening reveals human gut isolates able to generate TMA from choline.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
“These strains generated TMA only if the medium was supplemented with choline.”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > RESULTS AND DISCUSSION > In vitro screening reveals human gut isolates able to generate TMA from choline.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“We confirmed that TMA was derived from choline by inoculating cultures of TMA-producing strains with labeled choline [choline chloride-(trimethyl-d9)], which resulted in the appearance of labeled TMA (trimethyl-d9) (see Fig. S1 in the supplemental material).”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > RESULTS AND DISCUSSION > In vitro screening reveals human gut isolates able to generate TMA from choline.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“We screened a collection of 79 sequenced human intestinal isolates encompassing the major phyla found in the human gut and identified nine strains capable of producing TMA from choline in vitro.”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“None of the identified TMA-producing strains generated TMA from l-carnitine, another quaternary amine linked to TMAO accumulation, under the same test conditions (Table 1) (10).”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > RESULTS AND DISCUSSION > In vitro screening reveals human gut isolates able to generate TMA from choline.
What the sources say
- Not checked yetcites [10] Koeth RA, Wang Z, Levison BS, Buffa JA, 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 WHW, Bushman FD, Lusis AJ, Hazen SL 2013 Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 19: 576– 585. doi: 10.1038/nm.3145. 23563705 PMC3650111 source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“Addition of the TMA-producing species C. sporogenes, which represented only 0.15% ± 0.01% (average ± standard error of the mean [SEM]) of the cecal community, resulted in the significant reduction of fecal choline, accumulation of TMA in the cecum, and appearance of TMAO in serum (Fig. 1B to D).”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > RESULTS AND DISCUSSION > Colonization with TMA-producing bacteria modulates TMAO accumulation in gnotobiotic mice.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“colonization with TMA-producing bacteria results in a dramatic decrease in the abundance of choline in feces relative to mice colonized with only the “core” community (Fig. 1D).”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > RESULTS AND DISCUSSION > Colonization with TMA-producing bacteria decreases levels of choline available to the host.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“Similar trends were also seen in experiments performed in female mice (Fig. S4).”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > RESULTS AND DISCUSSION > Colonization with TMA-producing bacteria decreases levels of choline available to the host.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“Genome analysis for members of the “core plus all” community, using the curated database for metabolic pathways MetaCyc, disclosed that Clostridium hathewayi carries genes that encode proteins (3-α-hydroxysteroid dehydrogenase/carbonyl reductase and 3-oxo-cholyl-coenzyme A [CoA] oxidoreductase) predicted to be involved in the metabolism of cholic acid that were not detected in members of the “core”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > RESULTS AND DISCUSSION > Host genotype and community composition modulate FMO activity and TMAO accumulation in female mice.
What the sources say
- Not checked yetcites [28] Caspi R, Altman T, Billington R, Dreher K, Foerster H, Fulcher CA, Holland TA, Keseler IM, Kothari A, Kubo A, Krummenacker M, Latendresse M, Mueller LA, Ong Q, Paley S, Subhraveti P, Weaver DS, Weerasinghe D, Zhang P, Karp PD 2014 The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of pathway/genome databases. Nucleic Acids Res 42: D459– D471. doi: 10.1093/nar/gkt1103. 24225315 PMC3964957 source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 11
- Probably not a substantial claim. 12
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
“Different strains of the Edwardsiella tarda species varied in their ability to consume choline and generate TMA. While E. tarda ATCC 23685 strain generated TMA from choline, ATCC 15947 strain did not”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > RESULTS AND DISCUSSION > In vitro screening reveals human gut isolates able to generate TMA from choline.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“Measurements of serum TMAO levels as a function of microbiota composition revealed that both strains of female mice colonized with the “core plus all” community accumulated lower serum levels of TMAO and exhibited lower hepatic FMO activity than their counterparts colonized with the “core plus C. sporogenes” community (Fig. 3A and B).”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > RESULTS AND DISCUSSION > Host genotype and community composition modulate FMO activity and TMAO accumulation in female mice.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“however, P. rustiganii showed TMA accumulation after 72 h of incubation, whereas P. alcalifaciens did not generate TMA under any of the tested conditions (Table S1).”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > RESULTS AND DISCUSSION > In vitro screening reveals human gut isolates able to generate TMA from choline.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“We also identified two species—Providencia alcalifaciens and Providencia rustiganii—predicted to encode key components of the choline utilization TMA-producing pathway that did not generate TMA in our original screen”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > RESULTS AND DISCUSSION > In vitro screening reveals human gut isolates able to generate TMA from choline.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“In contrast, E. tarda strain 23685 produces TMA from choline but does not appear to contain these genes in the published draft genome”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > RESULTS AND DISCUSSION > In vitro screening reveals human gut isolates able to generate TMA from choline.
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“uHPLC-MS/MS analysis of samples collected at the time of sacrifice showed that mice with choline in their diet showed detectable levels of TMAO in their serum, whereas mice fed the choline-deficient diet did not (Fig. 4A).”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > RESULTS AND DISCUSSION > Dietary choline is necessary for TMA production but does not impact the abundance of TMA-producing bacteria in a low-complexity gut microbial consortium.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“Both C. hathewayi and P. rettgeri increased in their abundance in response to dietary choline together with C. asparagiforme (P = 0.10), whereas E. tarda (P = 0.06), and E. fergusonii (P = 0.09) showed decreased abundance, although these changes did not reach statistical significance in our experiments.”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > RESULTS AND DISCUSSION > Dietary choline is necessary for TMA production but does not impact the abundance of TMA-producing bacteria in a low-complexity gut microbial consortium.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“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).”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > INTRODUCTION
What the sources say
- Not checked yetcites [8] Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, DuGar B, Feldstein AE, Britt EB, Fu X, Chung Y-M, Wu Y, Schauer P, Smith JD, Allayee H, Tang WHW, DiDonato JA, Lusis AJ, Hazen SL 2011 Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472: 57– 63. doi: 10.1038/nature09922. 21475195 PMC3086762 source
- Not checked yetcites [10] Koeth RA, Wang Z, Levison BS, Buffa JA, 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 WHW, Bushman FD, Lusis AJ, Hazen SL 2013 Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 19: 576– 585. doi: 10.1038/nm.3145. 23563705 PMC3650111 source
- Not checked yetcites [17] Tang WHW, Wang Z, Kennedy DJ, Wu Y, Buffa JA, Agatisa-Boyle B, Li XS, Levison BS, Hazen SL 2015 Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ Res 116: 448– 455. doi: 10.1161/CIRCRESAHA.116.305360. 25599331 PMC4312512 source
- Not checked yetcites [18] Bae S, Ulrich CM, Neuhouser ML, Malysheva O, Bailey LB, Xiao L, Brown EC, Cushing-Haugen KL, Zheng Y, Cheng T-YD, Miller JW, Green R, Lane DS, Beresford SAA, Caudill MA 2014 Plasma choline metabolites and colorectal cancer risk in the women’s health initiative observational study. Cancer Res 74: 7442– 7452. doi: 10.1158/0008-5472.CAN-14-1835. 25336191 PMC4268282 source
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“TMAO exacerbates atherosclerosis in a genetic knockout mouse model, in part by promoting forward cholesterol transport and by inhibiting reverse cholesterol transport (8, 10, 19, 20).”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > INTRODUCTION
What the sources say
- Not checked yetcites [8] Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, DuGar B, Feldstein AE, Britt EB, Fu X, Chung Y-M, Wu Y, Schauer P, Smith JD, Allayee H, Tang WHW, DiDonato JA, Lusis AJ, Hazen SL 2011 Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472: 57– 63. doi: 10.1038/nature09922. 21475195 PMC3086762 source
- Not checked yetcites [10] Koeth RA, Wang Z, Levison BS, Buffa JA, 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 WHW, Bushman FD, Lusis AJ, Hazen SL 2013 Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 19: 576– 585. doi: 10.1038/nm.3145. 23563705 PMC3650111 source
- Not checked yetcites [19] Trøseid M, Ueland T, Hov JR, Svardal A, Gregersen I, Dahl CP, Aakhus S, Gude E, Bjørndal B, Halvorsen B, Karlsen TH, Aukrust P, Gullestad L, Berge RK, Yndestad A 1 12 2014 Microbiota-dependent metabolite trimethylamine-N-oxide is associated with disease severity and survival of patients with chronic heart failure. J Intern Med doi: 10.1111/joim.12328. 25382824 source
- Not checked yetcites [20] Wang Z, Tang WHW, Buffa JA, Fu X, Britt EB, Koeth RA, Levison BS, Fan Y, Wu Y, Hazen SL 2014 Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide. Eur Heart J 35: 904– 910. doi: 10.1093/eurheartj/ehu002. 24497336 PMC3977137 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“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).”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > INTRODUCTION
What the sources say
- Not checked yetcites [8] Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, DuGar B, Feldstein AE, Britt EB, Fu X, Chung Y-M, Wu Y, Schauer P, Smith JD, Allayee H, Tang WHW, DiDonato JA, Lusis AJ, Hazen SL 2011 Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472: 57– 63. doi: 10.1038/nature09922. 21475195 PMC3086762 source
- Not checked yetcites [10] Koeth RA, Wang Z, Levison BS, Buffa JA, 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 WHW, Bushman FD, Lusis AJ, Hazen SL 2013 Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 19: 576– 585. doi: 10.1038/nm.3145. 23563705 PMC3650111 source
- Not checked yetcites [17] Tang WHW, Wang Z, Kennedy DJ, Wu Y, Buffa JA, Agatisa-Boyle B, Li XS, Levison BS, Hazen SL 2015 Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ Res 116: 448– 455. doi: 10.1161/CIRCRESAHA.116.305360. 25599331 PMC4312512 source
- Not checked yetcites [18] Bae S, Ulrich CM, Neuhouser ML, Malysheva O, Bailey LB, Xiao L, Brown EC, Cushing-Haugen KL, Zheng Y, Cheng T-YD, Miller JW, Green R, Lane DS, Beresford SAA, Caudill MA 2014 Plasma choline metabolites and colorectal cancer risk in the women’s health initiative observational study. Cancer Res 74: 7442– 7452. doi: 10.1158/0008-5472.CAN-14-1835. 25336191 PMC4268282 source
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“This cluster includes cutC, which encodes a glycyl radical enzyme with choline trimethylamine-lyase activity; cutD, which encodes a glycyl radical-activating protein; and genes encoding proteins involved in the assembly of microcompartments which may sequester the acetaldehyde generated as a by-product during TMA production (22, 23).”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > INTRODUCTION
What the sources say
- Not checked yetcites [22] Craciun S, Balskus EP 2012 Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme. Proc Natl Acad Sci U S A 109: 21307– 21312. doi: 10.1073/pnas.1215689109. 23151509 PMC3535645 source
- Not checked yetcites [23] Thibodeaux CJ, van der Donk WA 2012 Converging on a mechanism for choline degradation. Proc Natl Acad Sci U S A 109: 21184– 21185. doi: 10.1073/pnas.1219534110. 23243142 PMC3535664 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“TMAO exacerbates atherosclerosis in a genetic knockout mouse model, in part by promoting forward cholesterol transport and by inhibiting reverse cholesterol transport (8, 10, 19, 20).”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > INTRODUCTION
What the sources say
- Not checked yetcites [8] Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, DuGar B, Feldstein AE, Britt EB, Fu X, Chung Y-M, Wu Y, Schauer P, Smith JD, Allayee H, Tang WHW, DiDonato JA, Lusis AJ, Hazen SL 2011 Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472: 57– 63. doi: 10.1038/nature09922. 21475195 PMC3086762 source
- Not checked yetcites [10] Koeth RA, Wang Z, Levison BS, Buffa JA, 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 WHW, Bushman FD, Lusis AJ, Hazen SL 2013 Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 19: 576– 585. doi: 10.1038/nm.3145. 23563705 PMC3650111 source
- Not checked yetcites [19] Trøseid M, Ueland T, Hov JR, Svardal A, Gregersen I, Dahl CP, Aakhus S, Gude E, Bjørndal B, Halvorsen B, Karlsen TH, Aukrust P, Gullestad L, Berge RK, Yndestad A 1 12 2014 Microbiota-dependent metabolite trimethylamine-N-oxide is associated with disease severity and survival of patients with chronic heart failure. J Intern Med doi: 10.1111/joim.12328. 25382824 source
- Not checked yetcites [20] Wang Z, Tang WHW, Buffa JA, Fu X, Britt EB, Koeth RA, Levison BS, Fan Y, Wu Y, Hazen SL 2014 Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide. Eur Heart J 35: 904– 910. doi: 10.1093/eurheartj/ehu002. 24497336 PMC3977137 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“Choline is a water-soluble nutrient essential for human life.”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > Abstract
What the sources say
- Not checked yetcites [11] Zeisel SH, da Costa K-A 2009 Choline: an essential nutrient for public health. Nutr Rev 67: 615– 623. doi: 10.1111/j.1753-4887.2009.00246.x. 19906248 PMC2782876 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“suggesting that the ability of microbes to convert choline to TMA is a strain-specific metabolic trait that may be acquired via lateral gene transfer.”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > RESULTS AND DISCUSSION > In vitro screening reveals human gut isolates able to generate TMA from choline.
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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
“Sterility of germ-free animals was assessed by incubating freshly collected fecal samples under aerobic and anaerobic conditions using standard microbiology methods.”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > MATERIALS AND METHODS > Gnotobiotic husbandry.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably 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
“Samples with less than 10,000 reads were not used for analysis.”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > RESULTS AND DISCUSSION > Host gender affects FMO activity and TMAO accumulation in gnotobiotic mice colonized with the same microbiota.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“Significant reduction in choline consumption leads to organ dysfunction and failure along with an increased risk of the development of heart disease, cancer, and liver disease (11, 26).”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > RESULTS AND DISCUSSION > Colonization with TMA-producing bacteria decreases levels of choline available to the host.
What the sources say
- Not checked yetcites [11] Zeisel SH, da Costa K-A 2009 Choline: an essential nutrient for public health. Nutr Rev 67: 615– 623. doi: 10.1111/j.1753-4887.2009.00246.x. 19906248 PMC2782876 source
- Not checked yetcites [26] Strilakou AA, Lazaris AC, Perelas AI, Mourouzis IS, Douzis IC, Karkalousos PL, Stylianaki AT, Pantos CI, Liapi CA 2013 Heart dysfunction induced by choline-deficiency in adult rats: the protective role of l-carnitine. Eur J Pharmacol 709: 20– 27. doi: 10.1016/j.ejphar.2013.03.025. 23562624 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“Host genotype and community composition modulate FMO activity and TMAO accumulation in female mice.”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > RESULTS AND DISCUSSION > Host genotype and community composition modulate FMO activity and TMAO accumulation in female mice.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“With the exception of A. hydrogenalis, all species introduced into the mice were detected in cecal samples at a sequencing depth of ≥10,000 reads/sample, which allows us to detect microbes that represent at least 0.1% of the community.”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > RESULTS AND DISCUSSION > Colonization with TMA-producing bacteria modulates TMAO accumulation in gnotobiotic mice.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“consistent with previous studies in conventionally raised mice which demonstrated that FMO3 is expressed at higher levels in females than in males (8, 27).”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > RESULTS AND DISCUSSION > Host gender affects FMO activity and TMAO accumulation in gnotobiotic mice colonized with the same microbiota.
What the sources say
- Not checked yetcites [8] Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, DuGar B, Feldstein AE, Britt EB, Fu X, Chung Y-M, Wu Y, Schauer P, Smith JD, Allayee H, Tang WHW, DiDonato JA, Lusis AJ, Hazen SL 2011 Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472: 57– 63. doi: 10.1038/nature09922. 21475195 PMC3086762 source
- Not checked yetcites [27] Bennett BJ, de Aguiar Vallim TQ, Wang Z, Shih DM, Meng Y, Gregory J, Allayee H, Lee R, Graham M, Crooke R, Edwards PA, Hazen SL, Lusis AJ 2013 Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab 17: 49– 60. doi: 10.1016/j.cmet.2012.12.011. 23312283 PMC3771112 source
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“Host gender affects FMO activity and TMAO accumulation in gnotobiotic mice colonized with the same microbiota.”
§ Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide > RESULTS AND DISCUSSION > Host gender affects FMO activity and TMAO accumulation in gnotobiotic mice colonized with the same microbiota.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper relies on this without support.
The diversity of gut microbes that contribute to TMA production in humans and the impact of these species on serum TMAO levels and choline bioavailability remain unknown.
“However, the diversity of gut microbes that contribute to TMA production in humans and the impact of these species on serum TMAO levels and choline bioavailability remain unknown.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Only Edwardsiella tarda does not express the TMA-producing genes discussed in Section 1 above but produces TMA nonetheless (96).”
From Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [96]
In the citing paper
“Colonization of gnotobiotic mice with choline-converting bacteria not only increases cecal TMA production but also lowers serum choline concentration (96).”
From Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [96]
In the citing paper
“We know that gut microbiota are required for these nutrients to be converted to TMA because gnotobiotic mice do not produce such TMA (1,96), and antibiotic treatment of standard mice decreases TMA formation (1).”
From Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [96]
In the citing paper
“the catalytic CutC protein and its activating partner, CutD, support choline TMA lyase enzyme activity32–34.”
From Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential (2018) · cites this paper as [33]
In the citing paper
“neither affected the growth rate of several known TMA-producing human commensals (P. mirabilis, E. fergusonii, and P. penneri)33,46 when cultured in nutrient-rich media under conditions showing complete inhibition in choline TMA lyase activity”
From Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential (2018) · cites this paper as [33]
In the citing paper
“Another recent study [10] demonstrated that colonization of the mouse gut with a specific consortium of CutC-encoding human isolates results in TMA synthesis and subsequent TMAO accumulation in the serum of animals”
From Uncovering the trimethylamine-producing bacteria of the human gut microbiota (2017) · cites this paper as [10]
In the citing paper
“where even minute concentrations of TMA producers (0.15% of the total community) were sufficient for substantial TMA production from choline.”
From Uncovering the trimethylamine-producing bacteria of the human gut microbiota (2017) · cites this paper as [10]
In the citing paper
“The presence of the microbial cutC/D genes in human microbiota are associated with the ability to generate TMA from choline120, and with subsequent TMAO accumulation121.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [120]
In the citing paper
“Studies in gnotobiotic mice have shown that TMAO accumulates in the serum of animals colonized with TMA-producing bacteria, but not in animals colonized with bacteria that do not generate TMA from choline in vitro [17].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [17]
In the citing paper
“Plasma level of TMAO is determined by a number of factors including diet, gut microbial flora and liver flavin monooxygenase activity.”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [17]
In the citing paper
“Recent studies using isolates of commensal bacteria in the human intestine have identified nine strains capable of producing TMA from choline in vitro: eight species representing two different phyla (Firmicutes and Proteobacteria) and six genera that showed significant choline consumption and TMA production including Anaerococcus hydrogenalis, Clostridium asparagiforme, C. hathewayi, C. sporogenes”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [17]
In the citing paper
“Circulating levels of TMAO are determined by a number of factors, including diet, gut microbial flora, liver FMO enzymes and kidney function [17].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [17]
In the citing paper
“Indeed, TMAO generated by gut microbiome exacerbates impaired glucose tolerance, inhibits hepatic insulin signaling, and promotes adipose tissue inflammation in mice that are maintained on a high-fat high-sugar diet [17].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [17]
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.
In vitro screening incubation time differs between Results and Methods
MinorThe Results state that the strains were incubated for 24 hours in the 96-well choline screen, while the Methods describe a 48-hour incubation for that screen.
“All strains were inoculated in a diluted gut medium (Table S2) supplemented with 15 mM choline and incubated for 24 h in a 96-well plate at 37°C (24).”
“Twenty-five microliters of frozen bacterial cultures were inoculated into 1 ml of Mega Medium supplemented with 15 mM choline chloride (Sigma-Aldrich) in a 96-well deep-well plate sealed with sterile foil, and incubated anaerobically for 48 h at 37°C.”
Citations
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Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk
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Metadata
- Authors
- Romano, K. A., Vivas, E. I., Amador-Noguez, D., & Rey, F. E.
- Affiliations
- University of Wisconsin–Madison (US)
- Department of Bacteriology, University of Wisconsin—Madison, Madison, Wisconsin, USA
- Corresponding author
- Rey, Federico E.
- ORCID
- Rey, Federico E.
- Venue
- mBio
- Publisher
- American Society for Microbiology
- Published
- 2015-05
- Volume
- 6
- Issue
- 2
- Pages
- e02481-e02481
- ISSN
- 2150-7511 (ISSN-L)
- 2161-2129
- PMC
- PMC4453578
- OpenAlex
- W2119343060
- Cited by
- 777
- References
- 31
- Citations by year
- 2026: 55 · 2025: 87 · 2024: 77 · 2023: 85 · 2022: 79 · 2021: 109 · 2020: 78 · 2019: 56 · 2018: 75 · 2017: 32 · 2016: 32 · 2015: 11
- FWCI
- 21.69
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- mBio (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (KL2TR000428, UL1TR000427)
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P2CHD047873)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Nutrition and Physiology
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
- Keywords
- trimethylamine, trimethylamine N-oxide, gut microbiota, atherosclerosis, cardiovascular disease, choline deficiency, gnotobiotic mice, dietary choline, host-microbe interactions
- MeSH terms
- Gastrointestinal Microbiome, Animals, Choline, Diet, Germ-Free Life, Humans, Methylamines, Molecular Sequence Data, Sequence Analysis, DNA, Mice, 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.
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