The DOI matches its Crossref record; 62 of the 62 references it cites were found in a registry or an index; 2 of the 42 sources its claims cite were checked for support.
Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential
Open accessAbstract
Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite that enhances both platelet responsiveness and in vivo thrombosis potential in animal models, and TMAO plasma levels predict incident atherothrombotic event risks in human clinical studies. TMAO is formed by gut microbe-dependent metabolism of trimethylamine (TMA) moiety-containing nutrients, which are abundant in a Western diet. Here, using a mechanism-based inhibitor approach targeting a major microbial TMA-generating enzyme pair, CutC and CutD (CutC/D), we developed inhibitors that are potent, time-dependent, and irreversible and that do not affect commensal viability. In animal models, a single oral dose of a CutC/D inhibitor significantly reduced plasma TMAO levels for up to 3 d and rescued diet-induced enhanced platelet responsiveness and thrombus formation, without observable toxicity or increased bleeding risk. The inhibitor selectively accumulated within intestinal microbes to millimolar levels, a concentration over 1-million-fold higher than needed for a therapeutic effect. These studies reveal that mechanism-based inhibition of gut microbial TMA and TMAO production reduces thrombosis potential, a critical adverse complication in heart disease. They also offer a generalizable approach for the selective nonlethal targeting of gut microbial enzymes linked to host disease limiting systemic exposure of the inhibitor in the host.
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62 Own result · 22 Not checked yet · 12 Own interpretation · 3 Own method · 2 No basis given · 1 Supported so far
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In the paper
“the catalytic CutC protein and its activating partner, CutD, support choline TMA lyase enzyme activity32–34.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Introduction
What the sources say
- Not checked yetcites [32] Craciun, S., Marks, J. A. & Balskus, E. P. Characterization of choline trimethylamine-lyase expands the chemistry of glycyl radical enzymes. ACS Chem. Biol. 9, 1408–1413 (2014). source
- Supportedcites [33] Romano, K. A., Vivas, E. I., Amador-Noguez, D. & Rey, F. E. Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide. MBio 6, e02481 (2015). source
The Introduction identifies cutC as encoding a glycyl radical enzyme with choline trimethylamine-lyase activity and cutD as encoding its activating protein. This supports the attributed roles of both proteins. (LLM, conf=0.94)
- Supportedcites [34] Martínez-del Campo, A. et al. Characterization and detection of a widely distributed gene cluster that predicts anaerobic choline utilization by human gut bacteria. MBio 6, e00042–15 (2015). source
The Results section identifies cutC as the choline TMA-lyase gene and cutD as its activase. It also reports that a strain with cutC but without cutD failed to convert choline to TMA, supporting the role of activated CutC in this activity (page not provided). (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Addition of FMC at increasing concentrations lowered maximal enzyme velocity (Vmax) with no apparent effect on substrate affinity (KM) (Supplementary Figure 5), indicating that FMC acts kinetically as a non-competitive inhibitor.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Design and development of potent, mechanism-based, non-lethal microbial CutC/D inhibitors
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In the paper
“The choline diet elicited no differences in multiple indices of platelet activation, including surface phosphatidylserine content (p=0.84) in ADP-stimulated washed platelets or levels of von Willebrand factor (p=0.14), alpha granule release (p=0.31), or prothrombotic microvesicle release (p=0.66) in platelet-rich plasma (PRP) in the absence of agonist”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > DMB, a microbial choline TMA lyase inhibitor, attenuates choline diet-enhanced platelet responsiveness and in vivo rate of thrombus formation
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“IMC displayed an in vitro potency (IC50) approximately 10,000 times greater than DMB against the recombinant P. mirabilis CutC/D lysate, recombinant D. alaskensis CutC/D lysate, and wild-type, whole-cell P. mirabilis in culture”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Design and development of potent, mechanism-based, non-lethal microbial CutC/D inhibitors
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“DMB was directly incubated with the PRP preparations, and no effects on the platelet aggregometry responses either alone, or in the presence of agonist (ADP), were observed”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > DMB, a microbial choline TMA lyase inhibitor, attenuates choline diet-enhanced platelet responsiveness and in vivo rate of thrombus formation
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Choline supplementation resulted in marked TMAO elevation and shortening of vessel occlusion time (p<0.0001) as previously reported15”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > DMB, a microbial choline TMA lyase inhibitor, attenuates choline diet-enhanced platelet responsiveness and in vivo rate of thrombus formation
What the sources say
- Not checked yetcites [15] Zhu, W. et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165, 111–124 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“both IMC and FMC demonstrated enhanced inhibitory potency following longer pre-incubation times with the enzyme prior to the addition of d9-choline substrate”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Design and development of potent, mechanism-based, non-lethal microbial CutC/D inhibitors
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“No signs of toxicity were observed in mice following chronic exposure to wholly effective doses of FMC (10 mg/kg) or IMC (100 mg/kg)”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > FMC and IMC suppress host TMA and TMAO levels for sustained periods of time with limited systemic exposure and without observed toxicity
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Modest but relatively equal amounts of FMC and FMB (Supplementary Figure 9) and IMC and IMB (Supplementary Figure 10) were observed in urine.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > FMC and IMC suppress host TMA and TMAO levels for sustained periods of time with limited systemic exposure and without observed toxicity
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“following single or chronic dosing with FMC or IMC, no changes were noted in plasma levels for homocysteine, dimethylglycine, or folate pathway-related metabolites (all p>0.05, data not shown).”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > FMC and IMC suppress host TMA and TMAO levels for sustained periods of time with limited systemic exposure and without observed toxicity
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“These same trends for TMA and TMAO were observed in the urine and feces following administration of either FMC or IMC”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > FMC and IMC suppress host TMA and TMAO levels for sustained periods of time with limited systemic exposure and without observed toxicity
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“both IMC and FMC were non-lethal, even at high concentrations (1 mM).”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Design and development of potent, mechanism-based, non-lethal microbial CutC/D inhibitors
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In studies with prolonged exposures to either IMC or FMC, no reduction in apparent microbial fitness (growth rate or density) were observed”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Design and development of potent, mechanism-based, non-lethal microbial CutC/D inhibitors
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“provision of IMC to the mice was shown to reverse choline diet-induced effects on not only multiple indices of platelet responsiveness using distinct agonists (e.g. ADP, collagen) in PRP, but also in ADP-stimulated isolated platelets”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Inhibition of gut microbial choline TMA lyase activity suppresses choline diet-enhanced platelet aggregation and in vivo rate of thrombus formation without increased bleeding time
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“other potential metabolites, including the halide-substituted versions of TMA, and the predicted intermediate trimethylhalide-imines (see Supplementary Figure 4), were not detected in plasma, urine or fecal samples.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > FMC and IMC suppress host TMA and TMAO levels for sustained periods of time with limited systemic exposure and without observed toxicity
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Plasma betaine levels were modestly increased, before returning to baseline, following gavage of either FMC (Figure 3b right) or IMC”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > FMC and IMC suppress host TMA and TMAO levels for sustained periods of time with limited systemic exposure and without observed toxicity
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“treating mice on a choline-supplemented diet with inhibitor via oral gavage once a day for 2 weeks, monitoring plasma TMAO at time of trough (24 hours post-gavage), resulting in virtually complete inhibition in circulating TMAO levels”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > FMC and IMC suppress host TMA and TMAO levels for sustained periods of time with limited systemic exposure and without observed toxicity
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“subsequent provision of either IMC or FMC as a single oral dose via gastric gavage resulted in marked inhibition of plasma TMAO levels (>95% inhibition, p<0.0001)”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > FMC and IMC suppress host TMA and TMAO levels for sustained periods of time with limited systemic exposure and without observed toxicity
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“we performed multiple mass spectrometry studies but were unable to find a covalent adduct between IMC or FMC with either CutC or CutD.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Design and development of potent, mechanism-based, non-lethal microbial CutC/D inhibitors
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“the inactivation of CutC/D by both IMC and FMC were irreversible, since dialysis failed to rescue enzyme activity.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Design and development of potent, mechanism-based, non-lethal microbial CutC/D inhibitors
plaindirect- Asserted: passes — The authors put it forward as true.
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In the 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”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Design and development of potent, mechanism-based, non-lethal microbial CutC/D inhibitors
What the sources say
- Not checked yetcites [33] Romano, K. A., Vivas, E. I., Amador-Noguez, D. & Rey, F. E. Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide. MBio 6, e02481 (2015). source
- Not checked yetcites [46] Sandhu, S. S. & Chase, T. Jr. Aerobic degradation of choline by Proteus mirabilis: enzymatic requirements and pathway. Can. J. Microbiol. 32, 743–750 (1986). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“we synthesized multiple alternative halomethylcholines, which as a group were remarkably effective in all lysate and whole-cell assays”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Design and development of potent, mechanism-based, non-lethal microbial CutC/D inhibitors
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“DMB-induced suppression of plasma TMAO levels and ADP-stimulated platelet aggregation responses in PRP recovered from choline-fed mice were completely reversed by direct injection of TMAO (p=0.32; Figure 1a).”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > DMB, a microbial choline TMA lyase inhibitor, attenuates choline diet-enhanced platelet responsiveness and in vivo rate of thrombus formation
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“intraperitoneal injection of TMAO completely reversed DMB-dependent inhibition in choline diet-enhanced rate of thrombus formation”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > DMB, a microbial choline TMA lyase inhibitor, attenuates choline diet-enhanced platelet responsiveness and in vivo rate of thrombus formation
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Since the proportions of several taxa reduced by inhibitor exposure were also associated with both TMAO levels and shortened time to arterial occlusion”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Importantly, no evidence of systemic toxicity was observed”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Discussion
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“our treatment did not adversely affect bleeding potential, a common side effect of traditional antiplatelet therapies.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Discussion
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Similar enhanced cutC expression was also seen with choline supplementation relative to chow.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Inhibition of gut microbial choline TMA lyase activity suppresses choline diet-enhanced platelet aggregation and in vivo rate of thrombus formation without increased bleeding time
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“both IMC and FMC treatment in choline-supplemented mice induced a significant increase in the proportions of Akkermansia”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Inhibition of microbial choline TMA lyase activity shifts intestinal microbial communities
What the sources say
- Not checked yetcites [51] Derrien, M., Belzer, C. & de Vos, W. M. Akkermansia muciniphila and its role in regulating host functions. Microb. Pathog. 106, 171–181 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“global cecal microbial cutC expression was significantly upregulated by the addition of either FMC or IMC in chow diet in the absence of added choline”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Inhibition of gut microbial choline TMA lyase activity suppresses choline diet-enhanced platelet aggregation and in vivo rate of thrombus formation without increased bleeding time
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“the impact of FMC treatment on choline diet-induced changes in cecal microbial composition showed analogous results”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Inhibition of microbial choline TMA lyase activity shifts intestinal microbial communities
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Addition of FMC or IMC to the choline-supplemented diet groups failed to further increase microbial expression of cutC”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Inhibition of gut microbial choline TMA lyase activity suppresses choline diet-enhanced platelet aggregation and in vivo rate of thrombus formation without increased bleeding time
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“We observed an almost complete reduction in TMA at the site of action in the large intestine”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Discussion
plaindirect- 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
“neither FMC nor IMC induced a significant change in bleeding potential, as monitored by multiple different measures including cumulative bleeding time (pANOVA=0.90) (Figure 4f), hemoglobin loss (pANOVA=0.14), and weight loss from bleeding (pANOVA=0.51)”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Inhibition of gut microbial choline TMA lyase activity suppresses choline diet-enhanced platelet aggregation and in vivo rate of thrombus formation without increased bleeding time
plain- 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
“with a parallel buildup of inhibitor within the microbe to concentrations a million-fold higher than necessary to achieve inhibition within the microbe.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > 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
“significant reductions in TMA/TMAO production can be detected rapidly at 1 hour post oral gavage of inhibitor concurrently with isotope-labeled choline precursor (Supplementary Figure 19).”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“Given the abundance of the choline moiety in both bile31 and common dietary staples (e.g. eggs, meat/fish, and some fruits/vegetables), microbial conversion of choline into TMA likely accounts for a significant portion of TMAO production in subjects, regardless of diet.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Introduction
What the sources say
- Not checked yetcites [31] Phillips, G. B. The lipid composition of human bile. Biochim. Biophys. Acta 41, 361–363 (1960). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“several recent meta-analyses confirm a strong clinical association between increased levels of TMAO and incident adverse cardiovascular event and mortality risks in multiple populations25–27.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Introduction
What the sources say
- Not checked yetcites [25] Heianza, Y., Ma, W., Manson, J. E., Rexrode, K. M. & Qi, L. Gut microbiota metabolites and risk of major adverse cardiovascular disease events and death: a systematic review and meta-analysis of prospective studies. J. Am. Heart Assoc. 6, e004947 (2017). source
- Not checked yetcites [26] Schiattarella, G. G. et al. Gut microbe–generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: a systematic review and dose–response meta-analysis. Eur. Heart J. 38, 2948–2956 (2017). source
- Not checked yetcites [27] Qi, J. et al. Circulating trimethylamine N-oxide and the risk of cardiovascular diseases: a systematic review and meta-analysis of 11 prospective cohort studies. J. Cell. Mol. Med. 22, 185–194 (2018). source
boostedcorrelational- 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.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“predicts incident atherothrombotic event risks in clinical studies”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Abstract
plaincorrelational- 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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None of the sources cited for this claim have been checked yet.
In the paper
“TMAO is generated via a meta-organismal pathway that begins with gut microbial conversion of dietary nutrients (e.g. phosphatidylcholine, choline, and carnitine) into trimethylamine (TMA), followed by host liver oxidation to TMAO by flavin monooxygenases (FMOs)29,30.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Introduction
What the sources say
- Not checked yetcites [29] Dolphin, C. T., Janmohamed, A., Smith, R. L., Shephard, E. A. & Phillips, I. R. Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome. Nat. Genet. 17, 491–494 (1997). source
- Not checked yetcites [30] Bennett, B. J. et al. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 17, 49–60 (2013). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“multiple human and animal studies supporting both mechanistic and clinical prognostic associations between TMAO formation and cardiometabolic disease risks have been reported8–16.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Introduction
What the sources say
- Not checked yetcites [8] Tang, W. H. W. et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl. J. Med. 368, 1575–1584 (2013). source
- Not checked yetcites [9] Koeth, R. A. et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19, 576–585 (2013). source
- Not checked yetcites [10] Wang, Z. et al. Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide. Eur. Heart J. 35, 904–910 (2014). source
- Not checked yetcites [11] Tang, W. H. W. et al. 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. 64, 1908–1914 (2014). source
- Not checked yetcites [12] Tang, W. H. W. et al. 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 (2015). source
- Not checked yetcites [13] Tang, W. H. W. et al. Intestinal microbiota–dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure. J. Card. Fail. 21, 91–96 (2015). source
- Not checked yetcites [14] Organ, C. L. et al. Choline diet and its gut microbe–derived metabolite, trimethylamine N-oxide, exacerbate pressure overload–induced heart failure. Circ. Heart Fail. 9, e002314 (2016). source
- Not checked yetcites [15] Zhu, W. et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165, 111–124 (2016). source
- Not checked yetcites [16] Senthong, V. et al. Intestinal microbiota–generated metabolite trimethylamine-N-oxide and 5-year mortality risk in stable coronary artery disease: the contributory role of intestinal microbiota in a COURAGE-like patient cohort. J. Am. Heart Assoc. 5, e002816 (2016). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Trimethylamine-N-oxide (TMAO), a microbiota-dependent metabolite derived from trimethylamine (TMA)-containing nutrients that are abundant in a Western diet”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Abstract
What the sources say
- Not checked yetcites [7] Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Parallel clinical studies reveal TMAO levels are associated with thrombotic event risks (heart attack and stroke)15”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Introduction
What the sources say
- Not checked yetcites [15] Zhu, W. et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165, 111–124 (2016). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“enhanced platelet reactivity and acute thrombotic occlusion of vessels are the proximate cause of myocardial infarction, stroke and the majority of deaths in patients with CVD36.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Introduction
What the sources say
- Not checked yetcites [36] Furie, B. & Furie, B. C. Mechanisms of thrombus formation. N. Engl. J. Med. 359, 938–949 (2008). source
plaindirect- 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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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
“Microbes in the immediate environment that are not as potently inhibited directly might still thus have reduced TMA generation as they become starved of extracellular choline substrate.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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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 suggest a new potential target for the treatment of subjects at risk for thrombotic complications and cardiovascular disease.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The mouse models used in these studies predict human TMAO metabolism, thrombosis, and therapeutic response.
- Rests on an assumption: The absence of systemic toxicity and bleeding effects in mice predicts safety in humans.
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
“our system of inhibition appears to create a positive feedback loop whereby the microbes in which the halomethylcholines potently blocks choline catabolism are transformed into virtual “vacuum sweepers” for both choline and inhibitor accumulation.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
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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
“This effect of the inhibitors appears to be secondary”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Discussion
hedgedconditional- 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 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
“with chronic inhibitor use, it appears likely that some of the potential efficacy of this family of inhibitors in suppressing TMAO levels also occurs by shifting of microbial composition to one less prone to produce TMA.”
- Also stated in: § Discussion · hedged
“A shift in cecal microbial community induced by the inhibitor was noted that chronically may contribute to reduction in systemic TMA/TMAO levels in the host.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Discussion · hedged
In the paper
“there are no known mammalian enzymes that can cleave the C-N bond of choline54.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Discussion
What the sources say
- Not checked yetcites [54] Craciun, S. & Balskus, E. P. Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme. Proc. Natl Acad. Sci. USA 109, 21307–21312 (2012). source
plain- Asserted: passes — The authors put it forward as true.
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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
“Thus, eliminating selective pressures may prove elusive when targeting the microbiome”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether 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. 43
- Probably not a substantial claim. 9
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
“Screening of IMC and FMC in a battery of pharmacological safety tests failed to show: (i) inhibition in hERG channel function; (ii) toxicity to mitochondria in HepG2 cells cultured in glucose- or galactose-supplemented media; (iii) adverse effects on the viability of HK-2 cells in culture; or (iv) adverse signals during AMES testing at levels up to 1000 μg/well”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > FMC and IMC suppress host TMA and TMAO levels for sustained periods of time with limited systemic exposure and without observed toxicity
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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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
“Both FMC and IMC induced an almost complete reduction in plasma TMA and TMAO levels following a single oral dose (via gavage) for a sustained period, with FMC demonstrating a striking trough that persisted for over 3 days (Figure 3b right), and IMC for over 2 days post-gavage”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > FMC and IMC suppress host TMA and TMAO levels for sustained periods of time with limited systemic exposure and without observed toxicity
boosteddirect- Asserted: passes — The authors put it forward as true.
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- 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
“reversible inhibition of CutC/D activity following dialysis was observed with an alternative, potent inhibitor developed, phenylcholine (IC50=150 nM against P. mirabilis CutC/D)”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Design and development of potent, mechanism-based, non-lethal microbial CutC/D inhibitors
plaindirect- 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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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
“the fluorinated choline analogue, fluoromethylcholine (FMC), was the most potent halomethylcholine examined (IC50=900 pM against P. mirabilis CutC/D), and in docking calculations, was predicted to have the tightest interaction with the active site”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Design and development of potent, mechanism-based, non-lethal microbial CutC/D inhibitors
plaincorrelational- 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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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
“Increasing concentrations of IMC similarly decreased Vmax, but also increased KM (Supplementary Figure 5), indicating IMC acts kinetically as a mixed mechanism inhibitor, with elements of both competitive and non-competitive inhibition.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Design and development of potent, mechanism-based, non-lethal microbial CutC/D inhibitors
hedgeddirect- 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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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
“despite the high dose of DMB provided, choline diet-associated TMAO elevations, increased platelet aggregation, and shortened in vivo thrombus formation were not fully rescued compared to chow-fed mice”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > DMB, a microbial choline TMA lyase inhibitor, attenuates choline diet-enhanced platelet responsiveness and in vivo rate of thrombus formation
plain- Asserted: passes — The authors put it forward as true.
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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
“the halomethylbetaines were found to act as CutC/D TMA lyase inhibitors but approximately 2–3 orders of magnitude weaker than their choline counterparts”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Design and development of potent, mechanism-based, non-lethal microbial CutC/D inhibitors
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether 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
“FMC and IMC were directly incubated with PRP from both mice and humans (with or without agonist), and no effects on platelet aggregometry responses were observed. Their primary in vivo metabolites, FMB and IMB, also did not affect platelet aggregometry responses in human PRP”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Inhibition of gut microbial choline TMA lyase activity suppresses choline diet-enhanced platelet aggregation and in vivo rate of thrombus formation without increased bleeding time
plain- 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
“In alternative studies in both male and female mice with more prolonged exposures (15–20 weeks) to IMC, no adverse effects were observed, including normal indices of renal function, liver function, and CBC with differential”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > FMC and IMC suppress host TMA and TMAO levels for sustained periods of time with limited systemic exposure and without observed toxicity
plain- 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
“analyses of feces revealed the majority of FMC and IMC remain in the gut luminal compartment, with only nominal levels of FMB or IMB present in fecal samples”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > FMC and IMC suppress host TMA and TMAO levels for sustained periods of time with limited systemic exposure and without observed toxicity
plain- 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
“choline supplementation resulted in 10-fold higher plasma TMAO levels (p<0.0001) and enhanced aggregometry response to submaximal levels of ADP (1 μM) in PRP (p<0.0001; Figure 1a).”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > DMB, a microbial choline TMA lyase inhibitor, attenuates choline diet-enhanced platelet responsiveness and in vivo rate of thrombus formation
plaindirect- 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
“both FMC and IMC demonstrated remarkable capacity to suppress production of d9-TMA (EC50=0.008 and 0.5 mg/kg, respectively; Supplementary Figure 8) and d9-TMAO (EC50=0.01 mg/kg and 0.2 mg/kg, respectively; Table 1, Figure 3a right).”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > FMC and IMC suppress host TMA and TMAO levels for sustained periods of time with limited systemic exposure and without observed toxicity
boosteddirect- 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
“the TMAO enhancing effect on stimulus-dependent platelet aggregation was also observed with washed platelets from mice fed the high choline diet (p=0.0002), and was greatest at submaximal levels of agonist”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > DMB, a microbial choline TMA lyase inhibitor, attenuates choline diet-enhanced platelet responsiveness and in vivo rate of thrombus formation
plaindirect- 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
“Analyses of fecal samples revealed significant increases in choline levels following FMC or IMC administration, which before addition of the inhibitor were extremely low (Supplementary Figures 9,10). Importantly, no significant effects on plasma choline levels were observed”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > FMC and IMC suppress host TMA and TMAO levels for sustained periods of time with limited systemic exposure and without observed toxicity
plaindirect- 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.
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
“FMC was also more potent than IMC against our polymicrobial, human fecal cultures (EC50=7.9 nM and 1.6 μM, respectively; Table 1).”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Design and development of potent, mechanism-based, non-lethal microbial CutC/D inhibitors
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.
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
“DMB significantly reduced both TMAO levels (p<0.0001) and stimulus-dependent (ADP) platelet aggregation (p=0.003) in PRP recovered from choline-supplemented mice”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > DMB, a microbial choline TMA lyase inhibitor, attenuates choline diet-enhanced platelet responsiveness and in vivo rate of thrombus formation
plaindirect- 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
“provision of DMB attenuated the choline diet-induced rise in TMAO and rate of clot formation (p=0.002; Figure 1b,c).”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > DMB, a microbial choline TMA lyase inhibitor, attenuates choline diet-enhanced platelet responsiveness and in vivo rate of thrombus formation
plaindirect- 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.
In the paper
“within the large intestine (cecum and colon), the anatomic location where the majority of choline TMA lyase harboring commensals reside49, we observed the selective accumulation of each inhibitor to the millimolar level (2–6 mM), virtually complete elimination in detectable luminal TMA (product), and a similar marked increase in intestinal microbial choline (substrate) levels”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > IMC and FMC are preferentially sequestered within gut microbes
What the sources say
- Not checked yetcites [49] Koeth, R. A. et al. γ-Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of l-carnitine to TMAO. Cell Metab. 20, 799–812 (2014). source
plaindirect- 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
“Results confirmed complete suppression of choline diet-enhanced TMAO generation and accompanying enhancement in ADP-dependent platelet aggregation response with provision of either FMC (p=0.0001) or IMC (p=0.001; Figure 4a).”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Inhibition of gut microbial choline TMA lyase activity suppresses choline diet-enhanced platelet aggregation and in vivo rate of thrombus formation without increased bleeding time
boosteddirect- 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
“both FMC and IMC showed dose-dependent suppression in both TMA production (EC50=4.5 and 31 mg/kg, respectively; Supplementary Figure 8) and systemic TMAO levels, with FMC demonstrating potency an order of magnitude greater than IMC (EC50=3.4 and 45 mg/kg, respectively; Table 1, Figure 3a right).”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > FMC and IMC suppress host TMA and TMAO levels for sustained periods of time with limited systemic exposure and without observed toxicity
boosteddirect- 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
“FMC and IMC were detectable at low (μM) levels only for the first few hours in plasma, but their halomethylbetaine oxidation products, fluoromethylbetaine (FMB) and iodomethylbetaine (IMB), were ~10-fold more abundant, reaching their peak level 2 hours post-gavage”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > FMC and IMC suppress host TMA and TMAO levels for sustained periods of time with limited systemic exposure and without observed toxicity
plain- 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.
In the paper
“resveratrol was largely ineffective in each of the screening assays employed (Figure 1e) and showed no effect on plasma TMAO levels in vivo when administered to mice on a choline-supplemented diet (p=0.91; data not shown)”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Design and development of potent, mechanism-based, non-lethal microbial CutC/D inhibitors
What the sources say
- Not checked yetcites [43] Chen, M. L. et al. Resveratrol attenuates trimethylamine-N-oxide (TMAO)-induced atherosclerosis by regulating TMAO synthesis and bile acid metabolism via remodeling of the gut microbiota. MBio 7, e02210–e02215 (2016).
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether 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
“Levels of halomethylbetaines in all intestinal segments were significantly lower than their halomethylcholine counterparts, and there was no significant effect on gut luminal betaine or TMAO levels”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > IMC and FMC are preferentially sequestered within gut microbes
plain- Asserted: passes — The authors put it forward as true.
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- 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
“Provision of a high-choline diet was associated with both significant increases (e.g. Dehalobacterium and Adlercreutzia) and reductions (e.g. Bifidobacterium) in the proportions of several genera, which were each also significantly associated with both TMAO levels and time to vessel occlusion; moreover, these shifts in proportions were reversed with the addition of IMC”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Inhibition of microbial choline TMA lyase activity shifts intestinal microbial communities
plaincorrelational- 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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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
“Principal Coordinates Analysis of microbial taxa revealed distinct clusters, indicating both dietary choline supplementation and IMC exposure each induced significant (p=0.001) rearrangements in microbial composition”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Inhibition of microbial choline TMA lyase activity shifts intestinal microbial communities
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether 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
“neither FMC (p=0.85) nor IMC (p=0.73) led to a prolongation in occlusion time beyond that observed with normal chow.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Inhibition of gut microbial choline TMA lyase activity suppresses choline diet-enhanced platelet aggregation and in vivo rate of thrombus formation without increased bleeding time
plain- Asserted: passes — The authors put it forward as true.
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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
“provision of either FMC (p<0.0001) or IMC (p<0.0001) completely blocked choline-supplemented diet-induced increases in both plasma TMAO and in vivo rate of clot formation”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Inhibition of gut microbial choline TMA lyase activity suppresses choline diet-enhanced platelet aggregation and in vivo rate of thrombus formation without increased bleeding time
plaindirect- Asserted: passes — The authors put it forward as true.
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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
“reversing choline diet-induced increases in platelet responses to agonists and thrombus formation in vivo.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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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
“Provision of IMC reversed choline diet-dependent increases in both TMAO levels and platelet adherence to collagen matrix to levels observed in chow-fed mice”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Inhibition of gut microbial choline TMA lyase activity suppresses choline diet-enhanced platelet aggregation and in vivo rate of thrombus formation without increased bleeding time
plaindirect- Asserted: passes — The authors put it forward as true.
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- 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
“It is also notable that both IMC and FMC induced a shift in mouse cecal microbiota composition, particularly on a choline-supplemented diet, reversing choline-induced changes in the proportions of certain taxa.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Discussion
plaindirect- 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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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
“by inhibiting gut microbial production of TMA, we suppressed plasma TMAO levels for prolonged periods with limited systemic exposure of the drugs within the host”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“even if the inhibitors are non-lethal to cultured bacteria in nutrient-rich broths and fail to demonstrate reduction in microbial fitness with prolonged exposures.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Discussion
plain- 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
“enhances both platelet responsiveness and in vivo thrombosis potential in animal models”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Abstract
plaindirect- 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 link between dietary phosphatidylcholine, a nutrient common in a Western diet, gut microbiota-dependent generation of the metabolite trimethylamine N-oxide (TMAO), and cardiovascular disease (CVD) pathogenesis, was first described7.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Introduction
What the sources say
- Not checked yetcites [7] Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011). 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.
In the paper
“recent studies reveal TMAO alters calcium signaling in platelets, enhancing responsiveness and in vivo thrombosis potential in animal models15.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Introduction
What the sources say
- Not checked yetcites [15] Zhu, W. et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165, 111–124 (2016). source
plaindirect- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“Use of antiplatelet agents has become a cornerstone for the treatment of CVD because of substantial reduction in CVD events and mortality37,38. However, more widespread use of antiplatelet agents has been limited by the increased risk of bleeding, which also leads to nonadherence39–41.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Introduction
What the sources say
- Not checked yetcites [37] Bobadilla, R. V. Acute coronary syndrome: focus on antiplatelet therapy. Crit. Care Nurse 36, 15–27 (2016). source
- Not checked yetcites [38] Levine, G. N. et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J. Thorac. Cardiovasc. Surg. 152, 1243–1275 (2016). source
- Not checked yetcites [39] Jennings, L. K. Mechanisms of platelet activation: need for new strategies to protect against platelet-mediated atherothrombosis. Thromb. Haemost. 102, 248–257 (2009). source
- Not checked yetcites [40] Manchikanti, L. et al. Assessment of bleeding risk of interventional techniques: a best evidence synthesis of practice patterns and perioperative management of anticoagulant and antithrombotic therapy. Pain. Physician 16, SE261–SE318 (2013).
- Not checked yetcites [41] Cohen, M. Expanding the recognition and assessment of bleeding events associated with antiplatelet therapy in primary care. Mayo Clin. Proc. 84, 149–160 (2009). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- 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.
In the paper
“When given to atherosclerosis-prone ApoE−/− mice on a choline-supplemented diet, plasma TMAO levels were significantly lowered, and concurrently, macrophage cholesterol accumulation, foam cell formation and atherosclerotic lesion development were attenuated35.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Introduction
What the sources say
- Not checked yetcites [35] Wang, Z. et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163, 1585–1595 (2015). source
plaindirect- 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 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
“Herein we show that a mechanism-based non-lethal inhibitor of the gut microbial TMAO pathway designed to selectively accumulate within the gut microbial compartment, can serve as a new therapeutic approach for attenuating thrombosis while simultaneously limiting systemic exposure in the host.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Introduction
plaindirect- 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.
- Rests on an assumption: The mouse models used for platelet function and thrombosis predict human clinical effects of the inhibitors.
In the paper
“We recently reported the use of a natural product, 3,3-dimethyl-1-butanol (DMB), as a tool drug that inhibits microbial choline TMA lyase activity in vitro and in vivo35.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Introduction
What the sources say
- Not checked yetcites [35] Wang, Z. et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163, 1585–1595 (2015). source
plaindirect- 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 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
“both IMC and FMC display numerous characteristics consistent with a covalent mode of inhibition (time-dependent, irreversible, and non-competitive inhibition)”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > Design and development of potent, mechanism-based, non-lethal microbial CutC/D inhibitors
hedgedcorrelational- 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 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
“Kinetic analyses demonstrate that IMC and FMC are non-competitive, time-dependent and irreversible, hallmarks of mechanism-based inhibitors.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Discussion
boosteddirect- 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 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
“inhibition in microbial TMAO generation would not hypothetically suppress platelet function “below normal” and thus heighten bleeding risks.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Discussion
hedged- 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 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 present studies suggest development of poorly absorbed suicide substrate inhibitors of gut microbial catabolic pathways mechanistically linked with disease pathogenesis deserves further investigation as a potentially generalizable approach to achieve therapeutic outcomes in the host.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Discussion
hedgedconditional- 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.
Probably not a substantial claim. It may state two separate claims as one.
- Rests on an assumption: The mouse models used in these studies predict human TMAO metabolism, thrombosis, and therapeutic response.
- Rests on an assumption: The inhibitor-induced changes in mouse cecal microbiota composition represent effects on the human gut microbiome.
- Rests on an assumption: The absence of systemic toxicity and bleeding effects in mice predicts safety in humans.
In the paper
“fluorine substitution can confer properties beneficial to the chemistry of suicide substrate inhibitors and their potential use as pharmaceuticals56.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Discussion
What the sources say
- Not checked yetcites [56] Clarke, D. D. Fluoroacetate and fluorocitrate: mechanism of action. Neurochem. Res. 16, 1055–1058 (1991). source
plaindirect- 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.
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
“Investigators were not blinded to mouse group allocation during the performance of animal husbandry requirements for experiments.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Methods > Statistical analyses
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.
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
“Investigators performing quantitative analyses of endpoints (e.g., plasma, urine, or fecal metabolite levels) were blinded to group allocation with samples labeled by code only.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Methods > Statistical analyses
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.
None of the sources cited for this claim have been checked yet.
In the paper
“many drugs induce shifts in microbial community composition57,58.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Discussion
What the sources say
- Not checked yetcites [57] Imhann, F. et al. Proton pump inhibitors affect the gut microbiome. Gut 65, 740–748 (2016). source
- Not checked yetcites [58] Rogers, M. A. M. & Aronoff, D. M. The influence of non-steroidal anti-inflammatory drugs on the gut microbiome. Clin. Microbiol. Infect. 22, 178.e1–178.e9 (2016). source
plaindirect- 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.
In the paper
“In a recent examination of over 1,000 clinically used drugs and their impact on a broad selection of human gut commensals, nearly a quarter demonstrated antibiotic-like side effects59.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Discussion
What the sources say
- Not checked yetcites [59] Maier, L. et al. Extensive impact of nonantibiotic drugs on human gut bacteria. Nature 555, 623–628 (2018). 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.
In the paper
“And in a recent elegant study with metformin, a shift in microbial community structure was suggested to contribute in part to its observed beneficial metabolic effects60.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Discussion
What the sources say
- Not checked yetcites [60] Wu, H. et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat. Med. 23, 850–858 (2017). source
hedgedconditional- 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 results suggest that inhibition in microbial choline utilization will not only suppress TMA/TMAO generation, but also may help enhance choline bioavailability for the host.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Discussion
hedgedconditional- 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.
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
“Results from all animals in a given experiment were included in the analyses.”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Methods > Statistical analyses
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.
The mouse models used for platelet function and thrombosis predict human clinical effects of the inhibitors.
“Herein we show that a mechanism-based non-lethal inhibitor of the gut microbial TMAO pathway designed to selectively accumulate within the gut microbial compartment, can serve as a new therapeutic approach for attenuating thrombosis while simultaneously limiting systemic exposure in the host.”
The paper relies on this without support.
The CutC/D enzymes and microbial cultures used in screening represent the diversity of human gut microbial choline TMA lyases.
“We developed a tiered screening assay system to test for broad efficacy among phylogenetically diverse commensal bacteria that contain CutC/D and robust choline TMA lyase activity.”
The paper relies on this without support.
The absence of toxicity in mice over the studied exposure periods predicts safety in humans.
“No signs of toxicity were observed in mice following chronic exposure to wholly effective doses of FMC (10 mg/kg) or IMC (100 mg/kg)”
The paper relies on this without support.
The mouse models used in these studies predict human TMAO metabolism, thrombosis, and therapeutic response.
“These studies suggest a new potential target for the treatment of subjects at risk for thrombotic complications and cardiovascular disease.”
The paper relies on this without support.
The inhibitor-induced changes in mouse cecal microbiota composition represent effects on the human gut microbiome.
“It is also notable that both IMC and FMC induced a shift in mouse cecal microbiota composition”
The paper relies on this without support.
The absence of systemic toxicity and bleeding effects in mice predicts safety in humans.
“Importantly, no evidence of systemic toxicity was observed and our treatment did not adversely affect bleeding potential”
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?
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
“This then induces expression of the entire choline utilization gene cluster, including both cutC and the microbial choline transporter.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [85]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Thus, decreasing systemic levels of TMAO has become a rational potential therapeutic strategy for decreasing risks for the development and progression of atherosclerotic heart disease.8,[13][14][15]”
From Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women (2019) · cites this paper as [13]
The cited source says what the claim attributes to it.
In the citing paper
“It has also been shown to promote platelet reactivity and thrombosis potential14, 83–85, vascular inflammation and inflammasome activation86–88, heightened heart failure89–91 and CKD92–95 related phenotypes in animal models (Figure 2).”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [85]
In the citing paper
“Interestingly, owing to their highly polar nature, FMC and related halomethylcholines were shown to be poorly absorbed into the host, limiting systemic exposure and thus chances of side effects.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [85]
In the citing paper
“The choline TMA lyase suicide substrate inhibitor fluoromethylcholine (FMC) was shown to be over 10,000 fold more potent an inhibitor of cutC than DMB, and markedly blocks microbial choline catabolism85.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [85]
In the citing paper
“In addition, cutC inhibition by FMC and iodomethylcholine (IMC) was shown to result in microbial cytosolic choline elevation, which appears to be sensed as an abundant fuel source by the microbe.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [85]
In the citing paper
“As intestinal luminal choline is depleted, microbial community TMA production is globally inhibited, even from neighboring community members who might otherwise not be potently inhibited85.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [85]
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
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Results > FMC and IMC suppress host TMA and TMAO levels for sustained periods of time with limited systemic exposure and without observed toxicity
“liver function tests (ALT, AST, BUN)”
§ Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential > Methods > In vivo toxicity studies
“Plasma was analyzed for liver (ALT, AST) and kidney function (BUN) using a Roche Cobas C 311 analyzer”
Citations
Cites
Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease
Wang, Z., Klipfell, E., Bennett, B. J., Koeth, R., Levison, B. S., DuGar, B., Feldstein, A. E., Britt, E. B., Fu, X., Chung, Y.-M., et al. (2011) · Nature · doi:10.1038/nature09922 · Cited by 5,597
Self-citationIntestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis
Koeth, R. A., Wang, Z., Levison, B. S., Buffa, J. A., Org, E., Sheehy, B. T., Britt, E. B., Fu, X., Wu, Y., Li, L., et al. (2013) · Nature Medicine · doi:10.1038/nm.3145 · Cited by 4,386
Self-citationIndigenous bacteria from the gut microbiota regulate host serotonin biosynthesis
Yano, J. M., Yu, K., Donaldson, G. P., Shastri, G. G., Ann, P., Ma, L., Nagler, C. R., Ismagilov, R. F., Mazmanian, S. K., & Hsiao, E. Y. (2015) · Cell · doi:10.1016/j.cell.2015.02.047 · Cited by 3,614
Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk
Tang, W. H. W., Wang, Z., Levison, B. S., Koeth, R. A., Britt, E. B., Fu, X., Wu, Y., & Hazen, S. L. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1109400 · Cited by 3,400
Self-citationHuman nutrition, the gut microbiome and the immune system
Kau, A. L., Ahern, P. P., Griffin, N. W., Goodman, A. L., & Gordon, J. I. (2011) · Nature · doi:10.1038/nature10213 · Cited by 2,588
Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk
Zhu, W., Gregory, J. C., Org, E., Buffa, J. A., Gupta, N., Wang, Z., Li, L., Fu, X., Wu, Y., Mehrabian, M., et al. (2016) · Cell · doi:10.1016/j.cell.2016.02.011 · Cited by 1,968
Self-citationMechanisms of Thrombus Formation
Furie, B., & Furie, B. C. (2008) · New England Journal of Medicine · doi:10.1056/nejmra0801082 · Cited by 1,926
Extensive impact of non-antibiotic drugs on human gut bacteria
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Self-citation
Metadata
- Authors
- Roberts, A. B., Gu, X., Buffa, J. A., Hurd, A. G., Wang, Z., Zhu, W., Gupta, N., Skye, S. M., Cody, D. B., Levison, B. S., Barrington, W. T., Russell, M. W., Reed, J. M., Duzan, A., Lang, J. M., Fu, X., Li, L., Myers, A. J., Rachakonda, S., DiDonato, J. A., Brown, J. M., Gogonea, V., Lusis, A. J., Garcia-Garcia, J. C., & Hazen, S. L.
- Affiliations
- Cleveland Clinic (US)
- Procter & Gamble (United States) (US)
- University of California, Los Angeles (US)
- Cleveland State University (US)
- Corresponding author
- Hazen, Stanley L.
- ORCID
- Venue
- Nature Medicine
- Published
- 2018-08-06
- Volume
- 24
- Issue
- 9
- Pages
- 1407-1417
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6129214
- OpenAlex
- W2884566703
- Cited by
- 552
- References
- 62
- Citations by year
- 2026: 56 · 2025: 66 · 2024: 54 · 2023: 77 · 2022: 80 · 2021: 76 · 2020: 77 · 2019: 47 · 2018: 18
- FWCI
- 19.46
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Cleveland Clinic
- National Institutes of Health (5t32dk007470-35)
- National Institute on Alcohol Abuse and Alcoholism (P50AA024333)
- National Heart, Lung, and Blood Institute (P01HL030568, R01HL126827, R01HL103866, R01HL122283, P01HL028481)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK106000, T32-DK 007470)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Keywords
- trimethylamine N-oxide, gut microbiota, thrombosis, platelet response, mechanism-based inhibitors, irreversible inhibitors, atherothrombosis, Western diet, thrombus formation
- MeSH terms
- Gastrointestinal Microbiome, Hexanols, Animals, Bacteria, Choline, Diet, Mice, Inbred C57BL, Oxidoreductases, N-Demethylating, Platelet Aggregation, Thrombosis
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 2026-10-07, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-07 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
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