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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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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- Findingown data
Eight species representing Firmicutes and Proteobacteria showed significant choline consumption and TMA accumulation in vitro.
“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).”
Quote in the paperSubstantial claim - Findingown data
The TMA-producing organisms consumed more than 60% of the choline provided in the growth media, unlike strains that did not make TMA.
“These organisms consumed more than 60% of the choline provided in the growth media, unlike strains that did not make TMA (Table S1).”
Quote in the paperNot a substantial claim - Findingown data
The identified TMA-producing strains generated TMA only if the medium was supplemented with choline.
“These strains generated TMA only if the medium was supplemented with choline.”
Quote in the paperSubstantial claim - Findingown data
TMA was derived from choline, confirmed by inoculating TMA-producing strains with labeled choline and observing labeled TMA.
“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).”
Quote in the paperSubstantial claim - Findingown data
Screening of 79 sequenced human intestinal isolates identified nine strains capable of producing TMA from choline in vitro.
“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.”
Quote in the paperSubstantial claim
- Findingown data
None of the identified TMA-producing strains generated TMA from l-carnitine under the same test conditions.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [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 in the free run.
- Findingown data
Addition of Clostridium sporogenes to the core community resulted in significant reduction of fecal choline.
“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).”
Quote in the paperSubstantial claim - Findingown data
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.
“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).”
Quote in the paperSubstantial claim - Findingown data
Similar trends in serum choline were seen in experiments performed in female mice.
“Similar trends were also seen in experiments performed in female mice (Fig. S4).”
Quote in the paperNot a substantial claim - Findingcitation
Clostridium hathewayi carries genes encoding proteins predicted to be involved in cholic acid metabolism that were not detected in members of the "core plus C. sporogenes" community.
“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”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [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
Not checked in the free run.
- Findingown data
Hepatic FMO enzymatic activity was significantly higher in females than in males.
“FMO activity measurements in hepatic tissue homogenates indicated significantly higher enzymatic activity in females than in males (Fig. 2C).”
Quote in the paperSubstantial claim - Findingown data
Similar differences in TMAO levels were observed between C57BL/6J and NMRI adult females colonized with the core plus C. sporogenes community.
“Similar differences in TMAO levels were observed between C57BL/6J and NMRI adult females colonized with the “core plus C. sporogenes” community (Fig. 3A).”
Quote in the paperNot a substantial claim - Findingown data
Addition of Clostridium sporogenes to the core community resulted in accumulation of TMA in the cecum.
“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).”
Quote in the paperSubstantial claim - Findingown data
TMAO does not accumulate in the serum of gnotobiotic animals colonized with intestinal isolates that do not generate 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.”
Quote in the paperSubstantial claim - Findingown data
Colonization with the core community did not result in accumulation of TMA or TMAO.
“uHPLC-MS/MS analysis indicates that colonization with the “core” community did not result in the accumulation of TMA or TMAO (Fig. 1B and C).”
Quote in the paperSubstantial claim - Findingown data
Cecal levels of TMA were not significantly different between the core plus all and core plus C. sporogenes groups.
“Despite this, cecal levels of TMA, fecal levels of choline, and serum levels of TMAO were not significantly different between these two groups of mice (Fig. 1B to D).”
Quote in the paperSubstantial claim - Findingown data
TMAO accumulates in the serum of gnotobiotic animals colonized with TMA-producing species.
“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.”
Quote in the paperSubstantial claim - Findingown data
The reduction in choline availability was more pronounced as the abundance of TMA-producing bacteria increased.
“This effect was more pronounced as the abundance of TMA-producing bacteria increased.”
Quote in the paperSubstantial claim - Findingown data
Addition of Clostridium sporogenes to the core community resulted in appearance of TMAO in serum.
“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).”
Quote in the paperSubstantial claim - Findingown data
Clostridium sporogenes represented only 0.15% ± 0.01% of the cecal community.
“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).”
Quote in the paperSubstantial claim - Findingown data
TMAO accumulated at significantly higher levels in females than in males in gnotobiotic mice colonized with the core plus all community.
“uHPLC-MS/MS analysis of serum revealed that TMAO accumulated at significantly higher levels in females than in their male counterparts (Fig. 2A).”
Quote in the paperSubstantial claim - Findingown data
Hepatic FMO enzyme activity was higher in NMRI females than in C57BL/6J females.
“hepatic FMO enzyme activity assays showed higher FMO activity in NMRI females than in C57BL/6J females (Fig. 3B).”
Quote in the paperSubstantial claim - Findingown data
Females harbored increased levels of TMA-producing bacteria compared to males.
“Although females harbored increased levels of TMA-producing bacteria, cecal levels of TMA were not significantly different between the two groups (Fig. 2B and D).”
Quote in the paperNot a substantial claim - Findingown data
E. tarda and E. fergusonii decreased in abundance in response to dietary choline (P = 0.06 and P = 0.09, not statistically significant).
“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.”
Quote in the paperNot a substantial claim - Findingown data
Colonization with the core plus all community resulted in a >100-fold increase in the relative abundance of TMA-producing bacteria in the distal gut compared to the core plus C. sporogenes community.
“Colonization with the “core plus all” community resulted in >100-fold increase in the relative abundance of TMA-producing bacteria in the distal gut compared to “core plus C. sporogenes” community (Fig. 1A).”
Quote in the paperSubstantial claim - Findingown data
TMA-consuming bacteria were present in the small intestines of mice, the main site of choline absorption.
“COPRO-seq analysis revealed that TMA-consuming bacteria were present in the small intestines of mice (the main site of choline absorption) (see Fig. S3, top row, in the supplemental material).”
Quote in the paperNot a substantial claim - Findingown data
Serum TMAO levels were similar among males of the C57BL/6J and NMRI strains.
“uHPLC-MS/MS analysis disclosed similar levels of TMAO among males of the two strains (P > 0.1) (see Fig. S5 in the supplemental material).”
Quote in the paperNot a substantial claim - Findingown data
There were no significant differences in the total abundance of TMA-producing bacteria in the cecum between choline-deficient and choline-fed mice (24.7% ± 2.2% vs 24.1% ± 1.8%).
“There were no significant differences in the total abundance of TMA-producing bacteria in the cecum in the two groups of mice (24.7% ± 2.2% for the choline-deficient mice and 24.1% ± 1.8% for the mice given choline [average ± SEM]) despite significant changes in the relative abundance of specific TMA-producing species (C. hathewayi and P. rettgeri; P < 0.05 by Student’s t test) (Fig. 4B).”
Quote in the paperSubstantial claim - Findingown data
Serum levels of TMAO were not significantly different between the core plus all and core plus C. sporogenes groups.
“Despite this, cecal levels of TMA, fecal levels of choline, and serum levels of TMAO were not significantly different between these two groups of mice (Fig. 1B to D).”
Quote in the paperSubstantial claim - Findingown data
Serum levels of choline significantly decreased as the relative abundance of TMA producers increased.
“Results disclosed a significant decrease in the serum levels of choline as the relative abundance of TMA producers increased (Fig. 1E).”
Quote in the paperSubstantial claim - Findingown data
Cecal levels of TMA were not significantly different between females and males.
“Although females harbored increased levels of TMA-producing bacteria, cecal levels of TMA were not significantly different between the two groups (Fig. 2B and D).”
Quote in the paperSubstantial claim - Findingnone given
Dietary choline does not impact the abundance of TMA-producing bacteria in a low-complexity gut microbial consortium.
“Dietary choline is necessary for TMA production but does not impact the abundance of TMA-producing bacteria in a low-complexity gut microbial consortium.”
Quote in the paperSubstantial claim - Findingown data
C. hathewayi and P. rettgeri increased in abundance in response to dietary choline.
“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.”
Quote in the paperNot a substantial claim - Findingown data
NMRI females showed a 2-fold increase in serum TMAO levels compared to their C57BL/6J counterparts.
“In contrast, NMRI females showed a 2-fold increase in serum TMAO levels compared to their C57BL/6J counterparts (Fig. 3A).”
Quote in the paperSubstantial claim - Findingown data
Male mice colonized by the "core plus all" and "core plus C. sporogenes" communities showed a similar trend in serum TMAO levels.
“A similar trend in serum TMAO levels was observed in male mice colonized by these two communities (Fig. 1C).”
Quote in the paperNot a substantial claim - Findingown data
There were significant changes in the relative abundance of specific TMA-producing species C. hathewayi and P. rettgeri (P < 0.05 by Student's t test).
“There were no significant differences in the total abundance of TMA-producing bacteria in the cecum in the two groups of mice (24.7% ± 2.2% for the choline-deficient mice and 24.1% ± 1.8% for the mice given choline [average ± SEM]) despite significant changes in the relative abundance of specific TMA-producing species (C. hathewayi and P. rettgeri; P < 0.05 by Student’s t test) (Fig. 4B).”
Quote in the paperNot a substantial claim - Findingown data
Similar results were observed in adult female mice: TMA and TMAO levels were detected only when animals were colonized with TMA-producing bacteria.
“Similar results were observed in adult female mice (i.e., TMA and TMAO levels were detected only when animals were colonized with TMA-producing bacteria).”
Quote in the paperSubstantial claim - Findingown data
Seven of the eight identified species encode components of the choline utilization TMA-producing pathway, including cutC, cutD, and microcompartment assembly genes.
“Seven of the eight identified species encode components of the choline utilization TMA-producing pathway described above (see Fig. S2 in the supplemental material), including cutC, cutD, and genes encoding proteins involved in assembly of microcompartments.”
Quote in the paperNot a substantial claim - Findingown data
Similar results for TMAO levels were observed when the experiment was conducted in NMRI mice.
“Similar results were observed when the experiment was conducted in NMRI mice (4 or 5 mice per group; see Fig. S6 in the supplemental material).”
Quote in the paperNot a substantial claim - Findingown data
Fecal levels of choline were not significantly different between the core plus all and core plus C. sporogenes groups.
“Despite this, cecal levels of TMA, fecal levels of choline, and serum levels of TMAO were not significantly different between these two groups of mice (Fig. 1B to D).”
Quote in the paperSubstantial claim - Findingown data
Low levels of colonization by TMA-producing bacteria significantly reduced choline levels available to the host.
“Remarkably, low levels of colonization by TMA-producing bacteria significantly reduced choline levels available to the host.”
Quote in the paperSubstantial claim - Premisecitation
The choline-degrading sulfate-reducing bacterium Desulfovibrio desulfuricans uses a pathway involving radical C-N bond cleavage of choline to generate TMA and acetaldehyde.
“Subsequent experiments with the choline-degrading sulfate-reducing bacterium Desulfovibrio desulfuricans (i) revealed a pathway that involves a radical C–N bond cleavage of choline to generate TMA and acetaldehyde and (ii) identified a gene cluster encoding this activity (22).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [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 in the free run.
- Premisecitation
Gut microbial metabolism of choline results in the production of trimethylamine (TMA).
“Previous studies have established that gut microbial metabolism of choline results in the production of trimethylamine (TMA) (12–14).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [12] Zeisel SH, Wishnok JS, Blusztajn JK 1983 Formation of methylamines from ingested choline and lecithin. J Pharmacol Exp Ther 225: 320– 324. 6842395 source
Not checked in the free run.
- cites [13] De la Huerga J, Popper H 1951 Urinary excretion of choline metabolites following choline administration in normals and patients with hepatobilary disease. J Clin Invest 30: 463– 470. doi: 10.1172/JCI102463. 14832377 PMC436280 source
Not checked in the free run.
- cites [14] Hayward HR 1960 Anaerobic degradation of choline. III. Acetaldehyde as an intermediate in the fermentation of choline by extracts of Vibrio cholinicus. J Biol Chem 235: 3592– 3596. 13712528 source
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- Premisecitation
Serum TMAO levels are positively correlated with cardiovascular disease in humans.
“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).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [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 in the free run.
- cites [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 in the free run.
- cites [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 in the free run.
- cites [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
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- Premisecitation
TMAO inhibits reverse cholesterol transport.
“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).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [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 in the free run.
- cites [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 in the free run.
- cites [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 in the free run.
- cites [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
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- Premisecitation
Once absorbed by the host, TMA is further metabolized by flavin monooxygenases 1 and 3 (FMO1 and FMO3) in the host liver to generate trimethylamine-N-oxide (TMAO).
“Once TMA is absorbed by the host, it is further metabolized by flavin monooxygenases 1 and 3 (FMO1 and FMO3) in the host liver to generate trimethylamine-N-oxide (TMAO) (8, 15, 16).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [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 in the free run.
- cites [15] Shih DM, Wang Z, Lee R, Meng Y, Che N, Charugundla S, Qi H, Wu J, Pan C, Brown JM, Vallim T, Bennett BJ, Graham M, Hazen SL, Lusis AJ 2015 Flavin containing monooxygenase 3 exerts broad effects on glucose and lipid metabolism and atherosclerosis. J Lipid Res 56: 22– 37. doi: 10.1194/jlr.M051680. 25378658 PMC4274068 source
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- cites [16] Baker JR, Chaykin S 1962 The biosynthesis of trimethylamine-N-oxide. J Biol Chem 237: 1309– 1313. doi: 10.1016/0006-3002(60)90062-7. 13864146 source
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- Premisecitation
Cholic acid stimulates FMO3 expression.
“Specifically, cholic acid stimulates FMO3 expression (27).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [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
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- Interpretationown data
Dietary choline is required for TMAO accumulation.
“FIG 4 Dietary choline is required for TMAO accumulation.”
Quote in the paperSubstantial claim - Interpretationown data
There is a causal link between gut microbial TMA-producing status and TMAO accumulation in vivo.
“These results demonstrate a causal link between gut microbial TMA-producing status and TMAO accumulation in vivo”
Quote in the paperSubstantial claim - Interpretationown data
Gender-associated differences in TMAO accumulation are likely not derived from higher levels of microbiota-generated TMA, but rather from higher FMO activity in females.
“These data suggest that gender-associated differences in TMAO accumulation are likely not derived from higher levels of microbiota-generated TMA (Fig. 2B), but rather higher FMO activity in females”
Quote in the paperSubstantial claim - Premisecitation
Gut microbes can convert otherwise beneficial dietary compounds, such as choline, into metabolites that are detrimental to human health.
“Likewise, gut microbes can also convert otherwise beneficial dietary compounds, such as choline, into metabolites that are detrimental to human health (7–10).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [7] Zeisel SH, daCosta KA, Youssef M, Hensey S 1989 Conversion of dietary choline to trimethylamine and dimethylamine in rats: dose-response relationship. J Nutr 119: 800– 804. 2723829 source
Not checked in the free run.
- cites [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 in the free run.
- cites [9] Tang WHW, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL 2013 Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 368: 1575– 1584. doi: 10.1056/NEJMoa1109400. 23614584 PMC3701945 source
Not checked in the free run.
- cites [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 in the free run.
- Interpretationown data
Colonization with TMA-producing bacteria decreases levels of choline available to the host.
“Colonization with TMA-producing bacteria decreases levels of choline available to the host.”
Quote in the paperSubstantial claim - Interpretationreasoning
At least one species present in the "core plus all" community reduces FMO activity.
“These results suggest that gut microbiota composition affects TMAO levels, independently of TMA production, and that at least one species present in the “core plus all” community reduces FMO activity.”
Quote in the paperSubstantial claim - Interpretationown data
Dietary choline is necessary for TMA production.
“Dietary choline is necessary for TMA production but does not impact the abundance of TMA-producing bacteria in a low-complexity gut microbial consortium.”
Quote in the paperSubstantial claim - Interpretationown data
Gut microbiota composition affects TMAO levels independently of TMA production.
“These results suggest that gut microbiota composition affects TMAO levels, independently of TMA production, and that at least one species present in the “core plus all” community reduces FMO activity.”
Quote in the paperSubstantial claim - Premisecitation
Although choline is synthesized endogenously, this synthesis does not meet the levels necessary for optimal health.
“Although choline is synthesized endogenously, this synthesis does not meet the levels necessary for optimal health (11).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [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 in the free run.
- Interpretationown data
Multiple factors, i.e., microbial, host, and environmental factors, modulate metabolism of choline to TMAO.
“Altogether, the presented results highlight the multiple factors, i.e., microbial, host, and environmental factors, that modulate metabolism of choline to TMAO.”
Quote in the paperSubstantial claim - Interpretationcitation
Other factors, such as host genotype, besides the abundance of TMA-producing bacteria may account for differences in TMAO accumulation.
“suggest that other factors (e.g., host genotype) besides the abundance of TMA-producing bacteria may account for differences in TMAO accumulation (25).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] Miller CA, Corbin KD, da Costa K-A, Zhang S, Zhao X, Galanko JA, Blevins T, Bennett BJ, O’Connor A, Zeisel SH 2014 Effect of egg ingestion on trimethylamine-N-oxide production in humans: a randomized, controlled, dose-response study. Am J Clin Nutr 100: 778– 786. doi: 10.3945/ajcn.114.087692. 24944063 PMC4135488 source
Not checked in the free run.
- Premisecitation
FMO3 expression is induced by bile acids via a mechanism involving the farnesoid X receptor (FXR).
“Expression of the main FMO enzyme involved in TMAO production from TMA, FMO3, is induced by bile acids via a mechanism that involves the farnesoid X receptor (FXR) (27).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [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
Not checked in the free run.
- Interpretationreasoning
The decreased serum TMAO levels in mice colonized with the "core plus all" community are plausibly caused by increased microbial degradation of cholic acid, which would result in lower fmo3 expression.
“Thus, it is plausible that the decreased levels of TMAO detected in sera of mice colonized with the “core plus all” community (Fig. 1C and Fig. 3A) are caused by increased microbial degradation of cholic acid, which would result in lower levels of fmo3 expression (27).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [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
Not checked in the free run.
- Interpretationown data
Phylogeny is a poor predictor of microbial TMA production from choline.
“suggest that phylogeny is a poor predictor of microbial TMA production from choline.”
Quote in the paperSubstantial claim
- May combine two claims. 11
- Classified as probably not a substantial claim. 12
May combine two claims.
Findingown dataDifferent strains of Edwardsiella tarda varied in their ability to consume choline and generate TMA; ATCC 23685 generated TMA, while ATCC 15947 did not.
“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”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataFemale mice colonized with the "core plus all" community accumulated lower serum TMAO levels and exhibited lower hepatic FMO activity than female mice colonized with the "core plus C. sporogenes" community.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataProvidencia rustiganii showed TMA accumulation after 72 h of incubation, whereas Providencia alcalifaciens did not generate TMA under any tested conditions.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataProvidencia alcalifaciens and Providencia rustiganii are predicted to encode key components of the choline utilization TMA-producing pathway but did not generate TMA in the original screen.
“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”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataEdwardsiella tarda strain 23685 produces TMA from choline but does not appear to contain the known choline utilization genes in its published draft genome.
“In contrast, E. tarda strain 23685 produces TMA from choline but does not appear to contain these genes in the published draft genome”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataMice with choline in their diet showed detectable levels of TMAO in their serum, whereas mice fed the choline-deficient diet did not.
“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).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataC. asparagiforme increased in abundance in response to dietary choline (P = 0.10, not statistically significant).
“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.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSerum TMAO levels are positively correlated with colorectal cancer in humans.
“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).”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [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 in the free run.
- cites [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 in the free run.
- cites [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 in the free run.
- cites [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
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTMAO promotes forward cholesterol transport.
“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).”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [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 in the free run.
- cites [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 in the free run.
- cites [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 in the free run.
- cites [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
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSerum TMAO levels are positively correlated with impaired renal function in humans.
“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).”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [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 in the free run.
- cites [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 in the free run.
- cites [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 in the free run.
- cites [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
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe choline utilization gene cluster includes cutC, cutD, and genes encoding proteins involved in assembly of microcompartments.
“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).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [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 in the free run.
- cites [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
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationTMAO exacerbates atherosclerosis in a genetic knockout mouse model.
“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).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [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 in the free run.
- cites [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 in the free run.
- cites [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 in the free run.
- cites [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
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCholine is a water-soluble nutrient essential for human life.
“Choline is a water-soluble nutrient essential for human life.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [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 in the free run.
May combine two claims.
Interpretationown dataThe ability of microbes to convert choline to TMA is a strain-specific metabolic trait that may be acquired via lateral gene transfer.
“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.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenSterility of germ-free animals was assessed by incubating freshly collected fecal samples under aerobic and anaerobic conditions using standard microbiology methods.
“Sterility of germ-free animals was assessed by incubating freshly collected fecal samples under aerobic and anaerobic conditions using standard microbiology methods.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenSamples with less than 10,000 reads were not used for analysis.
“Samples with less than 10,000 reads were not used for analysis.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationSignificant 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.
“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).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [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 in the free run.
- cites [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
Not checked in the free run.
May combine two claims.
Interpretationown dataHost genotype and community composition modulate FMO activity and serum TMAO levels in female mice.
“Host genotype and community composition modulate FMO activity and TMAO accumulation in female mice.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataWith 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 detection of microbes representing at least 0.1% of the community.
“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.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPrevious studies in conventionally raised mice demonstrated that FMO3 is expressed at higher levels in females than in males.
“consistent with previous studies in conventionally raised mice which demonstrated that FMO3 is expressed at higher levels in females than in males (8, 27).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [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 in the free run.
- cites [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
Not checked in the free run.
May combine two claims.
Interpretationown dataHost gender affects FMO activity and TMAO accumulation in gnotobiotic mice colonized with the same microbiota.
“Host gender affects FMO activity and TMAO accumulation in gnotobiotic mice colonized with the same microbiota.”
Quote in the paperSubstantial claim
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?
Edwardsiella tarda produces TMA even though it does not express the TMA-producing genes discussed.
“Only Edwardsiella tarda does not express the TMA-producing genes discussed in Section 1 above but produces TMA nonetheless (96).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [96]
Colonizing gnotobiotic mice with choline-converting bacteria raises cecal TMA production and lowers serum choline.
“Colonization of gnotobiotic mice with choline-converting bacteria not only increases cecal TMA production but also lowers serum choline concentration (96).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [96]
Gut microbiota are necessary for dietary choline, choline-containing compounds, betaine, and L-carnitine to be converted to TMA.
“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 <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [96]
CutC and its activating partner CutD support choline TMA lyase enzyme activity.
“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]
Neither IMC nor FMC affected the growth rate of P. mirabilis, E. fergusonii, and P. penneri under conditions showing complete inhibition of choline TMA lyase activity.
“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]
Colonization of the mouse gut with a specific consortium of CutC-encoding human isolates results in TMA synthesis and subsequent TMAO accumulation in serum.
“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]
Even minute concentrations of TMA producers, 0.15% of the total community, are sufficient for substantial TMA production from choline.
“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]
The presence of the microbial cutC/D genes in human microbiota is associated with the ability to generate trimethylamine from choline, and with subsequent trimethylamine N-oxide accumulation.
“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 gnotobiotic mice, 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.
“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]
Plasma level of TMAO is determined by factors including diet, gut microbial flora and liver flavin monooxygenase activity.
“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]
Nine strains of commensal human intestinal bacteria are capable of producing TMA from choline in vitro, including Anaerococcus hydrogenalis, Clostridium asparagiforme, C. hathewayi, C. sporogenes, Escherichia fergusonii, Proteus penneri, Providencia rettgeri, and Edwardsiella tarda.
“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]
Circulating levels of TMAO are determined by a number of factors, including diet, gut microbial flora, liver FMO enzymes and kidney function.
“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]
TMAO generated by gut microbiome exacerbates impaired glucose tolerance, inhibits hepatic insulin signaling, and promotes adipose tissue inflammation in mice maintained on a high-fat high-sugar diet.
“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.”
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 · see citing works
Functional interactions between the gut microbiota and host metabolism
Tremaroli, V., & Bäckhed, F. (2012) · Nature · doi:10.1038/nature11552 · Cited by 4,387 · see citing works
Intestinal 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 · see citing works
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 3,402 · see citing works
Caspi, R., Billington, R., Ferrer, L., Foerster, H., Fulcher, C. A., Keseler, I. M., Kothari, A., Krummenacker, M., Latendresse, M., Mueller, L. A., et al. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkv1164 · Cited by 3,395 · see citing works
Mechanisms underlying the resistance to diet-induced obesity in germ-free mice
Bäckhed, F., Manchester, J. K., Semenkovich, C. F., & Gordon, J. I. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0605374104 · Cited by 2,615 · see citing works
The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon
Donohoe, D. R., Garge, N., Zhang, X., Sun, W., O'Connell, T. M., Bunger, M. K., & Bultman, S. J. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.02.018 · Cited by 2,003 · see citing works
A Genomic View of the Human- <i>Bacteroides thetaiotaomicron</i> Symbiosis
Xu, J., Bjursell, M. K., Himrod, J., Deng, S., Carmichael, L. K., Chiang, H. C., Hooper, L. V., & Gordon, J. I. (2003) · Science · doi:10.1126/science.1080029 · Cited by 1,353 · see citing works
Tang, W. H. W., Wang, Z., Kennedy, D. J., Wu, Y., Buffa, J. A., Agatisa-Boyle, B., Li, X. S., Levison, B. S., & Hazen, S. L. (2015) · Circulation Research · doi:10.1161/circresaha.116.305360 · Cited by 1,223 · see citing works
Caspi, R., Altman, T., Billington, R., Dreher, K., Foerster, H., Fulcher, C. A., Holland, T. A., Keseler, I. M., Kothari, A., Kubo, A., et al. (2014) · Nucleic Acids Research · doi:10.1093/nar/gkt1103 · Cited by 1,204 · see citing works
Bennett, B. J., Vallim, T. Q. D. A., Wang, Z., Shih, D. M., Meng, Y., Gregory, J., Allayee, H., Lee, R., Graham, M., Crooke, R., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2012.12.011 · Cited by 1,070 · see citing works
Choline: an essential nutrient for public health
Zeisel, S. H., & da Costa, K.-A. (2009) · Nutrition Reviews · doi:10.1111/j.1753-4887.2009.00246.x · Cited by 1,062 · see citing works
Recognition and Degradation of Plant Cell Wall Polysaccharides by Two Human Gut Symbionts
Martens, E. C., Lowe, E. C., Chiang, H. C., Pudlo, N. A., Wu, M., McNulty, N. P., Abbott, D. W., Henrissat, B., Gilbert, H. J., Bolam, D. N., et al. (2011) · PLoS Biology · doi:10.1371/journal.pbio.1001221 · Cited by 847 · see citing works
Goodman, A. L., Kallstrom, G., Faith, J. J., Reyes, A., Moore, A. M., Dantas, G. A., & Gordon, J. I. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1102938108 · Cited by 779 · see citing works
Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme
Craciun, S., & Balskus, E. P. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1215689109 · Cited by 701 · see citing works
Wang, Z., Tang, W. H. W., Buffa, J. A., Fu, X., Britt, E. B., Koeth, R. A., Levison, B. S., Fan, Y., Wu, Y., & Hazen, S. L. (2014) · European Heart Journal · doi:10.1093/eurheartj/ehu002 · Cited by 559 · see citing works
McNulty, N. P., Yatsunenko, T., Hsiao, A., Faith, J. J., Muegge, B. D., Goodman, A. L., Henrissat, B., Oozeer, R., Cools-Portier, S., Gobert, G., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002701 · Cited by 544 · see citing works
Protocatechuic Acid Is the Major Human Metabolite of Cyanidin-Glucosides3
Vitaglione, P., Donnarumma, G., Napolitano, A., Galvano, F., Gallo, A., Scalfi, L., & Fogliano, V. (2007) · Journal of Nutrition · doi:10.1093/jn/137.9.2043 · Cited by 495 · see citing works
Trøseid, M., Ueland, T., Hov, J. R., Svardal, A., Gregersen, I., Dahl, C. P., Aakhus, S., Gude, E., Bjørndal, B., Halvorsen, B., et al. (2015) · Journal of Internal Medicine · doi:10.1111/joim.12328 · Cited by 464 · see citing works
Dietary trimethylamine N-oxide exacerbates impaired glucose tolerance in mice fed a high fat diet
Gao, X., Liu, X., Xu, J., Xue, C., Xue, Y., & Wang, Y. (2014) · Journal of Bioscience and Bioengineering · doi:10.1016/j.jbiosc.2014.03.001 · Cited by 360 · see citing works
Shih, D. M., Wang, Z., Lee, R., Meng, Y., Che, N., Charugundla, S., Qi, H., Wu, J., Pan, C., Brown, J. M., et al. (2015) · Journal of Lipid Research · doi:10.1194/jlr.m051680 · Cited by 335 · see citing works
Bae, S., Ulrich, C. M., Neuhouser, M. L., Malysheva, O., Bailey, L. B., Xiao, L., Brown, E. C., Cushing-Haugen, K. L., Zheng, Y., Cheng, T.-Y. D., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-1835 · Cited by 253 · see citing works
Formation of methylamines from ingested choline and lecithin.
Zeisel, S. H., Wishnok, J. S., & Blusztajn, J. K. (1983) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)33590-1 · Cited by 253 · see citing works
Miller, C. A., Corbin, K. D., da Costa, K.-A., Zhang, S., Zhao, X., Galanko, J. A., Blevins, T., Bennett, B. J., O’Connor, A., & Zeisel, S. H. (2014) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.114.087692 · Cited by 240 · see citing works
Zeisel, S. H., daCosta, K. A., Youssef, M., & Hensey, S. (1989) · The Journal of Nutrition · doi:10.1093/jn/119.5.800 · Cited by 151 · see citing works
The Biosynthesis of Trimethylamine-N-Oxide
Baker, J. R., & Chaykin, S. (1962) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)60325-4 · Cited by 146 · see citing works
de la Huerga, J., & Popper, H. (1951) · Journal of Clinical Investigation · doi:10.1172/jci102463 · Cited by 129 · see citing works
Anaerobic Degradation of Choline
Hayward, H. R. (1960) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)64514-4 · Cited by 40 · see citing works
Heart dysfunction induced by choline-deficiency in adult rats: The protective role of l-carnitine
Strilakou, A. A., Lazaris, A. C., Perelas, A. I., Mourouzis, I. S., Douzis, I. C., Karkalousos, P. L., Stylianaki, A. T., Pantos, C. I., & Liapi, C. A. (2013) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2013.03.025 · Cited by 36 · see citing works
The biosynthesis of trimethylamine-N-oxide
Baker, J., & Chaykin, S. (1960) · Biochimica et Biophysica Acta · doi:10.1016/0006-3002(60)90062-7 · Cited by 34 · see citing works
Converging on a mechanism for choline degradation
Thibodeaux, C. J., & van der Donk, W. A. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1219534110 · Cited by 28 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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 · see citing works
An insight into gut microbiota and its functionalities
Adak, A., & Khan, M. R. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2943-4 · Cited by 1,485 · see citing works
Gut microbial metabolites as multi-kingdom intermediates
Krautkramer, K. A., Fan, J., & Bäckhed, F. (2021) · Nature Reviews Microbiology · doi:10.1038/s41579-020-0438-4 · Cited by 1,398 · see citing works
Wang, Z., Roberts, A. B., Buffa, J. A., Levison, B. S., Zhu, W., Org, E., Gu, X., Huang, Y., Zamanian-Daryoush, M., Culley, M. K., et al. (2015) · Cell · doi:10.1016/j.cell.2015.11.055 · Cited by 1,317 · see citing works
Oliphant, K., & Allen-Vercoe, E. (2019) · Microbiome · doi:10.1186/s40168-019-0704-8 · Cited by 1,327 · see citing works
Chemical transformation of xenobiotics by the human gut microbiota
Koppel, N., Maini Rekdal, V., & Balskus, E. P. (2017) · Science · doi:10.1126/science.aag2770 · Cited by 1,080 · see citing works
Gut microbiota and cardiovascular disease.
Witkowski, M., Weeks, T. L., & Hazen, S. L. (2020) · Circulation Research · doi:10.1161/circresaha.120.316242 · Cited by 1,051 · see citing works
Postler, T. S., & Ghosh, S. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.05.008 · Cited by 876 · see citing works
“Interestingly, the same strains did not produce TMA from L-carnitine under the same experimental conditions (Romano et al., 2015).”
BackgroundDiscovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism
Maini Rekdal, V., Bess, E. N., Bisanz, J. E., Turnbaugh, P. J., & Balskus, E. P. (2019) · Science · doi:10.1126/science.aau6323 · Cited by 753 · see citing works
Gut microbes and metabolites as modulators of blood-brain barrier integrity and brain health
Parker, A., Fonseca, S., & Carding, S. R. (2019) · Gut Microbes · doi:10.1080/19490976.2019.1638722 · Cited by 722 · see citing works
Role of gut microbiota in atherosclerosis
Jonsson, A. L., & Bäckhed, F. (2016) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2016.183 · Cited by 647 · see citing works
Diet-Microbiota Interactions Mediate Global Epigenetic Programming in Multiple Host Tissues
Krautkramer, K. A., Kreznar, J. H., Romano, K. A., Vivas, E. I., Barrett-Wilt, G. A., Rabaglia, M. E., Keller, M. P., Attie, A. D., Rey, F. E., & Denu, J. M. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.10.025 · Cited by 607 · see citing works
Self-citationHow the immune system shapes atherosclerosis: roles of innate and adaptive immunity
Roy, P., Orecchioni, M., & Ley, K. F. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-021-00584-1 · Cited by 584 · see citing works
Ballestri, S., Nascimbeni, F., Baldelli, E., Marrazzo, A., Romagnoli, D., & Lonardo, A. (2017) · Advances in Therapy · doi:10.1007/s12325-017-0556-1 · Cited by 546 · see citing works
Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential
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., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0128-1 · Cited by 552 · see citing works
The role of the microbiome in NAFLD and NASH
Kolodziejczyk, A. A., Zheng, D., Shibolet, O., & Elinav, E. (2019) · EMBO Molecular Medicine · doi:10.15252/emmm.201809302 · Cited by 523 · see citing works
Intestinal Microbiota in Cardiovascular Health and Disease
Tang, W. H. W., Bäckhed, F., Landmesser, U., & Hazen, S. L. (2019) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2019.03.024 · Cited by 508 · see citing works
Uncovering the trimethylamine-producing bacteria of the human gut microbiota
Rath, S., Heidrich, B., Pieper, D. H., & Vital, M. (2017) · Microbiome · doi:10.1186/s40168-017-0271-9 · Cited by 515 · see citing works
Trimethylamine N-oxide: the good, the bad and the unknown.
Velasquez, M., Ramezani, A., Manal, A., & Raj, D. (2016) · Toxins · doi:10.3390/toxins8110326 · Cited by 504 · see citing works
Kerfeld, C. A., Aussignargues, C., Zarzycki, J., Cai, F., & Sutter, M. (2018) · Nature Reviews Microbiology · doi:10.1038/nrmicro.2018.10 · Cited by 445 · see citing works
Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease
Zeisel, S. H., & Warrier, M. (2017) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071816-064732 · Cited by 475 · see citing works
The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer’s disease
Vogt, N. M., Romano, K. A., Darst, B. F., Engelman, C. D., Johnson, S. C., Carlsson, C. M., Asthana, S., Blennow, K., Zetterberg, H., Bendlin, B. B., et al. (2018) · Alzheimer's Research & Therapy · doi:10.1186/s13195-018-0451-2 · Cited by 471 · see citing works
Self-citationLongitudinal Multi-omics Reveals Subset-Specific Mechanisms Underlying Irritable Bowel Syndrome
Mars, R. A. T., Yang, Y., Ward, T., Houtti, M., Priya, S., Lekatz, H. R., Tang, X., Sun, Z., Kalari, K. R., Korem, T., et al. (2020) · Cell · doi:10.1016/j.cell.2020.08.007 · Cited by 456 · see citing works
“In vitro and in vivo hypoxanthine consumption experiments—Bacteria were cultivated in Mega medium (Romano et al., 2015).”
Microbial modulation of cardiovascular disease
Brown, J. M., & Hazen, S. L. (2018) · Nature Reviews Microbiology · doi:10.1038/nrmicro.2017.149 · Cited by 440 · see citing works
Role of the gut microbiota in type 2 diabetes and related diseases
Yang, G., Wei, J., Liu, P., Zhang, Q., Tian, Y., Hou, G., Meng, L., Xin, Y., & Jiang, X. (2021) · Metabolism · doi:10.1016/j.metabol.2021.154712 · Cited by 418 · see citing works
Organ, C. L., Otsuka, H., Bhushan, S., Wang, Z., Bradley, J., Trivedi, R., Polhemus, D. J., Tang, W. H. W., Wu, Y., Hazen, S. L., et al. (2016) · Circulation: Heart Failure · doi:10.1161/circheartfailure.115.002314 · Cited by 382 · see citing works
Relationship between the gut microbiome and brain function
Mohajeri, M. H., La Fata, G., Steinert, R. E., & Weber, P. (2018) · Nutrition Reviews · doi:10.1093/nutrit/nuy009 · Cited by 376 · see citing works
Fennema, D., Phillips, I. R., & Shephard, E. A. (2016) · Drug Metabolism and Disposition · doi:10.1124/dmd.116.070615 · Cited by 355 · see citing works
Yang, S., Li, X., Yang, F., Zhao, R., Pan, X., Liang, J., Tian, L., Li, X., Liu, L., Xing, Y., et al. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.01360 · Cited by 347 · see citing works
l-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans
Koeth, R. A., Lam-Galvez, B. R., Kirsop, J., Wang, Z., Levison, B. S., Gu, X., Copeland, M. F., Bartlett, D., Cody, D. B., Dai, H. J., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci94601 · Cited by 327 · see citing works
Mirji, G., Worth, A., Bhat, S. A., El Sayed, M., Kannan, T., Goldman, A. R., Tang, H.-Y., Liu, Q., Auslander, N., Dang, C. V., et al. (2022) · Science Immunology · doi:10.1126/sciimmunol.abn0704 · Cited by 327 · see citing works
Dietary Choline Intake: Current State of Knowledge Across the Life Cycle
Wiedeman, A. M., Barr, S. I., Green, T., Xu, Z., Innis, S. M., & Kitts, D. D. (2018) · Nutrients · doi:10.3390/nu10101513 · Cited by 318 · see citing works
Trimethylamine‐<i>N</i>‐oxide promotes brain aging and cognitive impairment in mice
Li, D., Ke, Y., Zhan, R., Liu, C., Zhao, M., Zeng, A., Shi, X., Ji, L., Cheng, S., Pan, B., et al. (2018) · Aging Cell · doi:10.1111/acel.12768 · Cited by 304 · see citing works
TMAO: how gut microbiota contributes to heart failure
Zhang, Y., Wang, Y., Ke, B., & Du, J. (2020) · Translational research · doi:10.1016/j.trsl.2020.08.007 · Cited by 306 · see citing works
A review of metabolic potential of human gut microbiome in human nutrition
Yadav, M., Verma, M. K., & Chauhan, N. S. (2017) · Archives of Microbiology · doi:10.1007/s00203-017-1459-x · Cited by 288 · see citing works
Ke, Y., Li, D., Zhao, M., Liu, C., Liu, J., Zeng, A., Shi, X., Cheng, S., Pan, B., Zheng, L., et al. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.01.007 · Cited by 285 · see citing works
Gut-Resident Lactobacilli Activate Hepatic Nrf2 and Protect Against Oxidative Liver Injury
Saeedi, B. J., Liu, K. H., Owens, J. A., Hunter-Chang, S., Camacho, M. C., Eboka, R. U., Chandrasekharan, B., Baker, N. F., Darby, T. M., Robinson, B. S., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.03.006 · Cited by 295 · see citing works
Schugar, R. C., Shih, D. M., Warrier, M., Helsley, R. N., Burrows, A., Ferguson, D., Brown, A. L., Gromovsky, A. D., Heine, M., Chatterjee, A., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.05.077 · Cited by 291 · see citing works
Brunt, V. E., Gioscia‐Ryan, R. A., Casso, A. G., VanDongen, N. S., Ziemba, B. P., Sapinsley, Z. J., Richey, J. J., Zigler, M. C., Neilson, A. P., Davy, K. P., et al. (2020) · Hypertension · doi:10.1161/hypertensionaha.120.14759 · Cited by 285 · see citing works
Kamo, T., Akazawa, H., Suda, W., Saga-Kamo, A., Shimizu, Y., Yagi, H., Liu, Q., Nomura, S., Naito, A. T., Takeda, N., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0174099 · Cited by 265 · see citing works
The Mouse Microbiome Is Required for Sex-Specific Diurnal Rhythms of Gene Expression and Metabolism
Weger, B. D., Gobet, C., Yeung, J., Martin, E., Jimenez, S., Betrisey, B., Foata, F., Berger, B., Balvay, A., Foussier, A., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2018.09.023 · Cited by 269 · see citing works
Microbial impact on cholesterol and bile acid metabolism: current status and future prospects
Kriaa, A., Bourgin, M., Potiron, A., Mkaouar, H., Jablaoui, A., Gérard, P., Maguin, E., & Rhimi, M. (2019) · Journal of Lipid Research · doi:10.1194/jlr.r088989 · Cited by 264 · see citing works
Drug-microbiota interactions: an emerging priority for precision medicine
Zhao, Q. C., Chen, Y., Huang, W., Zhou, H., & Zhang, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01619-w · Cited by 296 · see citing works
Smits, L. P., Kootte, R. S., Levin, E., Prodan, A., Fuentes, S., Zoetendal, E. G., Wang, Z., Levison, B. S., Cleophas, M. C. P., Kemper, E. M., et al. (2018) · Journal of the American Heart Association · doi:10.1161/jaha.117.008342 · Cited by 250 · see citing works
Cronin, O., Barton, W., Skuse, P., Penney, N. C., Garcia-Perez, I., Murphy, E. F., Woods, T., Nugent, H., Fanning, A., Melgar, S., et al. (2018) · mSystems · doi:10.1128/msystems.00044-18 · Cited by 232 · see citing works
Microbiota and Thyroid Interaction in Health and Disease
Fröhlich, E., & Wahl, R. (2019) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2019.05.008 · Cited by 233 · see citing works
Gut bacterial metabolism contributes to host global purine homeostasis
Kasahara, K., Kerby, R. L., Zhang, Q., Pradhan, M., Mehrabian, M., Lusis, A. J., Bergström, G. M. L., Bäckhed, F., & Rey, F. E. (2023) · Cell Host & Microbe · doi:10.1016/j.chom.2023.05.011 · Cited by 233 · see citing works
Self-citationLiu, Y., & Dai, M. (2020) · Mediators of Inflammation · doi:10.1155/2020/4634172 · Cited by 231 · see citing works
Metabolic, Epigenetic, and Transgenerational Effects of Gut Bacterial Choline Consumption
Romano, K. A., Martinez-del Campo, A., Kasahara, K., Chittim, C. L., Vivas, E. I., Amador-Noguez, D., Balskus, E. P., & Rey, F. E. (2017) · Cell Host & Microbe · doi:10.1016/j.chom.2017.07.021 · Cited by 224 · see citing works
Self-citationTrimethylamine- N -Oxide: Friend, Foe, or Simply Caught in the Cross-Fire?
Cho, C. E., & Caudill, M. A. (2016) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2016.10.005 · Cited by 218 · see citing works
The promise of the gut microbiome as part of individualized treatment strategies
Schupack, D. A., Mars, R. A. T., Voelker, D. H., Abeykoon, J. P., & Kashyap, P. C. (2022) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00499-1 · Cited by 217 · see citing works
Sánchez-Rodríguez, E., Egea-Zorrilla, A., Plaza‐Díaz, J., Aragón‐Vela, J., Muñoz‐Quezada, S., Tercedor‐Sánchez, L., & Abadía‐Molina, F. (2020) · Nutrients · doi:10.3390/nu12030605 · Cited by 220 · see citing works
Zhang, Y., Chen, R., Zhang, D., Qi, S., & Liu, Y. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114295 · Cited by 209 · see citing works
Gut microbiota in atherosclerosis: focus on trimethylamine N‐oxide
Zhu, Y., Li, Q., & Jiang, H. (2020) · Apmis · doi:10.1111/apm.13038 · Cited by 204 · see citing works
Arias, N., Arboleya, S., Allison, J., Kaliszewska, A., Higarza, S. G., Gueimonde, M., & Arias, J. L. (2020) · Nutrients · doi:10.3390/nu12082340 · Cited by 200 · see citing works
Lyu, M., Wang, Y., Fan, G., Wang, X., Xu, S.-Y., & Zhu, Y. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.02146 · Cited by 193 · see citing works
Sherriff, J. L., O’Sullivan, T. A., Properzi, C., Oddo, J.-L., & Adams, L. A. (2016) · Advances in Nutrition · doi:10.3945/an.114.007955 · Cited by 191 · see citing works
Canyelles, M., Tondo, M., Cedó, L., Farràs, M., Escolá‐Gil, J. C., & Blanco‐Vaca, F. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19103228 · Cited by 194 · see citing works
Interactions between polysaccharides and gut microbiota: A metabolomic and microbial review
Zhang, D., Liu, J., Cheng, H., Wang, H., Tan, Y., Feng, W., & Peng, C. Y. (2022) · Food Research International · doi:10.1016/j.foodres.2022.111653 · Cited by 200 · see citing works
Microbiology Meets Big Data: The Case of Gut Microbiota–Derived Trimethylamine
Falony, G., Vieira-Silva, S., & Raes, J. (2015) · Annual Review of Microbiology · doi:10.1146/annurev-micro-091014-104422 · Cited by 187 · see citing works
Skye, S. M., Zhu, W., Romano, K. A., Guo, C.-J., Wang, Z., Jia, X., Kirsop, J., Haag, B., Lang, J. M., DiDonato, J. A., et al. (2018) · Circulation Research · doi:10.1161/circresaha.118.313142 · Cited by 189 · see citing works
Self-citationThe gut microbiota and its interactions with cardiovascular disease
Xu, H., Wang, X., Feng, W., Liu, Q., Zhou, S., Liu, Q., & Cai, L. (2020) · Microbial Biotechnology · doi:10.1111/1751-7915.13524 · Cited by 192 · see citing works
Gut microbiome variation modulates the effects of dietary fiber on host metabolism
Murga-Garrido, S. M., Hong, Q., Cross, T.-W., Hutchison, E. R., Han, J. H., Thomas, S. P., Vivas, E. I., Denu, J. M., Ceschin, D. G., Tang, Z.-Z., et al. (2021) · Microbiome · doi:10.1186/s40168-021-01061-6 · Cited by 184 · see citing works
Self-citationTrimethylamine N-Oxide (TMAO), Diet and Cardiovascular Disease
Thomas, M. S., & Fernández, M. L. (2021) · Current Atherosclerosis Reports · doi:10.1007/s11883-021-00910-x · Cited by 182 · see citing works
Cai, Y., Huang, F., Lao, X., Lu, Y., Gao, X. J., Alolga, R. N., Yin, K., Zhou, X., Wang, Y., Liu, B., et al. (2022) · npj Biofilms and Microbiomes · doi:10.1038/s41522-022-00273-4 · Cited by 178 · see citing works
Comparing metabolite profiles of habitual diet in serum and urine
Playdon, M. C., Sampson, J. N., Cross, A. J., Sinha, R. R., Guertin, K. A., Moy, K. A., Rothman, N., Irwin, M. L., Mayne, S. T., Stolzenberg‐Solomon, R. Z., et al. (2016) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.116.135301 · Cited by 175 · see citing works
Interaction between gut microbiome and cardiovascular disease
Peng, J., Xiao, X., Hu, M., & Zhang, X. (2018) · Life Sciences · doi:10.1016/j.lfs.2018.10.063 · Cited by 175 · see citing works
Fu, B. C., Hullar, M. A. J., Randolph, T. W., Franke, A. A., Monroe, K. R., Cheng, I. C., Wilkens, L. R., Shepherd, J., Madeleine, M. M., Marchand, L. L., et al. (2020) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqaa015 · Cited by 171 · see citing works
Sharpton, S. R., Ajmera, V. H., & Loomba, R. S. (2018) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2018.08.065 · Cited by 170 · see citing works
Lowe‐Power, T. M., Hendrich, C. G., von Roepenack‐Lahaye, E., Li, B., Wu, D., Mitra, R. M., Dalsing, B. L., Ricca, P., Naidoo, J., Cook, D. E., et al. (2017) · Environmental Microbiology · doi:10.1111/1462-2920.14020 · Cited by 162 · see citing works
Gut microbiota and hypertension: association, mechanisms and treatment
Yang, Z., Wang, Q., Liu, Y., Wang, L., Ge, Z., Li, Z., Feng, S., & Wu, C. (2023) · Clinical and Experimental Hypertension · doi:10.1080/10641963.2023.2195135 · Cited by 170 · see citing works
Li, X. S., Wang, Z., Čajka, T., Buffa, J. A., Nemet, I., Hurd, A. G., Gu, X., Skye, S. M., Roberts, A. B., Wu, Y., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.99096 · Cited by 166 · see citing works
Self-citationGut Bacteria and Hydrogen Sulfide: The New Old Players in Circulatory System Homeostasis
Tomášová, L., Konopelski, P., & Ufnal, M. (2016) · Molecules · doi:10.3390/molecules21111558 · Cited by 156 · see citing works
The Role of Oral Microbiota in Intra-Oral Halitosis
Hampelska, K., Jaworska, M. M., Babalska, Z. Ł., & Karpiński, T. M. M. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9082484 · Cited by 169 · see citing works
The gut microbiome and HIV-1 pathogenesis
Dillon, S. M., Frank, D. N., & Wilson, C. C. (2016) · AIDS · doi:10.1097/qad.0000000000001289 · Cited by 162 · see citing works
Chriswell, M. E., Lefferts, A. R., Clay, M. R., Hsu, A., Seifert, J. A., Feser, M. L., Rims, C. R., Bloom, M. S., Bemis, E. A., Liu, S., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abn5166 · Cited by 163 · see citing works
Benson, T. W., Conrad, K. A., Li, X. S., Wang, Z., Helsley, R. N., Schugar, R. C., Coughlin, T. M., Wadding-Lee, C., Fleifil, S., Russell, H., et al. (2023) · Circulation · doi:10.1161/circulationaha.122.060573 · Cited by 165 · see citing works
Microbiome, trimethylamine N-oxide, and cardiometabolic disease
Tang, W. H. W., & Hazen, S. L. (2017) · Translational Research · doi:10.1016/j.trsl.2016.07.007 · Cited by 160 · see citing works
Gut microbes impact stroke severity via the trimethylamine N-oxide pathway
Zhu, W., Romano, K. A., Li, L., Buffa, J. A., Sangwan, N., Prakash, P., Tittle, A. N., Li, X. S., Fu, X., Androjna, C., et al. (2021) · Cell Host & Microbe · doi:10.1016/j.chom.2021.05.002 · Cited by 165 · see citing works
Self-citationThe Influence of Gut Dysbiosis in the Pathogenesis and Management of Ischemic Stroke
Chidambaram, S. B., Rathipriya, A. G., Mahalakshmi, A. M., Sonali, S., Hediyal, T. A., Ray, B., Sunanda, T., Rungratanawanich, W., Kashyap, R. S., Qoronfleh, M. W., et al. (2022) · Cells · doi:10.3390/cells11071239 · Cited by 164 · see citing works
Zhu, Y., Dwidar, M., Nemet, I., Buffa, J. A., Sangwan, N., Li, X. S., Anderson, J. T., Romano, K. A., Fu, X., Funabashi, M., et al. (2022) · Cell Host & Microbe · doi:10.1016/j.chom.2022.11.015 · Cited by 163 · see citing works
Self-citationEffect of Functional Oligosaccharides and Ordinary Dietary Fiber on Intestinal Microbiota Diversity
Cheng, W., Lü, J., Li, B., Lin, W., Zhang, Z., Wei, X., Sun, C., Chi, M., Bi, W., Yang, B., et al. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.01750 · Cited by 156 · see citing works
Palau‐Rodriguez, M., Tulipani, S., Queipo‐Ortuño, M. I., Urpí-Sardà, M., Tinahones, F. J., & Andrés‐Lacueva, C. (2015) · Frontiers in Microbiology · doi:10.3389/fmicb.2015.01151 · Cited by 157 · see citing works
Diet, Microbiota, and Metabolic Health: Trade-Off Between Saccharolytic and Proteolytic Fermentation
Korpela, K. (2018) · Annual Review of Food Science and Technology · doi:10.1146/annurev-food-030117-012830 · Cited by 153 · see citing works
Implications of Gut Microbiota in Neurodegenerative Diseases
Zhang, H., Chen, Y., Wang, Z., Xie, G., Liu, M., Yuan, B., Chai, H., Wang, W., & Cheng, P. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.785644 · Cited by 157 · see citing works
Inhibition of microbiota-dependent TMAO production attenuates chronic kidney disease in mice
Zhang, W., Miikeda, A., Zuckerman, J. E., Jia, X., Charugundla, S., Zhou, Z., Kaczor‐Urbanowicz, K. E., Magyar, C. E., Guo, F., Wang, Z., et al. (2021) · Scientific Reports · doi:10.1038/s41598-020-80063-0 · Cited by 148 · see citing works
The Epigenetic Connection Between the Gut Microbiome in Obesity and Diabetes
Sharma, M., Li, Y., Stoll, M. L., & Tollefsbol, T. O. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2019.01329 · Cited by 152 · see citing works
Suzuki, A., & Diehl, A. M. (2016) · Annual Review of Medicine · doi:10.1146/annurev-med-051215-031109 · Cited by 159 · see citing works
The gut microbiome and cardiovascular disease: current knowledge and clinical potential
Ahmad, A. F., Dwivedi, G., O’Gara, F., Caparros-Martin, J. A., & Ward, N. C. (2019) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00376.2019 · Cited by 153 · see citing works
Li, X., Su, C., Jiang, Z., Yang, Y., Zhang, Y., Yang, M., Zhang, X., Du, Y., Zhang, J., Wang, L., et al. (2021) · npj Biofilms and Microbiomes · doi:10.1038/s41522-021-00205-8 · Cited by 153 · see citing works
Mucosal Interactions between Genetics, Diet, and Microbiome in Inflammatory Bowel Disease
Basson, A. R., Trotter, A., Rodriguez‐Palacios, A., & Cominelli, F. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00290 · Cited by 136 · see citing works
Trimethylamine N-Oxide in Relation to Cardiometabolic Health—Cause or Effect?
Papandreou, C., Moré, M. I., & Bellamine, A. (2020) · Nutrients · doi:10.3390/nu12051330 · Cited by 150 · see citing works
Carpi, R. Z., Barbalho, S. M., Sloan, K. P., Laurindo, L. F., Gonzaga, H. F., Grippa, P. C., Zutin, T. L. M., Gírio, R. J. S., Repetti, C. S. F., Detregiachi, C. R. P., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23158805 · Cited by 144 · see citing works
Beyond the gut: decoding the gut–immune–brain axis in health and disease
Park, J. C., Chang, L., Kwon, H.-K., & Im, S.-H. (2025) · Cellular & Molecular Immunology · doi:10.1038/s41423-025-01333-3 · Cited by 149 · see citing works
Li, J., Li, Y., Ivey, K. L., Wang, D. D., Wilkinson, J. E., Franke, A., Lee, K. H., Chan, A., Huttenhower, C., Hu, F. B., et al. (2022) · Gut · doi:10.1136/gutjnl-2020-322473 · Cited by 137 · see citing works
Cardiovascular and antiobesity effects of resveratrol mediated through the gut microbiota
Bird, J. K., Raederstorff, D., Weber, P., & Steinert, R. E. (2017) · Advances in Nutrition · doi:10.3945/an.117.016568 · Cited by 136 · see citing works
Ji, Y. S., Yin, Y., Sun, L., & Zhang, W. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093066 · Cited by 128 · see citing works
Metabolomic analysis in inflammatory bowel disease: A systematic review
Gallagher, K., Catesson, A., Griffin, J. L., Holmes, E., & Williams, H. R. T. (2021) · Journal of Crohn's and Colitis · doi:10.1093/ecco-jcc/jjaa227 · Cited by 133 · see citing works
Colon Carcinogenesis: The Interplay Between Diet and Gut Microbiota
Loke, Y. L., Chew, M. T., Ngeow, Y. F., Lim, W. W.-D., & Peh, S. C. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.603086 · Cited by 129 · see citing works
Nutrition, inflammation and liver-spleen axis
Barrea, L., Somma, C. D., Muscogiuri, G., Tarantino, G., Tenore, G. C., Orio, F., Colao, A., & Savastano, S. (2017) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2017.1353479 · Cited by 304 · see citing works
- 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
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