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Cited by 754Gut microbiota and healthSirtuins and Resveratrol in MedicineCholesterol and Lipid Metabolism

Resveratrol Attenuates Trimethylamine- N -Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota

Open access
Chen, Ming-liang, Yi, Long, Zhang, Yong, Zhou, Xi, Ran, Li, Yang, Jining, Zhu, Jun-dong, Zhang, Qian-yong +1 more·2016·mBio
DOI 10.1128/mbio.02210-15PMC PMC4817264
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Abstract

The gut microbiota is found to be strongly associated with atherosclerosis (AS). Resveratrol (RSV) is a natural phytoalexin with anti-AS effects; however, its mechanisms of action remain unclear. Therefore, we sought to determine whether the anti-AS effects of RSV were related to changes in the gut microbiota. We found that RSV attenuated trimethylamine- N -oxide (TMAO)-induced AS in ApoE −/− mice. Meanwhile, RSV decreased TMAO levels by inhibiting commensal microbial trimethylamine (TMA) production via gut microbiota remodeling in mice. Moreover, RSV increased levels of the genera Lactobacillus and Bifidobacterium , which increased the bile salt hydrolase activity, thereby enhancing bile acid (BA) deconjugation and fecal excretion in C57BL/6J and ApoE −/− mice. This was associated with a decrease in ileal BA content, repression of the enterohepatic farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) axis, and increased cholesterol 7a-hydroxylase (CYP7A1) expression and hepatic BA neosynthesis. An FXR antagonist had the same effect on FGF15 and CYP7A1 expression as RSV, while an FXR agonist abolished RSV-induced alterations in FGF15 and CYP7A1 expression. In mice treated with antibiotics, RSV neither decreased TMAO levels nor increased hepatic BA synthesis. Additionally, RSV-induced inhibition of TMAO-caused AS was also markedly abolished by antibiotics. In conclusion, RSV attenuated TMAO-induced AS by decreasing TMAO levels and increasing hepatic BA neosynthesis via gut microbiota remodeling, and the BA neosynthesis was partially mediated through the enterohepatic FXR-FGF15 axis. IMPORTANCE Recently, trimethylamine- N -oxide (TMAO) has been identified as a novel and independent risk factor for promoting atherosclerosis (AS) partially through inhibiting hepatic bile acid (BA) synthesis. The gut microbiota plays a key role in the pathophysiology of TMAO-induced AS. Resveratrol (RSV) is a natural phytoalexin with prebiotic benefits. A growing body of evidence supports the hypothesis that phenolic phytochemicals with poor bioavailability are possibly acting primarily through remodeling of the gut microbiota. The current study showed that RSV attenuated TMAO-induced AS by decreasing TMAO levels and increasing hepatic BA neosynthesis via gut microbiota remodeling. And RSV-induced hepatic BA neosynthesis was partially mediated through downregulating the enterohepatic farnesoid X receptor-fibroblast growth factor 15 axis. These results offer new insights into the mechanisms responsible for RSV’s anti-AS effects and indicate that the gut microbiota may become an interesting target for pharmacological or dietary interventions to decrease the risk of developing cardiovascular diseases.

AI snapshot

Written from the paper’s full text.

TL;DR

Resveratrol (RSV) attenuated trimethylamine-N-oxide (TMAO)-induced atherosclerosis in mice by remodeling the gut microbiota, reducing microbial TMA production, and increasing hepatic bile acid synthesis. The bile acid effects were partially mediated by downregulation of the enterohepatic FXR-FGF15 axis.

Key findings

  • RSV attenuated TMAO-induced atherosclerosis in ApoE−/− mice; this protection was markedly abolished by antibiotics, indicating dependence on the gut microbiota.
  • RSV decreased serum TMA and TMAO levels by inhibiting gut microbial TMA production, while increasing hepatic FMO3 expression and FMO activity, so the TMAO reduction was not due to decreased liver FMO3.
  • RSV increased Lactobacillus and Bifidobacterium, increased bile salt hydrolase (BSH) activity, enhanced bile acid deconjugation and fecal bile acid excretion, decreased ileal bile acid content, repressed ileal FXR-FGF15, and increased hepatic CYP7A1 expression and bile acid neosynthesis. An FXR antagonist mimicked RSV effects on FGF15/CYP7A1, while an FXR agonist abolished them.
  • In choline-treated ApoE−/− mice, RSV increased Bacteroidetes abundance from 20.6% to 34.0% and decreased Firmicutes from 60.1% to 50.1%; RSV also increased Bacteroides, Lactobacillus, Bifidobacterium, and Akkermansia and decreased Prevotella, Ruminococcaceae_unclassified, and Biophila.

Methods

  • Female 8-week-old C57BL/6J and ApoE−/− mice were fed chow with or without RSV (0.4%), in the presence or absence of choline (1%) and/or antibiotics; some experiments used single doses of choline (400 mg/kg) or TMA (40 mg/kg). Treatment durations were 30 days for C57BL/6J studies and 4 months for ApoE−/− atherosclerosis studies, with n = 5 or 10 per group.
  • TMA/TMAO and bile acids were measured by LC/MS; gut microbiota was analyzed by 16S rRNA gene sequencing and qPCR; liver/ileal expression was assessed by qPCR and Western blotting; FMO and BSH activities were measured; atherosclerosis was assessed by ultrasound, Oil red O staining, and aortic cholesterol content.
  • Statistical analysis used Student’s t test or one-way ANOVA with Tukey-Kramer post hoc tests; correlations used Pearson’s tests with FDR adjustment for multiple comparisons.

Limitations

  • The paper states that the exact mechanisms by which circulating TMAO promotes atherosclerosis, whether TMAO acts through a specific receptor, and whether RSV reverses other TMAO-caused signaling changes remain largely unknown and need further elucidation.
  • The paper notes that RSV has poor bioavailability, and the exact mechanisms linking RSV, SIRT1-FXR signaling, FMO3 regulation, and bile acid transport need further clarification.
  • Evident from the text: findings are from female mouse models only, with no human clinical outcomes; antibiotic treatment is nonselective and may affect microbiota beyond TMA production, so microbiota-dependent conclusions are correlative and ablation-based rather than mechanism-specific.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1128/mbio.02210-15

Cites

49 of 49 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 75 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    RSV reversed the choline-induced decrease of CYP7A1 mRNA and protein expression in ApoE−/− mice.

    “and reversed the choline-induced decrease of CYP7A1 mRNA and protein expression in ApoE−/− mice (Fig. 8G and H).”
    Quote in the paperSubstantial claim
  • Findingown data

    In choline-treated ApoE−/− mice, RSV reversed the choline-induced increase in serum total cholesterol and liver cholesterol levels.

    “these effects were reversed by treatment with RSV (Fig. 8A to E).”
    Quote in the paperSubstantial claim
  • Findingown data

    There were no significant differences in liver bile acid content among the groups in choline-treated ApoE−/− mice.

    “And there were no significant differences in liver BA content among the groups (Fig. 8F).”
    Quote in the paperNot a substantial claim
  • Findingown data

    The Proteobacteria and Actinobacteria phyla showed no significant changes after choline treatment in ApoE−/− mice.

    “The Proteobacteria and Actinobacteria phyla showed no significant changes after choline treatment in ApoE−/− mice (see Fig. S4A).”
    Quote in the paperNot a substantial claim
  • Findingown data

    When the gut microbiota was suppressed by antibiotics, RSV-induced inhibition of TMAO-caused atherosclerosis was significantly abolished in ApoE−/− mice.

    “Moreover, when the gut microbiota was suppressed by Abs, RSV-induced inhibition of TMAO-caused AS was significantly abolished (Fig. 6).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Antibiotic treatment suppresses the gut microbiota sufficiently to test its role in the effects of resveratrol.
  • May combine two claims. 43
  • The quote only partly states this claim. 8
  • Classified as probably not a substantial claim. 27

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Production of TMA from choline was higher in cecal content from choline-treated ApoE−/− mice, and this effect was reversed by RSV administration.

    “Additionally, via a direct ex vivo assay, we found that the production of TMA from choline was higher in cecal content from choline-treated mice and that the effect was reversed by RSV administration (Fig. 7I).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    RSV treatment reduced mRNA levels of the bile acid transporters OSTα and OSTβ in C57BL/6J mice.

    “Finally, we observed a reduction in the mRNA levels of the BA transporters organic solute transporter alpha (OSTα) and beta (OSTβ) in RSV-treated mice”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    RSV increased the bile TCA/TβMCA ratio and induced CYP7A1 mRNA and protein expression in C57BL/6J mice, and these effects were inhibited by antibiotics treatment.

    “As shown in Fig. 4G to I and in Table S4 in the supplemental material, RSV increased the bile TCA/TβMCA ratio and induced CYP7A1 mRNA and protein expression and the effects were inhibited by Abs treatment.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Antibiotic treatment suppresses the gut microbiota sufficiently to test its role in the effects of resveratrol.

  • May combine two claims.

    Findingown data

    In C57BL/6J mice given a single dose of TMA, RSV-treated mice had higher TMAO levels and lower TMA levels than control mice.

    “For RSV-treated mice given TMA, TMAO levels were higher and TMA levels were lower than those in the control group (Fig. 1D)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In ApoE−/− mice, atherosclerotic lesion area and cholesterol content in the whole aorta were much higher in mice fed choline than in chow-fed mice, and these effects were markedly reversed by RSV or antibiotics administration.

    “The atherosclerotic lesion area and the cholesterol content in the whole aorta, as indexes of AS severity, were much higher in mice fed with choline than in chow-fed mice, and the effects were markedly reversed by RSV or Abs administration (Fig. 6).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Antibiotic treatment suppresses the gut microbiota sufficiently to test its role in the effects of resveratrol.

  • May combine two claims.

    Findingown data

    RSV significantly decreased liver cholesterol level and increased bile acid pool size and gallbladder and small-intestine luminal bile acid content in C57BL/6J mice; these effects were reversed by antibiotics.

    “We found that RSV significantly decreased the liver cholesterol level and increased the BA pool size and the gallbladder and SI luminal BA content; these effects were reversed by treatment with Abs (Fig. 4A to D).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Antibiotic treatment suppresses the gut microbiota sufficiently to test its role in the effects of resveratrol.

  • The quote only partly states this claim.

    Findingown data

    RSV markedly increased FMO activity in the liver of C57BL/6J mice.

    “RSV also markedly increased FMO activity in the liver (Fig. 2C).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Compared to chow-fed ApoE−/− mice, choline significantly increased the number of Prevotella and decreased the concentrations of Bacteroides, Lactobacillus, and Bifidobacterium.

    “Moreover, compared to chow-fed ApoE−/− mice, choline significantly increased the number of Prevotella and decreased the concentrations of Bacteroides, Lactobacillus, and Bifidobacterium (see Fig. S4B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In C57BL/6J mice, peak serum concentrations of TMA and TMAO occurred 4 h after choline administration and 1 h after TMA administration.

    “Via liquid chromatography-tandem mass spectrometry (LC/MS), we found that peak concentrations of TMA and TMAO occurred 4 h after choline administration and 1 h after TMA administration (Fig. 1A and B).”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    There was a significant decrease in the fecal conjugated/unconjugated bile acid ratio, along with an increase in bile salt hydrolase (BSH) enzyme activity, in the feces of RSV-treated C57BL/6J mice.

    “In contrast, there was a significant decrease in the fecal conjugated/unconjugated BA ratio, along with an increase in bile salt hydrolase (BSH) enzyme activity, in the feces of RSV-treated mice (Fig. 3C and D; see also Table S4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In ApoE−/− mice, choline administration markedly increased the bacterial concentrations of Bacteroidetes phyla and decreased the concentrations of Firmicutes phyla compared to the control group.

    “Via qPCR and sequencing 16S rRNA assays, we found that choline administration markedly increased the bacterial concentrations of Bacteroidetes phyla and decreased the concentrations of Firmicutes phyla compared to the control group (see Fig. S4A in the supplemental material).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    RSV induced an increase in the relative abundances of Bacteroides, Lactobacillus, Bifidobacterium, and Akkermansia in C57BL/6J mice.

    “Genus-level analysis showed that RSV induced an increase in the relative abundances of Bacteroides, Lactobacillus, Bifidobacterium, and Akkermansia in mice (Fig. 2E and F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Addition of 1% choline over 30 days significantly increased serum TMA and TMAO levels in C57BL/6J mice, and this increase was reversed by RSV administration.

    “Moreover, the addition of 1% choline over 30 days significantly increased the levels of TMA and TMAO in mice; however, this was reversed by RSV administration (Fig. 1E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In ApoE−/− mice, RSV administration markedly decreased TMA and TMAO contents and increased the expression levels of liver FMO3 and FMO activity.

    “As shown in Fig. 7A to D, RSV administration markedly decreased TMA and TMAO contents and increased the expression levels of liver FMO3 and FMO activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the liver, RSV treatment had no significant effect on the mRNA level of the SHP gene and the mRNA and protein levels of FXR in C57BL/6J mice.

    “In the liver, RSV treatment appeared to have no significant effect on the mRNA level of the SHP gene and the mRNA and protein levels of FXR (see Fig. S3A and B in the supplemental material).”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    RSV significantly enhanced fecal bile acid loss in C57BL/6J mice, and this effect was inhibited by antibiotics.

    “RSV significantly enhanced fecal BA loss, which was inhibited by Abs (Fig. 3A).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Antibiotic treatment suppresses the gut microbiota sufficiently to test its role in the effects of resveratrol.

  • May combine two claims.

    Findingown data

    RSV increased the relative abundances of Bacteroides, Lactobacillus, Bifidobacterium, and Akkermansia and decreased the relative abundances of Prevotella, Ruminococcaceae_unclassified, and Biophila in choline-fed ApoE−/− mice.

    “RSV also increased the relative abundances of Bacteroides, Lactobacillus, Bifidobacterium, and Akkermansia and decreased the relative abundances of Prevotella, Ruminococcaceae_unclassified, and Biophila in choline-fed ApoE−/− mice (Fig. 7F and G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the same C57BL/6J mice, RSV treatment markedly decreased TMA and TMAO levels after choline treatment, but after washout with a chow diet for 1 month, RSV failed to reduce TMA and TMAO contents after choline administration.

    “Moreover, we found that the same mice fed with RSV could show markedly decreased TMA and TMAO levels after choline treatment; however, after washout with a chow diet for 1 month, they failed to reduce TMA and TMAO contents after choline administration (Fig. 2J).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Plasma RSV content was higher in mice fed RSV than in mice fed a standard diet.

    “Additionally, plasma RSV content was higher in mice fed RSV than in mice fed a standard diet (Fig. 1F).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    Production of TMA from choline was lower in cecal content from RSV-treated C57BL/6J mice than in control.

    “Via a direct ex vivo assay, we found that the production of TMA from choline was lower in cecal content from RSV-treated mice”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    RSV treatment resulted in a significant decrease in ileal FGF15 mRNA and protein levels in C57BL/6J mice, while ileal FXR mRNA and protein levels were unchanged.

    “RSV treatment resulted in a significant decrease in ileal FGF15 mRNA and protein levels; however, ileal FXR mRNA and protein levels were unchanged (Fig. 5A and B).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    The proportion of sequences assigned to Bacteroidetes was significantly increased in metagenomes of RSV-fed C57BL/6J animals at the expense of Firmicutes.

    “The proportion of sequences assigned to Bacteroidetes was significantly increased in metagenomes of RSV-fed animals at the expense of Firmicutes (Fig. 2D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    RSV did not change the mRNA level of SHP or the mRNA and protein levels of FXR in the liver in choline-treated ApoE−/− mice.

    “The mRNA level of the SHP gene and the mRNA and protein levels of FXR in the liver were unchanged by RSV (Fig. 9A and B).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    RSV significantly increased the expression of CYP7A1, subsequently inducing bile acid synthesis in the liver.

    “We observed that RSV significantly increased the expression of CYP7A1, subsequently inducing BA synthesis in the liver.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    RSV decreased the activity of ileal FXR and the expression of FGF15 in small intestinal tissues.

    “We also found that RSV decreased the activity of ileal FXR and the expression of FGF15 by decreasing the levels of FXR agonists (TCA and CDCA) in SI tissues (45, 46).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [45] De Aguiar Vallim TQ, Tarling EJ, Edwards PA 2013 Pleiotropic roles of bile acids in metabolism. Cell Metab 17: 657– 669. doi: 10.1016/j.cmet.2013.03.013. 23602448 PMC3654004 source

      Not checked in the free run.

    • cites [46] Sayin SI, Wahlström A, Felin J, Jäntti S, Marschall HU, Bamberg K, Angelin B, Hyötyläinen T, Orešič M, Bäckhed F 2013 Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 17: 225– 235. doi: 10.1016/j.cmet.2013.01.003. 23395169 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    When Z-Gug, a natural antagonist of FXR, was administered, RSV failed to reduce FGF15 expression and to induce the expression of CYP7A1 in mice.

    “When Z-Gug, a natural antagonist of FXR, was administered, RSV failed to reduce FGF15 expression and to induce the expression of CYP7A1 in mice.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Z-Gug and GW4064 specifically modulate FXR without off-target effects on FGF15 and CYP7A1 expression.

  • May combine two claims.

    Premisecitation

    TMAO generation is dependent on the gut microbiota, which first metabolizes dietary choline to trimethylamine (TMA), and TMA is then metabolized to TMAO by flavin monooxygenase (FMO) enzymes in the liver.

    “TMAO generation is dependent on the gut microbiota, which first metabolizes dietary choline to trimethylamine (TMA). Thereafter, the TMA is metabolized to TMAO by enzymes of the flavin monooxygenase (FMO) family in the liver (4).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, DiDonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WH 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.

  • Classified as probably not a substantial claim.

    Premisecitation

    Primary bile acids are synthesized from cholesterol in the liver and further metabolized by the gut microbiota into secondary bile acids via deconjugation, dehydrogenation, and dehydroxylation in the gut.

    “Primary BAs are synthesized from cholesterol in the liver and further metabolized by the gut microbiota into secondary BAs via deconjugation, dehydrogenation, and dehydroxylation in the gut (6).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Jones ML, Tomaro-Duchesneau C, Prakash S 2014 The gut microbiome, probiotics, bile acids axis, and human health. Trends Microbiol 22: 306– 308. doi: 10.1016/j.tim.2014.04.010. 24836108 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    RSV downregulated the ileal FXR-FGF15 axis, which might result from RSV-induced significant reduction in FXR agonists (TCA, DCA, CA, and CDCA) in small-intestine tissues.

    “These findings highlighted that RSV downregulated the ileal FXR-FGF15 axis, which might result from RSV-induced significant reduction in FXR agonists (TCA, DCA, CA, and CDCA) in SI tissues (see Table S4).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A polyphenol-rich cranberry extract and metformin attenuate diet-induced metabolic syndrome in mice in a gut microbiota-dependent manner.

    “Researchers have confirmed that a polyphenol-rich cranberry extract and metformin attenuate diet-induced metabolic syndrome in mice in a gut microbiota-dependent manner (16, 17).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] Shin NR, Lee JC, Lee HY, Kim MS, Whon TW, Lee MS, Bae JW 2014 An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 63: 727– 735. doi: 10.1136/gutjnl-2012-303839. 23804561 source

      Not checked in the free run.

    • cites [17] Anhê FF, Roy D, Pilon G, Dudonné S, Matamoros S, Varin TV, Garofalo C, Moine Q, Desjardins Y, Levy E, Marette A 2015 A polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased Akkermansia spp. population in the gut microbiota of mice. Gut 64: 872– 883 doi: 10.1136/gutjnl-2014-307142. 25080446 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    RSV attenuated TMAO-induced atherosclerosis by decreasing TMAO levels and increasing hepatic bile acid neosynthesis via gut microbiota remodeling, and the bile acid neosynthesis was partially mediated through the enterohepatic FXR-FGF15 axis.

    “In conclusion, RSV attenuated TMAO-induced AS by decreasing TMAO levels and increasing hepatic BA neosynthesis via gut microbiota remodeling, and the BA neosynthesis was partially mediated through the enterohepatic FXR-FGF15 axis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    VSL#3 probiotics can induce hepatic bile acid neosynthesis via downregulation of the gut-liver FXR-FGF15 axis.

    “VSL#3 probiotics can induce hepatic BA neosynthesis via downregulation of the gut-liver FXR-FGF15 axis (10).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Degirolamo C, Rainaldi S, Bovenga F, Murzilli S, Moschetta A 2014 Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the FXR-FGF15 axis in mice. Cell Rep 7: 12– 18. doi: 10.1016/j.celrep.2014.02.032. 24656817 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The gut microbiota can reduce levels of tauro-beta-muricholic acid (T-βMCA), a naturally occurring FXR antagonist, which subsequently inhibits CYP7A1 by activating FXR-FGF15 signaling and ultimately regulating bile acid metabolism in the liver.

    “Sayin et al. found that the gut microbiota can reduce the levels of tauro-beta-muricholic acid (T-βMCA), a naturally occurring FXR antagonist. This subsequently inhibits cholesterol 7a-hydroxylase (CYP7A1), the rate-limiting enzyme in BA synthesis, by activating FXR-FGF15 signaling and ultimately regulating BA metabolism in the liver (5, 11).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [5] Sayin SI, Wahlström A, Felin J, Jäntti S, Marschall HU, Bamberg K, Angelin B, Hyötyläinen T, Orešič M, Bäckhed F 2013 Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 17: 225– 235. doi: 10.1016/j.cmet.2013.01.003. 23395169 source

      Not checked in the free run.

    • cites [11] Miyata M, Sakaida Y, Matsuzawa H, Yoshinari K, Yamazoe Y 2011 Fibroblast growth factor 19 treatment ameliorates disruption of hepatic lipid metabolism in farnesoid X receptor (FXR)-null mice. Biol Pharm Bull 34: 1885– 1889. doi: 10.1248/bpb.34.1885. 22130247 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Resveratrol could be a good candidate for prebiotics and could be used to promote the growth of beneficial commensals and confer health benefits to the host.

    “These results suggested that RSV could be a good candidate for prebiotics and could be used to promote the growth of beneficial commensals and thus to confer health benefits to the host.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Resveratrol is a natural polyphenol that is beneficial for treatment of many metabolic diseases, including atherosclerosis.

    “Resveratrol (RSV) is a natural polyphenol that mainly occurs in grapes, berries, and other dietary constituents and is beneficial for treatment of many metabolic diseases, including AS (13).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Chung JH, Manganiello V, Dyck JR 2012 Resveratrol as a calorie restriction mimetic: therapeutic implications. Trends Cell Biol 22: 546– 554. doi: 10.1016/j.tcb.2012.07.004. 22885100 PMC3462230 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    RSV remodeled the gut microbiome in mice, which might contribute to decreased gut microbial TMA production, thereby inhibiting TMAO synthesis.

    “These results indicated that RSV remodeled the gut microbiome in mice, which might contribute to decreased gut microbial TMA production, thereby inhibiting TMAO synthesis.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Bile acid metabolism is controlled by a negative-feedback loop through activation of the nuclear farnesoid X receptor (FXR) in the ileum and liver.

    “This process is controlled by a negative-feedback loop through the activation of the nuclear farnesoid X receptor (FXR) in the ileum and liver (7, 8).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Li-Hawkins J, Gåfvels M, Olin M, Lund EG, Andersson U, Schuster G, Björkhem I, Russell DW, Eggertsen G 2002 Cholic acid mediates negative feedback regulation of bile acid synthesis in mice. J Clin Invest 110: 1191– 1200. doi: 10.1172/JCI16309. 12393855 PMC150802 source

      Not checked in the free run.

    • cites [8] Hylemon PB, Zhou H, Pandak WM, Ren S, Gil G, Dent P 2009 Bile acids as regulatory molecules. J Lipid Res 50: 1509– 1520. doi: 10.1194/jlr.R900007-JLR200. 19346331 PMC2724047 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Tempol can alter the gut microbiome, leading to accumulation of intestinal T-βMCA, thereby inhibiting intestinal FXR signaling and decreasing obesity.

    “Additionally, tempol, an antioxidant and protective agent against radiation, can alter the gut microbiome, leading to the accumulation of intestinal T-βMCA, thereby inhibiting intestinal FXR signaling and decreasing obesity (12).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Li F, Jiang CT, Krausz KW, Li YF, Albert I, Hao HP, Fabre KM, Mitchell JB, Patterson AD, Gonzalez FJ 2013 Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat Commun 4: 2384. doi: 10.1038/ncomms3384. 24064762 PMC6595219 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The physiological effects of dietary resveratrol are in striking contrast to its poor bioavailability, which is a major concern for developing this class of compounds into therapeutic agents.

    “Previous investigations have shown that the physiological effects of dietary RSV are in striking contrast to its poor bioavailability, which is a major concern for the development of this class of compounds into therapeutic agents (14, 15).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Subramanian L, Youssef S, Bhattacharya S, Kenealey J, Polans AS, van Ginkel PR 2010 Resveratrol: challenges in translation to the clinic—a critical discussion. Clin Cancer Res 16: 5942– 5948. doi: 10.1158/1078-0432.CCR-10-1486. 21045084 PMC3057445 source

      Not checked in the free run.

    • cites [15] Asensi M, Medina I, Ortega A, Carretero J, Baño MC, Obrador E, Estrela JM 2002 Inhibition of cancer growth by resveratrol is related to its low bioavailability. Free Radic Biol Med 33: 387– 398. doi: 10.1016/S0891-5849(02)00911-5. 12126761 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    RSV-induced modulation of the gut microbiome contributed to increased BSH activity and subsequently promoted the generation of unconjugated bile acids from conjugated bile acids, thereby enhancing fecal bile acid loss.

    “These results suggested that RSV-induced modulation of the gut microbiome contributed to increased BSH activity and subsequently promoted the generation of unconjugated BAs from conjugated BAs, thereby enhancing fecal BA loss.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The results in ApoE−/− mice were consistent with findings in C57BL/6J mice, suggesting an important role of the gut microbiota in the RSV-induced decrease of TMAO levels.

    “These results were consistent with our findings in C57BL/6J mice, suggesting the important role of the gut microbiota in the RSV-induced decrease of TMAO levels.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Chronic choline supplementation might alter cecal microbial composition, thereby enhancing the synthesis of TMA and TMAO and ultimately increasing atherosclerosis.

    “These results indicated that chronic choline supplementation might alter cecal microbial composition, thereby enhancing the synthesis of TMA and TMAO and ultimately increasing AS.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    RSV reduced TMAO levels by inhibiting gut microbial TMA formation via remodeling gut microbiota, thereby attenuating TMAO-induced atherosclerosis.

    “We found that RSV reduced TMAO levels by inhibiting gut microbial TMA formation via remodeling gut microbiota, thereby attenuating TMAO-induced AS.”
    • Also stated in: § DISCUSSION · plain
      “Here, we found that RSV inhibited TMAO synthesis by decreasing gut microbial TMA production through gut microbiota modulation, which subsequently attenuated TMAO-induced AS.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Suppression of gut microbiota by antibiotics specifically suppresses gut microbiota without affecting other host pathways relevant to bile acid synthesis and atherosclerosis.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Bacterial BSH activity affects systemic metabolic processes and adiposity in the host.

    “Bacterial BSH activity affects systemic metabolic processes and adiposity in the host.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Joyce SA, MacSharry J, Casey PG, Kinsella M, Murphy EF, Shanahan F, Hill C, Gahan CG 2014 Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut. Proc Natl Acad Sci U S A 111: 7421– 7426. doi: 10.1073/pnas.1323599111. 24799697 PMC4034235 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The gut microbiota is important for bile acid metabolism, as it mediates primary bile acid deconjugation and subsequent conversion to secondary bile acids, which are responsible for bile acid synthesis in the liver.

    “The gut microbiota is important for BA metabolism, as it mediates primary BA deconjugation and subsequent conversion to secondary BAs, which are responsible for BA synthesis in the liver (5).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Sayin SI, Wahlström A, Felin J, Jäntti S, Marschall HU, Bamberg K, Angelin B, Hyötyläinen T, Orešič M, Bäckhed F 2013 Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 17: 225– 235. doi: 10.1016/j.cmet.2013.01.003. 23395169 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    The results on RSV and ASBT contradict those previously published, possibly because the present experiments were in vivo, a more complex environment than in vitro.

    “Our results contradict those previously published, possibly because we were experimenting in vivo, which is a more complex environment than that in vitro.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Dietary RSV increases the expression of hepatic CYP7A1 and ameliorates hypercholesterolemia in high-fat-fed C57BL/6J mice.

    “Dietary RSV has been shown to increase the expression of hepatic CYP7A1 and to ameliorate hypercholesterolemia in high-fat-fed C57BL/6J mice (43).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Chen Q, Wang E, Ma L, Zhai P 2012 Dietary resveratrol increases the expression of hepatic 7alpha-hydroxylase and ameliorates hypercholesterolemia in high-fat fed C57BL/6J mice. Lipids Health Dis 11: 56. doi: 10.1186/1476-511X-11-56. 22607622 PMC3439360 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    RSV promotes degradation of ASBT in vitro.

    “RSV promotes the degradation of ASBT in vitro, which might have some clinical relevance with regard to the observed cholesterol-lowering effects of RSV (44).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Chothe PP, Swaan PW 2014 Resveratrol promotes degradation of the human bile acid transporter ASBT (SLC10A2). Biochem J 459: 301– 312. doi: 10.1042/BJ20131428. 24498857 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The gene encoding FMO3 is a direct FXR target gene.

    “It has been demonstrated that the gene encoding FMO3 is a direct FXR target gene, and FXR has been found to be a target of sirtuin 1 (SIRT1) in metabolic regulation (23, 34, 35).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [23] 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.

    • cites [34] Kemper JK, Xiao Z, Ponugoti B, Miao J, Fang S, Kanamaluru D, Tsang S, Wu SY, Chiang CM, Veenstra TD 2009 FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states. Cell Metab 10: 392– 404. doi: 10.1016/j.cmet.2009.09.009. 19883617 PMC2785075 source

      Not checked in the free run.

    • cites [35] Purushotham A, Xu Q, Lu J, Foley JF, Yan X, Kim DH, Kemper JK, Li X 2012 Hepatic deletion of SIRT1 decreases hepatocyte nuclear factor 1 alpha/farnesoid X receptor signaling and induces formation of cholesterol gallstones in mice. Mol Cell Biol 32: 1226– 1236. doi: 10.1128/MCB.05988-11. 22290433 PMC3302441 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    FXR is a target of SIRT1 in metabolic regulation.

    “It has been demonstrated that the gene encoding FMO3 is a direct FXR target gene, and FXR has been found to be a target of sirtuin 1 (SIRT1) in metabolic regulation (23, 34, 35).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [23] 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.

    • cites [34] Kemper JK, Xiao Z, Ponugoti B, Miao J, Fang S, Kanamaluru D, Tsang S, Wu SY, Chiang CM, Veenstra TD 2009 FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states. Cell Metab 10: 392– 404. doi: 10.1016/j.cmet.2009.09.009. 19883617 PMC2785075 source

      Not checked in the free run.

    • cites [35] Purushotham A, Xu Q, Lu J, Foley JF, Yan X, Kim DH, Kemper JK, Li X 2012 Hepatic deletion of SIRT1 decreases hepatocyte nuclear factor 1 alpha/farnesoid X receptor signaling and induces formation of cholesterol gallstones in mice. Mol Cell Biol 32: 1226– 1236. doi: 10.1128/MCB.05988-11. 22290433 PMC3302441 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    RSV is a well-known activator of SIRT1.

    “Moreover, RSV is a well-known activator of SIRT1 and our previous study also found that RSV improved hepatic steatosis partially by inducing autophagy via the SIRT1 signaling pathway in vitro and in vivo (36–38).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [36] Kulkarni SS, Cantó C 2015 The molecular targets of resveratrol. Biochim Biophys Acta 1852: 1114– 1123. doi: 10.1016/j.bbadis.2014.10.005. 25315298 source

      Not checked in the free run.

    • cites [37] El-Mowafy AM, El-Mesery ME, Salem HA, Al-Gayyar MM, Darweish MM 2010 Prominent chemopreventive and chemoenhancing effects for resveratrol: unraveling molecular targets and the role of C-reactive protein. Chemotherapy 56: 60– 65. doi: 10.1159/000298821. 20299793 source

      Not checked in the free run.

    • cites [38] Zhang Y, Chen ML, Zhou Y, Yi L, Gao YX, Ran L, Chen SH, Zhang T, Zhou X, Zou D, Wu B, Wu Y, Chang H, Zhu JD, Zhang QY, Mi MT 2015 Resveratrol improves hepatic steatosis by inducing autophagy through the cAMP signaling pathway. Mol Nutr Food Res 59: 1443– 1457. doi: 10.1002/mnfr.201500016. 25943029 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Bacterial BSH activity represents a key mechanistic target for the control of obesity and hypercholesterolemia, acting by deconjugating bile acids to generate unconjugated bile acids.

    “It also represents a key mechanistic target for the control of obesity and hypercholesterolemia, acting by deconjugating BAs to generate unconjugated BAs (42).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Joyce SA, MacSharry J, Casey PG, Kinsella M, Murphy EF, Shanahan F, Hill C, Gahan CG 2014 Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut. Proc Natl Acad Sci U S A 111: 7421– 7426. doi: 10.1073/pnas.1323599111. 24799697 PMC4034235 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    RSV increased BSH activity, thereby enhancing bile acid deconjugation.

    “Meanwhile, we found that RSV increased BSH activity, thereby enhancing BA deconjugation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    ASBT plays a key role in the enterohepatic recycling of bile acids and indirectly contributes to cholesterol homeostasis.

    “Recently, it was found that ASBT plays a key role in the enterohepatic recycling of BAs and indirectly contributes to cholesterol homoeostasis (26).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Alrefai WA, Gill RK 2007 Bile acid transporters: structure, function, regulation and pathophysiological implications. Pharm Res 24: 1803– 1823. doi: 10.1007/s11095-007-9289-1. 17404808 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    RSV attenuated TMAO-induced atherosclerosis, partially by regulating bile acid synthesis through the enterohepatic FXR-FGF15 axis in a gut microbiota-dependent manner.

    “Overall, we came to the conclusion that RSV attenuated TMAO-induced AS, partially by regulating BA synthesis through the enterohepatic FXR-FGF15 axis in a gut microbiota-dependent manner.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Suppression of gut microbiota by antibiotics specifically suppresses gut microbiota without affecting other host pathways relevant to bile acid synthesis and atherosclerosis.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Bile acids are synthesized from cholesterol by CYP7A1 in the liver and play a central role in cholesterol homeostasis.

    “BAs are synthesized from cholesterol by CYP7A1 in the liver and play a central role in cholesterol homoeostasis (8).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Hylemon PB, Zhou H, Pandak WM, Ren S, Gil G, Dent P 2009 Bile acids as regulatory molecules. J Lipid Res 50: 1509– 1520. doi: 10.1194/jlr.R900007-JLR200. 19346331 PMC2724047 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    RSV improved hepatic steatosis partially by inducing autophagy via the SIRT1 signaling pathway in vitro and in vivo.

    “Moreover, RSV is a well-known activator of SIRT1 and our previous study also found that RSV improved hepatic steatosis partially by inducing autophagy via the SIRT1 signaling pathway in vitro and in vivo (36–38).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [36] Kulkarni SS, Cantó C 2015 The molecular targets of resveratrol. Biochim Biophys Acta 1852: 1114– 1123. doi: 10.1016/j.bbadis.2014.10.005. 25315298 source

      Not checked in the free run.

    • cites [37] El-Mowafy AM, El-Mesery ME, Salem HA, Al-Gayyar MM, Darweish MM 2010 Prominent chemopreventive and chemoenhancing effects for resveratrol: unraveling molecular targets and the role of C-reactive protein. Chemotherapy 56: 60– 65. doi: 10.1159/000298821. 20299793 source

      Not checked in the free run.

    • cites [38] Zhang Y, Chen ML, Zhou Y, Yi L, Gao YX, Ran L, Chen SH, Zhang T, Zhou X, Zou D, Wu B, Wu Y, Chang H, Zhu JD, Zhang QY, Mi MT 2015 Resveratrol improves hepatic steatosis by inducing autophagy through the cAMP signaling pathway. Mol Nutr Food Res 59: 1443– 1457. doi: 10.1002/mnfr.201500016. 25943029 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    FXR activation induces SHP and FGF15, thereby suppressing CYP7A1 expression and ultimately inhibiting bile acid synthesis.

    “Previous studies have shown that FXR activation induces SHP and FGF15, thereby suppressing CYP7A1 expression and ultimately inhibiting BA synthesis (31, 32).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [31] Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, Luo G, Jones SA, Goodwin B, Richardson JA, Gerard RD, Repa JJ, Mangelsdorf DJ, Kliewer SA 2005 Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2: 217– 225. doi: 10.1016/j.cmet.2005.09.001. 16213224 source

      Not checked in the free run.

    • cites [32] Lu TT, Makishima M, Repa JJ, Schoonjans K, Kerr TA, Auwerx J, Mangelsdorf DJ 2000 Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell 6: 507– 515. doi: 10.1016/S1097-2765(00)00050-2. 11030331 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The gut microbiome produces potent ligands corresponding to bile acid receptors.

    “The gut microbiome produces potent ligands corresponding to BA receptors; probiotics or prebiotics could act as therapeutics of BA dysmetabolism, indicating that microbiota-targeted therapies could be effective in preventing and/or treating gut-related diseases, including AS (40).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Swann JR, Want EJ, Geier FM, Spagou K, Wilson ID, Sidaway JE, Nicholson JK, Holmes E 2011 Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proc Natl Acad Sci U S A 108: 4523– 4530. doi: 10.1073/pnas.1006734107. 20837534 PMC3063584 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The higher small intestinal luminal bile acid content upon RSV treatment was presumably a result of increased biliary output.

    “Interestingly, the SI lumenal BA content was higher upon RSV treatment, which was presumably a result of increased biliary output.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    3,3-Dimethyl-1-butanol can reduce TMAO levels by inhibiting the formation of TMA from microbes in mice, thereby attenuating choline diet-enhanced atherosclerosis.

    “Meanwhile, a recent report showed that 3,3-dimethyl-1-butanol can reduce TMAO levels by inhibiting the formation of TMA from microbes in mice, thereby attenuating choline diet-enhanced AS (39).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Wang Z, Roberts AB, Buffa JA, Levison BS, Zhu W, Org E, Gu X, Huang Y, Zamanian-Daryoush M, Culley MK, DiDonato AJ, Fu X, Hazen JE, Krajcik D, DiDonato JA, Lusis AJ, Hazen SL 2015 Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163: 1585– 1595. doi: 10.1016/j.cell.2015.11.055. 26687352 PMC4871610 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    FXR is required for the negative-feedback regulation of bile acid biosynthesis and the enterohepatic cycle.

    “FXR is required for the negative-feedback regulation of BA biosynthesis and the enterohepatic cycle (30).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ 2000 Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102: 731– 744. doi: 10.1016/S0092-8674(00)00062-3. 11030617 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    RSV could attenuate TMAO-caused atherosclerosis, partially by inducing bile acid synthesis in a gut microbiota-dependent manner.

    “Our findings were the first to indicate the crucial role of the gut microbiota in RSV-induced cholesterol metabolism in the liver, indicating that RSV could attenuate TMAO-caused AS, partially by inducing BA synthesis in a gut microbiota-dependent manner.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Suppression of gut microbiota by antibiotics specifically suppresses gut microbiota without affecting other host pathways relevant to bile acid synthesis and atherosclerosis.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    TMA has been reported to influence signal transduction by direct interaction with a family of G protein-coupled receptors.

    “whereas TMA has been reported to influence signal transduction by direct interaction with a family of G protein-coupled receptors (47).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Liberles SD, Buck LB 2006 A second class of chemosensory receptors in the olfactory epithelium. Nature 442: 645– 650. doi: 10.1038/nature05066. 16878137 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    TMAO is reportedly capable of directly inducing conformational changes in proteins and of stabilizing protein folding and acting as a small-molecule protein chaperone.

    “TMAO, a small quaternary amine with an aliphatic character, is reportedly capable of directly inducing conformational changes in proteins and of stabilizing protein folding and acting as a small-molecule protein chaperone (48, 49).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [48] Bai C, Biwersi J, Verkman AS, Matthay MA 1998 A mouse model to test the in vivo efficacy of chemical chaperones. J Pharmacol Toxicol Methods 40: 39– 45. doi: 10.1016/S1056-8719(98)00034-3. 9920533 source

      Not checked in the free run.

    • cites [49] Mello CC, Barrick D 2003 Measuring the stability of partly folded proteins using TMAO. Protein Sci 12: 1522– 1529. doi: 10.1110/ps.0372903. 12824497 PMC2323936 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Bile acid synthesis and modulation of the enterohepatic FXR-FGF15 axis are seen in germ-free, gnotobiotic, and antibiotic-treated animals.

    “BA synthesis and modulation of the enterohepatic FXR-FGF15 axis are seen in germ-free, gnotobiotic, and antibiotic-treated animals (5).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Sayin SI, Wahlström A, Felin J, Jäntti S, Marschall HU, Bamberg K, Angelin B, Hyötyläinen T, Orešič M, Bäckhed F 2013 Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 17: 225– 235. doi: 10.1016/j.cmet.2013.01.003. 23395169 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Probiotic VSL#3 affects hepatic bile acid synthesis by downregulating the gut-liver FXR-FGF15 axis.

    “Results from a recent study demonstrate that probiotic VSL#3 affects hepatic BA synthesis by downregulating the gut-liver FXR-FGF15 axis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Degirolamo C, Rainaldi S, Bovenga F, Murzilli S, Moschetta A 2014 Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the FXR-FGF15 axis in mice. Cell Rep 7: 12– 18. doi: 10.1016/j.celrep.2014.02.032. 24656817 source

      Not checked in the free run.

67 of 67

  • The paper relies on this without support.

    The mechanisms by which resveratrol exerts its anti-atherosclerosis effects remain unclear.

    “Resveratrol (RSV) is a natural phytoalexin with anti-AS effects; however, its mechanisms of action remain unclear.”

  • The paper relies on this without support.

    The gut microbiota is strongly associated with atherosclerosis.

    “The gut microbiota is found to be strongly associated with atherosclerosis (AS).”

  • The paper relies on this without support.

    Antibiotics have side effects and resistance potential that limit their utility.

    “However, the side effects and resistance potential of Abs limit their utility.”

  • The paper relies on this without support.

    Phenolic phytochemicals with poor bioavailability possibly act primarily through remodeling the gut microbiota.

    “However, a growing body of evidence supports the hypothesis that phenolic phytochemicals with poor bioavailability are possibly acting primarily through remodeling the gut microbiota.”

  • The paper relies on this without support.

    Antibiotic treatment suppresses the gut microbiota sufficiently to test its role in the effects of resveratrol.

    “Moreover, when the gut microbiota was suppressed by Abs, RSV-induced inhibition of TMAO-caused AS was significantly abolished (Fig. 6).”

  • The paper relies on this without support.

    Suppression of gut microbiota by antibiotics specifically suppresses gut microbiota without affecting other host pathways relevant to bile acid synthesis and atherosclerosis.

    “when the gut microbiota was suppressed by Abs”
    “in the absence or presence of Abs”

  • The paper relies on this without support.

    Z-Gug and GW4064 specifically modulate FXR without off-target effects on FGF15 and CYP7A1 expression.

    “When Z-Gug, a natural antagonist of FXR, was administered”
    “the presence of GW4064, a synthetic FXR agonist”
7 of 7

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?

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.

  • Opposite reported changes in the fecal conjugated/unconjugated BA ratio

    Minor

    The C57BL/6J results report a decrease in this ratio after RSV treatment, while the ApoE−/− results report an increase and describe the findings as similar. The reported directions are opposite.

  • Figure 9A is identified as different protein measurements

    Minor

    The results cite Figure 9A for the statement about hepatic FXR protein levels, but the Figure 9 caption identifies panel A as a Western blot of CYP7A1.

2 of 2

Cites

Flagged first, then by citations

1 of the 50 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. 10.1172/jci16309 · DOI · Paper page
  2. 10.1016/j.cmet.2013.01.003 · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Chen, M.-L., Yi, L., Zhang, Y., Zhou, X., Ran, L., Yang, J., Zhu, J.-D., Zhang, Q.-Y., & Mi, M.-T.
Affiliations
  • Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, People’s Republic of China
  • Army Medical University (CN)
ORCID
Venue
mBio
Publisher
American Society for Microbiology
Published
2016-05-04
Volume
7
Issue
2
Pages
e02210-15
ISSN
  • 2150-7511 (ISSN-L)
  • 2161-2129
DOI
10.1128/mbio.02210-15
PMC
PMC4817264
OpenAlex
W2324161694
Semantic Scholar
650b0822927c9be31027805f7cbd4489831ba45c
Cited by
754
References
50
Citations by year
2026: 45 · 2025: 76 · 2024: 93 · 2023: 98 · 2022: 107 · 2021: 92 · 2020: 82 · 2019: 71 · 2018: 51 · 2017: 30 · 2016: 8
FWCI
27.88
Type
journal article
Language
en
Open access
Licence
Locations
  • mBio (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
National Natural Science Foundation of China (81470562)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
resveratrol, trimethylamine N-oxide, atherosclerosis, gut microbiota, bile acid metabolism, bile salt hydrolase, farnesoid X receptor, FGF15, CYP7A1, hepatic bile acid synthesis, ApoE-deficient mice
MeSH terms
Gastrointestinal Microbiome, Resveratrol, Animals, Bacteria, Bile Acids and Salts, Cholesterol 7-alpha-Hydroxylase, Female, Humans, Liver, Methylamines, Mice, Inbred C57BL, Stilbenes, Atherosclerosis, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

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