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Cited by 626Gut microbiota and healthOral microbiology and periodontitis researchAtherosclerosis and Cardiovascular Diseases

Bacteroides vulgatus and Bacteroides dorei Reduce Gut Microbial Lipopolysaccharide Production and Inhibit Atherosclerosis

Yoshida, Naofumi, Emoto, Takuo, Yamashita, Tomoya, Watanabe, Hikaru, Hayashi, Tomohiro, Tabata, Tokiko, Hoshi, Namiko, Hatano, Naoya +8 more·2018·Circulation
DOI 10.1161/circulationaha.118.033714
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Abstract

Background: It is increasingly recognized that gut microbiota play a pivotal role in the development of atherosclerotic cardiovascular disease. Previously, we have reported that the abundance of genus Bacteroides is lower in patients with coronary artery disease (CAD) than in patients without CAD with coronary risk factors or in healthy volunteers. However, it remains unclear which and how specific gut bacteria contribute to the progression of atherosclerosis. Methods: We recruited patients with CAD patients and controls without CAD with coronary risk factors. We then compared gut microbial composition using 16S ribosomal RNA gene sequencing in fecal samples to detect species with differential abundance between 2 groups. Subsequently, we used atherosclerosis-prone mice to study the mechanisms underlying the relationship between such species and atherosclerosis. Results: Human fecal 16S ribosomal RNA gene sequencing revealed a significantly lower abundance of Bacteroides vulgatus and Bacteroides dorei in patients with CAD. This significant differential abundance was confirmed by quantitative polymerase chain reaction. Gavage with live B. vulgatus and B. dorei attenuated atherosclerotic lesion formation in atherosclerosis-prone mice, markedly ameliorating endotoxemia followed by decreasing gut microbial lipopolysaccharide production, effectively suppressing proinflammatory immune responses. Furthermore, fecal lipopolysaccharide levels in patients with CAD were significantly higher and negatively correlated with the abundance of B. vulgatus and B. dorei . Conclusions: Our translational research findings identify a previously unknown link between specific gut bacteria and atherosclerosis. Treatment with live B. vulgatus and B. dorei may help prevent CAD. Clinical Trial Registration: URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000018051 . Unique identifier: UMIN000015703.

AI snapshot

Written from the paper’s full text.

TL;DR

In patients with coronary artery disease (CAD), gut abundance of *Bacteroides vulgatus* and *Bacteroides dorei* was lower than in controls without CAD, and fecal lipopolysaccharide (LPS) levels were higher. In atherosclerosis-prone mice, oral gavage with live *B. vulgatus* and *B. dorei* reduced fecal and plasma LPS, dampened inflammation, and attenuated atherosclerotic plaque.

Key findings

  • In 30 patients with CAD versus 30 age- and sex-matched controls without CAD but with coronary risk factors, 16S rRNA sequencing showed relative depletion of *B. vulgatus* and *B. dorei* in CAD; qPCR confirmed significantly decreased abundance of these species.
  • Fecal LPS levels were significantly higher in patients with CAD than controls, and fecal LPS correlated negatively with *B. vulgatus*/*B. dorei* abundance in CAD (r=−0.541, P=0.002); genus *Bacteroides* showed a trend toward negative correlation (r=−0.227, P=0.0838).
  • In apolipoprotein E-deficient mice, gavage with live *B. vulgatus* and *B. dorei* (2.5×10⁹ cfu/100 μL, 5 times/week) significantly reduced aortic root and en face atherosclerotic lesion size, macrophage and CD4⁺ T-cell accumulation, plasma LPS, and proatherogenic cytokines, without significant differences in body weight, plasma cholesterol, or plasma glucose.
  • Live *Bacteroides* treatment decreased predicted microbial LPS biosynthesis genes *LpxA* and *LpxD* and dramatically lowered fecal LPS; heat-killed *Bacteroides* did not decrease fecal LPS, aortic sinus plaque, or plasma LPS compared with controls (reported P=0.92, P=0.74, and P=0.93, respectively).

Methods

  • Human study: 30 patients with CAD and 30 controls without CAD with coronary risk factors were recruited at Kobe University Hospital between October 2014 and July 2015; fecal samples underwent 16S rRNA gene sequencing (V3–V4 region), qPCR, PICRUSt functional prediction, and limulus amebocyte lysate assay for LPS.
  • Mouse study: 6-week-old female apolipoprotein E-deficient mice on C57BL/6 background were randomized to control, live *Bacteroides*, or heat-killed *Bacteroides* groups; mice were gavaged 5 times per week for 10 weeks and euthanized at 16 weeks for atherosclerosis, immune, gut permeability, and LPS analyses.
  • Statistical analysis used R, JMP, and Prism; Shapiro-Wilk test, Student’s t test or Mann-Whitney U test, Fisher exact or χ² test, Spearman correlation, one-way ANOVA, and Benjamini-Hochberg adjustment for multiple comparisons.

Limitations

  • The paper states that 16S rRNA sequencing has low phylogenetic power at the species level and poor discriminatory power for some genera, and that the human CAD gut microbial analysis was a single-center study with a relatively small number of patients.
  • The paper states that controls without CAD did not all undergo coronary angiography, so subclinical CAD may have been present; the limulus amebocyte lysate assay could not measure LPS immunogenicity or the impact of *Bacteroides* on LPS structure/function; mechanisms of atherosclerosis protection by lower LPS were not completely elucidated; mouse and human dominant microbiota differ; and only *B. vulgatus* and *B. dorei* were tested, so more effective strains may exist.
  • Evident from the text: the human findings are cross-sectional and cannot establish causality, and the causal evidence comes from a mouse gavage model rather than a human intervention.

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

Integrity signals

Registry

Crossref · 10.1161/circulationaha.118.033714

Cites

50 of 50 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 32 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Immunohistochemical staining revealed a marked reduction in macrophage and CD4+ T-cell accumulation in atherosclerotic lesions of mice gavaged with live Bacteroides compared with controls.

    “immunohistochemical staining followed by morphometric analysis of atherosclerotic lesions in the aortic sinus revealed a marked reduction in macrophage and CD4 + T-cell accumulation in mice gavaged with live Bacteroides compared with controls (Figure 2C and 2D).”
    Quote in the paperSubstantial claim
  • Findingown data

    HT29 cells stimulated with fecal supernatant from live Bacteroides-treated mice had significantly higher ZO-1 mRNA and protein expression than cells stimulated with control supernatant.

    “we observed significantly higher expression levels of ZO-1 (mRNA and protein) in HT29 cells stimulated with fecal supernatant from live Bacteroides-treated mice than in cells stimulated with fecal supernatant from control mice (Figure VD and VE in the online-only Data Supplement).”
    Quote in the paperSubstantial claim
  • Findingown data

    The abundance of Bacteroides vulgatus and Bacteroides dorei was decreased in patients with coronary artery disease.

    “we found that the abundance of Bacteroides vulgatus and Bacteroides dorei was decreased in patients with CAD.”
    • Also stated in: § Gut Microbial Profile in Patients With CAD · plain
      “patients with CAD showed a relative depletion of B. vulgatus and B. dorei”
    Quote in the paperSubstantial claim
  • Findingown data

    mRNA expression of several proatherogenic immune cell markers and chemokines/chemokine receptors was decreased in mice gavaged with live Bacteroides.

    “The mRNA expression of several proatherogenic immune cell markers and chemokines/ chemokine receptors was decreased in mice gavaged with live Bacteroides (Figure 2E).”
    Quote in the paperSubstantial claim
  • Findingown data

    Mice gavaged with live Bacteroides showed higher mean fluorescence intensity of ZO-1 in the colon.

    “reflected in higher mean fluorescence intensity of ZO-1 in the colon (Figure VC in the online-only Data Supplement).”
    Quote in the paperSubstantial claim
  • May combine two claims. 29
  • Classified as probably not a substantial claim. 21
  • The quote only partly states this claim. 2

  • May combine two claims.

    Findingown data

    Mice gavaged with Bacteroides exhibited decreased expression of MHC class II and CD86, and increased expression of PD-L1 and PD-L2 on splenic CD11c high dendritic cells.

    “mice gavaged with Bacteroides exhibited decreased expression of major histocompatibility complex class II and costimulatory molecule CD86, as well as increased expression of the coinhibitory molecules programmed death ligand-1 and programmed death ligand-2 on splenic CD11c high dendritic cells (Figure IIB in the online-only Data Supplement).”
    • Also stated in: § ORIGINAL RESEARCH ARTICLE · plain
      “Similar phenotypic changes along with increased expression of PD-L1 and PD-L2 in dendritic cells were observed in the spleen.”
    Quote in the paperSubstantial claim

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

    Findingown data

    Gut microbial samples clustered into three clusters at the genus level.

    “the samples were clustered into 3 clusters at the genus level”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mice gavaged with live Bacteroides showed significantly reduced lesion size in the aortic root and en face analysis of thoracoabdominal aortas.

    “mice gavaged with live Bacteroides showed significantly reduced lesion size in the aortic root and en face analysis of thoracoabdominal aortas (Figure 2A and 2B)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Controls without coronary artery disease were significantly more likely to be categorized into cluster 1, whereas few patients with coronary artery disease were categorized into this cluster.

    “The controls without CAD were significantly more likely to be categorized into cluster 1, whereas few patients with CAD were categorized into this cluster (Figure 1F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There was no significant difference in body weight, plasma cholesterol levels, or plasma glucose levels between live Bacteroides-gavaged mice and controls.

    “without significant difference in body weight (Figure 2F), plasma cholesterol levels (Figure 2G), or plasma glucose levels (data not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Each cluster was characterized by high abundance of a specific genus: Bacteroides in cluster 1, Prevotella in cluster 2, and Faecalibacterium, Ruminococcus, or Bifidobacterium in cluster 3.

    “Each cluster was characterized by a high abundance of a specific genus as follows: Bacteroides in cluster 1, Prevotella in cluster 2, and Faecalibacterium, Ruminococcus, or Bifidobacterium in cluster 3 (Figure 1E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Mice gavaged with live Bacteroides had lower numbers of effector CD44 high CD62Llow CD4+ T cells and a significantly higher proportion of CD4+CD25+Foxp3+ regulatory T cells, with higher levels of intracellular CTLA4.

    “Mice gavaged with live Bacteroides had lower numbers of effector CD44 high CD62Llow CD4 + T cells and a significantly higher proportion of CD4 + CD25 + Foxp3 + regulatory T cells, with higher levels of intracellular CTLA4 (Figure IID and IIE in the online-only Data Supplement)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Patients with coronary artery disease showed relative depletion of B. vulgatus and B. dorei and enrichment in Faecalibacterium prausnitzii and Prevotella copri.

    “patients with CAD showed a relative depletion of B. vulgatus and B. dorei and enrichment in Faecalibacterium prausnitzii and Prevotella copri (Figure 1H).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Alpha diversity, the Bacteroidetes/Firmicutes ratio, and the Gram-positive to Gram-negative strain ratio did not differ significantly between coronary artery disease patients and controls.

    “The α diversity, Bacteroidetes/Firmicutes ratio, and Gram-positive to Gramnegative strain ratio did not differ significantly between the 2 groups (Figure 1A and 1C).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    B. vulgatus and B. dorei were the two most abundant species within the genus Bacteroides in 16S rRNA gene sequencing analysis and are dominant species of genus Bacteroides in human gut microbiota.

    “were the 2 most abundant species within the genus Bacteroides in 16S rRNA gene sequencing analysis (Figure 1I).”
    • Also stated in: § DISCUSSION · plain
      “B. vulgatus and B. dorei are the dominant species of genus Bacteroides in human gut microbiota.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The Bacteroidetes/Firmicutes ratio, Gram-positive to Gram-negative strain ratio, and fecal water content did not differ significantly among the 3 groups.

    “The Bacteroidetes/Firmicutes ratio, Gram-positive to Gram-negative strain ratio, and fecal water content did not differ significantly among the 3 groups”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The number of CD4+ T cells and several markers on CD4+ T cells did not significantly change in mesenteric lymph nodes of Bacteroides-gavaged mice.

    “whereas the number of CD4 + T cells and several markers on CD4 + T cells did not significantly change (Figure VIC and VIF in the online-only Data Supplement).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    In patients with coronary artery disease, the abundance of B. vulgatus and B. dorei was significantly negatively correlated with fecal lipopolysaccharide levels (r=-0.541, P=0.002).

    “we found that fecal LPS levels were higher in patients with lower abundance of B. vulgatus and B. dorei.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Fecal lipopolysaccharide levels reflect colon lipopolysaccharide concentrations produced by gut microbiota.

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

    Premisecitation

    Trimethylamine and trimethylamine N-oxide, gut microbiota metabolites of dietary phosphatidylcholine, are associated with cardiovascular disease and with atherosclerosis.

    “Trimethylamine (TMA) and TMA N-oxide, which are gut microbiota metabolites of dietary phosphatidylcholine, are known to be associated with cardiovascular disease and with the atherosclerosis process in particular.3,4”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] source

      Not checked in the free run.

    • cites [4] source

      Not checked in the free run.

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

    Premisecitation

    Coronary artery disease remains the leading cause of morbidity and mortality worldwide despite widespread statin therapy.

    “CAD remains the leading cause of morbidity and mortality worldwide, despite the widespread use of statin therapy in the last decade.12”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Endotoxemia causes systemic inflammation leading to disruption of innate and adaptive immunity and development of atherosclerosis.

    “Endotoxemia is known to cause systemic inflammation leading to the disruption of innate and adaptive immunity and the development of atherosclerosis.[34][35][36]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [34]

      Not checked in the free run.

    • cites [35] source

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    • cites [36]

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

    Premisecitation

    Fish consumption drastically increases circulating trimethylamine N-oxide levels.

    “a recent clinical trial has shown contradictory results indicating that fish consumption drastically increases circulating TMA N-oxide levels”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] source

      Not checked in the free run.

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

    Study design and conductown data

    The study was approved by the Ethics Committee of Kobe University and registered with the University Hospital Medical Information Network Clinical Trials Registry.

    “This study was approved by the Ethics Committee of Kobe University (approval No. 1595) and registered with the University hospital Medical Information Network Clinical Trials Registry (trial registration No. UMIN000015703).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The success of heat-killing B. vulgatus and B. dorei was confirmed by absence of growth of plated heat-killed bacteria.

    “The success of the heat treatment was confirmed by the absence of growth of plated heat-killed bacteria.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All participants provided written informed consent and the study was conducted according to the Declaration of Helsinki.

    “All participants provided written informed consent on enrollment, and the study was conducted according to the guidelines of the Declaration of Helsinki.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All animal experiments were performed according to the Guidelines for Animal Experiments at Kobe University School of Medicine.

    “All experiments were performed according to the Guidelines for Animal Experiments in effect at Kobe University School of Medicine (guideline No. P160701).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    It remains unclear which specific Bacteroides species are involved and what their exact role is in coronary artery disease.

    “However, it remains unclear which specific Bacteroides species are involved and what their exact role is in CAD.11”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11]

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  • Classified as probably not a substantial claim.

    Study design and conductown data

    Six-week-old apolipoprotein E-deficient mice were randomly divided into three treatment groups.

    “Six-week-old mice were randomly divided into 3 treatment groups”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    B. vulgatus and B. dorei share similar 16S rRNA sequencing patterns, so they could not be distinguished by the study's methodology.

    “Because these 2 species share similar 16S rRNA sequencing patterns, 32 we were not able to distinguish them using our methodology.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32]

      Not checked in the free run.

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

    Study design and conductown data

    The study sample size was calculated to be 30 per group using R software with power 0.9, significance level 0.05, mean difference 6, and SD 7.

    “The sample size was calculated using R software (power=0.9,significance level=0.05,mean difference=6, SD=7; n=30 per group.).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The genus Bacteroides includes some of the predominant gut bacteria in humans and has an important role in maintaining a healthy gut ecosystem.

    “The genus Bacteroides includes some of the predominant gut bacteria in humans and is known to have an important role in maintaining a healthy gut ecosystem.7”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7]

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Lipopolysaccharide stimulates cells through TLR4 and upregulates costimulatory molecules on antigen-presenting cells.

    “Because LPS stimulates cells through TLR4 and upregulates costimulatory molecules on antigen-presenting cells, 37”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37]

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Replenishment of live B. vulgatus and B. dorei by oral gavage reduced plaque inflammation, attenuating atherosclerotic lesion formation.

    “These results suggested that replenishment of live B. vulgatus and B. dorei by oral gavage reduced plaque inflammation, attenuating atherosclerotic lesion formation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The effects of live B. vulgatus and B. dorei on atherosclerosis in apolipoprotein E-deficient mice are representative of human coronary artery disease.

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

    Premisecitation

    Lipopolysaccharide from Escherichia coli increases intestinal permeability in a TLR4-dependent manner.

    “Although LPS from E. coli increases intestinal permeability in a TLR4-dependent manner, 40,41”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [40]

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    • cites [41]

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

    Study design and conductreasoning

    We did not perform coronary angiography for all the controls without CAD, so there might have been individuals with subclinical CAD in the control group.

    “because we did not perform coronary angiography for all the controls without CAD, there might have been individuals with subclinical CAD in the control group”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    We did not fully elucidate the characteristics of gut microbial composition in CAD.

    “These limitations imply that we did not fully elucidate the characteristics of gut microbial composition in CAD”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    16S rRNA sequencing analysis helped to seek candidate and translate to animal experiments.

    “16S rRNA sequencing analysis helped to seek candidate and translate to animal experiments”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Gut microbiota-derived LPS and systemic endotoxemia are involved in the onset and progression of atherosclerosis and other prevalent disorders such as inflammatory bowel disease, obesity and related metabolic diseases, and nonalcoholic steatohepatitis.

    “Given that gut microbiota-derived LPS and systemic endotoxemia are involved in the onset and progression of not only atherosclerosis but also many prevalent disorders, such as inflammatory bowel disease, obesity and related metabolic diseases, and nonalcoholic steatohepatitis, [47][48][49]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47][48][49]

      Not checked in the free run.

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

    Study design and conductnone given

    The gut microbial analysis in patients with CAD was a single-center study with a relatively small number of patients.

    “the gut microbial analysis in patients with CAD was a single-center study with a relatively small number of patients”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    B. vulgatus and B. dorei have a causal relationship with atherosclerosis, clarified using a mouse model.

    “used a mouse model to clarify the causal relationship between B. vulgatus and B. dorei and atherosclerosis”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The lipopolysaccharide compounds penta- and tetraacylated lipid A of B. vulgatus and B. dorei are structurally distinct from the hexa-acylated lipopolysaccharide of Escherichia coli and elicit reduced TLR4 responses.

    “the LPS compounds penta-and tetraacylated lipid A of these Bacteroides species are structur-ally distinct from the hexa-acylated LPS of E.scherichia coli and elicit reduced TLR4 responses.33”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    B. vulgatus and B. dorei regulate gut microbial production of lipopolysaccharide and their activity can influence the progression of atherosclerosis in patients with coronary artery disease.

    “These results strongly support the idea that B. vulgatus and B. dorei regulate gut microbial production of LPS and that their activity can influence the progression of atherosclerosis in patients with CAD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Fecal lipopolysaccharide levels reflect colon lipopolysaccharide concentrations produced by gut microbiota.
    • Rests on an assumption: The effects of live B. vulgatus and B. dorei on atherosclerosis in apolipoprotein E-deficient mice are representative of human coronary artery disease.

  • May combine two claims.

    Interpretationcitation

    Augmentation of tolerogenic dendritic cell phenotype in mesenteric lymph nodes or spleen was suspected to migrate into the blood and was closely associated with attenuated atherosclerotic lesion formation.

    “we considered that augmentation of these tolerogenic dendritic cells' phenotype in MLNs or spleen was suspected to migrate into the blood and was closely associated with attenuated atherosclerotic lesion formation as previously reported.42,43,46”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [42]

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    • cites [43]

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    • cites [46]

      Not checked in the free run.

    • The authors state this as an assumption: Decreased circulating lipopolysaccharide levels after live Bacteroides treatment may reduce expression of TLR4, CCR7, CCL17, and CCL21 in the aorta, resulting in less macrophage and CD4+ T cell accumulation in atherosclerotic plaque.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    We performed gavage only with B. vulgatus and B. dorei.

    “we performed gavage only with B. vulgatus and B. dorei”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    B. vulgatus and B. dorei might improve the enteric environment, providing gut bacteria with good living conditions and having a beneficial effect on bacterial lipopolysaccharide production.

    “we believe that B. vulgatus and B. dorei might improve the enteric environment, providing gut bacteria with good living conditions and having a beneficial effect on bacterial LPS production.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    We did not completely elucidate the mechanisms of atherosclerosis protection by lower LPS concentrations in mice.

    “we did not completely elucidate the mechanisms of atherosclerosis protection by lower LPS concentrations in mice”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The limulus amebocyte lysate assay could not measure LPS immunogenicity and the impact of Bacteroides on the structure and function of LPS.

    “it could not measure LPS immunogenicity and the impact of Bacteroides on the structure and function of LPS”
    Quote in the paperNot a substantial claim
42 of 42

  • The authors state this as an assumption.

    Decreased circulating lipopolysaccharide levels after live Bacteroides treatment may reduce expression of TLR4, CCR7, CCL17, and CCL21 in the aorta, resulting in less macrophage and CD4+ T cell accumulation in atherosclerotic plaque.

    “it is intriguing to assume that decreased circulating LPS levels after live Bacteroides treatment may reduce the expression of TLR4, CCR7, CCL17, and CCL21 in the aorta, resulting in less macrophage and CD4 + T cell accumulation in atherosclerotic plaque.”

  • The paper relies on this without support.

    Fecal lipopolysaccharide levels reflect colon lipopolysaccharide concentrations produced by gut microbiota.

    “we measured fecal LPS levels as an indicator of colon LPS concentrations pro-duced by gut microbiota.”

  • The paper relies on this without support.

    The effects of live B. vulgatus and B. dorei on atherosclerosis in apolipoprotein E-deficient mice are representative of human coronary artery disease.

    “Bacteroides treatment may serve as a novel and attractive therapeutic strategy for suppressing lipopolysaccharide-induced inflammatory response in CAD.”

  • The paper relies on this without support.

    The hospital diet consumed by participants did not confound the gut microbiome or fecal lipopolysaccharide measurements.

    “Fecal samples were collected while participants were hospitalized and thus consuming a hospital diet for >1 day.”

  • The paper relies on this without support.

    The impact of colon lipopolysaccharide concentrations on intestinal permeability has not been fully investigated to date.

    “the impact of colon LPS concentrations on intestinal permeability has not been fully investigated to date.”

  • The paper relies on this without support.

    A specific gut microbiota-based target to prevent coronary artery disease has yet to emerge.

    “a specific gut microbiota-based target to prevent CAD has yet to emerge.”

  • The paper relies on this without support.

    Gut microbial profiles depend on age, sex, local food or lifestyle, and many other factors, making it difficult to define dysbiosis in atherosclerosis.

    “it is difficult to conclude the definition of dysbiosis in atherosclerosis because each gut microbial profile depends on age, sex, local food or lifestyle, and many other factors”

  • The paper relies on this without support.

    16S rRNA sequencing analysis has low phylogenetic power at the species level and poor discriminatory power for some genera.

    “It has low phylogenetic power at the species level and poor discriminatory power for some genera”

  • The paper relies on this without support.

    The relative abundances of most of the dominant gut microbiota in mice and humans are quite different.

    “the relative abundances of most of the dominant gut microbiota in mice and human are quite different”
9 of 9

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?

  • Gavage with gram-negative Bacteroides vulgatus and dorei that produce penta- and tetra-acylated lipid A reduced colonic inflammation, endotoxemia, and atherosclerosis in ApoE−/− mice.

    “For instance, gavage with the gram-negative Bacteroides (vulgatus and dorei) that produce penta- and tetra-acylated lipid A – in contrast to the hexa-acylated lipid A of e. coli, reduced colonic inflammation, endotoxemia, and atherosclerosis in ApoE−/− mice31.”

    From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [31]

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.

  • Two different articles are assigned the same DOI

    Minor

    References 31 and 33 give the identical DOI for articles with different titles, journals, and page ranges. At least one DOI is incorrect.

1 of 1

Cites

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Research works printed but not linked: 1

  1. 10.1002/art.39783 · DOI · Paper page

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Authors
Yoshida, N., Emoto, T., Yamashita, T., Watanabe, H., Hayashi, T., Tabata, T., Hoshi, N., Hatano, N., Ozawa, G., Sasaki, N., Mizoguchi, T., Amin, H. Z., Hirota, Y., Ogawa, W., Yamada, T., & Hirata, K.-I.
Affiliations
  • Kobe University (JP)
  • Tokyo Institute of Technology (JP)
  • Technosuruga Laboratory Co., Ltd. (Japan) (JP)
  • University of Indonesia (ID)
Corresponding author
  • Yoshida, Naofumi
  • Emoto, Takuo
ORCID
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2018-11-27
Volume
138
Issue
22
Pages
2486-2498
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/circulationaha.118.033714
OpenAlex
W2886282415
Cited by
619
References
50
Citations by year
2026: 52 · 2025: 105 · 2024: 112 · 2023: 113 · 2022: 101 · 2021: 75 · 2020: 47 · 2019: 13 · 2018: 1
FWCI
12.54
Type
journal article
Language
en
Open access
closed
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
  • Kobe University Repository Kernel (Kobe University) (submittedVersion)
Funders
Japan Society for the Promotion of Science (16H06279)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
Keywords
Bacteroides vulgatus, Bacteroides dorei, gut microbiota, atherosclerosis, coronary artery disease, lipopolysaccharide, endotoxemia, pro-inflammatory response, fecal microbiota transplantation, gut-heart axis
MeSH terms
Gastrointestinal Microbiome, Aged, Animals, Bacteroides, Feces, Female, Humans, Intestines, Lipopolysaccharides, Male, Mice, Inbred C57BL, Middle Aged, Risk Factors, RNA, Ribosomal, 16S, Sequence Analysis, RNA, Mice, Knockout, Immunity, Mucosal, Tight Junctions, 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 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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