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Cited by 625Gut microbiota and healthOral microbiology and periodontitis researchAtherosclerosis and Cardiovascular Diseases

The DOI matches its Crossref record; 50 of the 50 references it cites were found in a registry or an index; none of the 32 sources its claims cite is checked for support yet.

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, Ozawa, Genki, Sasaki, Naoto, Mizoguchi, Taiji, Amin, Hilman Zulkifli, Hirota, Yushi, Ogawa, Wataru, Yamada, Takuji, Hirata, Ken-ichi·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.

Overview

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.

Verification

Claims the paper makes

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

  • It may state two separate claims as one. 29
  • Probably not a substantial claim. 21
  • The quote only partly states this claim. 2
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

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  • 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.

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Metadata

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

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