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Bacteroides vulgatus and Bacteroides dorei Reduce Gut Microbial Lipopolysaccharide Production and Inhibit Atherosclerosis
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.
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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.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Gut Microbial Profile in Patients With CAD
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In the paper
“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).”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Live Bacteroides Treatment Strengthened Tight Junction Formation In Vivo and In Vitro
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In the paper
“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”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Abstract
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In the paper
“The mRNA expression of several proatherogenic immune cell markers and chemokines/ chemokine receptors was decreased in mice gavaged with live Bacteroides (Figure 2E).”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Gut Microbial Profile in Patients With CAD
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In the paper
“reflected in higher mean fluorescence intensity of ZO-1 in the colon (Figure VC in the online-only Data Supplement).”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Live Bacteroides Treatment Strengthened Tight Junction Formation In Vivo and In Vitro
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In the paper
“Although the expression of genes related to TMA synthesis (CutC, CutD) had no difference among the groups”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Gavage With Live Bacteroides Alters Gut Microbial LPS Production
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In the paper
“We found that the relative abundance of the genus Bacteroides was visibly lower in patients with CAD compared with controls (Figure 1G).”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Gut Microbial Profile in Patients With CAD
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In the paper
“The abundance of B. vulgatus and B. dorei was considerably higher in feces from live Bacteroides-gavaged mice (Figure IIIF in the online-only Data Supplement).”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Gavage With Live Bacteroides Alters Gut Microbial LPS Production
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In the paper
“the expression of genes involved in LPS biosynthesis, especially LpxA and LpxD, which are involved in lipid A biosynthesis and constitute the essential acyltransferases of the lipid A structure (Figure 3B), 38,39 was significantly decreased in mice gavaged with live Bacteroides (Figure 3A and 3C, Figure IV in the online-only Data Supplement).”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Gavage With Live Bacteroides Alters Gut Microbial LPS Production
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In the paper
“We also confirmed the significantly decreased abundance of B. vulgatus and B. dorei in patients with CAD by quantitative polymerase chain reaction (Figure 1J and Table II in the online-only Data Supplement).”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Gut Microbial Profile in Patients With CAD
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- It may state two separate claims as one. 29
- Probably not a substantial claim. 21
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > ORIGINAL RESEARCH ARTICLE
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- Also stated in: § ORIGINAL RESEARCH ARTICLE · plain
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In the paper
“the samples were clustered into 3 clusters at the genus level”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Gut Microbial Profile in Patients With CAD
Strength:plain· not yet calibratedn = 30Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“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)”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Gut Microbial Profile in Patients With CAD
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In the paper
“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).”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Gut Microbial Profile in Patients With CAD
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In the paper
“without significant difference in body weight (Figure 2F), plasma cholesterol levels (Figure 2G), or plasma glucose levels (data not shown).”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Gut Microbial Profile in Patients With CAD
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In the paper
“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).”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Gut Microbial Profile in Patients With CAD
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In the paper
“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)”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > ORIGINAL RESEARCH ARTICLE
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In the paper
“patients with CAD showed a relative depletion of B. vulgatus and B. dorei and enrichment in Faecalibacterium prausnitzii and Prevotella copri (Figure 1H).”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Gut Microbial Profile in Patients With CAD
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In the paper
“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).”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Gut Microbial Profile in Patients With CAD
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Gut Microbial Profile in Patients With CAD
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- Also stated in: § DISCUSSION · plain
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In the paper
“The Bacteroidetes/Firmicutes ratio, Gram-positive to Gram-negative strain ratio, and fecal water content did not differ significantly among the 3 groups”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Affiliations
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In the paper
“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).”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > ORIGINAL RESEARCH ARTICLE
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In the paper
“we found that fecal LPS levels were higher in patients with lower abundance of B. vulgatus and B. dorei.”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > DISCUSSION
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- Rests on an assumption: Fecal lipopolysaccharide levels reflect colon lipopolysaccharide concentrations produced by gut microbiota.
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In the paper
“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”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Abstract
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In the paper
“CAD remains the leading cause of morbidity and mortality worldwide, despite the widespread use of statin therapy in the last decade.12”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Abstract
What the sources say
- Not checked yetcites [12] source
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In the paper
“Endotoxemia is known to cause systemic inflammation leading to the disruption of innate and adaptive immunity and the development of atherosclerosis.[34][35][36]”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Gut Microbial Profile in Patients With CAD
What the sources say
- Not checked yetcites [34]
- Not checked yetcites [35] source
- Not checked yetcites [36]
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In the paper
“a recent clinical trial has shown contradictory results indicating that fish consumption drastically increases circulating TMA N-oxide levels”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Abstract
What the sources say
- Not checked yetcites [6] source
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“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).”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Recruitment of Patients With CAD and Controls
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In the paper
“The success of the heat treatment was confirmed by the absence of growth of plated heat-killed bacteria.”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Animals
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In the paper
“All participants provided written informed consent on enrollment, and the study was conducted according to the guidelines of the Declaration of Helsinki.”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Recruitment of Patients With CAD and Controls
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In the paper
“All experiments were performed according to the Guidelines for Animal Experiments in effect at Kobe University School of Medicine (guideline No. P160701).”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Animals
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In the paper
“However, it remains unclear which specific Bacteroides species are involved and what their exact role is in CAD.11”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Abstract
What the sources say
- Not checked yetcites [11]
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
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In the paper
“Six-week-old mice were randomly divided into 3 treatment groups”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Animals
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In the paper
“Because these 2 species share similar 16S rRNA sequencing patterns, 32 we were not able to distinguish them using our methodology.”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Gut Microbial Profile in Patients With CAD
What the sources say
- Not checked yetcites [32]
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In the paper
“The sample size was calculated using R software (power=0.9,significance level=0.05,mean difference=6, SD=7; n=30 per group.).”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Recruitment of Patients With CAD and Controls
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In the paper
“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”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Abstract
What the sources say
- Not checked yetcites [7]
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Because LPS stimulates cells through TLR4 and upregulates costimulatory molecules on antigen-presenting cells, 37”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Gut Microbial Profile in Patients With CAD
What the sources say
- Not checked yetcites [37]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results suggested that replenishment of live B. vulgatus and B. dorei by oral gavage reduced plaque inflammation, attenuating atherosclerotic lesion formation.”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > Gut Microbial Profile in Patients With CAD
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- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“Although LPS from E. coli increases intestinal permeability in a TLR4-dependent manner, 40,41”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > ORIGINAL RESEARCH ARTICLE
What the sources say
- Not checked yetcites [40]
- Not checked yetcites [41]
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > ORIGINAL RESEARCH ARTICLE
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“These limitations imply that we did not fully elucidate the characteristics of gut microbial composition in CAD”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > ORIGINAL RESEARCH ARTICLE
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“16S rRNA sequencing analysis helped to seek candidate and translate to animal experiments”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > ORIGINAL RESEARCH ARTICLE
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In the paper
“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]”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > ORIGINAL RESEARCH ARTICLE
What the sources say
- Not checked yetcites [47][48][49]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“the gut microbial analysis in patients with CAD was a single-center study with a relatively small number of patients”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > ORIGINAL RESEARCH ARTICLE
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“used a mouse model to clarify the causal relationship between B. vulgatus and B. dorei and atherosclerosis”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > ORIGINAL RESEARCH ARTICLE
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > DISCUSSION
What the sources say
- Not checked yetcites [33] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > ORIGINAL RESEARCH ARTICLE
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > ORIGINAL RESEARCH ARTICLE
What the sources say
- Not checked yetcites [42]
- Not checked yetcites [43]
- Not checked yetcites [46]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- 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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“we performed gavage only with B. vulgatus and B. dorei”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > ORIGINAL RESEARCH ARTICLE
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“we did not completely elucidate the mechanisms of atherosclerosis protection by lower LPS concentrations in mice”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > ORIGINAL RESEARCH ARTICLE
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“it could not measure LPS immunogenicity and the impact of Bacteroides on the structure and function of LPS”
§ Live Bacteroides Treatment Ameliorated Endotoxemia and Systemic Inflammation > ORIGINAL RESEARCH ARTICLE
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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”
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?
In the citing paper
“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
MinorReferences 31 and 33 give the identical DOI for articles with different titles, journals, and page ranges. At least one DOI is incorrect.
“Variation in microbiome LPS immunogenicity contributes to autoim- munity in humans. Cell. 2016;165:842-853. doi: 10.1002/art.39783”
“Dysbio- sis contributes to arthritis development via activation of autoreactive T cells in the intestine. Arthritis Rheumatol. 2016;68:2646-2661. doi: 10.1002/art.39783”
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Items 401–500 of 625
Wang, Y., Tang, Y., Huang, Q., An, J., Zhou, Y., Yang, H., Song, F., Zhang, X., & Huang, C. (2026) · International Journal of Oral Science · doi:10.1038/s41368-025-00418-z · Cited by 5
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Effects of salidroside on atherosclerosis: potential contribution of gut microbiota
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BackgroundMetagenomic Analysis of Gut Microbiota for Abdominal Aortic Aneurysm
Ito, E., Ohki, T., Toya, N., Emoto, T., Yamashita, T., Sugiyama, T., Yamada, T., Mori, H., Toyoda, A., & Hirata, K. (2025) · Annals of Vascular Diseases · doi:10.3400/avd.oa.24-00105 · Cited by 6
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Modulatory Role of Hesperetin–Copper(II) on Gut Microbiota in Type 2 Diabetes Mellitus Mice
Peng, X., Wei, Y., Gong, D., & Zhang, G. (2025) · Foods · doi:10.3390/foods14132390 · Cited by 5
“It was found that Bacteroides vulgatus and Bacteroides dorei were beneficial to diabetes, resulting in a decrease in intestinal permeability [62].”
Are an Aging Gut and a Decrease in Butyrate Production the Reasons for Atherosclerosis?
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Role of glycolysis in diabetic atherosclerosis
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Gut microbiota: a superior operator for dietary phytochemicals to improve atherosclerosis
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“Some specific gut bacteria have been considered pro-atherosclerotic phenotypes such as Desulfovibrio desulfuricans (K. Zhang, Qin, et al. 2023), while some are anti-atherosclerotic phenotypes such as Bacteroides vulgatus and Bacteroides dorei (Yoshida et al. 2018).”
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Epigenetics and the role of nutraceuticals in health and disease
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“The implantation of the patient’s gut with the normal inhabitant microbe Bacteroides vulgatus results in the improvement of the condition (Yoshida et al. 2018).”
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“A connection between low-grade inflammation, sustained by lipopolysaccharides (LPS), and the development of metabolic disorders is well established (28, 29).”
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Novel opportunity of treatment for psycho-cardiologic disease by gut microbiome
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Heart Failure and Cognitive Impairment Through the Lens of the Gut Microbiome: A Narrative Review
Rahmani, A. R., Madani, S. A., Aminov, E., Gogokhia, L., Bench, T. J., & Kalogeropoulos, A. P. (2025) · Journal of Personalized Medicine · doi:10.3390/jpm15120595 · Cited by 4
“Yoshida et al. [59] found that supplementation with Bacteroides vulgatus and Bacteroides dorei suppressed intestinal LPS biosynthesis, reduced systemic endotoxin burden, and attenuated vascular NF-κ B–mediated inflammatory signaling.”
Targeting the intestinal TLR4-GABAA axis to promote stroke recovery
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“Furthermore, Bacteroides interventions have been shown to reduce atherosclerotic lesion formation in susceptible mice by lowering gut-derived LPS production and suppressing pro-inflammatory immune responses [50].”
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Self-citationN-nitrosamines induced gender-dimorphic effects on infant rats at environmental levels
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“Bacteroides vulgatus and Bacteroides dorei upregulate the expression of tight junction genes in the colon, leading to decreased intestinal permeability, reduced LPS production, and alleviated endotoxemia [34].”
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“Bacteroides vulgatus can improve atherosclerosis by lowering blood endotoxin levels and produces N-acetylglucosamine to promote the growth of Akkermansia , thereby reducing obesity and regulating glucose metabolism [37,38].”
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“A human study and in vivo experiments showed Bacteroides vulgatus and Bacteroides dorei abundance is reduced in CAD patients, while administering these bacteria alleviates atherosclerotic lesion formation in mice and reduces gut microbiota LPS production (159).”
A multi-omic study profiles women with PCOS to reveal unique gut microbiome compositions
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“Studies have confirmed that Bacteroides can protect ApoE − / − mice from atherosclerosis [28].”
Ahmed, L. A., & Al‐Massri, K. F. (2025) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2025.178210 · Cited by 3
Li, Z., Qin, P., Sun, Z., Li, L., Liang, P., Zhao, Y., Ren, S., Wang, G., & Yang, J. (2026) · Communications Biology · doi:10.1038/s42003-026-09525-x · Cited by 5
“B. thetaiotaomicron has been reported to alleviate colitis 18,46,47 , allergic airway in fl ammation 48 , and fatty liver disease 49,50 , and B. vulgatus similarly exhibits anti-in fl ammatory properties, improving colitis 17,51 , atherosclerosis 52 , and osteoporosis 53 .”
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“In mice, P. vulgatus is beneficial for maintaining intestinal barrier function and preventing atherosclerosis by reducing gut microbial lipopolysaccharide production [54,59].”
The impact of IL-17A inhibitors on scalp and gut microbiota in psoriasis
Huang, W., Geng, Y., Gong, J., & Wu, W. (2025) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2025.1623003 · Cited by 3
Microbiome Diagnostics and Interventions in Health and Disease
Dasgupta, N., Srivastava, A., Rao, A., Murugkar, V., Shroff, R., & Das, G. (2021) · Springer eBooks · doi:10.1007/978-981-16-3156-6_10 · Cited by 3
Microbial Source Tracking: an Emerging Technology for Microbial Water Quality Assessment: A Review
Job, O., Bala, J. D., Abdulraham, A. A., Friday, N. N., Ibekie, S. A., Tsebam, C. J., & Abudullahi, D. (2023) · UMYU Journal of Microbiology Research (UJMR) · doi:10.47430/ujmr.2381.014 · Cited by 3
“The effectiveness of MST can be enhanced by gaining a comprehensive understanding of the abundance and distribution patterns of the subject (Yoshida et al., 2018).”
BackgroundLi, Z., Xu, Q., Huangfu, N., & Cui, H. (2024) · Coronary Artery Disease · doi:10.1097/mca.0000000000001377 · Cited by 4
“It has been reported that direct intervention with Bacteroides dorei and Bacteroides vulgatus can significantly inhibit the progression of AS disease [40].”
MAFLD under the lens: the role of gut microbiota
Sousa, P., & Machado, M. V. (2022) · Metabolism and Target Organ Damage · doi:10.20517/mtod.2022.15 · Cited by 3
Towards understanding the link between gut microbiota and heart failure in the heart–gut axis
Fung, E., & Tang, W. H. W. (2023) · European Journal of Preventive Cardiology · doi:10.1093/eurjpc/zwad200 · Cited by 3
Du, Y., Zuo, W., & Sun, F. (2024) · Journal of Computational Biology · doi:10.1089/cmb.2024.0663 · Cited by 2
“In contrast, B. vulgatus assumes vital roles in reducing the production of gut microbial lipopolysaccharides and inhibiting atherosclerosis (Yoshida et al., 2018).”
Cai, C., Zhang, Z., Alberti, G., Pereira, A. P. R., Barbieri, F. D., García, C., Wine, E., & Gana, J. C. (2025) · International Journal of Obesity · doi:10.1038/s41366-025-01737-1 · Cited by 2
Puel, E. M., Taruhn, L. F., Damé‐Teixeira, N., Stefani, C. M., & Lataro, R. M. (2025) · Nitric Oxide · doi:10.1016/j.niox.2025.04.001 · Cited by 2
Impact of Gut Microbiota on Atherosclerosis and Potential Therapeutic Strategies.
Rai, N., & Patel, K. (2025) · International Journal of Scientific Development and Research · doi:10.56975/ijsdr.v10i4.301408 · Cited by 2
“The degree of short-chain fatty acids (SCFA) decline was noted, without any correlation to trimethylamine N-oxide (TMAO) [44].”
Clostridium butyricum Ameliorates Atherosclerosis by Regulating Host Linoleic Acid Metabolism
Yin, C., Fan, P., Mou, X., & Zhao, W. (2025) · Microorganisms · doi:10.3390/microorganisms13061220 · Cited by 2
“Notably, the restored abundance of Bacteroidota—a phylum containing multiple species with documented anti-inflammatory properties [11,62,63]—indicates a potential microbiota-mediated mechanism through which C. butyricum might inhibit AS progression by indirectly attenuating systemic inflammation.”
In vitro fecal microbiota modulation properties of some dried apricots ( Prunus armeniaca L.)
Coşkuner, G., Alkay, Z., Arıoğlu-Tuncil, S., Gonzales, M. A. A., Lindemann, S. R., & Tunçil, Y. E. (2025) · Journal of the Science of Food and Agriculture · doi:10.1002/jsfa.70003 · Cited by 2
“55 Dried apricot DF fermentations resulted in signi fi cant ( P < 0.05) increases (7-to 11-fold increases) in the relative abundance of OTU2 Holdemanella ; however, inulin fermentation did not signi fi - cantly ( P > 0.05) impact its relative abundances.”
InfluentialYoung microbiome transplantation enhances recovery after myocardial infarction
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“P. vulgatus was involved with carbohydrate metabolism and was associated with colitis, atherosclerosis, and type 2 diabetes (35, 36).”
Zhang, X., Ding, H., He, W., Huang, S., & Lei, L. (2025) · Food Chemistry International · doi:10.1002/fci2.70018 · Cited by 3
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“Previous studies have linked Bacteroides dorei to various diseases, including liver cirrhosis [31], atherosclerosis [32], type 1 diabetes [33], polycystic ovary syndrome [34] and tumors, especially tumor immunotherapy [35 – 37].”
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“Mounting evidence indicates that gut microbiota dysbiosis contributes to the pathogenesis of CAD through multiple mechanisms, including low-grade endotoxemia, altered short-chain fatty acid production, and bile acid dysregulation [11, 12].”
Lin, M., Li, W. X., Wu, Y., Li, M., Li, Y., & Zhao, Y. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1776040 · Cited by 2
“Gavage with these live Bacteroides species reduced LPS production, suppressed pro-in fl ammatory immune responses, and effectively attenuated atherosclerotic lesions (231).”
Cheng, J., Le, S., Wang, D., Liu, P., Liu, C., Shen, D., & Wang, D. (2026) · Journal of Nanobiotechnology · doi:10.1186/s12951-026-04369-3 · Cited by 2
“Research has demonstrated that B. vulgatus can mitigate atherosclerosis by decreasing the synthesis of gut microbial lipopolysaccharides [33], and it is also implicated in the development of insulin resistance and modifications in bile acid metabolism [34].”
Gut Microbiota: A New Marker of Cardiovascular Disease
Pontarollo, G., Kiouptsi, K., Bayer, F., & Reinhardt, C. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-819265-8.00028-0 · Cited by 2
Impacts of Plant-derived Secondary Metabolites for Improving Flora in Type 2 Diabetes
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“The abundance of B. vulgatus has a direct impact on the synthesis of microbial lipopolysaccharides in the human gut, with a protective effect against atherosclerosis (Yoshida et al., 2018).”
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Analysis of Gut Microbiota and Their Metabolites in CADASIL Patients
Watanabe-Hosomi, A., Inoüe, R., Mizuta, I., Matsuura, J., Matsuura, H., Fukunaga, D., Ohara, T., Naito, Y., & Mizuno, T. (2025) · Journal of Clinical Neurology · doi:10.3988/jcn.2025.0231 · Cited by 2
Faecal Transplant Therapy: A Promising Treatment Modality for Cardiovascular Diseases
Pushkala, K., & Gupta Purshottam, D. (2023) · Journal of Cardiology and Cardiovascular Medicine · doi:10.29328/journal.jccm.1001162 · Cited by 2
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“In two different studies, the administration of P. dorei to mice decreased colon LPS and further displayed inhibitor activity on host innate immune signaling 48,49 .”
Ortañez, J., & Degnan, P. H. (2024) · Frontiers in Microbiology · doi:10.3389/fmicb.2024.1241582 · Cited by 1
The two-way interaction of tea polyphenols with gut microbiota and their effect on atherosclerosis
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Microbiome and atherosclerosis: state of the problem
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Chu, S., Fan, R., Dai, L., & Liu, M. (2025) · Frontiers in Microbiology · doi:10.3389/fmicb.2025.1551409 · Cited by 1
“A connection between low-grade inflammation, sustained by lipopolysaccharides (LPS), and the development of metabolic disorders is well established (Di Lorenzo et al., 2019; Yoshida et al., 2018).”
Yang, F., Qu, G., Wu, Y., Zhong, P., Chu, Z., He, Z., Wang, Y., Tang, Y., Sun, S., & Luo, F. (2025) · Journal of Dairy Science · doi:10.3168/jds.2024-26058 · Cited by 2
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“Naofumi Yoshida experimentally demonstrated that Bacteroidota tube feeding reduces the efects of atherosclerosis in mice, which is closely related to changes in fecal and plasma lipopolysaccharide levels [25].”
Low Bacteroides abundance is related to endothelial dysfunction in type 2 diabetes
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“While Bacteroides vulgatus and Bacteroides dorei reduce GM lipopolysaccharide production and exhibit anti-inflammatory properties through their structurally distinct LPSs compared with those of pathogenic enterobacteria [ 39], other Bacteroides species may have different metabolic profiles.”
Wang, Q., Niu, Y., Huang, J., Huang, J., Zhang, J., Zhang, B., Guo, Z., & Feng, S. (2025) · Frontiers in Microbiology · doi:10.3389/fmicb.2025.1641035 · Cited by 1
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Analysis of treatment-naïve gut microbiota in children with new-onset epilepsy
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Dietary Modulation of Gut Microbiome in High Cholesterol Diet–Induced Atherosclerosis
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Stress accelerates hepatocellular carcinoma progression via a gut microbial-metabolite axis
Hu, Z., Yue, P., Yuan, M., Zhang, Z., Li, Q., Yang, T., Li, Y., Ding, B., Fan, Z., Yang, B., et al. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1790214 · Cited by 2
“Phocaeicola also have been associated with alleviation of atherosclerosis and colitis, although the underlying molecular mechanism remains unclear (75, 76).”
The interplay between the microbiome and immune cells in metabolic homeostasis and disease
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“…insulin sensitivity and hepatic VLDL production, contributing to lower TG; donor-derived strains associated with immune regulation or reduced lipopolysaccharide (LPS) production (e.g., Bifidobacterium pseudocatenulatum and Bacteroides dorei ) have been described after allo-genic FMT [37, 42, 43].”
Li, J., Yang, D., Guo, Q., Zhang, Z., & Chen, L. (2026) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2026.125840 · Cited by 1
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
- Published
- 2018-11-27
- Volume
- 138
- Issue
- 22
- Pages
- 2486-2498
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- 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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