Cited by 775Gut microbiota and healthAtherosclerosis and Cardiovascular DiseasesOral microbiology and periodontitis research

The DOI matches its Crossref record; 50 of the 50 references it cites were found in a registry or an index; none of the 64 sources its claims cite is checked for support yet.

Akkermansia Muciniphila Protects Against Atherosclerosis by Preventing Metabolic Endotoxemia-Induced Inflammation in Apoe −/− Mice

Abstract

Background—: Altered composition of the gut microbiota is involved in both the onset and progression of obesity and diabetes mellitus. However, the link between gut microbiota and obesity-related cardiovascular complications has not been explored. The present study was designed to investigate the role of Akkermansia muciniphila , a mucin-degrading bacterium with beneficial effects on metabolism, in the pathogenesis of atherosclerosis in apolipoprotein E–deficient ( Apoe −/− ) mice. Methods and Results—: Apoe −/− mice on normal chow diet or a Western diet were treated with A muciniphila by daily oral gavage for 8 weeks, followed by histological evaluations of atherosclerotic lesion in aorta. Real-time polymerase chain reaction analysis demonstrated that the fecal abundance of A muciniphila was significantly reduced by Western diet. Replenishment with A muciniphila reversed Western diet–induced exacerbation of atherosclerotic lesion formation without affecting hypercholesterolemia. A muciniphila prevented Western diet–induced inflammation in both the circulation and local atherosclerotic lesion, as evidenced by reduced macrophage infiltration and expression of proinflammatory cytokines and chemokines. These changes were accompanied by a marked attenuation in metabolic endotoxemia. A muciniphila –mediated reduction in circulating endotoxin level could be attributed to the induction of intestinal expression of the tight junction proteins (zona occuldens protein-1 and occludin), thereby reversing Western diet–induced increases in gut permeability. Long-term infusion of endotoxin to Apoe −/− mice reversed the protective effect of A muciniphila against atherosclerosis. Conclusion—: A muciniphila attenuates atherosclerotic lesions by ameliorating metabolic endotoxemia-induced inflammation through restoration of the gut barrier.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In Apoe−/− mice, Western diet reduced gut *Akkermansia muciniphila* and exacerbated atherosclerosis; daily oral live *A. muciniphila* reduced lesion area and size by 31% and 48%, respectively, without changing hypercholesterolemia. The protection was linked to restored gut barrier, lower endotoxemia, and reduced local/systemic inflammation, and was reversed by long-term lipopolysaccharide infusion.

Key findings

  • Western diet reduced fecal *A. muciniphila*; live *A. muciniphila* (5×10⁹ cfu daily) reduced Western diet-induced lesion area by 31% and lesion size by 48%, whereas heat-killed bacteria had no effect.
  • *A. muciniphila* reduced macrophage infiltration and expression of ICAM-1, MCP-1, F4/80, and TNFα in lesions/aorta, and lowered circulating MCP-1, IL-1β, and sTNFR II; it did not affect adiponectin.
  • *A. muciniphila* lowered lipopolysaccharide levels in mesenteric adipose tissue and serum, reduced gut permeability, increased ileal occludin and ZO-1, and partially restored inner mucin layer thickness.
  • Long-term lipopolysaccharide infusion (250 µg/kg/day) restored serum lipopolysaccharide and reversed *A. muciniphila*’s protection against lesion area/size and inflammation.

Methods

  • Eight-week-old male Apoe−/− mice were fed normal chow or Western diet for 8 weeks; Western diet groups received daily oral gavage of live *A. muciniphila* (5×10⁹ cfu in 200 µL PBS), heat-killed *A. muciniphila*, or PBS. A separate group received lipopolysaccharide via osmotic pumps at 250 µg/kg/day for the last 4 weeks.
  • Lesion area/size were assessed by Oil Red O and hematoxylin and eosin staining with ImageJ; inflammation by immunofluorescence/immunohistochemistry and real-time PCR; gut permeability by FITC-dextran; lipopolysaccharide by LAL assay; Caco-2 cell experiments and denaturing gradient gel electrophoresis were also used.
  • Sample sizes were n=8–10 for main groups and n=5–7 for lipopolysaccharide infusion groups; statistics used one-way ANOVA with Tukey or Games-Howell post hoc tests, Kruskal-Wallis, or unpaired t tests.

Limitations

  • Stated: how gut-residing *A. muciniphila* increases tight junction protein expression remains to be determined.
  • Evident: all experiments are in male Apoe−/− mice; no human clinical outcomes or human atherosclerosis endpoints are reported.
  • Evident: the study tests one bacterial species under specific diets, with modest sample sizes (n=5–10 per group), and some mechanistic data are in online-only supplements.

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

Integrity signals

Registry

Crossref · 10.1161/circulationaha.115.019645

Cites

50 of 50 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

0 of 64 cited sources checked · 0 supported · 0 flagged

Show all 51 claims

  • It may state two separate claims as one. 36
  • Probably not a substantial claim. 32
58 of 58
  • The paper relies on this without support.

    The link between gut microbiota and obesity-related cardiovascular complications has not been explored.

    “However, the link between gut microbiota and obesity-related cardiovascular complications has not been explored.”
  • The paper relies on this without support.

    Direct evidence for the causative role of altered gut microbiota (dysbiosis) in the pathogenesis of atherosclerosis is still lacking.

    “However, direct evidence for the causative role of altered gut microbiota (dysbiosis) in the pathogenesis of atherosclerosis is still lacking.”
  • The paper relies on this without support.

    The beneficial role of A. muciniphila against obesity-related cardiovascular diseases remains to be addressed.

    “However, its beneficial role against obesity-related cardiovascular diseases remains to be addressed.”
  • The paper relies on this without support.

    Gut permeability is regulated by the mucus layer and tight junctions of the intestine.

    “Gut permeability is regulated by the mucus layer and tight junctions of intestine.”
  • The paper relies on this without support.

    Toll-like receptor 4 is expressed in various vascular cells, including endothelial cells, focal leukocytes, and macrophages.

    “Toll-like receptor 4 is expressed in various vascular cells, including endothelial cells, focal leukocytes, and macrophages.”
  • The paper relies on this without support.

    Activation of Toll-like receptor 4 by lipopolysaccharide stimulates release of proinflammatory molecules from vascular cells and inhibits cholesterol efflux from macrophages, facilitating foam cell formation.

    “Its activation by lipopolysaccharide not only stimulates the release of proinflammatory molecules from these cells but also inhibits cholesterol efflux from macrophages and thus facilitates foam cell formation.”
  • The paper relies on this without support.

    Lipopolysaccharide-induced inflammatory cytokines in perivascular adipose tissue can act in a paracrine manner to exacerbate vascular inflammation and atherosclerosis.

    “Furthermore, lipopolysaccharide-induced inflammatory cytokines in perivascular adipose tissue, which surrounds almost all the blood vessels, can act in a paracrine manner to exacerbate vascular inflammation and atherosclerosis.”
  • The paper relies on this without support.

    Whether altered gut microbiota contributes to the pathogenesis of atherosclerosis remains unknown.

    “However, whether altered gut microbiota contributes to the pathogenesis of atherosclerosis remains unknown.”
  • The paper relies on this without support.

    Hypercholesterolemia and chronic inflammation are the 2 important risk factors for atherosclerosis, which is a major cause of fatal cardiovascular complications.

    “Hypercholesterolemia and chronic inflammation are the 2 important risk factors for atherosclerosis, which is a major cause of fatal cardiovascular complications, including coronary heart disease and myocardial infarction.”
  • The paper relies on this without support.

    Although cholesterol-lowering drugs can effectively reduce the incidence of atherosclerosis, anti-inflammatory therapies against this disease have had limited success, partly because of the lack of understanding of etiological factors that trigger vascular inflammation.

    “Although cholesterollowering drugs can effectively reduce the incidence of atherosclerosis, anti-inflammatory therapies against this disease have had limited success, partly because of the lack of the understanding of etiological factors that trigger vascular inflammation.”
  • The paper relies on this without support.

    Previous clinical studies have reported a close association of bacterial infection and endotoxemia with cardiovascular diseases.

    “Previous clinical studies have reported a close association of bacterial infection and endotoxemia with cardiovascular diseases.”
11 of 11

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting durations of A muciniphila treatment in the LPS experiment

    Major

    The Results state that mice received daily A muciniphila for a total of 8 weeks, whereas the Figure 5 caption says it was given daily for 4 weeks before the subsequent 4-week infusion. This changes the treatment schedule for the experiment used to test the proposed mechanism.

  • Diet description conflicts with the cited germ-free mouse study

    Minor

    The text describes the germ-free Apoe-deficient mice as having been fed a high-cholesterol diet, but the title of its cited reference 14 specifies a standard low-cholesterol diet.

2 of 2

Citations

Cites

Flagged first, then by citations

Show all 50 references

Cited by

Sorted by citations

Items 701–773 of 773

Metadata

Authors
Li, J., Lin, S., Vanhoutte, P. M., Woo, C. W., & Xu, A.
Affiliations
Jinan University (CN)
Venue
Circulation
Published
2016-06-14
Volume
133
Issue
24
Pages
2434-2446
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
OpenAlex
W2344498019
Cited by
775
References
50
Citations by year
2026: 44 · 2025: 92 · 2024: 107 · 2023: 91 · 2022: 124 · 2021: 88 · 2020: 82 · 2019: 62 · 2018: 38 · 2017: 41 · 2016: 6
FWCI
25.46
Type
journal article
Language
en
Open access
closed
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
  • The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
Keywords
Akkermansia muciniphila, atherosclerosis, metabolic endotoxemia, gut microbiota, ApoE-deficient mice, Western diet, intestinal permeability, tight junction proteins, macrophage infiltration, inflammatory cytokines, chemokines, intestinal barrier, obesity-related cardiovascular disease, hypercholesterolemia
MeSH terms
Animals, Disease Models, Animal, Humans, Inflammation, Intestines, Male, Mice, Transgenic, Treatment Outcome, Caco-2 Cells, Endotoxemia, Atherosclerosis, Mice, Verrucomicrobia

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.

A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

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 ›

Are you an author, or do you see a problem with this page? Request a review