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.
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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.
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- Findingown data
These changes were accompanied by a marked attenuation in metabolic endotoxemia.
“These changes were accompanied by a marked attenuation in metabolic endotoxemia.”
Quote in the paperSubstantial claim - Findingown data
Treatment with heat-killed A. muciniphila did not have a significant effect on either macrophage accumulation or expression of MCP-1, ICAM-1 and TNFα in the local aortic tissues.
“muciniphila did not have a significant effect on either macrophage accumulation or expression of MCP-1, ICAM-1 and TNFα in the local aortic tissues (Figure 2A-2D and 3A-3D).”
Quote in the paperSubstantial claim - Findingown data
Western diet-induced aggravation of atherosclerotic lesion was accompanied by a marked reduction of A. muciniphila.
“Our results showed that Western diet-induced aggravation of atherosclerotic lesion was accompanied by a marked reduction of A muciniphila”
Quote in the paperSubstantial claim - Findingown data
Lipopolysaccharide infusion also augmented the number of infiltrated macrophages and the expression of the inflammatory molecules MCP-1 and ICAM-1 in the atherosclerotic lesions of mice treated with A. muciniphila.
“Lipopolysaccharide infusion also augmented the number of infiltrated macrophages and the expression of the inflammatory molecules MCP-1 and ICAM-1 in the atherosclerotic lesions of mice treated with A muciniphila (Figure 6A-6C).”
Quote in the paperSubstantial claim - Findingown data
Restoration of A. muciniphila by daily oral gavage substantially reduced atherosclerotic lesions in Apoe-/- mice.
“whereas restoration of A muciniphila by daily oral gavage substantially reduced atherosclerotic lesions in Apoe -/-mice.”
Quote in the paperSubstantial claim
- Findingown data
Treatment with propionate or butyrate in Caco-2 cells failed to increase the expression of either occludin or ZO-1.
“However, treatment with propionate or butyrate in Caco-2 cells failed to increase the expression of either occludin or ZO-1 (Figure IVC and IVD in the online-only Data Supplement).”
Quote in the paperNot a substantial claim - Findingown data
The fecal amounts of A. muciniphila were comparable between wild-type and Apoe-/- mice fed a normal chow diet (7.31±0.51 versus 7.04±0.69 log10 bacteria/g feces).
“the fecal amounts of this bacteria were comparable between wild-type and Apoe -/-mice fed a normal chow diet (7.31±0.51versus 7.04±0.69log10 bacteria/g feces in wild-type versus Apoe -/-)”
Quote in the paperNot a substantial claim - Findingown data
This increased level of lipopolysaccharide was able to reverse the protective effect of A. muciniphila treatment against atherosclerosis, as demonstrated by increased lesion area and size in Apoe-/- mice compared with the A. muciniphila-treated mice without infusion of lipopolysaccharide.
“Notably, this increased level of lipopolysaccharide was able to reverse the protective effect of A muciniphila treatment against atherosclerosis, as demonstrated by increased lesion area (Figure 5B and 5D) and size (Figure 5C and 5E) in Apoe -/-mice compared with the A muciniphila-treated mice without infusion of lipopolysaccharide.”
Quote in the paperSubstantial claim - Findingown data
Treatment with A. muciniphila inhibited the Western diet-induced protein expression of ICAM-1 and MCP-1.
“Likewise, treatment with A muciniphila inhibited the Western diet-induced protein expression of ICAM-1 and MCP-1”
Quote in the paperSubstantial claim - Findingown data
Treatment with the inoculating medium of A. muciniphila culture (100 μL/mL) in Caco-2 cells significantly upregulated the expression of occludin and ZO-1 compared with those treated with the plain inoculating medium.
“Treatment with the inoculating medium of A muciniphila culture (100 μL/mL) in Caco-2 cells, a human intestine epithelial cell line, significantly upregulated the expression of occludin and ZO-1 compared with those treated with the plain inoculating medium.”
Quote in the paperSubstantial claim - Findingown data
The Western diet substantially altered the gut microbiota pattern compared with normal chow diet.
“The Western diet substantially altered the gut microbiota pattern compared with normal chow diet (Figure IA in the online-only Data Supplement).”
Quote in the paperNot a substantial claim - Findingown data
Long-term infusion of lipopolysaccharide restored the serum level of lipopolysaccharide in A. muciniphila-treated mice to a level similar to that of the Western diet-fed mice without the bacterial treatment.
“Long-term infusion of lipopolysaccharide restored the serum level of lipopolysaccharide in A muciniphila-treated mice to a level similar to that of the Western dietfed mice without the bacterial treatment (Figure 5A).”
Quote in the paperSubstantial claim - Findingown data
Real-time PCR analysis showed a significantly reduced amount of A. muciniphila in the feces of Western diet-fed Apoe-/- mice compared with the mice fed a normal chow diet.
“Real-time PCR analysis showed a significantly reduced amount of A muciniphila in the feces of Western diet-fed Apoe -/-mice compared with the mice fed a normal chow diet (Figure 1A)”
Quote in the paperSubstantial claim - Findingown data
A. muciniphila treatment also increased the expression of another tight junction protein, ZO-1.
“A muciniphila treatment also increased the expression of another tight junction protein, ZO-1 (Figure 4C, 4E, and 4G).”
Quote in the paperSubstantial claim - Findingown data
Daily treatment with A. muciniphila had no obvious effect on the circulating level of adiponectin.
“However, daily treatment with A muciniphila had no obvious effect on the circulating level of adiponectin, an adipocyte-derived anti-inflammatory adipokine with antiatherosclerotic activity (Figure 3H).”
Quote in the paperNot a substantial claim - Findingown data
The Western diet-induced increase in circulating level of sTNFR II was significantly attenuated by the administration of live A. muciniphila.
“Similarly, the Western diet-induced increase in circulating level of sTNFR II, a prognostic marker of fatal complications of atherosclerosis, including congestive heart failure, 31 was significantly attenuated by the administration of live A muciniphila (Figure 3G).”
Quote in the paperSubstantial claim - Findingown data
The restoration of the gut barrier by A. muciniphila treatment led to a significant reduction in the Western diet-induced elevation of lipopolysaccharide levels in both mesenteric adipose tissue and circulation.
“Furthermore, the restoration of the gut barrier by A muciniphila treatment led to a significant reduction in the Western diet-induced elevation of lipopolysaccharide levels in both mesenteric adipose tissue and circulation (Figure 4H and 4I)”
Quote in the paperSubstantial claim - Findingown data
Administration of the same dose of heat-killed A. muciniphila did not show any improvement in lesion area or size in Apoe-/- mice.
“Administration of the same dose of heat-killed A muciniphila did not show any improvement in lesion area or size in Apoe -/- mice (Figure 1B-1E)”
Quote in the paperSubstantial claim - Findingown data
The suppressive effects of A. muciniphila on mRNA expression of F4/80, MCP-1, ICAM-1, and TNFα were reversed by lipopolysaccharide treatment.
“Real-time PCR analysis further demonstrated that the suppressive effects of A muciniphila on mRNA expression of F4/80, MCP-1, ICAM-1, and TNFα were reversed by lipopolysaccharide treatment (Figure 6D-6G).”
Quote in the paperSubstantial claim - Findingown data
A similar effect of A. muciniphila on suppression of the Western diet-induced mRNA expression of F4/80, MCP-1, ICAM-1, and TNFα was observed in the aortas of Apoe-/- mice.
“A similar effect of A muciniphila on suppression of the Western diet-induced mRNA expression of F4/80 (another macrophage marker), MCP-1, ICAM-1, and tumor necrosis factor-α (TNFα) was observed in the aortas of Apoe -/-mice (Figure 3A-3D).”
Quote in the paperSubstantial claim - Findingown data
The Western diet induced formation of atherosclerotic lesions.
“The Western diet induced formation of atherosclerotic lesions, as demonstrated by Oil Red O staining of longitudinally opened aortas and hematoxylin and eosin staining of aortic root regions (Figure 1B and 1C).”
Quote in the paperSubstantial claim - Findingown data
Daily oral gavage with 5×10^9 cfu live A. muciniphila was sufficient to restore the diminished level caused by the Western diet.
“Daily oral gavage with 5×10 9 cfu live A muciniphila was sufficient to restore the diminished level caused by the Western diet (Figure 1A).”
Quote in the paperSubstantial claim - Findingown data
This A. muciniphila-induced upregulation of the tight junction proteins was independent of its characteristic as a Gram-negative bacterium because treatment with inoculating medium of Escherichia coli did not show any effect.
“This A muciniphila-induced upregulation of the tight junction proteins was independent of its characteristic as a Gram-negative bacterium because treatment with inoculating medium of Escherichia coli did not show any effect (Figure IVA and IVB in the online-only Data Supplement).”
Quote in the paperNot a substantial claim - Findingown data
The fecal abundance of A. muciniphila was significantly reduced by Western diet.
“Real-time polymerase chain reaction analysis demonstrated that the fecal abundance of A muciniphila was significantly reduced by Western diet.”
Quote in the paperSubstantial claim - Findingown data
Long-term infusion of endotoxin to Apoe-/- mice reversed the protective effect of A. muciniphila against atherosclerosis.
“Long-term infusion of endotoxin to Apoe -/-mice reversed the protective effect of A muciniphila against atherosclerosis.”
Quote in the paperSubstantial claim - Findingown data
Long-term infusion of lipopolysaccharide reversed the effect of A muciniphila on alleviation of Western diet-induced local and systemic inflammation.
“Here, we show that long-term infusion of lipopolysaccharide reversed the effect of A muciniphila on alleviation of the Western diet-induced local and systemic inflammation”
- Also stated in: § CLINICAL PERSPECTIVE · plain
“Akkermansia muciniphila-mediated amelioration of local and systemic inflammation was reversed by long-term infusion of lipopolysaccharide (LPS).”
Quote in the paperSubstantial claim - Also stated in: § CLINICAL PERSPECTIVE · plain
- Findingown data
The beneficial effect of A muciniphila against atherosclerosis was abolished by long-term infusion with lipopolysaccharide.
“The beneficial effect of Akkermansia muciniphila against atherosclerosis was abolished by long-term infusion with lipopolysaccharide (LPS).”
Quote in the paperSubstantial claim - Findingown data
The amelioration of systemic inflammation by A. muciniphila, as determined by circulating levels of MCP-1, IL-1β and sTNFR II, was also abolished by long-term infusion of lipopolysaccharide.
“Notably, the amelioration of systemic inflammation by A muciniphila, as determined by circulating levels of MCP-1, IL-1β and sTNFR II, was also abolished by long-term infusion of lipopolysaccharide (Figure 6H-6J).”
Quote in the paperSubstantial claim - Findingown data
Our study showed a markedly reduced abundance of Akkermansia muciniphila in a murine model of Western diet-induced atherosclerosis.
“Our study showed a markedly reduced abundance of Akkermansia muciniphila, which is a strain of commensal bacteria in the gut, in a murine model of Western diet-induced atherosclerosis.”
Quote in the paperSubstantial claim - Findingown data
Treatment with inoculating medium of A muciniphila directly stimulated expression of tight junction proteins in intestinal epithelial cells.
“treatment with inoculating medium of A muciniphila directly stimulated the expression of these tight junction proteins in intestinal epithelial cells.”
Quote in the paperSubstantial claim - Findingown data
Replenishment of A. muciniphila by daily oral gavage reduced the size of atherosclerotic plaques in Western diet-fed Apoe-/- mice.
“Replenishment of A muciniphila by daily oral gavage reduced the size of atherosclerotic plaques in Western diet-fed Apoe -/- mice.”
Quote in the paperSubstantial claim - Findingown data
Daily oral gavage with A muciniphila, without obvious change in gut microbiota composition, is sufficient to reduce atherosclerosis in Apoe-/- mice.
“our result showed that daily oral gavage with the monospecific genus A muciniphila, without an obvious change in the composition of gut microbiota, is sufficient to reduce atherosclerosis”
- Also stated in: § CLINICAL PERSPECTIVE · plain
“Western diet-fed Apoe -/-mice treated with Akkermansia muciniphila exhibited reduced atherosclerosis.”
- Also stated in: § CLINICAL PERSPECTIVE · plain
“Replenishing this strain of bacteria by oral gavage substantially diminished the Western diet-induced atherosclerotic lesions.”
Quote in the paperSubstantial claim- Rests on an assumption: Whether altered gut microbiota contributes to the pathogenesis of atherosclerosis remains unknown.
- Also stated in: § CLINICAL PERSPECTIVE · plain
- Findingown data
Expression of tight junction proteins occludin and ZO-1 was increased in the ileum of Apoe-/- mice after administration of A muciniphila.
“The expression of the 2 tight junction proteins, occludin and ZO-1, was increased in the ileum of Apoe -/-mice after administration of A muciniphila”
Quote in the paperSubstantial claim - Findingown data
The Western diet led to hyperlipidemia in Apoe-/- mice compared with normal chow diet.
“the Western diet led to hyperlipidemia in Apoe -/-mice compared with normal chow diet”
Quote in the paperSubstantial claim - Premisecitation
Antibiotic therapy fails to elicit any beneficial effect on cardiovascular events in human trials.
“antibiotic therapy fails to elicit any beneficial effect on cardiovascular events in human trials.[14][15][16]”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Germ-free atherogenic mice lacking apolipoprotein E show a worsening of atherosclerotic lesions after being fed a high-cholesterol diet compared with conventionally raised mice.
“the germ-free atherogenic mice lacking apolipoprotein E (Apoe -/ ) mice, which are without the colonization of gut microbiota, show a worsening of atherosclerotic lesions after being fed a high-cholesterol diet compared with the conventionally raised mice”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
The protective effect of A. muciniphila was dependent on their viability.
“indicating that the protective effect of this bacteria was dependent on their viability.”
Quote in the paperSubstantial claim - Interpretationcitation
A. muciniphila has a beneficial effect in combating obesity-related metabolic disorders.
“suggesting a beneficial effect in combating obesity-related metabolic disorders.”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data
A. muciniphila attenuates atherosclerotic lesions by ameliorating metabolic endotoxemia-induced inflammation through restoration of the gut barrier.
“A muciniphila attenuates atherosclerotic lesions by ameliorating metabolic endotoxemia-induced inflammation through restoration of the gut barrier.”
Quote in the paperSubstantial claim- Rests on an assumption: Gut permeability is regulated by the mucus layer and tight junctions of the intestine.
- Interpretationown data
The findings suggest a causal role of the reduction in gut A. muciniphila in the Western diet-induced exacerbation of atherosclerosis.
“The findings suggest a causal role of the reduction in gut A muciniphila in the Western diet-induced exacerbation of atherosclerosis.”
Quote in the paperSubstantial claim- Rests on an assumption: Direct evidence for the causative role of altered gut microbiota (dysbiosis) in the pathogenesis of atherosclerosis is still lacking.
- Interpretationreasoning
Amelioration of adipose tissue inflammation by A. muciniphila was also attributed to its ability to reduce endotoxemia.
“suggesting that amelioration of adipose tissue inflammation by A muciniphila was also attributed to its ability to reduce endotoxemia.”
Quote in the paperSubstantial claim - Premisecitation
Inactivation of the lipopolysaccharide pathway by deletion of Toll-like receptor 4 or myeloid differentiation factor-88 or inhibition of lipopolysaccharide-binding protein reduces aortic lesions in Apoe-/- and Ldlr-/- mice.
“Inactivation of the lipopolysaccharide pathway by deletion of Toll-like receptor 4 or the downstream cytosolic adaptor myeloid differentiation factor-88 or the prevention of its transport by inhibiting lipopolysaccharide-binding protein reduces aortic lesions in Apoe -/-and low-density lipoprotein receptor-deficient (Ldlr -/-) mice.”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data
The beneficial role of A muciniphila against atherosclerosis was not attributed to altered lipid or glucose metabolism.
“implying that the beneficial role of A muciniphila against atherosclerosis was not attributed to altered lipid or glucose metabolism.”
Quote in the paperSubstantial claim - Interpretationreasoning
The antiatherosclerotic effect of A muciniphila is attributed mainly to its anti-inflammatory activity.
“suggesting that the antiatherosclerotic effect of A muciniphila is attributed mainly to its anti-inflammatory activity.”
Quote in the paperSubstantial claim - Premisecitation
Lipopolysaccharide, a ligand of Toll-like receptor 4, is a potent stimulus of inflammation.
“Lipopolysaccharide, a ligand of Toll-like receptor 4, is a potent stimulus of inflammation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [33] source
Not checked in the free run.
- Premisecitation
Penetration of lipopolysaccharide into the bloodstream is controlled by the integrity of the gut barrier.
“Penetration of lipopolysaccharide into the bloodstream is controlled by the integrity of the gut barrier.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [48] source
Not checked in the free run.
- Interpretationreasoning
Our study uncovered a key link among gut microbiota, gut permeability, and vascular system.
“Our study uncovered a key link among gut microbiota, gut permeability, and vascular system”
Quote in the paperSubstantial claim - Interpretationown data
These findings suggest an additional mechanism of preserving gut barrier by A muciniphila.
“These findings suggest an additional mechanism of preserving gut barrier by A muciniphila.”
Quote in the paperSubstantial claim - Premisecitation
The metabolic benefits of dietary polyphenol, cranberry extract, and metformin are associated with increased amount of A muciniphila in the gut.
“Furthermore, the metabolic benefits of dietary polyphenol, cranberry extract, and metformin are associated with increased amount of this bacterial species in the gut.”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
Administration of A muciniphila prevents thinning of mucus layer in mice with diet-induced obesity.
“Administration of A muciniphila has been shown to prevent the thinning of mucus layer in mice with diet-induced obesity.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] source
Not checked in the free run.
- Premisecitation
Lipopolysaccharide can act on Toll-like receptor 4 in adipocytes to stimulate production of proinflammatory adipokines and reinforce systemic inflammation.
“Lipopolysaccharide can also act on Toll-like receptor 4 in adipocytes to stimulate the production of proinflammatory adipokines and to further reinforce the systemic inflammation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [45] source
Not checked in the free run.
- May combine two claims. 36
- Classified as probably not a substantial claim. 32
May combine two claims.
Findingown dataWestern diet-fed Apoe-/- mice showed a significant decrease in the inner mucin layer thickness of ileum, and A. muciniphila treatment partially restored the thickness of this layer.
“Western diet-fed Apoe -/-mice showed a significant decrease in the inner mucin layer thickness of ileum, and A muciniphila treatment partially restored the thickness of this layer (Figure III in the online-only Data Supplement).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDaily oral gavage with A. muciniphila did not affect the overall pattern of gut microbiota and abundance of the above-mentioned bacterial species.
“However, the daily oral gavage with A muciniphila did not affect the overall pattern of gut microbiota and abundance of the above-mentioned bacterial species (Figure IA-IF in the online-only Data Supplement).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe expression of the epithelial tight junction protein occludin was significantly reduced by Western diet feeding but was upregulated by treatment with live A. muciniphila.
“the expression of the epithelial tight junction protein occludin was significantly reduced by Western diet feeding but was upregulated by treatment with live A muciniphila (Figure 4B, 4D, and 4F).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThis pattern change was characterized by increased amounts of Proteobacteria and Firmicutes and a decreased quantity of Bacteroidetes, Fusobacteria, and Tenericutes.
“This pattern change was characterized by increased amounts of Proteobacteria and Firmicutes and a decreased quantity of Bacteroidetes, Fusobacteria, and Tenericutes (Figure IB-IF in the online-only Data Supplement)”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn the atherogenic Apoe-/- model, there was no obvious change in food intake after A. muciniphila treatment, although there was a slight decrease in body weight and fat mass.
“In our atherogenic Apoe -/-model, there was no obvious change in food intake after A muciniphila treatment (Figure IG in the online-only Data Supplement), although there was a slight decrease in body weight and fat mass (Figure IH-IJ in the online-only Data Supplement).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe serum levels of MCP-1 and IL-1β were significantly increased in Western diet-fed Apoe-/- mice compared with the mice on normal chow diet, whereas these Western diet-induced elevations were obviously diminished by daily oral gavage with A. muciniphila but not the heat-killed bacteria.
“The serum levels of these 2 proinflammatory factors were significantly increased in Western diet-fed Apoe -/- mice compared with the mice on normal chow diet, whereas these Western diet-induced elevations were obviously diminished by daily oral gavage with A muciniphila but not the heat-killed bacteria (Figure 3E and 3F).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe Western diet resulted in a 3.7-fold increase in lesion area and a 2.9-fold increase in lesion size in Apoe-/- mice compared with normal chow diet.
“The Western diet resulted in a 3.7fold increase in lesion area and a 2.9-fold increase in lesion size in Apoe -/-mice compared with normal chow diet (Figure 1D and 1E).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTreatment with A. muciniphila substantially reduced the lesion area and size by 31% and 48%, respectively, in Apoe-/- mice fed a Western diet.
“Treatment with A muciniphila substantially reduced the lesion area and size by 31% and 48%, respectively, in Apoe -/-mice fed a Western diet (Figure 1D and 1E).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataA. 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.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe in vivo gut permeability was significantly higher in Western diet-fed Apoe-/- mice compared with the normal chow diet-fed controls, whereas the Western diet-induced increase of gut permeability was largely blocked by the treatment with live A. muciniphila.
“The in vivo gut permeability, as determined by oral administration of fluorescent labeled dextran (DX-4000-FITC) followed by measurement of its circulating concentration, was significantly higher in Western diet-fed Apoe -/-mice compared with the normal chow dietfed controls, whereas the Western diet-induced increase of gut permeability was largely blocked by the treatment with live A muciniphila”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn Apoe-/- mice on normal chow diet, treatment with A. muciniphila has no obvious effect on gut permeability, circulating levels of inflammatory markers (MCP-1, IL-1β, and sTNFR II), and atherosclerotic plaque formation.
“In Apoe -/-mice on normal chow diet, treatment with A muciniphila has no obvious effect on gut permeability (Figure VA in the online-only Data Supplement), circulating levels of inflammatory markers (MCP-1, IL-1β, and sTNFR II; Figure VB-VD in the online-only Data Supplement), and atherosclerotic plaque formation (Figure VE and VF in the online-only Data Supplement)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe number of macrophages in atherosclerotic lesions increased after Western diet feeding, and daily oral gavage with A. muciniphila significantly reduced the amount.
“The number of macrophages in atherosclerotic lesions increased after Western diet feeding, and daily oral gavage with A muciniphila significantly reduced the amount, as shown by immunofluorescent staining of the macrophage marker monocytes/macrophages antigen (Figure 2A and 2D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataReplenishment with A. muciniphila reversed Western diet-induced exacerbation of atherosclerotic lesion formation without affecting hypercholesterolemia.
“Replenishment with A muciniphila reversed Western diet-induced exacerbation of atherosclerotic lesion formation without affecting hypercholesterolemia.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataA muciniphila had no effect on Western diet-induced hypercholesterolemia or other metabolic profiles (serum lipids, fasting glucose, glucose tolerance) in Apoe-/- mice.
“In contrast, A muciniphila had no effect on the Western diet-induced hypercholesterolemia and alterations in other metabolic profiles”
- Also stated in: § CLINICAL PERSPECTIVE · plain
“the daily oral gavage with A muciniphila did not alter serum levels of total cholesterol, total triglyceride, low-density lipoprotein, and high-density lipoprotein”
- Also stated in: § CLINICAL PERSPECTIVE · plain
“A muciniphila treatment did not significantly affect fasting blood glucose level or glucose tolerance in Apoe -/-mice”
Quote in the paperSubstantial claim- Also stated in: § CLINICAL PERSPECTIVE · plain
May combine two claims.
Findingown dataThe present study demonstrates that the Western diet-induced deterioration of atherosclerosis in Apoe-/- mice is associated with an increased level of Firmicutes, a decreased amount of Bacteroidetes, and especially a marked reduction in A. muciniphila in the gut.
“The present study demonstrates that the Western diet-induced deterioration of atherosclerosis in Apoe -/-mice is associated with an increased level of Firmicutes, a decreased amount of Bacteroidetes, and especially a marked reduction in A muciniphila in the gut.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataA muciniphila treatment substantially reduced expression of chemokines and adhesion molecules MCP-1, TNFα, ICAM-1, and lowered aortic macrophage infiltration and atherosclerotic lesion in Apoe-/- mice.
“treatment with A muciniphila substantially reduced the expression of several chemokines and the adhesion molecules MCP-1, TNFα, and ICAM-1, along with lower aortic infiltration of macrophages and diminished atherosclerotic lesion in Apoe -/-mice.”
- Also stated in: § CLINICAL PERSPECTIVE · plain
“Local inflammation in aortic arch was reduced in Apoe -/-mice after oral gavage with Akkermansia muciniphila.”
- Also stated in: § CLINICAL PERSPECTIVE · plain
“Apoe -/-mice treated with Akkermansia muciniphila showed amelioration in both aortic expression and systemic levels of inflammatory molecules.”
Quote in the paperSubstantial claim- Also stated in: § CLINICAL PERSPECTIVE · plain
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationBacterial DNA has been detected in atherosclerotic lesions, and pyrosequencing reveals that the bacteria in lesions are derived from gut and oral cavity.
“Bacterial DNA has been detected in atherosclerotic lesions, and the pyrosequencing result reveals that the bacteria in lesions are derived from gut and oral cavity, 13”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSupplementation with Faecalibacterium prausnitzii improves the survival rate of chemical-induced colitis in animals.
“supplementation with one of the species in this phylum, Faecalibacterium prausnitzii, improves the survival rate of chemical-induced colitis in animals.5”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [5] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationChlamydia pneumonia is present in atherosclerotic lesions of patients with previous exposure, and infection with this bacterium exacerbates atherosclerosis in animals.
“Chlamydia pneumonia is present in atherosclerotic lesions of patients with previous exposure, and infection with this bacterium exacerbates atherosclerosis in animals.11,12”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [11]
Not checked in the free run.
- cites [12]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSupplementation with butyric acid improves the metabolic profiles in a dietary obese murine model.
“supplementation with butyric acid improves the metabolic profiles in a dietary obese murine model.8”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [8]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationHigher proportions of Firmicutes and lower levels of Bacteroidetes have been observed in obese individuals, and dietary intervention or bariatric surgery reverses these changes.
“higher proportions of Firmicutes and lower levels of Bacteroidetes have been observed in obese individuals, and dietary intervention or bariatric surgery reverses these changes.6”
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).
PremisecitationA lower proportion of butyrate-producing bacteria is found in individuals with autoimmune diabetes mellitus compared with healthy control subjects.
“A lower proportion of butyrate-producing bacteria have been found in individuals with autoimmune diabetes mellitus compared with healthy control subjects, 7”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationBacterial infection has been proposed as one of the triggers of inflammation in atherosclerosis.
“Bacterial infection has been proposed as one of the triggers of inflammation in atherosclerosis.11,12”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [11]
Not checked in the free run.
- cites [12]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDecreased diversity within the phylum Firmicutes in the gut microbiota is commonly found in patients with Crohn disease.
“decreased diversity within the phylum of Firmicutes in the gut microbiota is commonly found in patients with Crohn disease, 4”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [4]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAltered composition and function of gut microbiota have been linked to a number of chronic diseases, including colon cancer, irritated bowel syndrome, colitis, obesity, and diabetes mellitus.
“Altered composition and function of gut microbiota have been linked to a number of chronic diseases, including colon cancer, irritated bowel syndrome, colitis, obesity, and diabetes mellitus.3”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [3] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAtherosclerosis is the main contributor to cardiovascular mortality and is a chronic inflammatory disease.
“Atherosclerosis, the main contributor to cardiovascular mortality, is a chronic inflammatory disease.10”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA smaller amount of A. muciniphila in the gut has been observed in obese children and pregnant women.
“A smaller amount of A muciniphila in the gut has been observed in obese children and pregnant women.22,23”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [22] source
Not checked in the free run.
- cites [23]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationA. muciniphila accounts for approximately 1% to 3% of the microbial community in healthy subjects, and its abundance is inversely correlated with body weight in mice and humans.
“It accounts for ≈1% to 3% of the microbial community in healthy subjects, and its abundance is inversely correlated with body weight in mice and humans.20,21”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAkkermansia muciniphila is a mucin-degrading bacterium belonging to the genus Verrucomicrobia and is an important component of the gut microbial ecosystem.
“Akkermansia muciniphila, a mucin-degrading bacterium belonging to the generum of Verrucomicrobia, has recently emerged as an important component of the gut microbial ecosystem.19”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19]
Not checked in the free run.
May combine two claims.
PremisecitationIn mice fed a high-fat diet, A. muciniphila given by daily oral gavage reverses fat mass gain, adipose tissue inflammation, and insulin resistance.
“In mice fed a high-fat diet, A muciniphila given by daily oral gavage reverses fat mass gain, adipose tissue inflammation, and insulin resistance, 21,24”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationMetabolomics analysis shows that metabolism of dietary phosphatidylcholine by gut microbiota produces proatherogenic trimethylamine-N-oxide, which can accelerate atherosclerosis in mice.
“a metabolomics analysis shows that metabolism of dietary phosphatidylcholine by gut microbiota produces proatherogenic trimethylamine-N-oxide, which can accelerate atherosclerosis in mice.17,18”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
Interpretationown dataThe amount of intestinal A. muciniphila under normal diet is sufficient to maintain the integrity of the gut barrier, thereby preventing endotoxinemia-induced systemic inflammation and atherosclerosis.
“suggesting that the amount of intestinal A muciniphila under normal diet is sufficient to maintain the integrity of the gut barrier, thereby preventing endotoxinemiainduced systemic inflammation and atherosclerosis.”
Quote in the paperSubstantial claim- Rests on an assumption: Gut permeability is regulated by the mucus layer and tight junctions of the intestine.
May combine two claims.
InterpretationreasoningA. muciniphila blocked lipopolysaccharide penetration by preserving the gut barrier.
“suggesting that A muciniphila blocked lipopolysaccharide penetration by preserving the gut barrier.”
Quote in the paperSubstantial claim- Rests on an assumption: Gut permeability is regulated by the mucus layer and tight junctions of the intestine.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll animal experiments were approved by the Committee on the Use of Live Animals for Teaching and Research of the University of Hong Kong.
“All the animal experiments were approved by the Committee on the Use of Live Animals for Teaching and Research of the University of Hong Kong.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationMetabolic endotoxemia, defined as a 2- to 3-fold elevation of circulating endotoxin/lipopolysaccharide level, has been proposed as an initiating factor of obesity-related cardiometabolic dysfunction.
“Metabolic endotoxemia, defined as a 2-to 3-fold elevation of the circulating endotoxin/lipopolysaccharide level, has been proposed as an initiating factor of obesity-related cardiometabolic dysfunction.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationBacterial DNA from the gut microbiota has been detected in human atherosclerotic plaques.
“Bacterial DNA from the gut microbiota has been detected in human atherosclerotic plaques.13”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationInflammation and hypercholesterolemia are the 2 key etiological factors for atherosclerosis.
“Inflammation and hypercholesterolemia are the 2 key etiological factors for atherosclerosis.”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenData are presented as mean±SEM; n=5 to 7.
“Data are presented as mean±SEM; n=5 to 7.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationThe primary control of the gut barrier relies on an intact epithelium where tight junctions maintain epithelial integrity.
“the primary control of the gut barrier relies on an intact epithelium where tight junctions sealing the space between individual epithelial cells maintain the epithelial integrity.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [50]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationLoss of occludin leads to increased gut permeability, whereas deficiency of ZO-1 can interrupt tight junction assembly.
“Loss of occludin leads to an increase in gut permeability, whereas deficiency of ZO-1 can interrupt the assembly of tight junction by inhibiting the recruitment of other components.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [50]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSupplementation with prebiotics causes a >100-fold enrichment in gut A muciniphila.
“Notably, supplementation with prebiotics causes a >100-fold enrichment in gut A muciniphila.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningOur findings raise the possibility of targeting individual species of the gut microbiota for the treatment of atherosclerosis.
“Our findings raise the possibility of targeting individual species of the gut microbiota for the treatment of atherosclerosis.”
- Also stated in: § Discussion · hedged
“suggesting that therapeutic interventions targeting this single genus/species in gut microbiota may represent a promising strategy for the treatment and prevention of both metabolic and cardiovascular disorders.”
Quote in the paperNot a substantial claim- Also stated in: § Discussion · hedged
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSeveral recent studies have identified trimethylamine N-oxide, a metabolite of the gut microbiota, as an independent risk factor for cardiovascular disease.
“Several recent studies have identified trimethylamine N-oxide, a metabolite of the gut microbiota, as an independent risk factor for cardiovascular disease.17,18,34”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
Interpretationown dataThe antiatherogenic effect of A muciniphila is mediated by limiting the lipopolysaccharide level in the bloodstream and ameliorating metabolic endotoxemia.
“indicating that the antiatherogenic effect of A muciniphila is mediated by limiting the lipopolysaccharide level in the bloodstream and ameliorating metabolic endotoxemia.”
Quote in the paperSubstantial claim- Rests on an assumption: Toll-like receptor 4 is expressed in various vascular cells, including endothelial cells, focal leukocytes, and macrophages.
- Rests on an assumption: 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.
- Rests on an assumption: Lipopolysaccharide-induced inflammatory cytokines in perivascular adipose tissue can act in a paracrine manner to exacerbate vascular inflammation and atherosclerosis.
May combine two claims.
PremisecitationSubclinical endotoxemia is a strong risk factor for carotid atherosclerosis, and weekly injection of lipopolysaccharide worsens formation of atherosclerosis in animal models.
“A clinical study revealed that subclinical endotoxemia is a strong risk factor for carotid atherosclerosis and that weekly injection of lipopolysaccharide worsens the formation of atherosclerosis in animal models.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [41] source
Not checked in the free run.
- cites [42]
Not checked in the free run.
May combine two claims.
Interpretationown dataThe Western diet-induced atherosclerosis is caused partly by a reduction of A muciniphila in gut, resulting in compromised gut barrier and increased endotoxemia, which in turn exacerbate vascular inflammation.
“The Western diet-induced atherosclerosis is caused partly by a reduction of A muciniphila in gut, resulting in compromised gut barrier and increased endotoxemia, which in turn exacerbate vascular inflammation.”
- Also stated in: § CLINICAL PERSPECTIVE · plain
“The antiatherogenic effect of A muciniphila was attributed to its ability to reduce aortic and systemic inflammation by protecting the integrity of gut barrier, thereby leading to alleviation of endotoxemia.”
Quote in the paperSubstantial claim- Rests on an assumption: Toll-like receptor 4 is expressed in various vascular cells, including endothelial cells, focal leukocytes, and macrophages.
- Rests on an assumption: 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.
- Rests on an assumption: Lipopolysaccharide-induced inflammatory cytokines in perivascular adipose tissue can act in a paracrine manner to exacerbate vascular inflammation and atherosclerosis.
- Rests on an assumption: Whether altered gut microbiota contributes to the pathogenesis of atherosclerosis remains unknown.
- Rests on an assumption: Hypercholesterolemia and chronic inflammation are the 2 important risk factors for atherosclerosis, which is a major cause of fatal cardiovascular complications.
- Rests on an assumption: 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.
- Rests on an assumption: Previous clinical studies have reported a close association of bacterial infection and endotoxemia with cardiovascular diseases.
- Also stated in: § CLINICAL PERSPECTIVE · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLower diversity and abundance of gut microbiota is associated with certain diseases.
“lower diversity and abundance of gut microbiota is associated with certain diseases.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35]
Not checked in the free run.
May combine two claims.
PremisecitationAll these models showed a reduction of lesion area and lesional lipid content without significant alteration of plasma cholesterol levels.
“Notably, all these models showed a reduction of lesion area and lesional lipid content without any significant alteration of plasma cholesterol levels, which is similar to our findings of A muciniphila treatment.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [46]
Not checked in the free run.
- cites [47]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCurrent therapeutic options for treating or preventing atherosclerosis include mainly platelet aggregation inhibitors, statins, antihypertensives, and thrombolytic agents.
“Current therapeutic options for treating or preventing atherosclerosis include mainly platelet aggregation inhibitors, statins, antihypertensives, and thrombolytic agents.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [40]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn obesity, inflammatory factors in adipose tissue are the major contributors to systemic inflammation.
“In obesity, inflammatory factors in adipose tissue are the major contributors to systemic inflammation.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [45]
Not checked in the free run.
May combine two claims.
PremisecitationA positive correlation between serum lipopolysaccharide-binding protein level and carotid intima thickness and an association of Toll-like receptor 4 polymorphisms with decreased atherosclerosis have been found in humans.
“A positive correlation between serum lipopolysaccharide-binding protein level and carotid intima thickness and an association of Toll-like receptor 4 polymorphisms with decreased atherosclerosis have been found in humans.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [43]
Not checked in the free run.
- cites [44]
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationIn the initial stage of atherosclerosis, injured or inflamed endothelium secretes adhesion molecules and chemokines to facilitate recruitment and transmigration of leukocytes into the intima.
“In the initial stage of atherosclerosis, injured or inflamed endothelium secretes adhesion molecules and chemokines to facilitate the recruitment and transmigration of leukocytes into the intima.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe risks for fatal cardiovascular complications in these patients remain high because of unsolved inflammation.
“However, the risks for fatal cardiovascular complications in these patients remain high because of the unsolved inflammation.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe mucus layer is enriched with various mucins that form a hydrated gel layer covering the mucosal surface to prevent adhesion of harmful bacteria.
“The mucus layer is enriched with various mucins that form a hydrated gel layer covering the mucosal surface to prevent adhesion of harmful bacteria.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [49]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAnimal-based studies have reported effectiveness of several anti-inflammatory interventions in alleviating atherosclerosis, but clinical implications remain to be confirmed.
“Animal-based studies have reported the effectiveness of several anti-inflammatory interventions in alleviating atherosclerosis, including the CD40-TNF receptor-associated factor 6-specific blockade and IL-1 neutralization, but clinical implications of these findings remain to be confirmed.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] source
Not checked in the free run.
May combine two claims.
PremisecitationThe unresolved inflammation stimulates expression of macrophage scavenger receptors and promotes uptake of modified lipoproteins forming lipid-laden macrophages, driving the inflammatory loop.
“The unresolved inflammation stimulates the expression of macrophage scavenger receptors and promotes the uptake of modified lipoproteins forming lipid-laden macrophages, which drives the inflammatory loop for further migration and proliferation of leukocytes and smooth muscle cells in the lesion area.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA prebiotics-induced hypocholesterolemic effect has been reported in animals, suggesting a possible role in combating atherosclerosis.
“A prebiotics-induced hypocholesterolemic effect has been reported in animals, suggesting a possible role in combating atherosclerosis.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTight junction is a multiple protein complex including occludin, claudins, and ZOs.
“Tight junction is a multiple protein complex including occludin, claudins, and ZOs.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [50]
Not checked in the free run.
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.”
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 preclinical models, gavage of western diet-fed Apoe−/− mice with live Akkermansia muciniphila decreased intestinal permeability and lowered fecal and circulating lipopolysaccharide levels, which was associated with reduced aortic atherosclerosis independent of lipid metabolism.
“Indeed, in preclinical models, gavage of western diet–fed Apoe−/− mice with live Akkermansia muciniphila decreased intestinal permeability and lowered fecal and circulating LPS levels, which was associated with reduced aortic atherosclerosis independent of lipid metabolism28.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [28]
Provision of Akkermansia muciniphila is associated with reduced aortic atherosclerosis in the hypercholesterolemic Apoe−/− mouse model.
“In another recent study, provision of Akkermansia muciniphila was associated with reduced aortic atherosclerosis in the hypercholesterolemic Apoe−/− mouse model28.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [28]
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]”
From <i>Bacteroides vulgatus</i> and <i>Bacteroides dorei</i> Reduce Gut Microbial Lipopolysaccharide Production and Inhibit Atherosclerosis (2018) · cites this paper as [35]
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
MajorThe 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.
“A muciniphila was orally gavaged daily to Apoe -/-mice for a total of 8 weeks, and during the last 4 weeks, either lipopolysaccharide (250 µg/kg body weight per day) or PBS (vehicle control) was infused long term”
“either PBS (WD+PBS) or A muciniphila was given orally to Apoe -/-mice daily for 4 weeks, followed by long-term infusion of LPS (250 μg•kg -1 •d -1 ; WD+Akk+LPS) or vehicle control (WB+Akk) for another 4 weeks.”
Diet description conflicts with the cited germ-free mouse study
MinorThe 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.
“the germ-free atherogenic mice lacking apolipoprotein E (Apoe -/ ) mice, which are without the colonization of gut microbiota, show a worsening of atherosclerotic lesions after being fed a high-cholesterol diet compared with the conventionally raised mice”
“14. Stepankova R, Tonar Z, Bartova J, Nedorost L, Rossman P, Poledne R, Schwarzer M, Tlaskalova-Hogenova H. Absence of microbiota (germ-free conditions) accelerates the atherosclerosis in ApoE-deficient mice fed standard low cholesterol diet.”
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Innate immunity and adipose tissue biology
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Prebiotics and lipid metabolism
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Infectious Agents Are Not Necessary for Murine Atherogenesis
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The macrophage LBP gene is an LXR target that promotes macrophage survival and atherosclerosis
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Introduction to the human gut microbiota
Thursby, E., & Juge, N. (2017) · Biochemical Journal · doi:10.1042/bcj20160510 · Cited by 3,600 · see citing works
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Human gut microbiome: Hopes, threats and promises
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Akkermansia muciniphila: paradigm for next-generation beneficial microorganisms
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Dietary lipids, gut microbiota and lipid metabolism
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Next-Generation Beneficial Microbes: The Case of Akkermansia muciniphila
Cani, P. D., & de Vos, W. M. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.01765 · Cited by 1,058 · see citing works
“It is worth noting that all these findings have subsequently been confirmed by different groups and extended to other specific disorders such as atherosclerosis, hepatic inflammation and hypercholesterolemia (Shin et al., 2014; Li et al., 2016; Shen et al., 2016; Grander et al., 2017; Plovier et al., 2017).”
BackgroundGut microbiota and cardiovascular disease.
Witkowski, M., Weeks, T. L., & Hazen, S. L. (2020) · Circulation Research · doi:10.1161/circresaha.120.316242 · Cited by 1,051 · see citing works
The gut microbiome: Relationships with disease and opportunities for therapy
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“Protects against atherosclerosis by decreasing gut permeability and preventing endotoxemia-induced inflammation (Li et al., 2016a) Improves efficacy of anti-cancer immunotherapy (Routy et al., 2018)”
BackgroundInfluentialFactors affecting the composition of the gut microbiota, and its modulation
Hasan, N., & Yang, H. (2019) · PeerJ · doi:10.7717/peerj.7502 · Cited by 763 · see citing works
“…under dietary fiber deficiency causes the erosion of the colonic mucus barrier (Desai et al., 2016) and studies on experimental mice demonstrated that administration of Akkermansia muciniphila, mucin degrade, lead to restoration of the gut barrier (Everard et al., 2013; Li et al., 2016a).”
Background<i>Akkermansia muciniphila</i> is a promising probiotic
Zhang, T., Li, Q., Cheng, L., Buch, H., & Zhang, F. (2019) · Microbial Biotechnology · doi:10.1111/1751-7915.13410 · Cited by 708 · see citing works
Role of gut microbiota in atherosclerosis
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Role and Mechanism of Gut Microbiota in Human Disease
Chen, Y., Zhou, J., & Wang, L. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.625913 · Cited by 643 · see citing works
“The abundance of Enterobacteriaceae and Enterobacter aerogenes is much higher in atherosclerosis patients Frontiers in Cellular and Infection Microbiology | www.frontiersin.org 4 than in control samples, which inhibited the growth of beneficial bacteria (Li et al., 2016; Jie et al., 2017).”
BackgroundGrander, C., Adolph, T. E., Wieser, V., Lowe, P., Wrzosek, L., Gyongyosi, B., Ward, D. V., Grabherr, F., Gerner, R. R., Pfister, A., et al. (2018) · Gut · doi:10.1136/gutjnl-2016-313432 · Cited by 618 · see citing works
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“More recently, the bacterium was shown to protect against atherosclerosis in an Apoe−/− mouse model by attenuating metabolic endotoxemia-induced inflammation through restoration of the gut barrier [106].”
BackgroundA next generation probiotic, Akkermansia muciniphila
Zhai, Q., Feng, S., Narbad, A., & Chen, W. (2018) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2018.1517725 · Cited by 437 · see citing works
“IFN-c can specifically cause a decrease of A. muciniphila and impair glucose metabolism (Li et al. 2016).”
BackgroundXu, Y., Wang, N., Tan, H.-Y., Li, S., Zhang, C., & Feng, Y. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2020.00219 · Cited by 420 · see citing works
“However, oral administration of A. muciniphila did not change plasma lipid in normal chow diet-fed mice (Li et al., 2016).”
BackgroundInfluentialGut microbiota-mediated inflammation in obesity: a link with gastrointestinal cancer
Cani, P. D., & Jordan, B. F. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0025-6 · Cited by 383 · see citing works
RETRACTED ARTICLE: Role of the gut microbiome in chronic diseases: a narrative review
Vijay, A., & Valdes, A. M. (2022) · European Journal of Clinical Nutrition · doi:10.1038/s41430-021-00991-6 · Cited by 361 · see citing works
RetractedA Proinflammatory Gut Microbiota Increases Systemic Inflammation and Accelerates Atherosclerosis
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Rebuilding the Gut Microbiota Ecosystem
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“Akkermansia muciniphila Obesity Metabolism disorders Diabetic subjects Re-equilibrate gut microbiota dysbiosis Reverse atherosclerotic injuries [103,105,106]”
BackgroundProbiotics, prebiotics, synbiotics and insulin sensitivity
Kim, Y. A., Keogh, J. B., & Clifton, P. M. (2017) · Nutrition Research Reviews · doi:10.1017/s095442241700018x · Cited by 341 · see citing works
The mutual interplay of gut microbiota, diet and human disease
Illiano, P., Brambilla, R., & Parolini, C. (2020) · FEBS Journal · doi:10.1111/febs.15217 · Cited by 331 · see citing works
Fecal microbiota transplantation in metabolic syndrome: History, present and future
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Zhou, K. (2017) · Journal of Functional Foods · doi:10.1016/j.jff.2017.03.045 · Cited by 305 · see citing works
“These studies also suggest a causal role of intestinal barrier function and LPS in mediating A. muciniphila activities (Everard et al., 2013; Li et al., 2016).”
BackgroundResultInfluentialKetogenic diet enhances neurovascular function with altered gut microbiome in young healthy mice
Ma, D., Wang, A. C., Parikh, I. J., Green, S. J., Hoffman, J. D., Chlipala, G. E., Murphy, M. P., Sokola, B. S., Bauer, B., Hartz, A. M. S., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-25190-5 · Cited by 300 · see citing works
Trimethylamine N-oxide promotes atherosclerosis via CD36-dependent MAPK/JNK pathway
Geng, J., Yang, C., Wang, B., Zhang, X., Hu, T., Gu, Y., & Li, J. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2017.11.016 · Cited by 297 · see citing works
Self-citationAction and function of Akkermansia muciniphila in microbiome ecology, health and disease
Ottman, N., Geerlings, S. Y., Aalvink, S., de Vos, W. M., & Belzer, C. (2017) · Best Practice & Research Clinical Gastroenterology · doi:10.1016/j.bpg.2017.10.001 · Cited by 290 · see citing works
“muciniphila debilitated atherosclerotic lesions and alleviated inflammation induced by metabolic endotoxaemia [73].”
BackgroundProbiotic Supplementation in Patients with Alzheimer’s Dementia - An Explorative Intervention Study
Leblhuber, F., Steiner, K., Schuetz, B., Fuchs, D., & Gostner, J. M. (2018) · Current Alzheimer Research · doi:10.2174/1389200219666180813144834 · Cited by 269 · see citing works
“terms of prevention of cognitive decline and dementia [52, 53].”
Revisit gut microbiota and its impact on human health and disease
Ding, R., Goh, W.-R., Wu, R., Yue, X., Luo, X. G., Khine, W. W. T., Wu, J., & Lee, Y. K. (2019) · Journal of Food and Drug Analysis · doi:10.1016/j.jfda.2018.12.012 · Cited by 269 · see citing works
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Extracellular Vesicles from Child Gut Microbiota Enter into Bone to Preserve Bone Mass and Strength
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Lee, D. M., Battson, M. L., Jarrell, D. K., Hou, S., Ecton, K. E., Weir, T. L., & Gentile, C. L. (2018) · Cardiovascular Diabetology · doi:10.1186/s12933-018-0708-x · Cited by 246 · see citing works
Gut microbiota: A target for heavy metal toxicity and a probiotic protective strategy
Duan, H., Yu, L., Tian, F., Zhai, Q., Fan, L., & Chen, W. (2020) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2020.140429 · Cited by 247 · see citing works
Protective Effect of Akkermansia muciniphila against Immune-Mediated Liver Injury in a Mouse Model
Wu, W., Lv, L., Shi, D., Ye, J., Fang, D., Guo, F., Li, Y., He, X., & Li, L. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.01804 · Cited by 247 · see citing works
“Elevated IFN-γ can bind to IFNGR and inhibit transcription of Bcl-2; Bcl-2 is considered to be a potent anti-apoptosis factor and has beneficial effects on Con A-activated hepatocyte death (Li et al., 2016a).”
BackgroundInfluentialHersoug, L., Möller, P., & Loft, S. H. (2018) · Nutrition Research Reviews · doi:10.1017/s0954422417000269 · Cited by 246 · see citing works
Vallianou, N. G., Stratigou, T., Christodoulatos, G. S., Tsigalou, C., & Dalamaga, Μ. (2020) · Current Obesity Reports · doi:10.1007/s13679-020-00379-w · Cited by 251 · see citing works
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Qu, S., Fan, L., Qi, Y., Xu, C., Hu, Y., Chen, S., Liu, W., Liu, W., & Si, J. (2021) · Microbiology Spectrum · doi:10.1128/spectrum.00730-21 · Cited by 245 · see citing works
“muciniphila could protect against serious diseases such as atherosclerosis (17), ALS (amyotrophic lateral sclerosis) (18), and immune-mediated liver injury (19).”
BackgroundZheng, M., Han, R., Yuan, Y., Xing, Y., Zhang, W., Sun, Z., Liu, Y., Li, J., & Mao, T. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1089600 · Cited by 241 · see citing works
Self-citationInteraction Between Atypical Antipsychotics and the Gut Microbiome in a Bipolar Disease Cohort
Flowers, S. A., Evans, S. J., Ward, K. M., McInnis, M. G., & Ellingrod, V. L. (2017) · Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy · doi:10.1002/phar.1890 · Cited by 235 · see citing works
The influence of Akkermansia muciniphila on intestinal barrier function
Mo, C., Lou, X., Xue, J., Shi, Z., Zhao, Y., Wang, F., & Chen, G. (2024) · Gut Pathogens · doi:10.1186/s13099-024-00635-7 · Cited by 235 · see citing works
“Daily oral administration of Am or its representative membrane protein, AMUC-1100, reverses increased fat mass, adipose tissue inflammation, and insulin resistance in mouse models fed a high-fat diet [25, 28, 29].”
BackgroundThe Skin and Gut Microbiome and Its Role in Common Dermatologic Conditions
Ellis, S. R., Nguyen, M., Vaughn, A. R., Notay, M., Burney, W. A., Sandhu, S., & Sivamani, R. K. (2019) · Microorganisms · doi:10.3390/microorganisms7110550 · Cited by 236 · see citing works
Fusobacterium nucleatum promotes colorectal cancer metastasis by modulating KRT7-AS /KRT7
Chen, S., Su, T., Zhang, Y., Lee, A. A., He, J., Ge, Q., Wang, L., Si, J., Zhuo, W., & Wang, L. (2020) · Gut Microbes · doi:10.1080/19490976.2019.1695494 · Cited by 232 · see citing works
The Genetic Variability of APOE in Different Human Populations and Its Implications for Longevity
Abondio, P., Sazzini, M., Garagnani, P., Boattini, A., Monti, D., Franceschi, C., Luiselli, D., & Giuliani, C. (2019) · Genes · doi:10.3390/genes10030222 · Cited by 226 · see citing works
Liu, Y., & Dai, M. (2020) · Mediators of Inflammation · doi:10.1155/2020/4634172 · Cited by 231 · see citing works
“Additionally, Akkermansia muciniphila has been proven to be beneficial in the pathogenesis of AS [12].”
BackgroundDuttaroy, A. K. (2021) · Nutrients · doi:10.3390/nu13010144 · Cited by 232 · see citing works
The Role of Gut Microbiota in Atherosclerosis and Hypertension
Ma, J., & Li, H. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.01082 · Cited by 226 · see citing works
“In addition, Akkermansia muciniphila was found to improve gut barrier functions and exert protective effects against atherosclerosis (Li et al., 2016).”
BackgroundQiao, S., Liu, C., Sun, L., Wang, T., Dai, H., Wang, K., Li, B., Li, H., Wang, W., Liu, S., et al. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00649-y · Cited by 225 · see citing works
Obesity and disease severity magnify disturbed microbiome-immune interactions in asthma patients
Michalovich, D., Rodríguez‐Pérez, N., Smolińska, S., Pirożyński, M., Mayhew, D. N., Uddin, S., Horn, S. V., Sokołowska, M., Altunbulakli, C., Eljaszewicz, A., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-13751-9 · Cited by 216 · see citing works
Sánchez-Rodríguez, E., Egea-Zorrilla, A., Plaza‐Díaz, J., Aragón‐Vela, J., Muñoz‐Quezada, S., Tercedor‐Sánchez, L., & Abadía‐Molina, F. (2020) · Nutrients · doi:10.3390/nu12030605 · Cited by 220 · see citing works
“Circulating LPS is raised in at-risk individuals and predicts future CVD [145–147]; accordingly, administration of low-doses of LPS induces vascular inflammation and atherosclerosis in experimental animals [148,149].”
BackgroundVerhoog, S., Taneri, P. E., Roa‐Díaz, Z. M., Marques-Vidal, P. M., Troup, J. P., Bally, L., Franco, O. H., Glišić, M., & Muka, T. (2019) · Nutrients · doi:10.3390/nu11071565 · Cited by 205 · see citing works
“2019* [9] Randomized, double-blind placebo-controlled trial Mexico/30–60 Patients with Type 2 Diabetes 81 W and M 3 months A reduced-energy diet with a dietary portfolio (DP) (14 g of dehydrated nopal, 4 g of chia seeds, 30 g of soy protein and 4 g of inulin) Placebo (28 g of calcium caseinate and 15 g of maltodextrin…”
BackgroundMethodRole of gut microbiota in cardiovascular diseases
Novaković, M., Rout, A., Kingsley, T. C., Kirchoff, R. W., Singh, A., Verma, V. K., Kant, R., & Chaudhary, R. (2020) · World Journal of Cardiology · doi:10.4330/wjc.v12.i4.110 · Cited by 206 · see citing works
Emerging trends and research foci in gastrointestinal microbiome
Huang, X., Fan, X., Ying, J., & Chen, S. (2019) · Journal of Translational Medicine · doi:10.1186/s12967-019-1810-x · Cited by 195 · see citing works
Duan, R., Guan, X., Huang, K., Zhang, Y., Li, S., Xia, J., & Shen, M. (2021) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.1c01813 · Cited by 198 · see citing works
Catry, E., Bindels, L. B., Tailleux, A., Lestavel, S., Neyrinck, A. M., Goossens, J.-F., Lobysheva, I., Plovier, H., Essaghir, A., Demoulin, J.-B., et al. (2018) · Gut · doi:10.1136/gutjnl-2016-313316 · Cited by 194 · see citing works
Lyu, M., Wang, Y., Fan, G., Wang, X., Xu, S.-Y., & Zhu, Y. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.02146 · Cited by 193 · see citing works
El Hage, R., Hernandez-Sanabria, E., & Van de Wiele, T. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.01889 · Cited by 185 · see citing works
“Akkermansia muciniphila Recent evidence shows that there is a link between the altered gut microbiota and metabolic diseases like obesity, diabetes mellitus, and cardiovascular disease (Schneeberger et al., 2015; Dao et al., 2016; Li et al., 2016).”
BackgroundAlcohol or gut microbiota: who is the guilty?
Meroni, M., Longo, M., & Dongiovanni, P. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20184568 · Cited by 183 · see citing works
The gut microbiota as a novel regulator of cardiovascular function and disease
Battson, M. L., Lee, D. M., Weir, T. L., & Gentile, C. L. (2017) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2017.12.010 · Cited by 185 · see citing works
Santos-Marcos, J. A., Mora-Ortiz, M., Tena‐Sempere, M., López‐Miranda, J., & Camargo, A. (2023) · Biology of Sex Differences · doi:10.1186/s13293-023-00490-2 · Cited by 187 · see citing works
“This bacterium also contributes to the decrease in adipose tissue inflammation by reducing macrophage infiltration, restoring regulatory T cells (Treg cells), reducing pro-inflammatory cytokines (such as IL 6 and IL-1β), and increasing anti-inflammatory factors (such as α-tocopherol and β-sitosterol) [109, 111, 115].”
BackgroundInteractions between gut microbiota and polyphenols: A mechanistic and metabolomic review
Cheng, H., Zhang, D., Wu, J., Liu, J., Zhou, Y., Tan, Y., Feng, W., & Peng, C. Y. (2023) · Phytomedicine · doi:10.1016/j.phymed.2023.154979 · Cited by 188 · see citing works
Guo, X., Li, S., Zhang, J., Wu, F., Li, X., Wu, D., Zhang, M., Ou, Z., Jie, Z., Yan, Q., et al. (2017) · BMC Genomics · doi:10.1186/s12864-017-4195-3 · Cited by 177 · see citing works
“muciniphila and obesity and other diseases [14, 18, 34].”
Jian, H., Liu, Y., Wang, X., Dong, X., & Zou, X. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043900 · Cited by 177 · see citing works
“As explained above, Akk can ameliorate gut barrier impairment in the cases of obesity [22,39,40,47], metabolic diseases [71,76,85], inflammation [85,122,123], and aging [125,129–132]; therefore, it is necessary to know how”
BackgroundInfluentialUtilization of the microbiome in personalized medicine
Ratiner, K., Ciocan, D. M., Abdeen, S. K., & Elinav, E. (2023) · Nature Reviews Microbiology · doi:10.1038/s41579-023-00998-9 · Cited by 178 · see citing works
“Supplementation of Akkermansia muciniphila featured promising results in animal models of obesity and insulin resistance, response to anticancer immunotherapy 93 , amyotrophic lateral sclerosis 94 and atherosclerosis 95 .”
Jennis, M., Cavanaugh, C., Leo, G. C., Mabus, J. R., Lenhard, J. M., & Hornby, P. J. (2017) · Neurogastroenterology & Motility · doi:10.1111/nmo.13178 · Cited by 172 · see citing works
A. Muciniphila Suppresses Colorectal Tumorigenesis by Inducing TLR2/NLRP3-Mediated M1-Like TAMs
Fan, L., Xu, C., Ge, Q., Lin, Y., Wong, C. C., Qi, Y., Ye, B., Lian, Q., Zhuo, W., Si, J., et al. (2021) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-20-1019 · Cited by 175 · see citing works
Recent findings in Akkermansia muciniphila-regulated metabolism and its role in intestinal diseases
Liu, M., Yang, J.-Y., Yan, Z.-H., Hu, S., Li, J.-Q., Xu, Z., & Jian, Y. (2022) · Clinical Nutrition · doi:10.1016/j.clnu.2022.08.029 · Cited by 171 · see citing works
Self-citationβ-glucans: a potential source for maintaining gut microbiota and the immune system
Singh, R. P., & Bhardwaj, A. (2023) · Frontiers in Nutrition · doi:10.3389/fnut.2023.1143682 · Cited by 173 · see citing works
“A previous study showed that oat-β-glucan promotes the expansion of the Verrucomicrobia population (such as Akkermansia muciniphila), which has a prebiotic impact on alterations in circulatory lipids and decreases the number of plaques in the aortic walls as compared with simvastatin (is an oral antilipemic agent) (21…”
BackgroundLuo, Z., Xia, K., Liu, Y.-W., Liu, J., Rao, S., Hu, X., Chen, C., Xu, R., Wang, Z., & Xie, H. (2021) · International Journal of Nanomedicine · doi:10.2147/ijn.s304515 · Cited by 165 · see citing works
Zhang, J., Ni, Y., Qian, L., Fang, Q., Zheng, T., Zhang, M., Gao, Q., Zhang, Y., Ni, J., Hou, X., et al. (2021) · Advanced Science · doi:10.1002/advs.202100536 · Cited by 168 · see citing works
Self-citationShen, W., Shen, M., Zhao, X., Zhu, H., Yang, Y., Lu, S., Tan, Y., Li, G., Li, M., Wang, J., et al. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.00272 · Cited by 159 · see citing works
“The probiotic effects of A. muciniphila have been studied extensively in animals and clinical studies, and the potential mechanisms were reported from cell biology studies (Derrien et al., 2011; Everard et al., 2013; Lukovac et al., 2014; Li et al., 2016).”
BackgroundMicrobiome therapeutics: exploring the present scenario and challenges
Yadav, M., & Chauhan, N. S. (2021) · Gastroenterology report · doi:10.1093/gastro/goab046 · Cited by 157 · see citing works
“Akkermansia muciniphila relieves metabolic disorders and cooperates with the use of metformin in cancer therapeutics [20] as well as protects against atherosclerosis by reducing gut permeability and preventing inflammation [21].”
The gut microbiota: An emerging risk factor for cardiovascular and cerebrovascular disease
Ascher, S., & Reinhardt, C. (2017) · European Journal of Immunology · doi:10.1002/eji.201646879 · Cited by 150 · see citing works
Plant phenolics as functional food ingredients
Santos‐Buelga, C., Paramás, A. M. G., Taofiq, O., Ayuda‐Durán, B., & González‐Manzano, S. (2019) · Advances in food and nutrition research · doi:10.1016/bs.afnr.2019.02.012 · Cited by 160 · see citing works
Cheng, H., Liu, J., Zhang, D., Wang, J., Tan, Y., Feng, W., & Peng, C. Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.817600 · Cited by 147 · see citing works
“As a type of bacteria that settles on the mucus layer and uses mucin as a source of nutrition, the relative abundance of Akkermansia has been reported to be negatively correlated with intestinal inflammation and the Akkermansia species can enhance the function of the intestinal barrier by promoting tight junctions in…”
BackgroundInfection and atherosclerosis: TLR-dependent pathways
Li, B., Xia, Y., & Hu, B. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03453-7 · Cited by 148 · see citing works
Gut–Skin Axis: Unravelling the Connection between the Gut Microbiome and Psoriasis
Thye, A. Y.-K., Bah, Y.-R., Law, J. W.-F., Tan, L. T.-H., He, Y.-W., Wong, S.-H., Thurairajasingam, S., Chan, K.-G., Lee, L.-H., & Letchumanan, V. (2022) · Biomedicines · doi:10.3390/biomedicines10051037 · Cited by 156 · see citing works
Butyrate-producing bacteria and the gut-heart axis in atherosclerosis
Chen, W., Zhang, S., Wu, J., Ye, T., Wang, S., Wang, P., & Xing, D. (2020) · Clinica Chimica Acta · doi:10.1016/j.cca.2020.04.037 · Cited by 144 · see citing works
Yan, J., Pan, Y., Shao, W., Wang, C., Wang, R., He, Y., Zhang, M., Wang, Y., Li, T., Wang, Z., et al. (2022) · Microbiome · doi:10.1186/s40168-022-01390-0 · Cited by 148 · see citing works
“05% cysteine (Sigma– Aldrich) at 37°C for 2–3 days [70].”
BackgroundInfluentialEffects of subchronic oral toxic metal exposure on the intestinal microbiota of mice
Zhai, Q., Li, T., Yu, L., Xiao, Y., Feng, S., Wu, J., Zhao, J., Zhang, H., & Chen, W. (2017) · 中国科学通报：英文版 · doi:10.1016/j.scib.2017.01.031 · Cited by 142 · see citing works
Potential Benefits of Probiotics and Prebiotics for Coronary Heart Disease and Stroke
Wu, H., & Chiou, J. A. (2021) · Nutrients · doi:10.3390/nu13082878 · Cited by 147 · see citing works
“Intake of low-dose LPS in animal models resulted in vascular inflammation and atherosclerosis [52,53].”
BackgroundNext-generation probiotics: a promising approach towards designing personalized medicine
Singh, T. P., & Nataraj, B. H. (2021) · Critical Reviews in Microbiology · doi:10.1080/1040841x.2021.1902940 · Cited by 145 · see citing works
“Moreover, Li et al. (2016) reported that administration of A. muciniphila could reverse the atherosclerotic lesions, improve metabolic endotoxemia-induced inflammation, and ultimately, restore the gut barrier in Apoe–/– mice.”
BackgroundAstaxanthin Prevents Alcoholic Fatty Liver Disease by Modulating Mouse Gut Microbiota
Liu, H., Liu, M., Fu, X., Zhang, Z., Zhu, L., Zheng, X., & Liu, J. (2018) · Nutrients · doi:10.3390/nu10091298 · Cited by 137 · see citing works
“Akkermansia is a dominant genus in Verrucomicrobia and can degrade intestinal mucin [42], increasing mucus thickness and enhancing gut barrier function, which correlates inversely with the incidence of inflammation [43] and metabolic syndrome [18].”
BackgroundAkkermansia muciniphila : is it the Holy Grail for ameliorating metabolic diseases?
Yan, J., Sheng, L., & Li, H. (2021) · Gut Microbes · doi:10.1080/19490976.2021.1984104 · Cited by 142 · see citing works
“muciniphila reduced intestinal permeability by increasing the expression of occludin and ZO-1 in Apoe mice.(20) Similarly, Zhao et al.”
BackgroundCheng, H., Liu, J., Tan, Y., Feng, W., & Peng, C. Y. (2021) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2021.10.003 · Cited by 137 · see citing works
Postbiotics: metabolites and mechanisms involved in microbiota-host interactions
Peluzio, M. D. C. G., Martinez, J. A., & Milagro, F. I. (2021) · Trends in Food Science & Technology · doi:10.1016/j.tifs.2020.12.004 · Cited by 139 · see citing works
Coronary artery disease is associated with an altered gut microbiome composition
Toya, T., Corban, M., Marietta, E. V., Horwath, I. E., Lerman, L. O., Murray, J. A., & Lerman, A. (2020) · PLoS ONE · doi:10.1371/journal.pone.0227147 · Cited by 131 · see citing works
Gut Microbiome Toxicity: Connecting the Environment and Gut Microbiome-Associated Diseases
Tu, P., Chi, L., Bodnar, W. M., Zhang, Z., Gao, B., Bian, X., Stewart, J. R., Fry, R. C., & Lü, K. (2020) · Toxics · doi:10.3390/toxics8010019 · Cited by 130 · see citing works
Wu, W., Kaicen, W., Bian, X., Yang, L., Ding, S., Li, Y., Li, S., Zhuge, A., & Li, L. (2023) · Microbial Biotechnology · doi:10.1111/1751-7915.14293 · Cited by 129 · see citing works
Chen, Y., Xu, C., Huang, R., Song, J., Li, D., & Xia, M. (2018) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2018.02.011 · Cited by 127 · see citing works
Zhao, L., Chen, J., Bai, B., Song, G.-L., Zhang, J.-W., Yu, H., Huang, S.-W., Wang, Z., & Lu, G.-H. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1333986 · Cited by 143 · see citing works
Jiang, Z., Zhao, M., Zhang, H., Yang, L., Liu, M., & Feng, F. (2017) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201700547 · Cited by 125 · see citing works
“Specific and significant increase of Akkermansia muciniphila (widely considered as mucos-protection bacterium) [34-36] in the gut was important for reducing the host”
BackgroundOuyang, J., Lin, J., Isnard, S., Fombuena, B., Peng, X., Marette, A., Routy, B., Messaoudene, M., Chen, Y., & Routy, J.-P. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00645 · Cited by 124 · see citing works
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Atorvastatin Treatment Modulates the Gut Microbiota of the Hypercholesterolemic Patients
Khan, T. J., Ahmed, Y. M., Zamzami, M. A., Siddiqui, A. M., Khan, I., Baothman, O. A. S., Mehanna, M. G., Kuerban, A., Mohammed, K., & Yasir, M. (2018) · OMICS A Journal of Integrative Biology · doi:10.1089/omi.2017.0130 · Cited by 116 · see citing works
“…proin-flammatory bacteria and taxa associated with atherosclerosis formation and CVD progression (Gregory et al., 2015; Karls-son et al., 2012; Koren et al., 2011) and increase the abundance of health beneficial bacteria, particularly the anti-inflammatory taxa (Li et al., 2016; Rossi et al., 2016).”
InfluentialMilk Polar Lipids: Underappreciated Lipids with Emerging Health Benefits
Anto, L., Warykas, S. W., Torres‐Gonzalez, M., & Blesso, C. N. (2020) · Nutrients · doi:10.3390/nu12041001 · Cited by 117 · see citing works
- 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
- Semantic Scholar
- c6057c9cf032a166c2516e352216f0144b27de52
- 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
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