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Cited by 1,638Gut microbiota and healthOral microbiology and periodontitis researchNutritional Studies and Diet

The gut microbiome in atherosclerotic cardiovascular disease

Open access
Jie, Zhuye, Xia, Huihua, Zhong, Shi-Long, Feng, Qiang, Li, Shenghui, Liang, Suisha, Zhong, Huanzi, Liu, Zhipeng +34 more·2017·Nature Communications
DOI 10.1038/s41467-017-00900-1PMC PMC5635030
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Abstract

The gut microbiota has been linked to cardiovascular diseases. However, the composition and functional capacity of the gut microbiome in relation to cardiovascular diseases have not been systematically examined. Here, we perform a metagenome-wide association study on stools from 218 individuals with atherosclerotic cardiovascular disease (ACVD) and 187 healthy controls. The ACVD gut microbiome deviates from the healthy status by increased abundance of Enterobacteriaceae and Streptococcus spp. and, functionally, in the potential for metabolism or transport of several molecules important for cardiovascular health. Although drug treatment represents a confounding factor, ACVD status, and not current drug use, is the major distinguishing feature in this cohort. We identify common themes by comparison with gut microbiome data associated with other cardiometabolic diseases (obesity and type 2 diabetes), with liver cirrhosis, and rheumatoid arthritis. Our data represent a comprehensive resource for further investigations on the role of the gut microbiome in promoting or preventing ACVD as well as other related diseases.

AI snapshot

Written from the paper’s full text.

TL;DR

In a metagenome-wide association study of 405 Chinese fecal samples, atherosclerotic cardiovascular disease (ACVD) was associated with altered gut microbiome composition and function, including increased Enterobacteriaceae and Streptococcus and reduced butyrate-producing bacteria. A microbiome-based classifier distinguished ACVD from controls with an AUC of 0.86, and cross-disease comparisons linked cardiometabolic diseases and cirrhosis to a less fermentative, more inflammatory gut environment.

Key findings

  • ACVD samples differed from controls in multivariate analyses (PERMANOVA P < 10⁻⁶ with or without medication adjustment), with increased Enterobacteriaceae, Streptococcus spp., Ruminococcus gnavus, and Eggerthella lenta, and depletion of butyrate producers such as Roseburia intestinalis and Faecalibacterium cf. prausnitzii.
  • Of 2,982 metagenomic linkage groups (MLGs) with >100 genes, 536 differed significantly between ACVD and controls (Wilcoxon rank-sum, BH q < 0.05), with 320 more abundant in ACVD; these represented on average 56.5% of relative abundance across all MLGs.
  • A random forest classifier using 47 MLGs achieved an AUC of 0.86 for ACVD, whereas TMA lyases alone gave an AUC of 0.63; ACVD-enriched bacteria encoded choline-TMA lyase (CutC) and/or the promiscuous TMA lyase YeaW/X.
  • Functionally, ACVD microbiomes showed higher potential for simple sugar and amino acid transport, O-antigen LPS synthesis, glycerolipid metabolism, fatty acid degradation, and TMA production, but lower potential for most vitamin biosynthesis, tetrahydrofolate synthesis, glycan degradation, and butyrate/propionate synthesis.

Methods

  • Metagenomic shotgun sequencing was performed on 405 fecal samples from 218 ACVD patients (≥50% stenosis in one or more vessels) and 187 healthy controls; after filtering, 2.2 Tb of high-quality reads (average 55.2 million reads/sample) were mapped to a 9.9-million-gene reference catalog, with average mapping of 80.0 ± 3.5%.
  • Genes were clustered into 2,982 MLGs (>100 genes) based on co-abundance; differential abundance used Wilcoxon rank-sum tests with BH q < 0.05, and analyses included PCA, dbRDA, PERMANOVA, random forest cross-validation, group LASSO, MaAsLin, KEGG reporter scores, and PanPhlAn.
  • Cross-disease comparisons mapped published Chinese metagenomic data to the same catalog and pipeline: liver cirrhosis (120 cases/111 controls), obesity (72/79), type 2 diabetes (171/174), and rheumatoid arthritis (95/74), totaling 1,250 samples across diseases.

Limitations

  • The paper states that drug treatment may affect gut microbiota composition and constitutes a confounding factor, although ACVD status, not current drug use, was the major distinguishing feature; effects of different drugs remain to be explored in intervention trials in larger cohorts.
  • The paper states that validation of the identified markers would require independent and much larger cohorts.
  • Evident from the text: this is a cross-sectional case–control study, so it cannot establish causality; additionally, only Chinese cohorts were used because of substantial population differences in the gut microbiome, limiting generalizability.

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

Integrity signals

Registry

Crossref · 10.1038/s41467-017-00900-1

Cites

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Statistics

Nothing to recompute.

Claims the paper makes

0 of 85 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    ACVD and control samples showed separation in PCA and dbRDA plots.

    “The ACVD and control samples also showed separation in PCA (principal component analysis) and dbRDA (distance-based redundancy analysis) plots (Fig. 1)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fig. 1

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  • Findingown data

    The ACVD gut microbiome deviates functionally from the healthy status in the potential for metabolism or transport of several molecules important for cardiovascular health.

    “and, functionally, in the potential for metabolism or transport of several molecules important for cardiovascular health.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Stool samples are representative of the gut microbiome.
    • Rests on an assumption: The functional potential inferred from metagenomic gene content reflects actual metabolic activity of the gut microbiome.
  • Findingown data

    The ACVD gut microbiome deviates from the healthy status by increased abundance of Enterobacteriaceae and Streptococcus spp.

    “The ACVD gut microbiome deviates from the healthy status by increased abundance of Enterobacteriaceae and Streptococcus spp.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Stool samples are representative of the gut microbiome.
  • Findingown data

    ACVD and control samples were significantly different in multivariate analyses, with ACVD status showing a P-value <10−6 in PERMANOVA, with or without adjustment for medication.

    “The ACVD and control samples were significantly different in multivariate analyses. ACVD status showed a P-value <10−6 in permutational multivariate analysis of variance (PERMANOVA), with or without adjustment for medication (Supplementary Table 1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Supplementary Table 1

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    • The authors state this as an assumption: Stool samples are representative of the gut microbiome.
  • Findingown data

    The abundance of Ruminococcus gnavus was higher in ACVD samples than in control samples.

    “The abundance of Ruminococcus gnavus, a bacterium previously associated with inflammatory bowel diseases and low gut microbial richness8, 20–22 was higher in ACVD samples than in control samples (q-value <0.05, Fig. 2, Supplementary Data 3).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Fig. 2

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    • cites Supplementary Data 3

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  • May combine two claims. 28
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Findingown data

    Major genera of the gut microbiome showed a relative reduction in Bacteroides and Prevotella and enrichment in Streptococcus and Escherichia in ACVD.

    “which was corroborated by abundance differences between the two groups in major genera of the gut microbiome, such as a relative reduction in Bacteroides and Prevotella, and enrichment in Streptococcus and Escherichia in ACVD (Fig. 1b).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fig. 1b

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  • May combine two claims.

    Findingown data

    For combinations such as either acarbose or atorvastatin, the AUC was lower between ACVD patients treated with the drugs and healthy controls than between ACVD patients without the drugs and healthy controls, meaning the medication weakened the disease signal.

    “For combinations such as either acarbose or atorvastatin, the AUC was lower between ACVD patients treated with the drugs and healthy controls than between ACVD patients without the drugs and healthy controls (Supplementary Data 4), i.e., the medication weakened the disease signal, meaning an even more significant difference would be expected if the cohort was free of medication.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Supplementary Data 4

      Not checked in the free run.

  • May combine two claims.

    Findingreasoning

    The module comprising genes required for the synthesis of the O-antigen of lipopolysaccharides (LPS) was enriched in ACVD samples, whereas the lipid A synthesis module was relatively depleted.

    “Consistent with the enrichment of Enterobacteriaceae in ACVD (Figs. 1 and 2), the module comprising genes required for the synthesis of the O-antigen of lipopolysaccharides (LPS) was enriched in ACVD samples, whereas the lipid A synthesis module was relatively depleted, most likely due to a lower level of the otherwise abundant Gram-negative genus Bacteroides (Figs. 1 and 6).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Figs. 1 and 6

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    • Rests on an assumption: The functional potential inferred from metagenomic gene content reflects actual metabolic activity of the gut microbiome.

  • May combine two claims.

    Findingown data

    K. oxytoca showed increased abundance in ACVD patients and correlated positively with serum levels of AST, HBDH, and CKMB.

    “K. oxytoca that showed increased abundance in ACVD patients, correlated positively with serum levels of aspartate transaminase (AST, a marker for acute myocardial infarction as well as other conditions), α-hydroxybutyrate dehydrogenase (HBDH), and creatine kinase (CKMB).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Fig. 4

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  • May combine two claims.

    Findingown data

    The relative abundances of three MLGs positively correlated with metoprolol use and two MLGs positively correlated with atorvastatin, but none fulfilled criteria for species annotation.

    “The relative abundances of three MLGs positively correlated with metoprolol use and two MLGs positively correlated with atorvastatin, but none of the MLGs fulfilled the criteria for species annotation (Supplementary Fig. 3, Supplementary Data 3).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Supplementary Fig. 3

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    • cites Supplementary Data 3

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  • May combine two claims.

    Findingown data

    A total of 536 MLGs differed significantly in abundance between ACVD and control samples, with 320 being more abundant in ACVD samples.

    “A total of 536 of the MLGs differed significantly in abundance between ACVD and control samples (Wilcoxon-rank sum test, Benjamin–Hochberg q-value <0.05), with 320 of these being more abundant in ACVD samples (Fig. 2, Supplementary Data 3).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Fig. 2

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    • cites Supplementary Data 3

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    • The authors state this as an assumption: Stool samples are representative of the gut microbiome.

  • May combine two claims.

    Findingown data

    There was no significant difference between ACVD and control samples in either gene richness or diversity.

    “we observed no significant difference between the ACVD and control samples in either gene richness or diversity (Supplementary Fig. 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Supplementary Fig. 1

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  • May combine two claims.

    Findingown data

    The gut microbiome of ACVD patients showed a reduced potential for the synthesis of tetrahydrofolate and altered potential for homocysteine metabolism compared with controls.

    “we observed a reduced potential for the synthesis of tetrahydrofolate and altered potential for homocysteine metabolism in the gut microbiome of ACVD patients compared with controls (Fig. 6, Supplementary Fig. 4a and b).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Fig. 6

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    • cites Supplementary Fig. 4a and b

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    • Rests on an assumption: The functional potential inferred from metagenomic gene content reflects actual metabolic activity of the gut microbiome.

  • May combine two claims.

    Findingown data

    The samples from ACVD patients displayed higher potential for transport of simple sugars (PTS) and amino acids, whereas the potential for biosynthesis of most vitamins was lower.

    “The samples from ACVD patients displayed higher potential for transport of simple sugars (phosphotransferase systems (PTS)) and amino acids, whereas the potential for biosynthesis of most vitamins was lower (Figs. 6 and 7, Supplementary Data 6 and 7).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Figs. 6 and 7

      Not checked in the free run.

    • cites Supplementary Data 6 and 7

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    • Rests on an assumption: The functional potential inferred from metagenomic gene content reflects actual metabolic activity of the gut microbiome.

  • May combine two claims.

    Findingown data

    The gut microbiome of each disease (CMDs and cirrhosis) exhibited unique features in functional capacity, and in species and gene compositions.

    “Besides the common denominators identified to characterize the gut microbiome in patients with CMDs and cirrhosis, the gut microbiome of each disease also exhibited unique features in functional capacity, and in species and gene compositions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the model distinguishing CMDs and cirrhosis, among the top 50 determining species, ACVD-enriched MLGs such as S. anginosis, S. vestibularis, and L. salivarius were most important, while ACVD-depleted MLGs such as F. cf. prausnitzii, Bacteroides cellulosilyticus, R. intestinalis, and MLGs not significantly different in the ACVD cohort were also selected as important features.

    “Among the top 50 determining species, the ACVD-enriched MLGs such as S. anginosis, S. vestibularis, and L. salivarius were identified to be most important for the model, while ACVD-depleted MLGs such as F. cf. prausnitzii, Bacteroides cellulosilyticus, R.intestinalis, and MLGs not significantly different in the ACVD cohort were also selected as important features (Supplementary Fig. 9a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    A number of bacteriophages were more abundant or less abundant in the gut microbiome of individuals with ACVD compared to healthy controls, and several of these were also highly enriched in cirrhosis patients.

    “In addition to bacteria and archaea, a number of bacteriophages were more abundant or less abundant in the gut microbiome of individuals with ACVD compared to healthy controls (Supplementary Fig. 6), and several of these were also highly enriched in cirrhosis patients.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Supplementary Fig. 6

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  • May combine two claims.

    Findingown data

    The ACVD-based classifier contained features such as Streptococcus spp. that were also abundant in cirrhosis patients, but a number of Eggerthella MLGs were not enriched in individuals with cirrhosis.

    “The ACVD-based classifier (Fig. 3) contained features such as Streptococcus spp. that were also abundant in the cirrhosis patients, however, a number of Eggerthella MLGs were not enriched in the individuals with cirrhosis (Supplementary Fig. 5).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Supplementary Fig. 5

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The potential for the metabolism of glycerolipids and degradation of fatty acids was elevated in ACVD, whereas the potential for synthesis of the anti-inflammatory short-chain fatty acid (SCFA) butyrate was lower.

    “The potential for the metabolism of glycerolipids and degradation of fatty acids was elevated in ACVD (Fig. 7), whereas the potential for synthesis of the anti-inflammatory short-chain fatty acid (SCFA) butyrate was lower (Fig. 8a).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Fig. 7

      Not checked in the free run.

    • cites Fig. 8a

      Not checked in the free run.

    • Rests on an assumption: The functional potential inferred from metagenomic gene content reflects actual metabolic activity of the gut microbiome.

  • May combine two claims.

    Findingown data

    In patients with RA, there was no striking enrichment of many modules of the PTS; instead only a few modules were enriched in controls compared to cases.

    “By contrast, in patients with RA, we did not observe the striking enrichment of many modules of the PTS, instead only a few modules were enriched in controls compared to cases.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The functional potential inferred from metagenomic gene content reflects actual metabolic activity of the gut microbiome.

  • May combine two claims.

    Findingown data

    The gut microbiome collectively is less fermentative and more inflammatory in patients with CMDs and liver cirrhosis, in contrast to that of patients with the autoimmune disease RA.

    “We observed that the gut microbiome collectively is less fermentative and more inflammatory in patients with CMDs and liver cirrhosis, in contrast to that of patients with the autoimmune disease RA, suggesting that the restoration of a few members of the healthy gut microbiome might alleviate or at least reduce the risk for multiple CMDs and possibly liver cirrhosis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The majority of E. coli MLGs enriched in individuals with ACVD did not show significant differences between cases and controls within the other diseases, indicating that both common and unique features of the gut microbiome could be identified in ACVD.

    “Moreover, the majority of E. coli MLGs enriched in individuals with ACVD did not show significant differences between cases and controls within the other diseases (Supplementary Fig. 5), indicating that both common and unique features of the gut microbiome could be identified in ACVD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Supplementary Fig. 5

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

    Findingown data

    A model could be constructed based on KEGG Orthology (KO) modules using cross-validated group LASSO.

    “A model could also be constructed based on KEGG Orthology (KO) modules using cross-validated group LASSO (Supplementary Fig. 9b).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In RA patients, modules involved in glutamine and arginine transport and modules involved in LPS biosynthesis were enriched in controls compared to cases, whereas modules for host glycan degradation were enriched in RA patients.

    “Further, in RA patients modules involved in glutamine and arginine transport and modules involved in LPS biosynthesis were enriched in controls compared to cases, in contrast, modules for host glycan degradation were enriched in RA patients (Figs. 6 and 7, Supplementary Data 6).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Figs. 6 and 7

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    • cites Supplementary Data 6

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    • Rests on an assumption: The functional potential inferred from metagenomic gene content reflects actual metabolic activity of the gut microbiome.

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

    Premisecitation

    Bacterial DNA has been detected in atherosclerotic plaques.

    “Bacterial DNA has also been detected in atherosclerotic plaques15–17.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [15] Ott, S. J. et al. Detection of diverse bacterial signatures in atherosclerotic lesions of patients with coronary heart disease. Circulation 113, 929–937 (2006). source

      Not checked in the free run.

    • cites [16] Koren, O. et al. Human oral, gut, and plaque microbiota in patients with atherosclerosis. Proc. Natl Acad. Sci. USA 108, 4592–4598 (2011). source

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    • cites [17] Lanter, B. B., Sauer, K. & Davies, D. G. Bacteria present in carotid arterial plaques are found as biofilm deposits which may contribute to enhanced risk of plaque rupture. MBio 5, e01206–e01214 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    ACVD status, and not current drug use, is the major distinguishing feature in this cohort.

    “Although drug treatment represents a confounding factor, ACVD status, and not current drug use, is the major distinguishing feature in this cohort.”
    • Also stated in: § Influence of drugs on the gut microbiota · hedged
      “Thus, these results suggest that ACVD status, and not current drug use, is the major distinguishing feature in this cohort.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Folate plays a role in cardiovascular disease due to its function in homocysteine metabolism.

    “Folate is known to play a role in cardiovascular disease due to its function in homocysteine metabolism40”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Loria, C. M., Ingram, D. D., Feldman, J. J., Wright, J. D. & Madans, J. H. Serum folate and cardiovascular disease mortality among US men and women. Arch. Intern. Med. 160, 3258–3262 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The MLG-based classifier had an AUC larger than the AUC of 0.63 using TMA lyases only, indicating that factors in addition to TMAO are implicated in ACVD.

    “Concomitantly, we noted that the MLG-based classifier had an AUC that was larger than the AUC of 0.63 using TMA lyases only (CutC/D and YeaW/X, Fig. 3), indicating that factors in addition to TMAO are implicated in ACVD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fig. 3

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  • May combine two claims.

    Premisecitation

    Studies comparing T2D individuals treated or not with metformin identified a higher level of E. coli and a lower level of Intestinibacter in metformin-treated individuals, and reduced levels of butyrate-producing bacteria in untreated individuals compared to healthy controls.

    “Studies comparing individuals with T2D treated or not with metformin identified a higher level of E. coli and a lower level of Intestinibacter in the metformin-treated individuals, while confirming reduced levels of butyrate-producing bacteria such as Roseburia spp., F. prausnitzii, and unnamed Clostridiales in the untreated individuals compared to healthy controls5, 6, 34, 35.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [5] Karlsson, F. H. et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498, 99–103 (2013). source

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    • cites [6] Forslund, K. et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528, 262–266 (2015). source

      Not checked in the free run.

    • cites [34] Zhernakova, A. et al. Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science 352, 565–569 (2016). source

      Not checked in the free run.

    • cites [35] Wu, H. et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat. Med. 23, 850–858 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The ACVD gut microbiome shows profound imbalances in composition and inter-species relationships compared to healthy controls.

    “These results demonstrated profound imbalances in the composition and inter-species relationship in the gut microbiome of ACVD patients as compared to healthy controls.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Drug treatment may to varying extent affect the composition of the gut microbiota and thus constitute a confounding factor.

    “Still, drug treatment may to varying extent affect the composition of the gut microbiota and thus constitute a confounding factor.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Fivefold cross-validation was performed on a random forest model using the MLG abundance profile of the samples.

    “Fivefold cross-validation was performed on a random forest model (R 3.3.0, randomForest 4.6-12 package) using the MLG abundance profile of the samples.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The MWAS controlled for multiple testing with q-value <0.05.

    “The 2982 MLG that contained over 100 genes were tested for enrichment or depletion in individuals with ACVD (218 ACVD cases and 187 controls) according to the non-parametric method, Wilcoxon rank-sum test, and controlled for multiple testing (q-value <0.05)55, 60.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [55] Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. Series B 57, 289–300 (1995). source

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    • cites [60] Storey, J. D. A direct approach to false discovery rates. J. R. Stat. Soc. Series B Stat. Methodol. 64, 479–498 (2002). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Restoration of a few members of the healthy gut microbiome might alleviate or at least reduce the risk for multiple CMDs and possibly liver cirrhosis.

    “We observed that the gut microbiome collectively is less fermentative and more inflammatory in patients with CMDs and liver cirrhosis, in contrast to that of patients with the autoimmune disease RA, suggesting that the restoration of a few members of the healthy gut microbiome might alleviate or at least reduce the risk for multiple CMDs and possibly liver cirrhosis.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    CMD/cirrhosis-specific MLGs were selected by a random forest model with downsampling to account for the unequal sample size across diseases.

    “CMD/cirrhosis-specific MLGs were also selected by a random forest model, with downsampling to account for the unequal sample size across diseases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The gut microbiome of liver cirrhosis, colorectal cancer, RA, and ACVD patients have all showed an increase in the abundance of oral bacteria.

    “Although the gut microbiome of liver cirrhosis, colorectal cancer, RA, and ACVD patients have all showed an increase in the abundance of oral bacteria3, the set of oral bacterial species were, however, observed to differ, and only RA and ACVD have been epidemiologically associated with periodontitis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Wang, J. & Jia, H. Metagenome-wide association studies: fine-mining the microbiome. Nat. Rev. Microbiol. 14, 508–522 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    All 1250 samples were analyzed in the same manner, eliminating technical biases in MWAS between studies.

    “All 1250 samples were analyzed in the same manner, eliminating technical biases in MWAS between studies3.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Wang, J. & Jia, H. Metagenome-wide association studies: fine-mining the microbiome. Nat. Rev. Microbiol. 14, 508–522 (2016). source

      Not checked in the free run.

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

    Study design and conductnone given

    The study was approved by the Medical Ethical Review Committee of the Guangdong General Hospital and the Institutional Review Board at BGI-Shenzhen, and informed consent was obtained from all participants.

    “The study was approved by the Medical Ethical Review Committee of the Guangdong General Hospital and the Institutional Review Board at BGI-Shenzhen. Informed consent was obtained from all participants.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The DegS-DegU two component system can trigger biofilm formation in response to impeded flagellar rotation.

    “The top-ranked module for the CMDs and liver cirrhosis was the ACVD-microbiome depleted DegS-DegU two component system, which can trigger biofilm formation in response to impeded flagellar rotation49.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Cairns, L. S., Marlow, V. L., Bissett, E., Ostrowski, A. & Stanley-Wall, N. R. A mechanical signal transmitted by the flagellum controls signalling in Bacillus subtilis. Mol. Microbiol. 90, 6–21 (2013). source

      Not checked in the free run.

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

    Study design and conductown data

    PERMANOVA was performed on the MLG abundance profile of all samples to assess impact from each of the factors listed.

    “PERMANOVA39 was performed on the MLG abundance profile of all samples to assess impact from each of the factors listed (Supplementary Table 2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] McArdle, B. H. & Anderson, M. J. Fitting multivariate models to community data: a comment on distance-based redundancy analysis. Ecology 82, 290–297 (2001). source

      Not checked in the free run.

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

    Study design and conductown data

    Potential influences of medication on the ACVD-associated gut microbiome were analyzed by three complementing methods.

    “Potential influences of medication on the ACVD-associated gut microbiome were analyzed by three complementing methods.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    The altered microbiome of CMD patients might be a read-out of the systemic inflammatory component of CMDs and cirrhosis, illustrating an ongoing interaction between the gut microbiome composition and the inflammatory status of these diseases that is detectable as a CMD/cirrhosis-specific gut microbiome signature.

    “Alternatively, the altered microbiome of CMD patients might be a read-out of the systemic inflammatory component of CMDs and cirrhosis, hence illustrating an ongoing interaction between the gut microbiome composition and the inflammatory status of these diseases that is detectable as a CMD/cirrhosis-specific gut microbiome signature.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    If the altered microbiome is a read-out of systemic inflammation, then restoration toward a healthy microbiome might involve concomitant anti-inflammatory treatments.

    “If so, then the restoration toward a healthy microbiome might involve concomitant anti-inflammatory treatments.”
    Quote in the paperNot a substantial claim
38 of 38

  • The authors state this as an assumption.

    Stool samples are representative of the gut microbiome.

    “we sequenced stool samples, representative of the gut microbiome, from 218 individuals with atherosclerotic cardiovascular disease (ACVD) and 187 healthy controls”

  • The paper relies on this without support.

    The functional potential inferred from metagenomic gene content reflects actual metabolic activity of the gut microbiome.

    “functionally, in the potential for metabolism or transport of several molecules important for cardiovascular health”

  • The paper relies on this without support.

    Only RA and ACVD have been epidemiologically associated with periodontitis.

    “Although the gut microbiome of liver cirrhosis, colorectal cancer, RA, and ACVD patients have all showed an increase in the abundance of oral bacteria3, the set of oral bacterial species were, however, observed to differ, and only RA and ACVD have been epidemiologically associated with periodontitis.”

  • The paper relies on this without support.

    Taurine is important for cardiometabolic health.

    “The ACVD-microbiome depleted taurine transport system was also important for this classifier (Supplementary Figs. 2c and 9b, Supplementary Data 6), consistent with the importance of taurine for cardiometabolic health.”
4 of 4

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Authors
Jie, Z., Xia, H., Zhong, S.-L., Feng, Q., Li, S., Liang, S., Zhong, H., Liu, Z., Gao, Y., Zhao, H., Zhang, D., Su, Z., Fang, Z., Lan, Z., Li, J., Xiao, L., Li, J., Li, R., Li, X., Li, F., Ren, H., Huang, Y., Peng, Y., Li, G., Wen, B., Dong, B., Chen, J.-Y., Geng, Q.-S., Zhang, Z.-W., Yang, H., Wang, J., Wang, J., Zhang, X., Madsen, L., Brix, S., Ning, G., Xu, X., Liu, X., Hou, Y., Jia, H., He, K., & Kristiansen, K.
Affiliations
  • BGI Group (China) (CN)
  • Chinese PLA General Hospital (CN)
  • Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
  • Technical University of Denmark (DK)
  • Shanghai Jiao Tong University (CN)
Corresponding author
  • Jia, Huijue
  • He, Kunlun
  • Kristiansen, Karsten
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2017-10-10
Volume
8
Issue
1
Pages
845-845
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-017-00900-1
PMC
PMC5635030
OpenAlex
W2761865284
Semantic Scholar
bbbdec858cf2aa4e8dc28515da9ceed20fc5f668
Cited by
1,638
References
65
Citations by year
2026: 134 · 2025: 197 · 2024: 252 · 2023: 202 · 2022: 232 · 2021: 235 · 2020: 193 · 2019: 125 · 2018: 57 · 2017: 4
FWCI
42.76
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Technical University of Denmark, DTU Orbit (Technical University of Denmark, DTU) (submittedVersion, cc-by)
Funders
  • National Natural Science Foundation of China (81373486, 81673514)
  • Government of Jiangxi Province
  • Fundo para o Desenvolvimento das Ciências e da Tecnologia
  • National Key Research and Development Program of China
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
Keywords
gut microbiota, atherosclerotic cardiovascular disease, Enterobacteriaceae, Streptococcus, metagenome-wide association study, stool microbiome, cardiovascular health, cardiometabolic disease, obesity, type 2 diabetes, liver cirrhosis, rheumatoid arthritis, microbial metabolism
MeSH terms
Gastrointestinal Microbiome, Fermentation, Humans, Inflammation, Liver Cirrhosis, Case-Control Studies, Atherosclerosis, Metagenome, Genome-Wide Association Study, Metagenomics

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

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

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.

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