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Cited by 61Gut microbiota and healthGastrointestinal motility and disordersAnimal Nutrition and Physiology

Cholestasis induced by bile duct ligation promotes changes in the intestinal microbiome in mice

Open access
Cabrera-Rubio, Raul, Patterson, Angela M., Cotter, Paul D., Beraza, Naiara·2019·Scientific Reports
DOI 10.1038/s41598-019-48784-zPMC PMC6707139
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Abstract

Increasing evidence point to the relevance of intestinal disfunction and changes in the microbiome composition during chronic liver disease. More specifically, recent studies have highlighted that cholestatic diseases associate with a reduction in the microbiome diversity in patients. Still, the dynamics of the changes in the microbiome composition observed, as well as their implication in contributing to the pathogenesis of this disease remain largely undefined. Hence, experimental mouse models resembling the human pathogenesis are crucial to move forward our understanding on the mechanisms underpinning cholestatic disease and to enable the development of effective therapeutics. Our results show that the bile duct ligation (BDL) experimental model of cholestasis leads to rapid and significant changes in the microbiome diversity, with more than 100 OTUs being significantly different in faecal samples obtained from WT mice at 3 days and 7 days after BDL when compared to control animals. Changes in the microbial composition in mice after BDL included the enrichment of Akkermansia,Prevotella,Bacteroides and unclassified Ruminococcaceae in parallel with a drastic reduction of the presence of Faecalibacterium prausnitzii. In conclusion, our results support that bile duct ligation induces changes in the microbiome that partly resemble the gut microbial changes observed during human cholestatic disease.

AI snapshot

Written from the paper’s full text.

TL;DR

Bile duct ligation (BDL) in mice rapidly alters the intestinal microbiome, with reduced diversity and taxonomic shifts partly resembling human cholestatic disease. The model also shows liver injury, inflammation, colon damage, and increased intestinal permeability at 3 and 7 days after BDL.

Key findings

  • BDL increased serum ALT, AP, and bilirubin, caused liver necrosis, increased liver CD11b+/F4/80+ macrophages, shortened colon crypts, and increased intestinal permeability by FITC-dextran at 3 and 7 days.
  • More than 100 OTUs (117 OTUs) were significantly different in faecal samples from BDL mice versus controls; beta diversity differed significantly after BDL (PCoA P = 0.001; pairwise UniFrac Control vs BDL 3d P < 0.013, Control vs BDL 7d P < 0.006, BDL 3d vs BDL 7d P < 0.006).
  • BDL enriched Akkermansia, Prevotella, Bacteroides, and unclassified Ruminococcaceae, while drastically reducing Faecalibacterium prausnitzii; Clostridium was also increased in BDL groups.
  • The Firmicutes/Bacteroidetes ratio was 1.082 in BDL 3d versus 0.75 in controls and 0.72 in BDL 7d; exclusive OTUs were 257 (18.9%) in controls, 187 (13.8%) in BDL 3d, and 149 (11%) in BDL 7d, with a core of 582 OTUs (42.9%).

Methods

  • Male C57/B6J mice aged 8–12 weeks underwent bile duct ligation and were sacrificed at 3 or 7 days; controls were compared. Liver and colon histology, liver immune-cell flow cytometry, and FITC-dextran intestinal permeability assays were performed.
  • Fresh faecal pellets were analysed by 16S rRNA sequencing on Illumina MiSeq (2 × 250 bp); sequences were filtered, joined, clustered into OTUs at 97% identity with UPARSE, and taxonomically assigned against RDP.
  • Analyses included alpha diversity (Fisher, Shannon, Simpson), beta diversity (unweighted UniFrac, PERMANOVA), mvabund heatmaps, LefSe LDA effect size >2, and Kruskal–Wallis, Mann–Whitney U, or negative binomial models with Benjamini–Hochberg correction.

Limitations

  • The paper states there is no unique animal model fully recapitulating human cholestatic disease, and that future research is needed to define causality of microbiome changes in disease progression.
  • It notes conflicting prior BDL microbiome results and attributes discrepancies to sample origin (cecal/mucosal vs faecal), sequencing methodology, and timepoints after BDL.
  • Evident from the text: the study is a mouse BDL model using 16S rRNA compositional profiling, so functional consequences and direct causality are not established; group sizes are not reported in the provided text.

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

Integrity signals

Registry

Crossref · 10.1038/s41598-019-48784-z

Cites

65 of 65 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 78 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    BDL in mice leads to enrichment of unclassified Ruminococcaceae in the intestinal microbiome.

    “Changes in the microbial composition in mice after BDL included the enrichment of Akkermansia, Prevotella, Bacteroides and unclassified Ruminococcaceae in parallel with a drastic reduction of the presence of Faecalibacterium prausnitzii.”
    • Also stated in: § Bile duct ligation promotes early changes in the intestinal microbiome · plain
      “More specifically, a significant reduction in unclassified Porphyromonadaceae (p < 0.05) and Sutterellaceae (p < 0.05), as well as an increase of unclassified Ruminococaceae and unclassified Lactobacillaceae in the BDL 3d group compared to control samples (Fig. 4A).”
    Quote in the paperSubstantial claim
  • Findingown data

    Bile duct ligation (BDL) in mice leads to rapid and significant changes in the intestinal microbiome diversity at 3 and 7 days after BDL compared to control animals.

    “Our results show that the bile duct ligation (BDL) experimental model of cholestasis leads to rapid and significant changes in the microbiome diversity, with more than 100 OTUs being significantly different in faecal samples obtained from WT mice at 3 days and 7 days after BDL when compared to control animals.”
    • Also stated in: § Bile duct ligation promotes early changes in the intestinal microbiome · plain
      “Fisher’s alpha diversity index showed significant differences between Control vs BDL 3d and BDL 3d vs BDL 7d groups (P < 0,05; Fig. 2A).”
    Quote in the paperSubstantial claim
  • Findingown data

    BDL in mice leads to enrichment of Akkermansia in the intestinal microbiome.

    “Changes in the microbial composition in mice after BDL included the enrichment of Akkermansia, Prevotella, Bacteroides and unclassified Ruminococcaceae in parallel with a drastic reduction of the presence of Faecalibacterium prausnitzii.”
    • Also stated in: § Bile duct ligation promotes early changes in the intestinal microbiome · plain
      “We found an increase in the genus Akkermansia at 7days after BDL with respect to the other groups of samples (Fig. 4C).”
    Quote in the paperNot a substantial claim
  • Findingown data

    More than 100 OTUs were significantly different in faecal samples from WT mice at 3 and 7 days after BDL compared to control animals.

    “Our results show that the bile duct ligation (BDL) experimental model of cholestasis leads to rapid and significant changes in the microbiome diversity, with more than 100 OTUs being significantly different in faecal samples obtained from WT mice at 3 days and 7 days after BDL when compared to control animals.”
    • Also stated in: § Bile duct ligation promotes early changes in the intestinal microbiome · plain
      “The impact of bile duct ligation in promoting changes in the microbiota was also evidenced by a statistically significant decrease in proportions of more than 100 OTUs (117 OTUs) when mice subjected to BDL were compared individually to control animals (Fig. 3C).”
    Quote in the paperSubstantial claim
  • Findingown data

    BDL in mice leads to enrichment of Prevotella in the intestinal microbiome.

    “Changes in the microbial composition in mice after BDL included the enrichment of Akkermansia, Prevotella, Bacteroides and unclassified Ruminococcaceae in parallel with a drastic reduction of the presence of Faecalibacterium prausnitzii.”
    • Also stated in: § Bile duct ligation promotes early changes in the intestinal microbiome · plain
      “Abundance of the Prevotella (p < 0.05) genus was increased in samples from BDL 7d mice when compared to BDL 3d samples, while Dialister (p < 0.05) and Veillonella (p < 0.05) were more abundant in BDL 3d compared to BDL 7d (Fig. 4B).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 43
  • Classified as probably not a substantial claim. 28

  • May combine two claims.

    Findingown data

    When BDL 3d and BDL 7d groups were compared, greater proportions of unclassified Ruminococcaceae and unclassified Enterobacteriaceae were found in BDL 3d group, and lower presence of Porphyromonadaceae, which was enriched in BDL 7d samples.

    “Finally, when the BDL 3d and BDL 7d groups were compared, we found greater proportions of unclassified Ruminococcaceae (p < 0.05) and unclassified Enterobacteriaceae in BDL 3d group and lower presence of Porphyromonadaceae (p < 0.05), which was enriched in BDL 7d samples with respect to the BDL 3d samples (Fig. 4A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At genus level in BDL 3d samples, LDA showed statistically significant increase in the genus Bacteroides and Parabacteroides, whereas proportions in the genus Parasutterella were reduced compared to controls.

    “At genus level in BDL 3d samples, LDA showed statistically significant increase in the genus Bacteroides (p < 0.05) and Parabacteroides (p < 0.05), whereas proportions in the genus Parasutterella (p < 0.05) were reduced when compared to controls.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Paired comparisons highlighted 67 common OTUs (4.9%) to control and BDL 3d samples only, 58 OTUs (4.3%) common to control and BDL 7d groups only and another 58 OTUs (4.3%) common to the BDL 3d and BDL 7d groups only.

    “Paired comparisons highlighted 67 common OTUs (4.9%) to control and BDL 3d samples only, 58 OTUs (4.3%) common to control and BDL 7d groups only and another 58 OTUs (4.3%) common to the BDL 3d and BDL 7d groups only (Fig. 3D).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LDA LefSe at family level showed a significant reduction in unclassified Porphyromonadaceae and Sutterellaceae, and an increase of unclassified Ruminococaceae and unclassified Lactobacillaceae in the BDL 3d group compared to control samples.

    “More specifically, a significant reduction in unclassified Porphyromonadaceae (p < 0.05) and Sutterellaceae (p < 0.05), as well as an increase of unclassified Ruminococaceae and unclassified Lactobacillaceae in the BDL 3d group compared to control samples (Fig. 4A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    A transient decrease in the genus Akkermansia occurred in BDL 3d samples, followed by an abrupt increase in BDL 7d samples.

    “a transient decrease in the genus Akkermansia in the BDL 3d sample group that increases very abruptly in the BDL 7d sample where it shows high values (Fig. 2C).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the Venn diagram, 257 OTUs (18.9%) were found in the control group, 187 OTUs (13.8%) in BDL 3d group and 149 OTUs (11%) in BDL 7d group; the core microbiome was composed of 582 OTUs (42.9%).

    “More specifically, as shown in the Venn diagram, 257 OTUs (18.9%) were found in the control group, 187 OTUs (13.8%) in BDL 3d group and 149 OTUs (11%) in BDL 7d group (Fig. 3D). The core microbiome was composed of 582 OTUs (42.9%).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In BDL 7d samples, there was a statistically significant increase in the genus falsiporphyromonas, whereas proportions in the genus Rickenella, Parasutterella and Olsenella were reduced compared to controls.

    “Also, we found statistically significant increase in the genus falsiporphyromonas (p < 0.05), whereas proportions in the genus Rickenella (p ≤ 0.05), Parasutterella (p < 0.05) and Olsenella (p < 0.05) were reduced in BDL 7d samples when compared to controls.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    BDL is associated with histopathological disruption in the colon, including shortening of crypt length, epithelial cell atrophy, and increase in intraepithelial lymphocytes and immune cell infiltrates.

    “BDL was associated with changes of the intestinal architecture as observed histologically, including histopathological disruption in the colon with the shortening of crypt length (Fig. 1E,F), epithelial cell atrophy, and increase in intraepithelial lymphocytes and immune cell infiltrates (Fig. 1E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    UniFrac unweighted distances showed significant differences for Control vs BDL 3d, Control vs BDL 7d, and BDL 3d vs BDL 7d.

    “Here, UniFrac unweighted distances were calculated by pairwise comparison of the groups of samples, and significant differences were detected when the following comparisons were done; Control vs BDL 3d (P < 0.013), Control vs BDL 7d (P < 0.006) and BDL 3d vs BDL 7d (P < 0.006) (Fig. 2B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    An average of 613.12 OTUs were obtained, assigned mainly to the phyla Firmicutes, Bacteroidetes and Proteobacteria.

    “With respect to taxonomy, an average of 613.12 (±66.72 SD) OTUs were obtained, being assigned mainly to the phyla Firmicutes, Bacteroidetes and Proteobacteria (Fig. 3A, Supplemental Fig. S1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The Firmicutes/Bacteroidetes ratio was higher in BDL 3d samples (1.082) compared to control (0.75), and BDL 7d samples (0.72) recovered the initial ratio.

    “The differences were already at this level, observing higher levels in the ratio Firmicutes/Bacteroidetes (ratio F/B) in the BDL 3d samples (ratio F/B = 1.082) compared to the group of control samples (ratio F/B = 0.75) and finally the BDL 7d samples (ratio F/B = 0.72) recover the initial ratio.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The paper's work provides improved statistical results that demonstrate the reduction of the microbiome diversity at early stages of cholestasis, while these do not reach statistical significance at later timepoints.

    “our work provides improved statistical results that demonstrate the reduction of the microbiome diversity at early stages of cholestasis, while these do not reach statistical significance at later timepoints.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Livers obtained from mice at 7 days after BDL do not show evidence of cirrhosis, although fibrosis is obvious.

    “While livers obtained from mice at 7days after BDL do not show evidences of cirrhosis (although fibrosis is obvious in these animals50)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] Blokker, B. A. et al. Fine-Tuning of Sirtuin 1 Expression Is Essential to Protect the Liver From Cholestatic Liver Disease. Hepatology 69, 699–716, https://doi.org/10.1002/hep.30275 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    In BDL mice, Prevotella abundance was reduced at 3 days after BDL but increased at 7 days.

    “in PSC patients we found reduction of Prevotella in mice at 3days after BDL though the abundance was increased at the later timepoint (7d).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Cholestasis occurs when the natural flux of bile acids from the liver to the gut is impaired, mainly as a result of damage in the biliary ducts, causing accumulation of toxic bile acids in the liver that promote cell death, inflammation, fibrogenesis and ultimately cirrhosis and cancer.

    “Cholestasis occurs when the natural flux of bile acids from the liver to the gut is impaired, mainly as a result of damage in the biliary ducts, causing accumulation of toxic bile acids in the liver that promote cell death, inflammation, fibrogenesis and ultimately cirrhosis and cancer15.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Beuers, U., Trauner, M., Jansen, P. & Poupon, R. New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond. J Hepatol 62, S25–37, https://doi.org/10.1016/j.jhep.2015.02.023 (2015). source

      Not checked in the free run.

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

    Premisecitation

    Cholestasis results from different primary aetiologies but also is a frequent secondary event occurring during most chronic liver diseases.

    “Cholestasis results from different primary aetiologies but also is a frequent secondary event occurring during most chronic liver diseases16.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Jungst, C. et al. Intrahepatic cholestasis in common chronic liver diseases. Eur J Clin Invest 43, 1069–1083, https://doi.org/10.1111/eci.12128 (2013). source

      Not checked in the free run.

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

    Premisecitation

    The available treatments for PBC patients are limited to ursodeoxycholic acid (UDCA) and the recently licenced obeticholic acid (OCA) as a second-line approach.

    “The available treatments for PBC patients are limited to ursodeoxycholic acid (UDCA) and the recently licenced obeticholic acid (OCA) as a second-line approach17,18.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Hirschfield, G. M. et al. The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines. Gut 67, 1568–1594, https://doi.org/10.1136/gutjnl-2017-315259 (2018). source

      Not checked in the free run.

    • cites [18] Trauner, M. et al. Long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis: 3-year results of an international open-label extension study. Lancet Gastroenterol Hepatol 4, 445–453, https://doi.org/10.1016/S2468-1253(19)30094-9 (2019). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The current consensus is that there is not a unique animal model fully recapitulating human cholestatic disease.

    “Based on the complexity of the multiple molecular events undergoing during cholestasis, involving interactions between different liver cell types and the gut-microbiome-liver axis, the current consensus is that there is not a unique animal model fully recapitulating human cholestatic disease20.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Pollheimer, M. J., Trauner, M. & Fickert, P. Will we ever model PSC? - “it’s hard to be a PSC model!”. Clin Res Hepatol Gastroenterol 35, 792–804, https://doi.org/10.1016/j.clinre.2011.04.014 (2011). source

      Not checked in the free run.

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

    Premisecitation

    The 'leaky gut' hypothesis proposes that intestinal bacteria, endotoxin or other bacterial products translocate from the permeable gut into the liver via the porta circulation, triggering hepatic inflammation and fibrosis further contributing to the progression of chronic liver disease.

    “The ‘leaky gut’ hypothesis proposes that intestinal bacteria, endotoxin or other bacterial products translocate from the permeable gut into the liver via the porta circulation, triggering hepatic inflammation and fibrosis further contributing to the progression of chronic liver disease5,7.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] Konturek, P. C. et al. Gut(−)Liver Axis: How Do Gut Bacteria Influence the Liver? Med Sci (Basel) 6, https://doi.org/10.3390/medsci6030079 (2018). source

      Not checked in the free run.

    • cites [7] Schnabl, B. Linking intestinal homeostasis and liver disease. Curr Opin Gastroenterol 29, 264–270, https://doi.org/10.1097/MOG.0b013e32835ff948 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic liver disorders are associated with changes in gut microbiome composition and disruption of the intestinal barrier.

    “Chronic liver disorders have also been associated with changes in gut microbiome composition and the disruption of the intestinal barrier3,5–8.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [3] Marchesi, J. R. et al. The gut microbiota and host health: a new clinical frontier. Gut 65, 330–339, https://doi.org/10.1136/gutjnl-2015-309990 (2016). source

      Not checked in the free run.

    • cites [5] Konturek, P. C. et al. Gut(−)Liver Axis: How Do Gut Bacteria Influence the Liver? Med Sci (Basel) 6, https://doi.org/10.3390/medsci6030079 (2018). source

      Not checked in the free run.

    • cites [6] Puri, P. & Sanyal, A. J. The Intestinal Microbiome in Nonalcoholic Fatty Liver Disease. Clin Liver Dis 22, 121–132, https://doi.org/10.1016/j.cld.2017.08.009 (2018). source

      Not checked in the free run.

    • cites [7] Schnabl, B. Linking intestinal homeostasis and liver disease. Curr Opin Gastroenterol 29, 264–270, https://doi.org/10.1097/MOG.0b013e32835ff948 (2013). source

      Not checked in the free run.

    • cites [8] Tilg, H., Cani, P. D. & Mayer, E. A. Gut microbiome and liver diseases. Gut 65, 2035–2044, https://doi.org/10.1136/gutjnl-2016-312729 (2016). source

      Not checked in the free run.

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

    Premisecitation

    There is currently no available treatment for PSC patients and liver transplantation is the only curative option.

    “In this line, there is currently no available treatment for PSC patients and liver transplantation is the only curative option, which has obvious shortcomings including scarcity of donors and a high incidence of recurrence19.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Alabraba, E. et al. A re-evaluation of the risk factors for the recurrence of primary sclerosing cholangitis in liver allografts. Liver Transpl 15, 330–340, https://doi.org/10.1002/lt.21679 (2009). source

      Not checked in the free run.

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

    Premisecitation

    Antibiotics can induce chronic cholestasis and DILI.

    “Although these antibiotic-based treatments have transient benefits in cholestasis patients, antibiotics can induce chronic cholestasis and DILI (reviewed in22).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Sundaram, V. & Bjornsson, E. S. Drug-induced cholestasis. Hepatol Commun 1, 726–735, https://doi.org/10.1002/hep4.1088 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Changes at genera level in cholestatic patients differ among studies and include enrichment in Veillonella, Akkermansia, Ruminococcaceae (undefined genus) and Clostridium and decrease in Prevotella.

    “The changes described at genera level differ among studies9–12 and include the enrichment in Veillonella, Akkermansia, Ruminococcaceae (undefined genus) and Clostridium9 and the decrease in Prevotella10, overall supporting the association between changes in the microbiome and cholestatic disease.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [9] Kummen, M. et al. The gut microbial profile in patients with primary sclerosing cholangitis is distinct from patients with ulcerative colitis without biliary disease and healthy controls. Gut 66, 611–619, https://doi.org/10.1136/gutjnl-2015-310500 (2017). source

      Not checked in the free run.

    • cites [10] Quraishi, M. N. et al. The gut-adherent microbiota of PSC-IBD is distinct to that of IBD. Gut 66, 386–388, https://doi.org/10.1136/gutjnl-2016-311915 (2017). source

      Not checked in the free run.

    • cites [11] Sabino, J. et al. Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD. Gut 65, 1681–1689, https://doi.org/10.1136/gutjnl-2015-311004 (2016). source

      Not checked in the free run.

    • cites [12] Torres, J. et al. The features of mucosa-associated microbiota in primary sclerosing cholangitis. Aliment Pharmacol Ther 43, 790–801, https://doi.org/10.1111/apt.13552 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Some changes found during human disease are replicated in mice after BDL, as we observed a significant enrichment of Akkermansia, in line with the observations in the study by Kummen and colleagues.

    “More importantly, some of the changes found during human disease are replicated in mice after BDL as we observed a significant enrichment of Akkermansia, in line with the observations in the study by Kummen and colleagues9.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Kummen, M. et al. The gut microbial profile in patients with primary sclerosing cholangitis is distinct from patients with ulcerative colitis without biliary disease and healthy controls. Gut 66, 611–619, https://doi.org/10.1136/gutjnl-2015-310500 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Our results are in line with those found in other models of cholestatic disease like the genetically modified Mdr2−/− mice, which show certain similarities in bacterial composition to mice undergoing BDL, including enrichment of Lactobacillus, Prevotella and Clostridiaceae.

    “Interestingly, our results are in line with those found in other models of cholestatic disease like the genetically modified Mdr2−/− mice27, which show certain similarities in bacterial composition to mice undergoing BDL, including enrichment of Lactobacillus, Prevotella and Clostridiaceae as we show in the present study.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Tedesco, D. et al. Alterations in Intestinal Microbiota Lead to Production of Interleukin 17 by Intrahepatic gammadelta T-Cell Receptor-Positive Cells and Pathogenesis of Cholestatic Liver Disease. Gastroenterology 154, 2178–2193, https://doi.org/10.1053/j.gastro.2018.02.019 (2018). source

      Not checked in the free run.

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

    Interpretationcitation

    The mucus degrading activity of Akkermansia leads to enhanced mucus production, which could determine its beneficial or detrimental impact on different disease settings by regulating the thickness of the mucus layer.

    “The mucus degrading activity of Akkermansia leads to enhanced mucus production31, which could determine its beneficial or detrimental impact on the different disease settings by regulating the thickness of the mucus layer.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Derrien, M., Vaughan, E. E., Plugge, C. M. & de Vos, W. M. Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. Int J Syst Evol Microbiol 54, 1469–1476, https://doi.org/10.1099/ijs.0.02873-0 (2004). source

      Not checked in the free run.

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

    Premisecitation

    The role of mucins during liver disease remains controversial as mucin deficiency protects from alcohol induced hepatitis in mice, while enhanced mucus thickness relates to improved liver function in another study of experimental ALD.

    “Interestingly, the role of mucins (the glycoproteins that compose the mucus) during liver disease remains controversial as mucin deficiency protects from alcohol induced hepatitis in mice32, while enhanced mucus thickness relates to improved liver function in other study of experimental ALD33.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [32] Hartmann, P. et al. Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice. Hepatology 58, 108–119, https://doi.org/10.1002/hep.26321 (2013). source

      Not checked in the free run.

    • cites [33] Grander, C. et al. Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease. Gut 67, 891–901, https://doi.org/10.1136/gutjnl-2016-313432 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Microbiome analysis in Fouts et al. was performed at later timepoints (10 days) after BDL, while our analyses comprised earlier timepoints after surgery (3 and 7 days after BDL).

    “In addition, microbiome analysis was performed at later timepoints (10 days) after BDL, while our analyses comprised earlier timepoints after surgery; 3 and 7 days after BDL.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Fouts, D. E., Torralba, M., Nelson, K. E., Brenner, D. A. & Schnabl, B. Bacterial translocation and changes in the intestinal microbiome in mouse models of liver disease. J Hepatol 56, 1283–1292, https://doi.org/10.1016/j.jhep.2012.01.019 (2012). source

      Not checked in the free run.

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

    Premisecitation

    Fouts et al. described that BDL did not alter the microbiome in mice.

    “While Fouts et al.26 described that BDL did not alter the microbiome in mice, Alaish et al.25 described changes in Bl6/C57 mice at late stages after BDL (14 days) that the authors discussed to be associated with advanced fibrogenesis (cirrhosis).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Fouts, D. E., Torralba, M., Nelson, K. E., Brenner, D. A. & Schnabl, B. Bacterial translocation and changes in the intestinal microbiome in mouse models of liver disease. J Hepatol 56, 1283–1292, https://doi.org/10.1016/j.jhep.2012.01.019 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased mucus thickness has been observed after BDL, pointing to a role of mucins and likely mucus-degrading bacteria during cholestasis.

    “Interestingly, increased mucus thickness has been observed after BDL34 pointing to a role of mucins and likely mucus-degrading bacteria during cholestasis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Vega-Magana, N. et al. Bacterial Translocation Is Linked to Increased Intestinal IFN-gamma, IL-4, IL-17, and mucin-2 in Cholestatic Rats. Ann Hepatol 17, 318–329, https://doi.org/10.5604/01.3001.0010.8662 (2018). source

      Not checked in the free run.

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

    Premisecitation

    A specific strain of Ruminococcacea (R. gnavus) modifies sialic acid in the mucus thus limiting the availability of feed to other bacteria species.

    “Interestingly, it has been recently described that a specific strain of Ruminococcacea (R. gnavus) modifies sialic acid in the mucus thus limiting the availability of feed to other bacteria species35.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Tailford, L. E. et al. Discovery of intramolecular trans-sialidases in human gut microbiota suggests novel mechanisms of mucosal adaptation. Nat Commun 6, 7624, https://doi.org/10.1038/ncomms8624 (2015). source

      Not checked in the free run.

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

    Premisecitation

    Ruminococcaceae are mucin-degrading bacteria that can both influence mucus thickness and glycan composition.

    “Ruminocccaceae are mucin-degrading bacteria that can both influence mucus thickness and glycan composition35.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Tailford, L. E. et al. Discovery of intramolecular trans-sialidases in human gut microbiota suggests novel mechanisms of mucosal adaptation. Nat Commun 6, 7624, https://doi.org/10.1038/ncomms8624 (2015). source

      Not checked in the free run.

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

    Premisecitation

    Recent studies described that cholestatic patients with PSC have an overall less diverse microbiome composition.

    “Recent studies described that cholestatic patients with PSC have an overall less diverse microbiome composition.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [9] Kummen, M. et al. The gut microbial profile in patients with primary sclerosing cholangitis is distinct from patients with ulcerative colitis without biliary disease and healthy controls. Gut 66, 611–619, https://doi.org/10.1136/gutjnl-2015-310500 (2017). source

      Not checked in the free run.

    • cites [10] Quraishi, M. N. et al. The gut-adherent microbiota of PSC-IBD is distinct to that of IBD. Gut 66, 386–388, https://doi.org/10.1136/gutjnl-2016-311915 (2017). source

      Not checked in the free run.

    • cites [11] Sabino, J. et al. Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD. Gut 65, 1681–1689, https://doi.org/10.1136/gutjnl-2015-311004 (2016). source

      Not checked in the free run.

    • cites [12] Torres, J. et al. The features of mucosa-associated microbiota in primary sclerosing cholangitis. Aliment Pharmacol Ther 43, 790–801, https://doi.org/10.1111/apt.13552 (2016). source

      Not checked in the free run.

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

    Premisecitation

    Alaish et al. described changes in Bl6/C57 mice at late stages after BDL (14 days) that the authors discussed to be associated with advanced fibrogenesis (cirrhosis).

    “While Fouts et al.26 described that BDL did not alter the microbiome in mice, Alaish et al.25 described changes in Bl6/C57 mice at late stages after BDL (14 days) that the authors discussed to be associated with advanced fibrogenesis (cirrhosis).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Alaish, S. M. et al. Gut microbiota, tight junction protein expression, intestinal resistance, bacterial translocation and mortality following cholestasis depend on the genetic background of the host. Gut Microbes 4, 292–305, https://doi.org/10.4161/gmic.24706 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    BDL promotes changes in the composition of the microbiome and changes already occur at early stages of the disease, supporting the active role of the microbiome in the pathogenesis of this condition.

    “Our current study supports that indeed, BDL promotes changes in the composition of the microbiome and that changes already occur at early stages of the disease, supporting the active role of the microbiome in the pathogenesis of this condition.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Few studies have investigated the composition of the microbiome in PBC patients and show some similarities with those observed in PSC.

    “Few studies have investigated the composition of the microbiome in PBC patients and importantly show some similarities with those observed in PSC13,14.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [13] Tang, R. et al. Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy. Gut 67, 534–541, https://doi.org/10.1136/gutjnl-2016-313332 (2018). source

      Not checked in the free run.

    • cites [14] Kummen, M. & Hov, J. R. The gut microbial influence on cholestatic liver disease. Liver Int 39, 1186–1196, https://doi.org/10.1111/liv.14153 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Fouts and colleagues used pyrosequencing while we used Illumina sequencing, which provides a higher number of sequences per sample and greater depth of sequences corresponding to the hypervariable zone V3-V4, as opposed to the hypervariable V1-V3 region targeted in the Fouts et al. work.

    “Also, the sequencing methodology used in that study was different that the one we have applied. Fouts and colleagues used pyrosequencing26 while we used Illumina sequencing in our work, which provides a higher number of sequences per sample and greater depth of sequences corresponding to the hypervariable zone V3-V4, as opposed to the hypervariable V1–V3 region targeted in the Fouts et al. work26.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Fouts, D. E., Torralba, M., Nelson, K. E., Brenner, D. A. & Schnabl, B. Bacterial translocation and changes in the intestinal microbiome in mouse models of liver disease. J Hepatol 56, 1283–1292, https://doi.org/10.1016/j.jhep.2012.01.019 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There are very limited available studies focused on characterising the microbiome composition during experimental cholestasis and these studies have shown conflicting results.

    “Moreover, there are very limited available studies focused on characterising the microbiome composition during experimental cholestasis and these studies have shown conflicting results25,26.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [25] Alaish, S. M. et al. Gut microbiota, tight junction protein expression, intestinal resistance, bacterial translocation and mortality following cholestasis depend on the genetic background of the host. Gut Microbes 4, 292–305, https://doi.org/10.4161/gmic.24706 (2013). source

      Not checked in the free run.

    • cites [26] Fouts, D. E., Torralba, M., Nelson, K. E., Brenner, D. A. & Schnabl, B. Bacterial translocation and changes in the intestinal microbiome in mouse models of liver disease. J Hepatol 56, 1283–1292, https://doi.org/10.1016/j.jhep.2012.01.019 (2012). source

      Not checked in the free run.

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

    Premisecitation

    Akkermansia, a mucus degrading bacteria, negatively correlates with obesity in patients and mice, although it is enriched in stool samples from alcohol-induced steatohepatitis in mice.

    “The abundance of Akkermansia, a mucus degrading bacteria, has been described to negatively correlate with obesity in patients28 and mice29 although it is enriched in stool samples from alcohol-induced steatohepatitis in mice30.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [28] Dao, M. C. et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut 65, 426–436, https://doi.org/10.1136/gutjnl-2014-308778 (2016). source

      Not checked in the free run.

    • cites [29] Everard, A. et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci USA 110, 9066–9071, https://doi.org/10.1073/pnas.1219451110 (2013). source

      Not checked in the free run.

    • cites [30] Yan, A. W. et al. Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology 53, 96–105, https://doi.org/10.1002/hep.24018 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The BDL experimental model is suitable as an effective tool to investigate the role of the microbiome in the progression of cholestasis and as a platform to test therapeutic approaches focused on the modulation of the microbiome, applicable for human disease.

    “Overall, our results support the suitability of the BDL experimental model as an effective tool to investigate the role of the microbiome in the progression of cholestasis as well as a platform to test therapeutic approaches focused on the modulation of the microbiome, applicable for human disease.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Clostridium difficile infection is a common complication of IBD.

    “C difficile infection is a common complication of IBD45.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Monaghan, T. M., Cockayne, A. & Mahida, Y. R. Pathogenesis of Clostridium difficile Infection and Its Potential Role in Inflammatory Bowel Disease. Inflamm Bowel Dis 21, 1957–1966, https://doi.org/10.1097/MIB.0000000000000461 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ruminococcaceae have been found to be enriched in samples from fibrotic patients with NAFLD/NASH, supporting their role in the pathogenesis of other chronic liver diseases that also associate with impaired intestinal barrier function.

    “Interestingly, Ruminococcaceae have been found to be enriched in samples from fibrotic patients with NAFLD/NASH36,37, supporting their role in the pathogenesis of other chronic liver diseases that also associate with impaired intestinal barrier function.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [36] Loomba, R. et al. Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease. Cell Metab 25, 1054–1062 e1055, https://doi.org/10.1016/j.cmet.2017.04.001 (2017). source

      Not checked in the free run.

    • cites [37] Boursier, J. et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 63, 764–775, https://doi.org/10.1002/hep.28356 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The composition of the microbiome was altered in all these patients regardless of the lack of statistically significant changes in diversity.

    “the composition of the microbiome was altered in all these patients regardless of the lack of statistically significant changes in diversity”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [48] Caussy, C. et al. A gut microbiome signature for cirrhosis due to nonalcoholic fatty liver disease. Nat Commun 10, 1406, https://doi.org/10.1038/s41467-019-09455-9 (2019). source

      Not checked in the free run.

    • cites [51] Chen, Y. et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 54, 562–572, https://doi.org/10.1002/hep.24423 (2011). source

      Not checked in the free run.

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

    Premisecitation

    In patients with NAFLD/NASH, there is an increased abundance of Bacteroides.

    “As well, in those studies it was shown that NALFD/NASH in patients associated with increased abundance of Bacteroides abundance36,37.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [36] Loomba, R. et al. Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease. Cell Metab 25, 1054–1062 e1055, https://doi.org/10.1016/j.cmet.2017.04.001 (2017). source

      Not checked in the free run.

    • cites [37] Boursier, J. et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 63, 764–775, https://doi.org/10.1002/hep.28356 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Clostridium is increased in PSC patients and PBC patients.

    “which is in agreement with what was found in PSC patients9 as well as in PBC patients13.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Kummen, M. et al. The gut microbial profile in patients with primary sclerosing cholangitis is distinct from patients with ulcerative colitis without biliary disease and healthy controls. Gut 66, 611–619, https://doi.org/10.1136/gutjnl-2015-310500 (2017). source

      Not checked in the free run.

    • cites [13] Tang, R. et al. Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy. Gut 67, 534–541, https://doi.org/10.1136/gutjnl-2016-313332 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chen et al. found a similar Chao index in cirrhotic patients and a non-significant Shannon index when compared to healthy controls.

    “Chen et al.51 found a similar Chao index in cirrhotic patients and a non-significant Shannon index when compared to healthy controls.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Chen, Y. et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 54, 562–572, https://doi.org/10.1002/hep.24423 (2011). source

      Not checked in the free run.

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

    Premisecitation

    This mechanism is particularly relevant in IBD, where an increase in R gnavus has been described.

    “This mechanism is particularly relevant in IBD, where an increase in R gnavus has been described35.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Tailford, L. E. et al. Discovery of intramolecular trans-sialidases in human gut microbiota suggests novel mechanisms of mucosal adaptation. Nat Commun 6, 7624, https://doi.org/10.1038/ncomms8624 (2015). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Clostridium and Bacteroides associate with increased LPS and liver injury in a mouse model after high fat diet.

    “Clostridium, as well as Bacteroides, associate with increased LPS and liver injury in a mouse model after high fat diet46.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] Xie, G. et al. Distinctly altered gut microbiota in the progression of liver disease. Oncotarget 7, 19355–19366, https://doi.org/10.18632/oncotarget.8466 (2016). source

      Not checked in the free run.

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

    Study design and conductcitation

    The analyses adjusted for multiple testing (FDR/Benjamini-Hochberg) and significance was based on corrected p-values.

    “with pairwise adonis with FDR corrections.”
    • Also stated in: § Statistical analysis · plain
      “using the function anova.manyglm, adjusted for multiple testing”
    • Also stated in: § Statistical analysis · plain
      “Statistical differences between multiple samples at Phylum, Family and Genera-level were estimated by Kruskal-Wallis or Mann–Whitney U-test or Negative Binomial distribution65 by adjusted for multiple testing according to the method of Benjamini and Hochberg66. Significance (p < 0.05) was based on the corrected p-values.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [65] Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq. 2. Genome Biol 15, 550, https://doi.org/10.1186/s13059-014-0550-8 (2014). source

      Not checked in the free run.

    • cites [66] Benjamini, Y. & Hochberg, Y. Controlling the False Discovery Rate - a Practical and Powerful Approach to Multiple Testing. J Roy Stat Soc B Met 57, 289–300 (1995). source

      Not checked in the free run.

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

    Premisecitation

    Faecalibacterium prausnitzii is depleted in IBD patients, including ulcerative colitis.

    “The depletion of F prausnitzii in IBD patients3,41,42, including ulcerative colitis43”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [3] Marchesi, J. R. et al. The gut microbiota and host health: a new clinical frontier. Gut 65, 330–339, https://doi.org/10.1136/gutjnl-2015-309990 (2016). source

      Not checked in the free run.

    • cites [41] Sokol, H. et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci USA 105, 16731–16736, https://doi.org/10.1073/pnas.0804812105 (2008). source

      Not checked in the free run.

    • cites [42] Fujimoto, T. et al. Decreased abundance of Faecalibacterium prausnitzii in the gut microbiota of Crohn’s disease. J Gastroenterol Hepatol 28, 613–619, https://doi.org/10.1111/jgh.12073 (2013). source

      Not checked in the free run.

    • cites [43] Machiels, K. et al. A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut 63, 1275–1283, https://doi.org/10.1136/gutjnl-2013-304833 (2014). source

      Not checked in the free run.

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

    Premisecitation

    Increased abundance of Clostridium has been linked to IBD.

    “increased abundance of Clostridium has been linked to IBD”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Monaghan, T. M., Cockayne, A. & Mahida, Y. R. Pathogenesis of Clostridium difficile Infection and Its Potential Role in Inflammatory Bowel Disease. Inflamm Bowel Dis 21, 1957–1966, https://doi.org/10.1097/MIB.0000000000000461 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The colonisation of the intestinal microbiome with oral-related bacteria is gradual in time and likely occurring at later stages of the disease.

    “may indicate that this colonisation is gradual in time and likely occurring at later stages of the disease”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Enterobacteriaceae abundance is increased in NASH patients compared to obese individuals and in NAFLD/cirrhotic patients.

    “which abundance is increased in NASH patients when compared to obese47 and in NAFLD/cirrhotics48.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [47] Zhu, L. et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 57, 601–609, https://doi.org/10.1002/hep.26093 (2013). source

      Not checked in the free run.

    • cites [48] Caussy, C. et al. A gut microbiome signature for cirrhosis due to nonalcoholic fatty liver disease. Nat Commun 10, 1406, https://doi.org/10.1038/s41467-019-09455-9 (2019). source

      Not checked in the free run.

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

    Premisecitation

    Changes in the composition of the oral microbiome and colonisation of the lower intestinal tract by oral-specific bacteria are related to cirrhosis.

    “Changes in the composition of the oral microbiome and the colonisation of the lower intestinal tract by oral-specific bacteria has been related to cirrhosis49.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Qin, N. et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 513, 59–64, https://doi.org/10.1038/nature13568 (2014). source

      Not checked in the free run.

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

    Premisecitation

    Previous studies found that microbiome diversity was significantly lower in NAFLD patients without fibrosis, whereas diversity in patients with advanced fibrosis was restored to comparable levels to healthy individuals.

    “previous studies where the diversity of the microbiome was significantly lower in NAFLD patients without fibrosis, whereas the diversity in patients with advanced fibrosis was ‘restored’ to comparable levels to healthy individuals48.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [48] Caussy, C. et al. A gut microbiome signature for cirrhosis due to nonalcoholic fatty liver disease. Nat Commun 10, 1406, https://doi.org/10.1038/s41467-019-09455-9 (2019). source

      Not checked in the free run.

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

    Interpretationcitation

    The regulation of bacterial communities by pH could be relevant in the context of cholestasis, where the presence of bile acids in the intestine decreases.

    “The regulation of bacterial communities by pH40 could be relevant in the context of cholestasis where the presence of bile acids in the intestine decreases.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Walker, A. W., Duncan, S. H., McWilliam Leitch, E. C., Child, M. W. & Flint, H. J. pH and peptide supply can radically alter bacterial populations and short-chain fatty acid ratios within microbial communities from the human colon. Appl Environ Microbiol 71, 3692–3700, https://doi.org/10.1128/AEM.71.7.3692-3700.2005 (2005). source

      Not checked in the free run.

    • Rests on an assumption: In cholestasis, the presence of bile acids in the intestine decreases.

  • May combine two claims.

    Premisecitation

    Bacteroides increase their abundance when the intestinal pH changes from acid to more basic, at the expense of butyrate-producing bacteria such as Faecalibacterium prausnitzii.

    “Interestingly, Bacteroides (enriched in BDL 3d) increase their abundance when the intestinal pH changes from acid to more basic, in detriment of bacteria (e.g. Faecalibacterium prausnitzii) that produce butyrate, a short chain fatty acid with well-known beneficial functions in the intestine38,39.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Walker, A. W., Duncan, S. H., McWilliam Leitch, E. C., Child, M. W. & Flint, H. J. pH and peptide supply can radically alter bacterial populations and short-chain fatty acid ratios within microbial communities from the human colon. Appl Environ Microbiol 71, 3692–3700, https://doi.org/10.1128/AEM.71.7.3692-3700.2005 (2005). source

      Not checked in the free run.

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

    Premisecitation

    Prevotella is increased in cirrhotics.

    “Increased presence of Prevotella has been found in cirrhotics49”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Qin, N. et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 513, 59–64, https://doi.org/10.1038/nature13568 (2014). source

      Not checked in the free run.

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

    Premisecitation

    Butyrate is a short-chain fatty acid with well-known beneficial functions in the intestine.

    “a short chain fatty acid with well-known beneficial functions in the intestine38,39.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [38] den Besten, G. et al. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res 54, 2325–2340, https://doi.org/10.1194/jlr.R036012 (2013). source

      Not checked in the free run.

    • cites [39] Berni Canani, R., Di Costanzo, M. & Leone, L. The epigenetic effects of butyrate: potential therapeutic implications for clinical practice. Clin Epigenetics 4, 4, https://doi.org/10.1186/1868-7083-4-4 (2012). source

      Not checked in the free run.

59 of 59

  • The paper relies on this without support.

    The role of the microbiome during the pathogenesis of cholestatic liver disease is still poorly understood.

    “The role of the microbiome during the pathogenesis of cholestatic liver disease is still poorly understood.”

  • The paper relies on this without support.

    In cholestasis, the presence of bile acids in the intestine decreases.

    “The regulation of bacterial communities by pH40 could be relevant in the context of cholestasis where the presence of bile acids in the intestine decreases.”

  • The paper relies on this without support.

    During cholestasis, there is increased permeability and loss of intestinal barrier function.

    “its lower abundance after BDL may contribute to the increased permeability and loss of intestinal barrier function during cholestasis.”

  • The paper relies on this without support.

    Enterobacteriaceae are gram-negative LPS-producing bacteria with pro-inflammatory activity.

    “Enterobacteriaceae are also gram negative-LPS producing bacteria with pro-inflammatory activity”

  • The paper relies on this without support.

    Prevotella is distinctively found in the oral cavity.

    “Prevotella is distinctively found in the oral cavity.”

  • The paper relies on this without support.

    LPS-induced liver injury and inflammation promote progression of liver disease.

    “may contribute to the overall progression of liver disease by promoting LPS-induced liver injury and inflammation.”
6 of 6

Claims other papers make about this one

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

Self-check

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

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

  • Veillonella and Dialister trends are reversed in the discussion

    Major

    The Results say both genera were more abundant at BDL 3d than at BDL 7d, but the Discussion says BDL 7d was enriched for both relative to BDL 3d.

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Authors
Cabrera-Rubio, R., Patterson, A. M., Cotter, P. D., & Beraza, N.
Affiliations
  • Norwich Research Park (GB)
  • Teagasc - The Irish Agriculture and Food Development Authority (IE)
Corresponding author
Beraza, Naiara
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2019-08-23
Volume
9
Issue
1
Pages
12324-12324
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-019-48784-z
PMC
PMC6707139
OpenAlex
W2969448053
Semantic Scholar
c2577e02b90ddb9c7e8133ea1709e9f803e875ff
Cited by
61
References
65
Citations by year
2026: 3 · 2025: 13 · 2024: 13 · 2023: 9 · 2022: 7 · 2021: 9 · 2020: 6 · 2019: 1
FWCI
1.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Arrow@dit (Dublin Institute of Technology) (acceptedVersion)
  • Cork Open Research Archive (University College Cork, Ireland) (acceptedVersion, cc-by)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (acceptedVersion, other-oa)
  • Arrow@dit (Dublin Institute of Technology) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • T-Stór (Teagasc) (submittedVersion, cc-by-nc-sa)
Funders
RCUK | Biotechnology and Biological Sciences Research Council (BB/J004529/1, BB/R012490/1, BBS/E/F/000PR10355, BB/CCG1860/1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Nutrition and Physiology
Keywords
cholestasis, bile duct ligation, gut microbiota, gut dysbiosis, microbiome diversity, Akkermansia, Prevotella, Bacteroides, Ruminococcaceae, Faecalibacterium prausnitzii, chronic liver disease, mouse model
MeSH terms
Gastrointestinal Microbiome, Animals, Bacteria, Bile Ducts, Cholestasis, Inflammation, Intestines, Ligation, Liver, Male, Mice, Inbred C57BL, Permeability, Principal Component Analysis

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 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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