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Cited by 634Gut microbiota and healthHepatocellular Carcinoma Treatment and PrognosisLiver physiology and pathology

The gut microbiome and liver cancer: mechanisms and clinical translation

Open access
Yu, Le-Xing, Schwabe, Robert F.·2017·Nature Reviews Gastroenterology & Hepatology
DOI 10.1038/nrgastro.2017.72PMC PMC6467288
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Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of worldwide cancer mortality. HCC almost exclusively develops in patients with chronic liver disease, driven by a vicious cycle of liver injury, inflammation and regeneration that typically spans decades. Increasing evidence points towards a key role of the bacterial microbiome in promoting the progression of liver disease and the development of HCC. Here, we will review mechanisms by which the gut microbiota promotes hepatocarcinogenesis, focusing on the leaky gut, bacterial dysbiosis, microbe-associated molecular patterns and bacterial metabolites as key pathways that drive cancer-promoting liver inflammation, fibrosis and genotoxicity. On the basis of accumulating evidence from preclinical studies, we propose the intestinal-microbiota-liver axis as a promising target for the simultaneous prevention of chronic liver disease progression and HCC development in patients with advanced liver disease. We will review in detail therapeutic modalities and discuss clinical settings in which targeting the gut-microbiota-liver axis for the prevention of disease progression and HCC development seems promising.

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  • Premisecitation

    The gut microbiota makes a key contribution to early alcoholic liver disease.

    “The key contribution of the gut microbiota to early stages of ALD has been firmly established in the past two decades.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Pradere, J. P., Troeger, J. S., Dapito, D. H., Mencin, A. A. & Schwabe, R. F. Toll-like receptor 4 and hepatic fibrogenesis. Semin. Liver Dis. 30, 232–244 (2010). source

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  • Premisecitation

    Bacterial DNA, a TLR9 agonist, is increased in the peripheral blood of patients with chronic liver disease.

    “Moreover, there is an increase in bacterial DNA , a well-established TLR9 agonist, in the peripheral blood of patients with CLD29.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • Interpretationreasoning

    Liver cirrhosis is the most important unifying risk factor for hepatocellular carcinoma.

    “Hence, the presence of liver cirrhosis represents the most important unifying risk factor for the development of HCC.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [37] Cabrera, R. & Nelson, D. R. Review article: the management of hepatocellular carcinoma. Aliment. Pharmacol. Ther. 31, 461–476 (2010). source

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    • Rests on an assumption: Hepatocellular carcinoma almost exclusively develops in patients with chronic liver disease and almost never occurs spontaneously without liver disease.
  • Premisecitation

    Serum lipopolysaccharide levels are increased in patients with chronic alcohol abuse.

    “Likewise, serum LPS levels are increased in patients with chronic alcohol abuse16.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Pradere, J. P., Troeger, J. S., Dapito, D. H., Mencin, A. A. & Schwabe, R. F. Toll-like receptor 4 and hepatic fibrogenesis. Semin. Liver Dis. 30, 232–244 (2010). source

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  • Interpretationreasoning

    The chronically injured liver is exposed to more TLR ligands and other bacterial products and metabolites.

    “Together, these findings demonstrate that the chronically injured liver is subject to increased exposure to a wide range of TLR ligands as well as other bacterial products and metabolites.”
    Quote in the paperSubstantial claim
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    Premisecitation

    The underlying liver disease type carries a specific hepatocellular carcinoma risk in cirrhosis, with chronic hepatitis B or C and haemochromatosis at relatively high risk and autoimmune hepatitis or alcoholic liver disease at relatively low risk.

    “However, additional factors are involved and each type of underlying liver disease entails a specific risk for the development of HCC in cirrhosis; diseases such as chronic hepatitis B and C or haemochromatosis entail a relatively high risk and diseases such as autoimmune hepatitis or ALD a relatively low risk38–40.”
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    Premisecitation

    Patients with cirrhosis have increased Enterobacteriaceae and oral-type taxa such as Veillonellaceae and Streptococcaceae, consistent with microorganisms moving from the mouth to the gut.

    “Studies in the past few years have demonstrated profound alterations of the intestinal microbiota in patients with cirrhosis, showing increased Enterobacteriacea as well as strains that are typically found in the oral microbiota, such as Veillonellaceae and Streptococcaceae, consistent with an invasion of microorganisms from the mouth to the gut in liver cirrhosis32,33.”
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    Premisecitation

    Gut microbiota alterations occur in earlier stages of liver disease and in animal models.

    “Likewise, a number of studies have demonstrated alterations of the gut microbiota in earlier stages of liver disease 35,36 as well as in animal models16,31.”
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    • cites [16] Pradere, J. P., Troeger, J. S., Dapito, D. H., Mencin, A. A. & Schwabe, R. F. Toll-like receptor 4 and hepatic fibrogenesis. Semin. Liver Dis. 30, 232–244 (2010). source

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    Premisecitation

    Mice receiving intragastric alcohol feeding show gut microbiota perturbations and reduced synthesis of long-chain fatty acids.

    “Moreover, mice receiving intragastric alcohol feeding show perturbations of the intestinal microbiota, with reduced synthesis of long-chain fatty acids44.”
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    Premisecitation

    Alcoholic liver disease may have a lower relative hepatocellular carcinoma risk than other chronic liver diseases, but its absolute hepatocellular carcinoma burden is high because many patients have alcoholic cirrhosis.

    “Although ALD might have a lower relative risk of causing HCC than other types of CLD39, the sheer number of patients with alcoholic cirrhosis means that the absolute number of HCCs caused by ALD is high.”
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    • cites [39] Sanyal, A. J., Yoon, S. K. & Lencioni, R. The etiology of hepatocellular carcinoma and consequences for treatment. Oncologist 15 (Suppl. 4), 14–22 (2010). source

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    Premisecitation

    Increased blood lipopolysaccharide reflects gut leakiness and is accompanied by greater intestinal permeability to high molecular weight polyethylene glycol in alcoholic liver disease and to FITC-dextran in mouse models of alcoholic and biliary liver disease.

    “Increases in blood LPS levels reflect gut leakiness and are mirrored by a number of other alterations such as increased intestinal permeability to high molecular weight polyethylene glycol in patients with ALD26 and to FITC-dextran in mouse models of alcoholic and biliary liver disease27,28.”
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    Premisecitation

    Cirrhosis stage correlates positively with Enterobacteriaceae and negatively with Lachnospiraceae.

    “These changes seem to develop progressively, as cirrhosis stage is positively correlated with Enterobacteriaceae and negatively correlated with Lachnospiraceae33,34.”
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    • cites [33] Chen, Y. et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 54, 562–572 (2011). source

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    • cites [34] Bajaj, J. S., Betrapally, N. S. & Gillevet, P. M. Decompensated cirrhosis and microbiome interpretation. Nature 525, E1–E2 (2015). source

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    Premisecitation

    In chronic liver disease, a failing gut barrier and altered gut microbiota drive chronic inflammation and liver disease progression, which raises the risk of hepatocellular carcinoma.

    “However, a failing gut barrier and alterations of the gut microbiota in chronic liver disease (CLD) contribute to chronic inflammation and the progression of liver diseases12, and thereby increase risk for the development of hepatocellular carcinoma (HCC) as the final stage of the disease process 13–15.”
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    • cites [13] Dapito, D. H. et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21, 504–516 (2012). source

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    • Rests on an assumption: The multi-layer intestinal barrier normally keeps hepatic exposure to pro-inflammatory microbe-associated molecular patterns minimal.

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    Premisecitation

    These pro-inflammatory mediators promote chronic liver disease and create conditions for hepatocellular carcinoma development.

    “These pro-inflammatory mediators not only promote the development of CLD but also set the stage for the development of HCC13–15.”
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    • cites [13] Dapito, D. H. et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21, 504–516 (2012). source

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    • cites [14] Yu, L. X. et al. Endotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents. Hepatology 52, 1322–1333 (2010). source

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

    Premisecitation

    Alcoholic liver disease accounts for about half of all cirrhosis cases and is a cofactor in liver disease caused by HBV, HCV and NASH.

    “ALD contributes to about half of all cirrhosis cases41 and is a cofactor in liver disease induced by HBV, HCV and NASH.”
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    About 80-90% of hepatocellular carcinomas arise in advanced fibrotic or cirrhotic livers, and roughly one in three patients with compensated cirrhosis develops hepatocellular carcinoma during their lifetime.

    “Moreover, ~80–90% of HCCs occur in advanced fibrotic or cirrhotic livers, which translates to around one in three patients with compensated liver cirrhosis developing HCC in their lifetimes37,38.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [37] Cabrera, R. & Nelson, D. R. Review article: the management of hepatocellular carcinoma. Aliment. Pharmacol. Ther. 31, 461–476 (2010). source

      Not checked in the free run.

    • cites [38] El-Serag, H. B. Hepatocellular carcinoma. N. Engl. J. Med. 365, 1118–1127 (2011). source

      Not checked in the free run.

    • Rests on an assumption: Hepatocellular carcinoma almost exclusively develops in patients with chronic liver disease and almost never occurs spontaneously without liver disease.

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

    Premisecitation

    NAFLD is the most prevalent liver disease and is projected to become the leading contributor to chronic liver disease and hepatocellular carcinoma.

    “Although recognized as a disease only about two decades ago, NAFLD represents the most prevalent liver disease, and is projected to become the leading contributor to CLD and the development of HCC51.”
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    Premisecitation

    Patients with NAFLD show dysbiosis, but bacterial abundance patterns are inconsistent across studies, with Bacteroidetes increased in some and decreased in others, and substantial overlap with healthy individuals.

    “However, bacterial abundance patterns were not consistent between studies, with levels of Bacteroidetes increased in some studies36,56 and decreased in other studies57,58, and a substantial overlap with healthy individuals59.”
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    Premisecitation

    Low plasma phosphatidylcholine impairs VLDL secretion, reducing hepatic lipid export and contributing to fatty liver.

    “These low levels of phosphatidylcholine impaired secretion of VLDL, thereby reducing hepatic lipid export and contributing to fatty liver61.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    The gut microbiota of obese individuals is more efficient at energy extraction and contributes to obesity.

    “Metagenomic and microbiota transplantation studies have shown that the gut microbiota from obese individuals is more efficient at energy extraction and thereby contributes to obesity53,54.”
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    Interpretationcitation

    Alcohol abuse is an important cofactor for liver disease and hepatocellular carcinoma in chronic HCV infection, suggesting a possible role for the LPS-TLR4 axis in this synergy.

    “This finding fits well with the well-established clinical observation that alcohol abuse is an important cofactor in promoting liver disease development and HCC in patients with chronic HCV infection 50 and suggests a potential role for the LPS–TLR4 axis in the synergy between alcohol and HCV.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    Germ-free mice show increased liver fibrosis, which seemingly contradicts the decreased fibrosis seen in gut-sterilized mice.

    “However, recent studies have demonstrated an increase in liver fibrosis in germ-free mice75,76, which seemingly contradicts the decrease of liver fibrosis seen in gut-sterilized mice.”
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    Premisecitation

    The endogenous commensal microbiota provides hepatoprotective signals; complete absence of the gut microbiota increases liver injury, probably through lack of TLR4-mediated anti-apoptotic NF-κB signalling, and increases liver fibrosis.

    “It has become apparent that the endogenous commensal microbiota provides hepatoprotective signals and that complete absence of the gut microbiota results in increased liver injury — probably owing to an absence of TLR4-mediated activation of anti-apoptotic NF-κB signalling — and a subsequent increase in liver fibrosis, as demonstrated in several models13,75,76.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [13] Dapito, D. H. et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21, 504–516 (2012). source

      Not checked in the free run.

    • cites [75] Mazagova, M. et al. Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice. FASEB J. 29, 1043–1055 (2015). source

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    • cites [76] Tabibian, J. H. et al. Absence of the intestinal microbiota exacerbates hepatobiliary disease in a murine model of primary sclerosing cholangitis. Hepatology 63, 185–196 (2016). source

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    Premisecitation

    Global TLR4 deficiency in mice and gut sterilization with nonabsorbable antibiotics in rats reduce hepatic steatosis, oxidative stress and inflammation.

    “Global TLR4 deficiency in mice as well as gut sterilization with nonabsorbable antibiotics in rats reduces hepatic steatosis, oxidative stress and inflammation46–48.”
    Quote in the paperSubstantial claim0 of 3 sources checked
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    Premisecitation

    In ethanol-fed transgenic mice with global TLR4 deficiency and NS5A HCV protein expression, hepatocellular carcinoma development is reduced, suggesting TLR4 signalling synergizes with HCV to promote hepatocellular carcinoma.

    “In one study, ethanol-fed transgenic mice with global TLR4 deficiency, which additionally expressed the NS5A HCV protein, were protected from HCC development, suggesting that TLR4 signalling synergizes with HCV to promote HCC49.”
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    Premisecitation

    A high-fat diet increases intestinal permeability in mice, with a two-to-three-fold increase in systemic lipopolysaccharide levels.

    “High-fat diet increases intestinal permeability in mice with a two-to-three-fold increase in systemic LPS levels62.”
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    Premisecitation

    The gut microbiota controls immune responses and tolerance to HBV in adult mice, and six weeks of antibiotic treatment prevented HBV clearance.

    “A recent study demonstrated that the gut microbiota controls immune responses and tolerance to HBV in adult mice, with 6 weeks of antibiotic treatment preventing the clearance of HBV68.”
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    Premisecitation

    The bacterial microbiota promotes hepatocellular carcinoma in the setting of liver fibrosis, as shown by reduced hepatocellular carcinoma formation in TLR4-deficient, germ-free and antibiotic-treated mice in a DEN plus CCl4 model.

    “Nonetheless, the bacterial microbiota has an important role in promoting HCC in the setting of liver fibrosis, as demonstrated by reduced HCC formation in TLR4-deficient, germ-free and antibiotic-treated mice in a diethylnitrosamine (DEN) plus CCl4 model of HCC13.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Dapito, D. H. et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21, 504–516 (2012). source

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  • May combine two claims.

    Premisecitation

    NAFLD carries a low relative individual risk for hepatocellular carcinoma but contributes greatly at the population level because of its high prevalence.

    “In comparison to other CLDs, NAFLD carries a low relative individual risk for HCC development, but makes a big population-wide contribution to HCC development owing to its high prevalence51.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Antibiotics prevent hepatic injury and fibrosis induced by CCl4 treatment, bile duct ligation or a choline-deficient diet, and endotoxin enhances hepatic fibrosis induced by a choline-deficient diet.

    “Studies from the past six decades have shown that antibiotics prevent hepatic injury and fibrosis induced by CCl4 treatment, bile duct ligation or a choline-deficient diet, and that endotoxin enhances hepatic fibrosis induced by a choline-deficient diet71–73.”
    Quote in the paperSubstantial claim0 of 3 sources checked
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    Premisecitation

    In the methionine-choline-deficient diet model, the microbiota has a key role in NASH exacerbation; co-housing transmitted NASH risk and antibiotics reduced NASH risk.

    “In the MCD diet model, the microbiota has a key role in NASH exacerbation as demonstrated by experiments, in which co-housing transmitted NASH risk and antibiotics reduced NASH risk65.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    Epiregulin is an epidermal growth factor family member with a potent mitogenic effect on hepatocytes.

    “Epiregulin is an epidermal growth factor family member with a potent mitogenic effect on hepatocytes82.”
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    Premisecitation

    Recent studies show differences in duodenal and salivary microbiota between healthy controls and patients with cirrhosis, suggesting upper gastrointestinal changes may link to distal microbiota and contribute to chronic liver disease pathophysiology and hepatocellular carcinoma.

    “Recent studies have demonstrated differences in the duodenal and salivary microbiota between healthy controls and patients with cirrhosis86,88, suggesting that there are also qualitative and quantitative changes in the upper gastrointestinal tract that might be linked to changes in the more distal microbiota and contribute to the pathophysiology of CLD as well as the development of HCC.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Interpretationcitation

    The intestinal microbiota of patients with compensated cirrhosis differs from that of patients with decompensated cirrhosis, suggesting cirrhosis stage rather than underlying liver disease drives gut microbiota changes.

    “The finding that the intestinal microbiota of patients with compensated cirrhosis differs from that of patients with decompensated cirrhosis34 suggests that cirrhosis stage, rather than the underlying liver disease, drives gut microbiota changes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    TLR4 activation by lipopolysaccharide in hepatocellular carcinoma cell lines enhances invasive potential and induces epithelial-mesenchymal transition.

    “In addition, TLR4 activation in HCC cell lines by LPS enhances their invasive potential and induces the epithelial–mesenchymal transition83.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    Key changes in the intestinal microbiota in cirrhosis include enrichment of Veillonella or Streptococcus and decreased bacteria from the order Clostridiales.

    “Key changes in the composition of the intestinal microbiota in cirrhosis include enrichment of Veillonella or Streptococcus as well as decreased bacteria from the order Clostridiales32.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Qin, N. et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 513, 59–64 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Perturbation of gut eubiosis by penicillin increased hepatocellular carcinoma formation in rats, and this increase could be suppressed by probiotics.

    “As such, perturbation of the gut eubiosis by penicillin increased HCC formation in rats77, which could be suppressed by probiotics77.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Zhang, H. L. et al. Profound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats. J. Hepatol. 57, 803–812 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The majority of patient-enriched species in cirrhosis are of buccal origin, suggesting invasion of the gut from the mouth.

    “Of note, the majority of the patient-enriched species were of buccal origin, suggesting an invasion of the gut from the mouth in liver cirrhosis32.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Qin, N. et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 513, 59–64 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Dysbiosis and the leaky gut are probably intimately linked, and intestinal dysbiosis likely contributes to a leaky gut through multiple mechanisms.

    “Dysbiosis (discussed below) and the leaky gut are probably intimately linked; it is likely that intestinal dysbiosis contributes to a leaky gut by multiple mechanisms, such as dysbiosis-induced alterations of the intestinal barrier as well as a shift to bacterial species with increased propensity to translocate.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Gut microbial imbalance affects liver disease and hepatocellular carcinoma development through bacterial metabolites, and these effects may differ by disease.

    “Recent evidence suggests that the effects of dysbiosis on the development of liver disease and HCC are mediated by bacterial metabolites, possibly in a disease-specific manner.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In mice fed a high-fat diet, dysbiosis with increased Gram-negative bacteria and a reduced Bacteroidetes to Firmicutes ratio occurred; transplanting this microbiota into control-diet-fed mice after bile duct ligation increased liver damage and fibrosis.

    “In one study, high-fat diet feeding in mice resulted in dysbiosis, with increased abundance of Gram-negative bacteria and a reduced ratio of Bacteroidetes to Firmicutes . Transplantation of these dysbiotic microbiota into control-diet-fed mice that had undergone bile duct ligation increased liver damage and fibrosis in the recipient89.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] De Minicis, S. et al. Dysbiosis contributes to fibrogenesis in the course of chronic liver injury in mice. Hepatology 59, 1738–1749 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Disruption of the gut barrier by dextran sulfate sodium increases systemic lipopolysaccharide levels and liver fibrosis and promotes hepatocellular carcinoma formation in mice.

    “Likewise, disruption of the gut barrier by administration of dextran sulfate sodium not only results in increased systemic LPS levels and increased liver fibrosis, but also promotes HCC formation in mice80,81.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [80] Gabele, E. et al. DSS induced colitis increases portal LPS levels and enhances hepatic inflammation and fibrogenesis in experimental NASH. J. Hepatol. 55, 1391–1399 (2011). source

      Not checked in the free run.

    • cites [81] Achiwa, K. et al. DSS colitis promotes tumorigenesis and fibrogenesis in a choline-deficient high-fat diet-induced NASH mouse model. Biochem. Biophys. Res. Commun. 470, 15–21 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The gut microbiomes of patients with advanced liver disease and cirrhosis are characterized by increased potentially pathogenic bacteria and reduced beneficial bacteria.

    “The gut microbiomes of patients with advanced liver disease and cirrhosis are characterized by an increase in potentially pathogenic bacteria, along with reduced numbers of bacteria with beneficial properties32,84,85.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [32] Qin, N. et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 513, 59–64 (2014). source

      Not checked in the free run.

    • cites [84] Wei, X. et al. Cirrhosis related functionality characteristic of the fecal microbiota as revealed by a metaproteomic approach. BMC Gastroenterol. 16, 121 (2016). source

      Not checked in the free run.

    • cites [85] Lv, L. X. et al. Alterations and correlations of the gut microbiome, metabolism and immunity in patients with primary biliary cirrhosis. Environ. Microbiol. 18, 2272–2286 (2016). source

      Not checked in the free run.

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

    Premisecitation

    Short-chain fatty acids are a primary energy source for intestinal epithelial cells.

    “One example is the production of short-chain fatty acids (SCFAs), which are a primary energy source for intestinal epithelial cells91”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Lee, W. J. & Hase, K. Gut microbiota-generated metabolites in animal health and disease. Nat. Chem. Biol. 10, 416–424 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Norfloxacin effectively reduces small intestinal bacterial overgrowth and bacterial translocation in advanced cirrhosis patients.

    “Although these data show that norfloxacin can effectively reduce small intestinal bacteria overgrowth and bacterial translocation in patients with advanced cirrhosis, the effects of norfloxacin on HCC development in patients with liver cirrhosis are not known.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The effects of norfloxacin on HCC development in patients with liver cirrhosis are unknown.

  • May combine two claims.

    Interpretationreasoning

    Reducing total gut bacteria and eliminating highly translocating bacteria lowers bacterial translocation and proinflammatory signalling from a leaky gut.

    “Decreasing the overall number of bacteria in the gut and eliminating bacteria that have a high ability to translocate will reduce bacterial translocation and thereby inhibit proinflammatory signals coming from leaky gut.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Targeting the gut-microbiota-liver axis reduces spontaneous bacterial peritonitis and hepatic encephalopathy in patients.

    “and spontaneous bacterial peritonitis98 and hepatic encephalopathy99 in patients.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [98] Lutz, P. et al. Impact of rifaximin on the frequency and characteristics of spontaneous bacterial peritonitis in patients with liver cirrhosis and ascites. PLoS ONE 9, e93909 (2014). source

      Not checked in the free run.

    • cites [99] Bass, N. M. et al. Rifaximin treatment in hepatic encephalopathy. N. Engl. J. Med. 362, 1071–1081 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rifaximin appears to reduce spontaneous bacterial peritonitis and may improve portal hypertension, suggesting it effectively targets the gut-liver axis in advanced liver disease.

    “Moreover, rifaximin appears to reduce the development of spontaneous bacterial peritonitis and may improve portal hypertension, suggesting that it effectively targets the gut–liver axis in advanced liver disease93,114,115.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [93] Vlachogiannakos, J. et al. Long-term administration of rifaximin improves the prognosis of patients with decompensated alcoholic cirrhosis. J. Gastroenterol. Hepatol. 28, 450–455 (2013). source

      Not checked in the free run.

    • cites [114] Vlachogiannakos, J. et al. Intestinal decontamination improves liver haemodynamics in patients with alcohol-related decompensated cirrhosis. Aliment. Pharmacol. Ther. 29, 992–999 (2009). source

      Not checked in the free run.

    • cites [115] Kalambokis, G. N. et al. Rifaximin improves systemic hemodynamics and renal function in patients with alcohol-related cirrhosis and ascites. Clin. Gastroenterol. Hepatol. 10, 815–818 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Mouse findings cannot be directly translated to patients because long-term use of the antibiotic cocktail would deplete almost all detectable commensal microbiota and includes nephrotoxic drugs such as neomycin.

    “However, findings from mice cannot be translated directly to patients as long-term administration of the employed antibiotic cocktail would be deleterious due to the depletion of almost all detectable commensal microbiota (>99.5%)73,104 and the inclusion of nephrotoxic drugs, such as neomycin.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [73] Seki, E. et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat. Med. 13, 1324–1332 (2007). source

      Not checked in the free run.

    • cites [104] Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Targeting the gut-microbiota-liver axis reduces liver fibrosis and portal hypertension in rodents.

    “targeting the gut-microbiota–liver axis has been shown to reduce liver fibrosis 73,96 and portal hypertension97 in rodents”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [73] Seki, E. et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat. Med. 13, 1324–1332 (2007). source

      Not checked in the free run.

    • cites [96] Zhu, Q. et al. Intestinal decontamination inhibits TLR4 dependent fibronectin-mediated cross-talk between stellate cells and endothelial cells in liver fibrosis in mice. J. Hepatol. 56, 893–899 (2012). source

      Not checked in the free run.

    • cites [97] Steib, C. J. et al. Intraperitoneal LPS amplifies portal hypertension in rat liver fibrosis. Lab. Invest. 90, 1024–1032 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Murine data show that nonabsorbable antibiotics and norfloxacin improve alcoholic liver disease and insulin resistance in NAFLD.

    “As data from murine studies show that non-absorbable antibiotics and norfloxacin improve ALD48,116 and insulin resistance in NAFLD117, they might be particularly attractive for HCC prevention in these patient groups.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [48] Adachi, Y., Moore, L. E., Bradford, B. U., Gao, W. & Thurman, R. G. Antibiotics prevent liver injury in rats following long-term exposure to ethanol. Gastroenterology 108, 218–224 (1995). source

      Not checked in the free run.

    • cites [116] Chen, P., Starkel, P., Turner, J. R., Ho, S. B. & Schnabl, B. Dysbiosis-induced intestinal inflammation activates tumor necrosis factor receptor I and mediates alcoholic liver disease in mice. Hepatology 61, 883–894 (2015). source

      Not checked in the free run.

    • cites [117] Membrez, M. et al. Gut microbiota modulation with norfloxacin and ampicillin enhances glucose tolerance in mice. FASEB J. 22, 2416–2426 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rifaximin reduces HCC development in the DEN-CCl4 model, though less efficiently than the quadruple antibiotic cocktail.

    “Of note, rifaximin reduces HCC development in the DEN–CCl4 model of HCC, albeit less efficiently than the quadruple antibiotics cocktail described above13.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Dapito, D. H. et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21, 504–516 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Liver fibrosis often precedes HCC and is a risk factor for HCC in chronic liver disease.

    “Moreover, this antibiotic cocktail also reduced liver fibrosis 73, which often precedes HCC and represents a risk factor for HCC development in CLD70.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [70] Affo, S., Yu, L. X. & Schwabe, R. F. The role of cancer-associated fibroblasts and fibrosis in liver cancer. Annu. Rev. Pathol. 12, 153–186 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gram-negative bacteria are the most adept at translocating to mesenteric lymph nodes and are the most frequent cause of spontaneous bacterial infections in cirrhosis patients.

    “Gram-negative bacteria have been found to be the most adept at translocating to the mesenteric lymph nodes and are the most frequent cause of spontaneous bacterial infections in patients with cirrhosis105–107.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [105] Steffen, E. K., Berg, R. D. & Deitch, E. A. Comparison of translocation rates of various indigenous bacteria from the gastrointestinal tract to the mesenteric lymph node. J. Infect. Dis. 157, 1032–1038 (1988). source

      Not checked in the free run.

    • cites [106] Navasa, M. et al. Randomized, comparative study of oral ofloxacin versus intravenous cefotaxime in spontaneous bacterial peritonitis. Gastroenterology 111, 1011–1017 (1996). source

      Not checked in the free run.

    • cites [107] Bert, F. et al. Genetic diversity and virulence profiles of Escherichia coli isolates causing spontaneous bacterial peritonitis and bacteremia in patients with cirrhosis. J. Clin. Microbiol. 48, 2709–2714 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Norfloxacin and rifaximin have shown beneficial effects in patients with chronic liver disease or in murine HCC models and meet the criteria for clinically feasible antibiotics.

    “Currently, two antibiotics, norfloxacin and rifaximin, have shown beneficial effects in patients with CLD or murine HCC models and fulfill these criteria.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Rifaximin is a nonabsorbable antibiotic with broad-spectrum antimicrobial activity and an excellent safety profile.

    “Rifaximin is a nonabsorbable antibiotic with broad-spectrum antimicrobial activity and an excellent safety profile113 that was initially approved for the treatment of traveller’s diarrhoea but is increasingly used for the prevention of hepatic encephalopathy99.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Koo, H. L. & DuPont, H. L. Rifaximin: a unique gastrointestinal-selective antibiotic for enteric diseases. Curr. Opin. Gastroenterol. 26, 17–25 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Norfloxacin may be suitable for weeks to months of treatment but not for long-term or life-long use in cirrhosis patients.

    “A major problem with the use of norfloxacin is the development of antibiotic resistance110–112, suggesting that it might be suitable for treatment lasting weeks to months but not for long-term or life-long application in patients with cirrhosis.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [110] Fernandez, J. et al. Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis. Hepatology 35, 140–148 (2002). source

      Not checked in the free run.

    • cites [111] Fernandez, J. et al. Prevalence and risk factors of infections by multiresistant bacteria in cirrhosis: a prospective study. Hepatology 55, 1551–1561 (2012). source

      Not checked in the free run.

    • cites [112] Tandon, P., Delisle, A., Topal, J. E. & Garcia-Tsao, G. High prevalence of antibiotic-resistant bacterial infections among patients with cirrhosis at a US liver center. Clin. Gastroenterol. Hepatol. 10, 1291–1298 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Eritoran and resatorvid improved survival in animal sepsis models but did not reduce mortality in patients with severe sepsis.

    “Eritoran130 and resatorvid131 improved survival in animal models of sepsis, but did not reduce mortality in patients with severe sepsis132,133.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [130] Barochia, A., Solomon, S., Cui, X., Natanson, C. & Eichacker, P. Q. Eritoran tetrasodium (E5564) treatment for sepsis: review of preclinical and clinical studies. Expert Opin. Drug Metab. Toxicol. 7, 479–494 (2011). source

      Not checked in the free run.

    • cites [131] Naugler, W. E. et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317, 121–124 (2007). source

      Not checked in the free run.

    • cites [132] Opal, S. M. et al. Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA 309, 1154–1162 (2013). source

      Not checked in the free run.

    • cites [133] Rice, T. W. et al. A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis. Crit. Care Med. 38, 1685–1694 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Long-term TLR4 inhibition could cause immunosuppression, which may be harmful given the severely immunocompromised state of chronic liver disease patients.

    “Although TLR antagonists represent an exciting opportunity, long-term inhibition of TLR4 could result in immunosuppression, which might be deleterious due to the severely immunocompromised state of CLD patients.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a rat model of DEN-induced hepatocarcinogenesis, VSL#3 mitigated enteric dysbiosis, reduced intestinal inflammation, and decreased liver tumour growth and multiplicity.

    “In a rat model of DEN-induced hepatocarcinogenesis, administration of VSL#3 (containing Streptococcus thermophiles, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus delbrueckii subsp. Bulgaricus) mitigated enteric dysbiosis, ameliorated intestinal inflammation and decreased liver tum”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Zhang, H. L. et al. Profound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats. J. Hepatol. 57, 803–812 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Possible probiotic mechanisms include modulation of the host microbiota, improvement of gut barrier function, and modulation of the immune system.

    “The possible mechanisms of action include modulation of the host microbiota123, improvement of gut barrier function and modulation of the immune system.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Arthur, J. C. et al. VSL#3 probiotic modifies mucosal microbial composition but does not reduce colitis-associated colorectal cancer. Sci. Rep. 3, 2868 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fxr-deficient mice have compromised intestinal integrity, further deterioration after bile duct ligation, and a high incidence of HCC.

    “Fxr-deficient mice exhibit compromised intestinal integrity, with further deterioration after bile duct ligation20, and a high incidence of HCC140.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [20] Inagaki, T. et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc. Natl Acad. Sci. USA 103, 3920–3925 (2006). source

      Not checked in the free run.

    • cites [140] Kim, I. et al. Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. Carcinogenesis 28, 940–946 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients receiving FMT for recurrent C. difficile infection have usually had multiple antibiotic courses and have markedly reduced microbial diversity.

    “However, one needs to keep in mind that patients receiving FMT for recurrent C. difficile infection have usually undergone multiple courses of antibiotic treatment, and present with a marked reduction of microbial diversity 18.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] van Nood, E. et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl. J. Med. 368, 407–415 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FXR is a bile acid receptor that mediates effects on the intestinal epithelial barrier and multiple liver effects including suppression of bile acid synthesis, inhibition of liver inflammation, promotion of liver regeneration and tumour suppression.

    “FXR is a receptor for bile acids that mediates their effects on the intestinal epithelial barrier as well as multiple effects on the liver, such as suppression of bile acid synthesis, inhibition of liver inflammation, promotion of liver regeneration and tumour suppression (reviewed elsewhere136).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [136] Schaap, F. G., Trauner, M. & Jansen, P. L. Bile acid receptors as targets for drug development. Nat. Rev. Gastroenterol. Hepatol. 11, 55–67 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Obeticholic acid has a high safety profile in NASH patients in the FLINT trial, with pruritus and serum lipid alterations as major adverse effects.

    “OCA has a high safety profile in patients with NASH as demonstrated in the FLINT trial, with the major adverse effects being pruritus and alterations of serum lipid profiles144.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [144] Neuschwander-Tetri, B. A. et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385, 956–965 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A double-blind trial showed that daily VSL#3 reduced hospitalization risk for hepatic encephalopathy and improved Child-Turcotte-Pugh and MELD scores in cirrhosis patients.

    “A double-blind trial showed that daily intake of VSL#3 reduced the risk of hospitalization for hepatic encephalopathy, as well as Child–Turcotte–Pugh and model for end-stage liver disease (MELD) scores, in patients with cirrhosis121.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [121] Dhiman, R. K. et al. Probiotic VSL#3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial. Gastroenterology 147, 1327–1337.e3 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FMT has been used successfully in patients with C. difficile infection, restoring eubiosis and producing clinical improvements superior to standard antibiotic therapy.

    “FMT has successfully been used in patients with C. difficile infection, resulting in restoration of eubiosis and clinical improvements that were superior to standard antibiotic therapy18.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] van Nood, E. et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl. J. Med. 368, 407–415 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Obeticholic acid is a promising candidate for HCC prevention and may be particularly effective by correcting multiple gut-liver axis abnormalities that promote chronic inflammation and HCC in cirrhosis.

    “Thus, OCA seems to be a promising candidate for HCC prevention therapies, and could be particularly effective by correcting multiple abnormalities in the gut–liver axis that promote the development of chronic inflammation and HCC in patients with cirrhosis.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Malnutrition is common in chronic liver disease patients and is associated with increased morbidity and mortality.

    “Malnutrition is common in patients with CLD and is associated with increased morbidity and mortality (reviewed elsewhere149).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [149] Kalaitzakis, E. Gastrointestinal dysfunction in liver cirrhosis. World J. Gastroenterol. 20, 14686–14695 (2014). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Primary prevention most likely requires long-term, if not life-long, treatment.

    “Primary prevention most likely requires long-term, if not life-long treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Rifaximin is probably the candidate with the best safety profile, and strong evidence indicates it positively affects additional chronic liver disease complications such as hepatic encephalopathy, portal hypertension and liver fibrosis, and may improve overall survival.

    “In this regard, rifaximin is probably the candidate with the best safety profile, and there is strong evidence that it positively affects additional complications of CLD such as hepatic encephalopathy, portal hypertension and liver fibrosis, and possibly even improves overall survival.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Translating anti-TNF findings to patients may be difficult because TNF inhibitors are strongly immunosuppressive and increase severe infection rates.

    “However, translating these findings to patients might be difficult because of strong immunosuppressive effects of TNF inhibitors and increased rates of severe infection.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Interpretationreasoning

    The efficacy of targeting the gut-liver axis for secondary prevention could be tested in patients who have undergone curative HCC resection.

    “The efficacy of targeting the gut–liver axis for secondary prevention could be tested in patients who have undergone curative HCC resection.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    Primary prevention is the most appealing approach and could be tested prospectively in large cohorts of cirrhosis patients at high HCC risk.

    “Primary prevention seems the most appealing approach, and could be tested prospectively in large cohorts of patients with liver cirrhosis and at high risk for HCC development.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Some gut microbiota alterations are probably disease-specific, and therefore some mechanisms by which the microbiota promotes liver disease and HCC may be at least partly disease-specific.

    “Some alterations of the gut microbiota are probably disease-specific, and therefore some mechanisms by which the gut microbiota promotes the progression of liver disease and HCC could be — at least in part — disease-specific.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cisapride decreases intestinal transit time and inhibits intestinal bacterial overgrowth and bacterial translocation in animal models and cirrhosis patients.

    “The prokinetic drug cisapride not only decreases intestinal transit time but also inhibits intestinal bacterial overgrowth and bacterial translocation, both in animal models150,151 and in patients with cirrhosis150,152.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [150] Pardo, A. et al. Effect of cisapride on intestinal bacterial overgrowth and bacterial translocation in cirrhosis. Hepatology 31, 858–863 (2000). source

      Not checked in the free run.

    • cites [151] Zhang, S. C. et al. Effect of cisapride on intestinal bacterial and endotoxin translocation in cirrhosis. World J. Gastroenterol. 9, 534–538 (2003). source

      Not checked in the free run.

    • cites [152] Madrid, A. M., Hurtado, C., Venegas, M., Cumsille, F. & Defilippi, C. Long-term treatment with cisapride and antibiotics in liver cirrhosis: effect on small intestinal motility, bacterial overgrowth, and liver function. Am. J. Gastroenterol. 96, 1251–1255 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Malnutrition increases intestinal permeability and facilitates bacterial translocation.

    “Of note, malnutrition increases intestinal permeability and facilitates bacterial translocation159.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [159] De Santis, S., Cavalcanti, E., Mastronardi, M., Jirillo, E. & Chieppa, M. Nutritional keys for intestinal barrier modulation. Front. Immunol. 6, 612 (2015). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Good safety and beneficial effects on non-HCC complications of chronic liver disease are the most important selection criteria for the best drug candidates.

    “As discussed in the previous sections, good safety and beneficial effects on non-HCC complications of CLD are the most important selection criteria for the best-suited drug candidates.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The mechanisms by which the gut microbiota promotes liver disease and HCC include dysbiosis that alters bacterial metabolites such as the cancer-promoting secondary bile acid DCA, and a leaky gut that promotes chronic hepatic inflammation through TLR-mediated signals.

    “The mechanisms by which the gut microbiota promotes the development of liver disease and HCC include dysbiosis — which results in altered bacterial metabolites such as the cancer-promoting secondary bile acid DCA — as well as a leaky gut, which promotes chronic hepatic inflammation via TLR-mediated signals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Nonselective β-adrenergic blockers decrease intestinal transit time and reduce intestinal bacterial overgrowth, intestinal permeability and bacterial translocation in experimental cirrhosis and patients.

    “Accordingly, nonselective β-adrenergic blockers decrease intestinal transit time and reduce intestinal bacterial overgrowth, intestinal permeability and bacterial translocation in experimental models of cirrhosis as well as in patients153–157.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [153] Perez-Paramo, M. et al. Effect of propranolol on the factors promoting bacterial translocation in cirrhotic rats with ascites. Hepatology 31, 43–48 (2000). source

      Not checked in the free run.

    • cites [154] Madsen, B. S., Havelund, T. & Krag, A. Targeting the gut-liver axis in cirrhosis: antibiotics and non-selective beta-blockers. Adv. Ther. 30, 659–670 (2013). source

      Not checked in the free run.

    • cites [155] Mookerjee, R. P. et al. Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure. J. Hepatol. 64, 574–582 (2016). source

      Not checked in the free run.

    • cites [156] Senzolo, M. et al. Oral propranolol decreases intestinal permeability in patients with cirrhosis: another protective mechanism against bleeding? Am. J. Gastroenterol. 104, 3115–3116 (2009). source

      Not checked in the free run.

    • cites [157] Senzolo, M. et al. β-blockers protect against spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. Liver Int. 29, 1189–1193 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Current mouse-model data suggest that targeting the gut-liver axis may have a role in primary or secondary HCC prevention but not in HCC treatment.

    “Current data from mouse models suggest that targeting the gut–liver axis has a potential role for the primary or secondary prevention of HCC, but not for the treatment of HCC (Table 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Table 2

      Not checked in the free run.

    • Rests on an assumption: No data currently support targeting the gut–microbiota–liver axis for HCC treatment.
76 of 76

  • The paper relies on this without support.

    Hepatocellular carcinoma almost exclusively develops in patients with chronic liver disease and almost never occurs spontaneously without liver disease.

    “HCC almost exclusively develops in patients with chronic liver disease”
    “HCC is typically the result of chronic disease processes in the liver and almost never occurs spontaneously in the absence of liver disease.”

  • The paper relies on this without support.

    Liver fibrosis is common to all types of advanced chronic liver disease.

    “Liver fibrosis is part of the hepatic wound healing response and common to all types of advanced CLD.”

  • The paper relies on this without support.

    TLR4 is expressed on multiple hepatic cell types, including Kupffer cells, hepatic stellate cells, endothelial cells and hepatocytes.

    “TLR4 is present in multiple hepatic cell types, including Kupffer cells, hepatic stellate cells (HSCs), endothelial cells and hepatocytes.”

  • The paper relies on this without support.

    The multi-layer intestinal barrier normally keeps hepatic exposure to pro-inflammatory microbe-associated molecular patterns minimal.

    “The multi-layer intestinal barrier ensures that hepatic exposure to pro-inflammatory MAMPs is minimal.”

  • The paper relies on this without support.

    No therapeutic options for HCC prevention exist other than treating the underlying liver disease.

    “Currently, there are no therapeutic options for HCC prevention besides treating the underlying disease.”

  • The paper relies on this without support.

    No clinical studies have tested targeting the gut–microbiota–liver axis for HCC prevention.

    “With a complete lack of clinical studies testing this strategy, targeting the gut-microbiota–liver axis represents an exciting and understudied clinical opportunity”

  • The paper relies on this without support.

    No data currently support targeting the gut–microbiota–liver axis for HCC treatment.

    “Although there is accumulating evidence that the gut microbiota modulates responses to chemotherapy100,101 and immunomodulatory therapies102,103, there is currently no data supporting the concept of targeting the gut-microbiota–liver axis for the treatment of HCC.”

  • The paper relies on this without support.

    The effects of norfloxacin on HCC development in patients with liver cirrhosis are unknown.

    “the effects of norfloxacin on HCC development in patients with liver cirrhosis are not known.”

  • The paper relies on this without support.

    The effects of rifaximin on HCC development remain unknown.

    “Despite the large number of patients receiving rifaximin for the prevention of hepatic encephalopathy, the effects of rifaximin on HCC development remain unknown.”

  • The paper relies on this without support.

    Clinically relevant resistance to rifaximin has not been reported.

    “In contrast to norfloxacin, clinically relevant development of resistance to rifaximin has not been reported, suggesting that it is well-suited for long-term or even life-long treatment.”

  • The paper relies on this without support.

    Probiotics have so far been investigated only in murine HCC models, and patient data are lacking.

    “So far, probiotics have only been investigated in murine HCC models and data in patients are lacking (Table 1).”

  • The paper relies on this without support.

    The effects of probiotics on endogenously arising tumours are unknown.

    “However, the effects of probiotics on endogenously arising tumours are not known.”

  • The paper relies on this without support.

    There are several clinical trials of probiotics in chronic liver disease patients but none in HCC patients.

    “To date, there are several clinical trials on probiotics in patients with CLD but none in patients with HCC.”

  • The paper relies on this without support.

    No data currently support the idea that FMT reduces or delays HCC development.

    “However, there are currently no data supporting this premise and a number of hurdles have to be overcome.”

  • The paper relies on this without support.

    None of the TLR4 antagonists have been tested in clinical trials in chronic liver disease or HCC patients.

    “So far, none of these agents have been tested in clinical trials in patients with CLD or HCC.”

  • The paper relies on this without support.

    Bile acids are an important regulator of the gut barrier.

    “Bile acids are an important regulator of the gut barrier.”

  • The paper relies on this without support.

    The long-term benefits of prokinetics such as cisapride in chronic liver disease patients have not been determined.

    “However, the long-term benefits of prokinetics such as cisapride have yet to be determined in patients with CLD (Table 1).”

  • The paper relies on this without support.

    Increased adrenergic activity is one purported mechanism for altered motility in cirrhosis.

    “One of the purported mechanisms for altered motility in cirrhosis is increased adrenergic activity.”

  • The paper relies on this without support.

    Current understanding of the gut microbiota's contribution is largely based on animal models and faecal microbiota samples from patients.

    “Moreover, our current understanding of the contribution of the gut microbiota is largely based on animal models and faecal microbiota samples from patients.”

  • The paper relies on this without support.

    Many key changes in the gut–liver axis occur in the small intestine and possibly within mucosa-adherent microbiota.

    “As many of the key changes in the gut–liver axis occur in the small intestine and possibly also within mucosa-adherent microbiota, better analysis of the human microbiome at different anatomic sites is needed.”

  • The paper relies on this without support.

    Many types of chronic liver disease that confer high HCC risk cannot be perfectly modeled in mice.

    “Finally, many types of CLD that confer a high risk for HCC development cannot be perfectly modeled in mice.”
21 of 21

Claims other papers make about this one

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

  • In the context of chronic liver diseases, there is a significant increase in portal and systemic LPS, owing to dysbiosis and increased gut permeability.

    “However, in the context of chronic liver diseases, there is a significant increase in portal and systemic LPS, owing to dysbiosis and increased gut permeability [61] (Fig. 2).”

    From Gut microbiota-mediated immunomodulation in tumor (2021) · cites this paper as [61]

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.

  • Claim of no evidence for effects on liver-arising tumours conflicts with rat study

    Minor

    The review says the effects of probiotics on tumours arising within the host are unknown, but it earlier reports reduced tumour growth and multiplicity in a rat model of DEN-induced liver cancer. Those tumours arose in the liver rather than being transplanted.

1 of 1

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Related

Authors
Yu, L.-X., & Schwabe, R. F.
Affiliations
Columbia University Irving Medical Center (US)
Corresponding author
Schwabe, Robert F.
ORCID
Venue
Nature Reviews Gastroenterology & Hepatology
Publisher
Springer Science and Business Media LLC
Published
2017-07-05
Volume
14
Issue
9
Pages
527-539
ISSN
  • 1759-5045 (ISSN-L)
  • 1759-5053
DOI
10.1038/nrgastro.2017.72
PMC
PMC6467288
OpenAlex
W2726093206
Cited by
634
References
161
Citations by year
2026: 46 · 2025: 67 · 2024: 71 · 2023: 73 · 2022: 110 · 2021: 110 · 2020: 84 · 2019: 48 · 2018: 24 · 2017: 1
FWCI
4.25
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Reviews Gastroenterology & Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Alcohol Abuse and Alcoholism (U01AA021912)
  • National Cancer Institute (R01CA190844, R01CA200597)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
gut microbiota, hepatocellular carcinoma, chronic liver disease, hepatocarcinogenesis, bacterial dysbiosis, leaky gut, microbe-associated molecular patterns, bacterial metabolites, liver inflammation, liver fibrosis, genotoxicity, microbiota-targeted therapy
MeSH terms
Gastrointestinal Microbiome, Carcinoma, Hepatocellular, Humans, Liver Neoplasms

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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 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

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