The gut microbiome and liver cancer: mechanisms and clinical translation

In the paper

“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.”

What the sources say

• Supported

  The Discussion calls the emergence of quinolone-resistant bacteria during long-term norfloxacin prophylaxis “a problem of major concern.” It also reports a higher proportion of quinolone-resistant spontaneous bacterial peritonitis among patients receiving long-term norfloxacin. The citing authors’ suggestion about limiting treatment duration is their own inference, not part of the claim assessed here. (LLM, conf=0.94)

  cites [110] Fernandez, J. et al. Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis. Hepatology 35, 140–148 (2002). source
• Supported

  The Discussion describes the rapid development of quinolone-resistant bacteria in patients receiving long-term norfloxacin prophylaxis. The Abstract also identifies long-term norfloxacin prophylaxis as independently associated with multiresistant infections. The citing authors’ suggestion about limiting treatment duration is their own inference, not part of the claim assessed here. (LLM, conf=0.92)

  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
• Supported

  The Discussion (page not provided) reports that norfloxacin prophylaxis has been identified as a predictor of antibiotic-resistant bacterial infections in patients with cirrhosis. It also reports higher rates of fluoroquinolone-resistant organisms with prophylaxis and similar findings in this study. The recommendation about how long to use norfloxacin is the citing authors’ inference, not part of the claim attributed to this source. (LLM, conf=0.90)

  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

In the paper

“Accordingly, FXR activation by agonists GW4064 or obeticholic acid (OCA) attenuates mucosal injury, ileal barrier permeability, bacterial overgrowth and bacterial translocation in mice and rats 20,21,141,142.”

What the sources say

• Not checked yetcites [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 yetcites [21] Gadaleta, R. M. et al. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 60, 463–472 (2011). source
• Partly supported

  The section on FXR deactivation and intestinal bacterial translocation reports that obeticholic acid (INT-747) reduced ileal permeability and bacterial translocation in bile-duct-ligated rats. Our copy does not establish that GW4064 had these effects, that they occurred in mice, or that either agonist reduced mucosal injury or bacterial overgrowth; those parts of the broader claim are unsupported by this source. (LLM, conf=0.87)

  cites [141] Verbeke, L. et al. The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats. Am. J. Pathol. 185, 409–419 (2015). sourceExperimental — accuracy not yet measured
• Not checked yetcites [142] Ubeda, M. et al. Obeticholic acid reduces bacterial translocation and inhibits intestinal inflammation in cirrhotic rats. J. Hepatol. 64, 1049–1057 (2016). source

In the paper

“The key contribution of the gut microbiota to early stages of ALD has been firmly established in the past two decades.”

What the sources say

• Not checked yetcites [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

In the paper

“Moreover, there is an increase in bacterial DNA , a well-established TLR9 agonist, in the peripheral blood of patients with CLD29.”

What the sources say

• Not checked yetcites [29] Bellot, P. et al. Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis. Hepatology 52, 2044–2052 (2010). source

In the paper

“Hence, the presence of liver cirrhosis represents the most important unifying risk factor for the development of HCC.”

What the sources say

• Not checked yetcites [37] Cabrera, R. & Nelson, D. R. Review article: the management of hepatocellular carcinoma. Aliment. Pharmacol. Ther. 31, 461–476 (2010). source
• Not checked yetcites [38] El-Serag, H. B. Hepatocellular carcinoma. N. Engl. J. Med. 365, 1118–1127 (2011). source

In the paper

“Likewise, serum LPS levels are increased in patients with chronic alcohol abuse16.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“At the same time, there is decreased abundance of beneficial bacteria in the gut, such as Lachnospiraceae33.”

What the sources say

• Not checked yetcites [33] Chen, Y. et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 54, 562–572 (2011). source

In the paper

“Likewise, chronic alcohol intake increases endotoxin levels in peripheral blood from 2.5 pg/ml in healthy individuals to 14–19 pg/ml in patients with alcoholic liver disease (ALD)25.”

What the sources say

• Not checked yetcites [25] Fukui, H., Brauner, B., Bode, J. C. & Bode, C. Plasma endotoxin concentrations in patients with alcoholic and non-alcoholic liver disease: reevaluation with an improved chromogenic assay. J. Hepatol. 12, 162–169 (1991). source

In the paper

“Moreover, subgroups of patients, such as those with cirrhosis, men, patients >55 years of age, individuals positive for antibodies against hepatitis B core protein (anti-HBc) as well as patients with high cumulative consumption of alcohol, might have extremely high risk development for HCC development, risk that may be >40% in a 10-year period42.”

What the sources say

• Not checked yetcites [42] Joshi, K., Kohli, A., Manch, R. & Gish, R. Alcoholic liver disease: high risk or low risk for developing hepatocellular carcinoma? Clin. Liver Dis. 20, 563–580 (2016). source

In the paper

“Mean portal vein LPS levels increase in chronic liver injury from <3 pg/ml in healthy volunteers to 4.9 pg/ml, 7.9 pg/ml and 10.2 pg/ml in patients with Child–Turcotte-Pugh cirrhosis stage A, B and C, respectively24.”

What the sources say

• Not checked yetcites [24] Lin, R. S. et al. Endotoxemia in patients with chronic liver diseases: relationship to severity of liver diseases, presence of esophageal varices, and hyperdynamic circulation. J. Hepatol. 22, 165–172 (1995). source

In the paper

“The ability of ethanol and its metabolite acetaldehyde to disrupt tight junctions contributes to the high levels of bacterial translocation in ALD43.”

What the sources say

• Not checked yetcites [43] Rao, R. K., Seth, A. & Sheth, P. Recent advances in alcoholic liver disease I. Role of intestinal permeability and endotoxemia in alcoholic liver disease. Am. J. Physiol. Gastrointest. Liver Physiol. 286, G881–G884 (2004). source

In the paper

“Even a single binge of alcohol is sufficient to increase bacterial translocation, as evidenced by an increase of LPS in portal blood rats from undetectable levels to 30–80 pg/ml after ethanol administration 16.”

What the sources say

• Not checked yetcites [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

In the paper

“Thus, alterations in choline metabolism might link dysbiosis to the development of NAFLD.”

In the paper

“Interestingly, dysbiotic microbiota from mice fed a high-fat diet metabolize and convert dietary choline into methylamines, resulting in low circulating levels of plasma phosphatidylcholine60.”

What the sources say

• Not checked yetcites [60] Dumas, M. E. et al. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc. Natl Acad. Sci. USA 103, 12511–12516 (2006). source

In the paper

“There is strong evidence for an important contribution of the microbiota–TLR4 axis to liver fibrosis.”

What the sources say

• Not checked yetcites [71] Luckey, T. D., Reyniers, J. A., Gyorgy, P. & Forbes, M. Germfree animals and liver necrosis. Ann. NY Acad. Sci. 57, 932–935 (1954). source
• Not checked yetcites [72] Rutenburg, A. M. et al. The role of intestinal bacteria in the development of dietary cirrhosis in rats. J. Exp. Med. 106, 1–14 (1957). source
• Not checked yetcites [73] Seki, E. et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat. Med. 13, 1324–1332 (2007). source

In the paper

“High circulating LPS levels in mice and patients with CLD as well as in HCC14,24,77,78 demonstrate the presence of a leaky gut during multiple stages of CLD and hepatocarcinogenesis (FIG. 1).”

What the sources say

• Not checked yetcites [14] Yu, L. X. et al. Endotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents. Hepatology 52, 1322–1333 (2010). source
• Not checked yetcites [24] Lin, R. S. et al. Endotoxemia in patients with chronic liver diseases: relationship to severity of liver diseases, presence of esophageal varices, and hyperdynamic circulation. J. Hepatol. 22, 165–172 (1995). source
• Not checked yetcites [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 yetcites [78] Nolan, J. P. The role of intestinal endotoxin in liver injury: a long and evolving history. Hepatology 52, 1829–1835 (2010). source

In the paper

“As such, germ-free mice display decreased body weight despite increased food intake52.”

What the sources say

• Not checked yetcites [52] Backhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718–15723 (2004). source

In the paper

“Likewise, intestinal permeability is increased in patients with NAFLD63.”

What the sources say

• Not checked yetcites [63] Miele, L. et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 49, 1877–1887 (2009). source

In the paper

“A number of functional studies have shown a key contribution of the gut-microbiota–TLR4 axis to ALD45:”

What the sources say

• Not checked yetcites [45] Szabo, G. Gut-liver axis in alcoholic liver disease. Gastroenterology 148, 30–36 (2015). source

In the paper

“Hence, treatment with antibiotics ameliorates high-fat-diet-induced NAFLD in mice55.”

What the sources say

• Not checked yetcites [55] Jiang, C. et al. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J. Clin. Invest. 125, 386–402 (2015). source

In the paper

“Consistent with previous studies71–73, treatment with nonabsorbable antibiotics resulted in a strong reduction of fibrosis despite increased liver injury13.”

What the sources say

• Not checked yetcites [13] Dapito, D. H. et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21, 504–516 (2012). source

In the paper

“Conversely, fecal microbiota transplantation from healthy mice attenuated steatohepatitis in high fat diet treated mice 66.”

What the sources say

• Not checked yetcites [66] Zhou, D. et al. Total fecal microbiota transplantation alleviates high-fat diet-induced steatohepatitis in mice via beneficial regulation of gut microbiota. Sci. Rep. 7, 1529 (2017). source

In the paper

“Notably, there is a strong correlation between hepatic fibrosis and HCC development with 80–90% of HCCs developing in fibrotic or cirrhotic livers.”

What the sources say

• Not checked yetcites [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

In the paper

“Hence, the gut microbiota might control antiviral responses that affect disease progression and HCC development.”

In the paper

“Studies in knockout mice have highlighted a key role for TLR4 and other important mediators in the TLR4 signalling pathway, such as CD14 and lipopolysaccharide-binding protein (LBP), in experimental models of toxic and cholestatic liver fibrosis73,74.”

What the sources say

• Not checked yetcites [73] Seki, E. et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat. Med. 13, 1324–1332 (2007). source
• Not checked yetcites [74] Isayama, F. et al. LPS signaling enhances hepatic fibrogenesis caused by experimental cholestasis in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G1318–G1328 (2006). source

In the paper

“The gut microbiota also has an important part in promoting HCC development in a mouse model in which HCC is driven by the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) and subsequent high-fat diet15.”

What the sources say

• Not checked yetcites [15] Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013). source

In the paper

“In a model of NASH triggered by high-fat and high-cholesterol diet given to ApoE-deficient mice, TLR4 deficiency reduced hepatic inflammation and injury64.”

What the sources say

• Not checked yetcites [64] Ye, D. et al. Toll-like receptor-4 mediates obesity-induced non-alcoholic steatohepatitis through activation of X-box binding protein-1 in mice. Gut 61, 1058–1067 (2012). source

In the paper

“Notably, HBV titres in patients positively correlate with risk for disease progression and HCC development69.”

What the sources say

• Not checked yetcites [69] Chen, C. J. et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 295, 65–73 (2006). source

In the paper

“Current data suggest that dysbiosis and alterations of the gut–liver axis in patients with end-stage viral hepatitis and cirrhosis are similar to alterations in patients with cirrhosis from other causes67.”

What the sources say

• Not checked yetcites [67] Bajaj, J. S. et al. HCV eradication does not impact gut dysbiosis or systemic inflammation in cirrhotic patients. Aliment. Pharmacol. Ther. 44, 638–643 (2016). source

In the paper

“Accordingly, chronic infusion of low-dose LPS via osmotic pumps promotes HCC development in mice13.”

What the sources say

• Not checked yetcites [13] Dapito, D. H. et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21, 504–516 (2012). source

In the paper

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

In the paper

“Metagenomic studies have revealed substantial alterations in the composition of the gut microbiota in a range of CLD as well as in patients with cirrhosis12,32.”

What the sources say

• Not checked yetcites [12] Schnabl, B. & Brenner, D. A. Interactions between the intestinal microbiome and liver diseases. Gastroenterology 146, 1513–1524 (2014). source
• Not checked yetcites [32] Qin, N. et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 513, 59–64 (2014). source

In the paper

“Experiments in bone-marrow-chimeric mice demonstrated that TLR4 expressed on liver-resident cells (which include hepatocytes, HSCs and Kupffer cells) is responsible for promotion of fibrogenesis and hepatocarcinogenesis13.”

What the sources say

• Not checked yetcites [13] Dapito, D. H. et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21, 504–516 (2012). source

In the paper

“The key role of DCA in hepatocarcinogenesis was further demonstrated in experiments that showed increased HCC development in mice after supplementing diets with DCA, and decreased HCC formation after inhibition of 7α-dehydroxylation15.”

What the sources say

• Not checked yetcites [15] Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013). source

In the paper

“Functional studies utilizing co-housing and faecal transplantation have provided evidence that dysbiosis is a transmissible driver of liver disease development and progression 65,89.”

What the sources say

• Not checked yetcites [65] Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012). source
• Not checked yetcites [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

In the paper

“The key role of DCA in hepatocarcinogenesis was further demonstrated in experiments that showed increased HCC development in mice after supplementing diets with DCA, and decreased HCC formation after inhibition of 7α-dehydroxylation15.”

What the sources say

• Not checked yetcites [15] Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013). source

In the paper

“In HSCs, TLR4 activation leads to an NF-κB-mediated upregulation of the hepatomitogen epiregulin13.”

What the sources say

• Not checked yetcites [13] Dapito, D. H. et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21, 504–516 (2012). source

In the paper

“Together, these data clearly show that the leaky gut, via MAMP–TLR-mediated signals, contributes to hepatocarcinogenesis.”

In the paper

“As such, HCC development induced by the combination of DEN and CCl4 was attenuated in gut-sterilized and germ-free mice compared with their specific pathogen-free counterparts13.”

What the sources say

• Not checked yetcites [13] Dapito, D. H. et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21, 504–516 (2012). source

In the paper

“Conversely, inhibition of TLR4 signalling suppresses liver inflammation, fibrosis and HCC formation in mice and rats13,14,73.”

What the sources say

• Not checked yetcites [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 yetcites [14] Yu, L. X. et al. Endotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents. Hepatology 52, 1322–1333 (2010). source
• Not checked yetcites [73] Seki, E. et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat. Med. 13, 1324–1332 (2007). source

In the paper

“Moreover, it has been demonstrated that activation of the LPS–TLR4 signalling pathway in Kupffer cells leads to TNF- and IL6-dependent compensatory hepatocyte proliferation as well as reduced oxidative stress and apoptosis14.”

What the sources say

• Not checked yetcites [14] Yu, L. X. et al. Endotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents. Hepatology 52, 1322–1333 (2010). source

In the paper

“The key role of DCA in hepatocarcinogenesis was further demonstrated in experiments that showed increased HCC development in mice after supplementing diets with DCA, and decreased HCC formation after inhibition of 7α-dehydroxylation15.”

What the sources say

• Not checked yetcites [15] Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013). source

In the paper

“Accordingly, epiregulin-deficient mice displayed reduced hepatocarcinogenesis when treated with DEN+CCl413.”

What the sources say

• Not checked yetcites [13] Dapito, D. H. et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21, 504–516 (2012). source

In the paper

“In concert with TLR2 agonist lipoteichoic acid, DCA promoted a senescence-associated secretory phenotype in hepatic stellate cells, which in turn suppressed anti-tumor immunity through a prostaglandin E2-dependent mechanisms90.”

What the sources say

• Not checked yetcites [90] Loo, T. M. et al. Gut microbiota promotes obesity-associated liver cancer through PGE2-mediated suppression of antitumor immunity. Cancer Discov. 7, 522–538 (2017). source

In the paper

“and might provide a link between dysbiosis and alterations of the intestinal barrier that lead to a leaky gut and increased risk for HCC development, as discussed above.”

In the paper

“At the same time, this treatment led to increased serum levels of deoxycholic acid (DCA), a secondary bile acid whose production depends on 7α-dehydroxylation of primary bile acids by the bacterial microbiota, notably Clostridium clusters.”

What the sources say

• Not checked yetcites [15] Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013). source

In the paper

“Accordingly, expression of the apoptosis marker cleaved caspase 3 in TLR4-deficient and gut-sterilized mice is inversely correlated with the formation of tumours13.”

What the sources say

• Not checked yetcites [13] Dapito, D. H. et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21, 504–516 (2012). source

In the paper

“Similarly, dysbiosis represented a transmissible risk factor in a genetic NASH model in which NASH was triggered by inflammasome deficiency; co-housing of dysbiotic inflammasome-deficient mice with control mice resulted in the development of NASH in control mice65.”

What the sources say

• Not checked yetcites [65] Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012). source

In the paper

“In concert with TLR2 agonist lipoteichoic acid, DCA promoted a senescence-associated secretory phenotype in hepatic stellate cells, which in turn suppressed anti-tumor immunity through a prostaglandin E2-dependent mechanisms90.”

What the sources say

• Not checked yetcites [90] Loo, T. M. et al. Gut microbiota promotes obesity-associated liver cancer through PGE2-mediated suppression of antitumor immunity. Cancer Discov. 7, 522–538 (2017). source

In the paper

“In a mouse model of NASH-induced HCC, triggered by the combination of DMBA and high-fat diet, there was a strong increase in Gram-positive bacterial strains, in particular of specific Clostridium clusters15.”

What the sources say

• Not checked yetcites [15] Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013). source

In the paper

“Another key mechanism by which the LPS–TLR4 axis promotes HCC formation is via NF-κB-mediated prevention of hepatocyte apoptosis.”

In the paper

“Together, these studies link bacterial dysbiosis to altered immune responses via bacterial metabolites and MAMPs.”

In the paper

“At the same time, this treatment led to increased serum levels of deoxycholic acid (DCA), a secondary bile acid whose production depends on 7α-dehydroxylation of primary bile acids by the bacterial microbiota, notably Clostridium clusters.”

What the sources say

• Not checked yetcites [15] Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013). source

In the paper

“In addition to alterations in bacterial composition, there is evidence for bacterial overgrowth in the upper gastrointestinal tract, which in turn is associated with increased circulating LPS levels 87.”

What the sources say

• Not checked yetcites [87] Bauer, T. M. et al. Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxemia. Am. J. Gastroenterol. 97, 2364–2370 (2002). source

In the paper

“Increasing evidence supports a key role for dysbiosis in the development of CLD and HCC (FIG. 1).”

In the paper

“However, a recent small-scale study described differences in the gut microbiota between different types of underlying liver disease86.”

What the sources say

• Not checked yetcites [86] Chen, Y. et al. Dysbiosis of small intestinal microbiota in liver cirrhosis and its association with etiology. Sci. Rep. 6, 34055 (2016). source

In the paper

“Therefore, the use of single antibiotics with a high safety profile in patients with CLD represents the only clinically feasible approach.”

In the paper

“Because antibiotics target several pathways through which the gut microbiota promote HCC development (Table 1), they could represent one of the most efficient strategies to interrupt the tumor-promoting gut liver axis in CLD”

What the sources say

• Not checked yetcites Table 1

In the paper

“Similar to norfloxacin, rifaximin has been noted to increased survival in patients with advanced liver cirrhosis in several small-scale trials92–95.”

What the sources say

• Not checked yetcites [92] Fernandez, J. et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology 133, 818–824 (2007). source
• Not checked yetcites [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 yetcites [94] Elfert, A., Abo Ali, L., Soliman, S., Ibrahim, S. & Abd-Elsalam, S. Randomized-controlled trial of rifaximin versus norfloxacin for secondary prophylaxis of spontaneous bacterial peritonitis. Eur. J. Gastroenterol. Hepatol. 28, 1450–1454 (2016). source
• Not checked yetcites [95] Sharma, B. C. et al. A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am. J. Gastroenterol. 108, 1458–1463 (2013). source

In the paper

“Clinical trials in patients with advanced cirrhosis have shown that long-term use of orally administered norfloxacin is safe, produces a marked reduction of gram-negative bacteria in the faecal microbiota109, reduces the 1-year probability of developing spontaneous bacterial peritonitis and hepatorenal syndrome and improves 3-month survival92.”

What the sources say

• Not checked yetcites [109] Gines, P. et al. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial. Hepatology 12, 716–724 (1990). source
• Not checked yetcites [92] Fernandez, J. et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology 133, 818–824 (2007). source

In the paper

“supported by a large number of studies preclinical studies showing a drastic (≈80%) reduction of HCC development in murine models13–15.”

What the sources say

• Not checked yetcites [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 yetcites [14] Yu, L. X. et al. Endotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents. Hepatology 52, 1322–1333 (2010). source
• Not checked yetcites [15] Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013). source

In the paper

“Moreover, this antibiotic cocktail also reduced liver fibrosis 73, which often precedes HCC and represents a risk factor for HCC development in CLD70.”

What the sources say

• Not checked yetcites [73] Seki, E. et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat. Med. 13, 1324–1332 (2007). source

In the paper

“Moreover, several small-scale clinical studies have suggested that antibiotics such as norfloxacin and rifaximin increase survival in patients with liver cirrhosis92–95.”

What the sources say

• Not checked yetcites [92] Fernandez, J. et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology 133, 818–824 (2007). source
• Not checked yetcites [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 yetcites [94] Elfert, A., Abo Ali, L., Soliman, S., Ibrahim, S. & Abd-Elsalam, S. Randomized-controlled trial of rifaximin versus norfloxacin for secondary prophylaxis of spontaneous bacterial peritonitis. Eur. J. Gastroenterol. Hepatol. 28, 1450–1454 (2016). source
• Not checked yetcites [95] Sharma, B. C. et al. A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am. J. Gastroenterol. 108, 1458–1463 (2013). source

In the paper

“Clinical trials in patients with advanced cirrhosis have shown that long-term use of orally administered norfloxacin is safe, produces a marked reduction of gram-negative bacteria in the faecal microbiota109, reduces the 1-year probability of developing spontaneous bacterial peritonitis and hepatorenal syndrome and improves 3-month survival92.”

What the sources say

• Not checked yetcites [92] Fernandez, J. et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology 133, 818–824 (2007). source

In the paper

“Clinical trials in patients with advanced cirrhosis have shown that long-term use of orally administered norfloxacin is safe, produces a marked reduction of gram-negative bacteria in the faecal microbiota109, reduces the 1-year probability of developing spontaneous bacterial peritonitis and hepatorenal syndrome and improves 3-month survival92.”

What the sources say

• Not checked yetcites [109] Gines, P. et al. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial. Hepatology 12, 716–724 (1990). source

In the paper

“Of note, administration of antibiotics at late stages of carcinogenesis, when microscopic tumours already existed, was more efficient at reducing HCC in mice than administration at earlier stages13.”

What the sources say

• Not checked yetcites [13] Dapito, D. H. et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21, 504–516 (2012). source

In the paper

“preventative strategies that target the gut–liver axis seem most promising in patients with cirrhosis and at high risk for HCC development”

In the paper

“Moreover, targeting the gut microbiota-liver axis is unlikely to have a major effect on patients in which the gut–liver axis is not a dominant driver of disease progression, HCC development and mortality, for example those with perinatal HBV infection, high HBV titres and minimal liver fibrosis.”

In the paper

“Continuous gut sterilization by a cocktail of oral antibiotics, consisting of ampicillin, neomycin, metronidazole and vancomycin, effectively reduced the number and size of HCC induced by DEN+CCl4 or DMBA+HFD in mice13,15.”

What the sources say

• Not checked yetcites [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 yetcites [15] Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013). source

In the paper

“Clinical trials in patients with advanced cirrhosis have shown that long-term use of orally administered norfloxacin is safe, produces a marked reduction of gram-negative bacteria in the faecal microbiota109, reduces the 1-year probability of developing spontaneous bacterial peritonitis and hepatorenal syndrome and improves 3-month survival92.”

What the sources say

• Not checked yetcites [92] Fernandez, J. et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology 133, 818–824 (2007). source

In the paper

“Vancomycin, another antibiotic that has shown effectiveness as monotherapy in the prevention of HCC in the combined DMBA and high-fat diet mouse model15, is rarely used for long-term therapy in patients and may cause a number of potentially severe adverse effects.”

What the sources say

• Not checked yetcites [15] Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013). source

In the paper

“Moreover, HCC prevention with antibiotics would require long-term, possibly life-long administration.”

In the paper

“At the same time, selective antibiotics might also block the production of HCC-promoting bacterial metabolites, such as DCA15, by reducing the number of bacteria that produce specific metabolites.”

What the sources say

• Not checked yetcites [15] Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013). source

In the paper

“These data support the concept that HCC prevention by antibiotic treatment could be applied even at late stages, i.e. in patients with advanced cirrhosis and high risk for HCC development.”

In the paper

“On the basis of its important contribution to CLD progression and hepatocarcinogenesis in particular, the gut-microbiota–liver axis represents a promising target for preventative approaches (FIG. 1).”

In the paper

“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.”

In the paper

“Norfloxacin, a poorly absorbed quinolone, is currently one of the drugs of choice for the primary or secondary prophylaxis of spontaneous bacterial peritonitis and infections in high-risk patients with cirrhosis 108.”

What the sources say

• Not checked yetcites [108] Jalan, R. et al. Bacterial infections in cirrhosis: a position statement based on the EASL Special Conference 2013. J. Hepatol. 60, 1310–1324 (2014). source

In the paper

“Notably, these effects are attenuated after oral administration of bile acids in different experimental cirrhotic models20,134,135.”

What the sources say

• Not checked yetcites [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 yetcites [134] Lorenzo-Zuniga, V. et al. Oral bile acids reduce bacterial overgrowth, bacterial translocation, and endotoxemia in cirrhotic rats. Hepatology 37, 551–557 (2003). source
• Not checked yetcites [135] Ding, J. W., Andersson, R., Soltesz, V., Willen, R. & Bengmark, S. The role of bile and bile acids in bacterial translocation in obstructive jaundice in rats. Eur. Surg. Res. 25, 11–19 (1993). source

In the paper

“Increased production of TNF by monocytes in mesenteric lymph nodes constitutes one of the main factors increasing tight junction permeability145,146.”

What the sources say

• Not checked yetcites [145] Munoz, L. et al. Mesenteric Th1 polarization and monocyte TNF-alpha production: first steps to systemic inflammation in rats with cirrhosis. Hepatology 42, 411–419 (2005). source
• Not checked yetcites [146] Genesca, J. et al. Increased tumour necrosis factor alpha production in mesenteric lymph nodes of cirrhotic patients with ascites. Gut 52, 1054–1059 (2003). source

In the paper

“Currently, FMT is being evaluated in clinical trials for a number of additional diseases including NASH124 and cirrhosis125.”

What the sources say

• Not checked yetcites [124] US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02496390 (2016).
• Not checked yetcites [125] US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02862249 (2016).

In the paper

“targeting the gut barrier seems an attractive therapeutic approach (Table 1) that might avoid some of the complications of targeting the microbiota (such as development of resistance and/or decreased microbial diversity) or receptors that mediate the disease-promoting effects of a leaky gut (such as immunosuppression resulting from TLR4 antagonism.”

What the sources say

• Not checked yetcites Table 1

In the paper

“Although a large number of studies have demonstrated the effectiveness of probiotics in treating liver diseases both in animal models and in patients (reviewed elsewhere118,119), substantial controversy remains”

What the sources say

• Not checked yetcites [118] Natividad, J. M. & Verdu, E. F. Modulation of intestinal barrier by intestinal microbiota: pathological and therapeutic implications. Pharmacol. Res. 69, 42–51 (2013). source
• Not checked yetcites [119] Cesaro, C. et al. Gut microbiota and probiotics in chronic liver diseases. Dig. Liver Dis. 43, 431–438 (2011). source

In the paper

“Many of the hepatic effects of FXR activation are mediated by intestinal FXR receptors, resulting in the release of FGF19, which then acts on targets in the liver136–139.”

What the sources say

• Not checked yetcites [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 yetcites [137] Thomas, C., Pellicciari, R., Pruzanski, M., Auwerx, J. & Schoonjans, K. Targeting bile-acid signalling for metabolic diseases. Nat. Rev. Drug Discov. 7, 678–693 (2008). source
• Not checked yetcites [138] Degirolamo, C. et al. Prevention of spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice by intestinal-specific farnesoid X receptor reactivation. Hepatology 61, 161–170 (2015). source
• Not checked yetcites [139] Marschall, H.-U. et al. The farnesoid X receptor (FXR) agonist (OCA) increases plasma FGF-19 concentrations and decreases bile acid synthesis in primary biliary cirrhosis (PBC). J. Hepatol. 56, S377 (2012). source

In the paper

“Moreover, OCA improves portal hypertension (which might contribute to bacterial translocation in cirrhosis) in thioacetamide- or bile duct ligation-treated rats143.”

What the sources say

• Not checked yetcites [143] Verbeke, L. et al. Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology 59, 2286–2298 (2014). source

In the paper

“On the basis of these findings, blocking the TLR4 pathway might represent another avenue for HCC prevention (Table 1).”

What the sources say

• Not checked yetcites Table 1

In the paper

“Another randomized trial showed that 4-month supplementation with VSL#3 improves NAFLD in children122.”

What the sources say

• Not checked yetcites [122] Alisi, A. et al. Randomised clinical trial: the beneficial effects of VSL#3 in obese children with non-alcoholic steatohepatitis. Aliment. Pharmacol. Ther. 39, 1276–1285 (2014). source

In the paper

“Several studies have shown a key role for the TLR4 pathway as a mediator of the disease-promoting effects of the gut–liver axis in CLD and hepatocarcinogenesis13,14,73.”

What the sources say

• Not checked yetcites [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 yetcites [14] Yu, L. X. et al. Endotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents. Hepatology 52, 1322–1333 (2010). source
• Not checked yetcites [73] Seki, E. et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat. Med. 13, 1324–1332 (2007). source

In the paper

“A randomized controlled trial demonstrated amelioration of hepatic and peripheral insulin resistance in patients with metabolic syndrome who had received microbiota from lean donors126.”

What the sources say

• Not checked yetcites [126] Vrieze, A. et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 143, 913–916.e7 (2012). source

In the paper

“Decreased bile secretion in rodents by either ligation of the common bile duct or induction of cirrhosis contributes to bacterial translocation, which is not only caused by intestinal bacterial overgrowth but also by increased gut permeability20,28,134.”

What the sources say

• Not checked yetcites [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 yetcites [28] 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 (2012). source
• Not checked yetcites [134] Lorenzo-Zuniga, V. et al. Oral bile acids reduce bacterial overgrowth, bacterial translocation, and endotoxemia in cirrhotic rats. Hepatology 37, 551–557 (2003). source

In the paper

“On the basis that the leaky gut is a major driver of liver disease progression and HCC development (FIG. 1), targeting the gut barrier seems an attractive therapeutic approach (Table 1)”

What the sources say

• Not checked yetcites FIG. 1

In the paper

“Another factor that contributes to intestinal bacteria overgrowth in liver cirrhosis is gut dysmotility149.”

What the sources say

• Not checked yetcites [149] Kalaitzakis, E. Gastrointestinal dysfunction in liver cirrhosis. World J. Gastroenterol. 20, 14686–14695 (2014). source

In the paper

“Owing to these adverse effects, long-term anti-TNF therapy might confer more harm than benefit, and further efforts need to be made to develop therapies that act locally to improve gut barrier function without negatively affecting systemic immune responses.”

In the paper

“Interestingly, a retrospective long-term observational study suggests that propranolol treatment might decrease HCC occurrence in patients with HCV cirrhosis158, suggesting a potential role for HCC prevention.”

What the sources say

• Not checked yetcites [158] Nkontchou, G. et al. Effect of long-term propranolol treatment on hepatocellular carcinoma incidence in patients with HCV-associated cirrhosis. Cancer Prev. Res. (Phila.) 5, 1007–1014 (2012). source

In the paper

“Overwhelming evidence from the past three decades support a key contribution of the gut microbiota to multiple aspects of liver disease progression, thereby contributing to a hepatic environment that promotes that development and progression of HCC.”

In the paper

“TNF increases tight junction permeability by decreasing expression of tight junction proteins as well as by activating myosin light chain kinase (MLCK)147.”

What the sources say

• Not checked yetcites [147] Taylor, C. T., Dzus, A. L. & Colgan, S. P. Autocrine regulation of epithelial permeability by hypoxia: role for polarized release of tumor necrosis factor alpha. Gastroenterology 114, 657–668 (1998). source

In the paper

“Treatment with an anti-TNF monoclonal antibody decreases the incidence of bacterial translocation in experimental cirrhosis in rats148.”

What the sources say

• Not checked yetcites [148] Frances, R. et al. Bacterial translocation is downregulated by anti-TNF-alpha monoclonal antibody administration in rats with cirrhosis and ascites. J. Hepatol. 46, 797–803 (2007). source