The gut microbiome and liver cancer: mechanisms and clinical translation

In the paper

“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.”

What the sources say

• Not checked yetcites [38] El-Serag, H. B. Hepatocellular carcinoma. N. Engl. J. Med. 365, 1118–1127 (2011). source
• Not checked yetcites [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
• Not checked yetcites [40] Singal, A. G. & El-Serag, H. B. Hepatocellular carcinoma from epidemiology to prevention: translating knowledge into practice. Clin. Gastroenterol. Hepatol. 13, 2140–2151 (2015). source

In the paper

“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.”

What the sources say

• Not checked yetcites [32] Qin, N. et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 513, 59–64 (2014). source
• 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, 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.”

What the sources say

• Not checked yetcites [35] Mouzaki, M. et al. Bile acids and dysbiosis in non-alcoholic fatty liver disease. PLoS ONE 11, e0151829 (2016). source
• Not checked yetcites [36] Boursier, J. et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 63, 764–775 (2016). source
• 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
• Not checked yetcites [31] Wiest, R. & Garcia-Tsao, G. Bacterial translocation (BT) in cirrhosis. Hepatology 41, 422–433 (2005). source

In the paper

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

What the sources say

• Not checked yetcites [44] Chen, P. et al. Supplementation of saturated long-chain fatty acids maintains intestinal eubiosis and reduces ethanol-induced liver injury in mice. Gastroenterology 148, 203–214.e16 (2015). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [26] Parlesak, A., Schafer, C., Schutz, T., Bode, J. C. & Bode, C. Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-induced liver disease. J. Hepatol. 32, 742–747 (2000). source
• Not checked yetcites [27] Yan, A. W. et al. Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology 53, 96–105 (2011). 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

In the paper

“These changes seem to develop progressively, as cirrhosis stage is positively correlated with Enterobacteriaceae and negatively correlated with Lachnospiraceae33,34.”

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
• Not checked yetcites [34] Bajaj, J. S., Betrapally, N. S. & Gillevet, P. M. Decompensated cirrhosis and microbiome interpretation. Nature 525, E1–E2 (2015). source

In the paper

“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.”

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 [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

“These pro-inflammatory mediators not only promote the development of CLD but also set the stage for the development of HCC13–15.”

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

“ALD contributes to about half of all cirrhosis cases41 and is a cofactor in liver disease induced by HBV, HCV and NASH.”

What the sources say

• Not checked yetcites [41] Gao, B. & Bataller, R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 141, 1572–1585 (2011). source

In the paper

“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.”

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

“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.”

What the sources say

• Not checked yetcites [51] Michelotti, G. A., Machado, M. V. & Diehl, A. M. NAFLD, NASH and liver cancer. Nat. Rev. Gastroenterol. Hepatol. 10, 656–665 (2013). source

In the paper

“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.”

What the sources say

• Not checked yetcites [36] Boursier, J. et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 63, 764–775 (2016). source
• Not checked yetcites [56] Zhu, L. et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 57, 601–609 (2013). source
• Not checked yetcites [57] Del Chierico, F. et al. Gut microbiota profiling of pediatric NAFLD and obese patients unveiled by an integrated meta-omics based approach. Hepatology 65, 451–464 (2016). source
• Not checked yetcites [58] Mouzaki, M. et al. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology 58, 120–127 (2013). source
• Not checked yetcites [59] Leung, C., Rivera, L., Furness, J. B. & Angus, P. W. The role of the gut microbiota in NAFLD. Nat. Rev. Gastroenterol. Hepatol. 13, 412–425 (2016). source

In the paper

“These low levels of phosphatidylcholine impaired secretion of VLDL, thereby reducing hepatic lipid export and contributing to fatty liver61.”

What the sources say

• Not checked yetcites [61] Jiang, X. C. et al. Phospholipid transfer protein deficiency impairs apolipoprotein-B secretion from hepatocytes by stimulating a proteolytic pathway through a relative deficiency of vitamin E and an increase in intracellular oxidants. J. Biol. Chem. 280, 18336–18340 (2005). source

In the paper

“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.”

What the sources say

• Not checked yetcites [53] Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006). source
• Not checked yetcites [54] Turnbaugh, P. J. et al. A core gut microbiome in obese and lean twins. Nature 457, 480–484 (2009). source

In the paper

“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.”

What the sources say

• Not checked yetcites [50] Siu, L., Foont, J. & Wands, J. R. Hepatitis C virus and alcohol. Semin. Liver Dis. 29, 188–199 (2009). source

In the paper

“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.”

What the sources say

• Not checked yetcites [75] Mazagova, M. et al. Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice. FASEB J. 29, 1043–1055 (2015). source
• Not checked yetcites [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

In the paper

“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.”

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 [75] Mazagova, M. et al. Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice. FASEB J. 29, 1043–1055 (2015). source
• Not checked yetcites [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

In the paper

“Global TLR4 deficiency in mice as well as gut sterilization with nonabsorbable antibiotics in rats reduces hepatic steatosis, oxidative stress and inflammation46–48.”

What the sources say

• Not checked yetcites [46] Uesugi, T., Froh, M., Arteel, G. E., Bradford, B. U. & Thurman, R. G. Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice. Hepatology 34, 101–108 (2001). source
• Not checked yetcites [47] Hritz, I. et al. The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88. Hepatology 48, 1224–1231 (2008). source
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [49] Machida, K. et al. Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog. Proc. Natl Acad. Sci. USA 106, 1548–1553 (2009). source

In the paper

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

What the sources say

• Not checked yetcites [62] Cani, P. D. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772 (2007). source

In the paper

“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.”

What the sources say

• Not checked yetcites [68] Chou, H. H. et al. Age-related immune clearance of hepatitis B virus infection requires the establishment of gut microbiota. Proc. Natl Acad. Sci. USA 112, 2175–2180 (2015). source

In the paper

“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.”

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 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.”

What the sources say

• Not checked yetcites [51] Michelotti, G. A., Machado, M. V. & Diehl, A. M. NAFLD, NASH and liver cancer. Nat. Rev. Gastroenterol. Hepatol. 10, 656–665 (2013). source

In the paper

“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.”

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

“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.”

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

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

What the sources say

• Not checked yetcites [82] Toyoda, H. et al. Epiregulin. A novel epidermal growth factor with mitogenic activity for rat primary hepatocytes. J. Biol. Chem. 270, 7495–7500 (1995). source

In the paper

“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.”

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
• Not checked yetcites [88] Bajaj, J. S. et al. Salivary microbiota reflects changes in gut microbiota in cirrhosis with hepatic encephalopathy. Hepatology 62, 1260–1271 (2015). source

In the paper

“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.”

What the sources say

• Not checked yetcites [34] Bajaj, J. S., Betrapally, N. S. & Gillevet, P. M. Decompensated cirrhosis and microbiome interpretation. Nature 525, E1–E2 (2015). source

In the paper

“In addition, TLR4 activation in HCC cell lines by LPS enhances their invasive potential and induces the epithelial–mesenchymal transition83.”

What the sources say

• Not checked yetcites [83] Jing, Y. Y. et al. Toll-like receptor 4 signaling promotes epithelial-mesenchymal transition in human hepatocellular carcinoma induced by lipopolysaccharide. BMC Med. 10, 98 (2012). source

In the paper

“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.”

What the sources say

• 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

“As such, perturbation of the gut eubiosis by penicillin increased HCC formation in rats77, which could be suppressed by probiotics77.”

What the sources say

• 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

In the paper

“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.”

What the sources say

• 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

“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.”

In the paper

“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.”

In the paper

“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.”

What the sources say

• 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

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [32] Qin, N. et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 513, 59–64 (2014). source
• Not checked yetcites [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 yetcites [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

In the paper

“One example is the production of short-chain fatty acids (SCFAs), which are a primary energy source for intestinal epithelial cells91”

What the sources say

• Not checked yetcites [91] Lee, W. J. & Hase, K. Gut microbiota-generated metabolites in animal health and disease. Nat. Chem. Biol. 10, 416–424 (2014). source

In the paper

“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.”

In the paper

“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.”

In the paper

“and spontaneous bacterial peritonitis98 and hepatic encephalopathy99 in patients.”

What the sources say

• Not checked yetcites [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 yetcites [99] Bass, N. M. et al. Rifaximin treatment in hepatic encephalopathy. N. Engl. J. Med. 362, 1071–1081 (2010). source

In the paper

“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.”

What the sources say

• 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 [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 yetcites [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

In the paper

“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.”

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 [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

In the paper

“targeting the gut-microbiota–liver axis has been shown to reduce liver fibrosis 73,96 and portal hypertension97 in rodents”

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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [117] Membrez, M. et al. Gut microbiota modulation with norfloxacin and ampicillin enhances glucose tolerance in mice. FASEB J. 22, 2416–2426 (2008). source

In the paper

“Of note, rifaximin reduces HCC development in the DEN–CCl4 model of HCC, albeit less efficiently than the quadruple antibiotics cocktail described above13.”

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

“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 [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

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [113] Koo, H. L. & DuPont, H. L. Rifaximin: a unique gastrointestinal-selective antibiotic for enteric diseases. Curr. Opin. Gastroenterol. 26, 17–25 (2010). source

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

• Not checked yetcites [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 yetcites [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 yetcites [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

“Eritoran130 and resatorvid131 improved survival in animal models of sepsis, but did not reduce mortality in patients with severe sepsis132,133.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

In the paper

“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”

What the sources say

• 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

In the paper

“The possible mechanisms of action include modulation of the host microbiota123, improvement of gut barrier function and modulation of the immune system.”

What the sources say

• Not checked yetcites [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

In the paper

“Fxr-deficient mice exhibit compromised intestinal integrity, with further deterioration after bile duct ligation20, and a high incidence of HCC140.”

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

In the paper

“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.”

What the sources say

• Not checked yetcites [18] van Nood, E. et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl. J. Med. 368, 407–415 (2013). source

In the paper

“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).”

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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [18] van Nood, E. et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl. J. Med. 368, 407–415 (2013). source

In the paper

“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.”

In the paper

“Malnutrition is common in patients with CLD and is associated with increased morbidity and mortality (reviewed elsewhere149).”

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

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

In the paper

“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.”

In the paper

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

In the paper

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

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“Of note, malnutrition increases intestinal permeability and facilitates bacterial translocation159.”

What the sources say

• Not checked yetcites [159] De Santis, S., Cavalcanti, E., Mastronardi, M., Jirillo, E. & Chieppa, M. Nutritional keys for intestinal barrier modulation. Front. Immunol. 6, 612 (2015). source

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites Table 2