Dysregulated Microbial Fermentation of Soluble Fiber Induces Cholestatic Liver Cancer.

Dietary soluble fibers are fermented by gut bacteria into short-chain fatty acids (SCFA), which are considered broadly health-promoting. Accordingly, consumption of such fibers ameliorates metabolic syndrome. However, incorporating soluble fiber inulin, but not insoluble fiber, into a compositionally defined diet, induced icteric hepatocellular carcinoma (HCC). Such HCC was microbiota-dependent and observed in multiple strains of dysbiotic mice but not in germ-free nor antibiotics-treated mice. Furthermore, consumption of an inulin-enriched high-fat diet induced both dysbiosis and HCC in wild-type (WT) mice. Inulin-induced HCC progressed via early onset of cholestasis, hepatocyte death, followed by neutrophilic inflammation in liver. Pharmacologic inhibition of fermentation or depletion of fermenting bacteria markedly reduced intestinal SCFA and prevented HCC. Intervening with cholestyramine to prevent reabsorption of bile acids also conferred protection against such HCC. Thus, its benefits notwithstanding, enrichment of foods with fermentable fiber should be approached with great caution as it may increase risk of HCC.

Dynamic changes of gut microbiota in mouse models of metabolic dysfunction-associated steatohepatitis and its transition to hepatocellular carcinoma.

Dysbiosis of gut microbiota may account for pathobiology in simple fatty liver (SFL), metabolic dysfunction-associated steatohepatitis (MASH), fibrotic progression, and transformation to MASH-associated hepatocellular carcinoma (MASH-HCC). The aim of the present study is to investigate gut dysbiosis in this progression. Fecal microbial rRNA-16S sequencing, absolute quantification, histopathologic, and biochemical tests were performed in mice fed high fat/calorie diet plus high fructose and glucose in drinking water (HFCD-HF/G) or control diet (CD) for 2, 16 weeks, or 14 months. Histopathologic examination verified an early stage of SFL, MASH, fibrotic, or MASH-HCC progression with disturbance of lipid metabolism, liver injury, and impaired gut mucosal barrier as indicated by loss of occludin in ileum mucosa. Gut dysbiosis occurred as early as 2 weeks with reduced α diversity, expansion of Kineothrix, Lactococcus, Akkermansia; and shrinkage in Bifidobacterium, Lactobacillus, etc., at a genus level. Dysbiosis was found as early as MAHS initiation, and was much more profound through the MASH-fibrotic and oncogenic progression. Moreover, the expansion of specific species, such as Lactobacillus johnsonii and Kineothrix alysoides, was confirmed by an optimized method for absolute quantification. Dynamic alterations of gut microbiota were characterized in three stages of early SFL, MASH, and its HCC transformation. The findings suggest that the extent of dysbiosis was accompanied with MASH progression and its transformation to HCC, and the shrinking or emerging of specific microbial species may account at least in part for pathologic, metabolic, and immunologic alterations in fibrogenic progression and malignant transition in the liver.

Defining the temporal evolution of gut dysbiosis and inflammatory responses leading to hepatocellular carcinoma in Mdr2 -/- mouse model.

BACKGROUND: Emerging evidence implicates the gut microbiome in liver inflammation and hepatocellular carcinoma (HCC) development. We aimed to characterize the temporal evolution of gut dysbiosis, in relation to the phenotype of systemic and hepatic inflammatory responses leading to HCC development. In the present study, Mdr2 -/- mice were used as a model of inflammation-based HCC. Gut microbiome composition and function, in addition to serum LPS, serum cytokines/chemokines and intrahepatic inflammatory genes were measured throughout the course of liver injury until HCC development. RESULTS: Early stages of liver injury, inflammation and cirrhosis, were characterized by dysbiosis. Microbiome functional pathways pertaining to gut barrier dysfunction were enriched during the initial phase of liver inflammation and cirrhosis, whilst those supporting lipopolysaccharide (LPS) biosynthesis increased as cirrhosis and HCC ensued. In parallel, serum LPS progressively increased during the course of liver injury, corresponding to a shift towards a systemic Th1/Th17 proinflammatory phenotype. Alongside, the intrahepatic inflammatory gene profile transitioned from a proinflammatory phenotype in the initial phases of liver injury to an immunosuppressed one in HCC. In established HCC, a switch in microbiome function from carbohydrate to amino acid metabolism occurred. CONCLUSION: In Mdr2 -/- mice, dysbiosis precedes HCC development, with temporal evolution of microbiome function to support gut barrier dysfunction, LPS biosynthesis, and redirection of energy source utilization. A corresponding shift in systemic and intrahepatic inflammatory responses occurred supporting HCC development. These findings support the notion that gut based therapeutic interventions could be beneficial early in the course of liver disease to halt HCC development.

Lenvatinib for Hepatocellular Carcinoma Patients with Nonviral Infection Who Were Unlikely to Respond to Immunotherapy: A Retrospective, Comparative Study.

AIM: Atezolizumab plus bevacizumab (atezo + bev) shows a good overall survival (OS) in advanced hepatocellular carcinoma (HCC) patients. However, the OS of patients with nonviral infection is quite worse than that in those with viral infection. The present study investigated the efficacy and safety of lenvatinib in patients with nonviral infection, who were unlikely to obtain benefit from atezo + bev. METHODS: We conducted a multicenter retrospective study that included 139 advanced HCC patients treated with lenvatinib between March 2018 and September 2020. RESULTS: The median age was 72 years, and 116 patients (83.5%) were male. Based on the etiology of liver disease, 84 (60.4%) and 55 patients (39.6%) were assigned to the viral infection and nonviral infection groups, respectively. The significant extents in patient characteristics were not observed in both groups. The objective response rate per mRECIST and progression-free survival (PFS) did not differ significantly between the viral infection and nonviral infection groups (36.0 vs. 33.0%, p = 0.85; and 7.6 vs. 7.5 months, p = 0.94, respectively). The 1-year survival rates were 68.7% (95% confidence interval [CI] 57.7-79.7%) in the viral infection group and 59.5% (95% CI 45.2-73.8%) in the nonviral infection group. The viral infection group was not a significant factor associated with the PFS or OS in a multivariate analysis. CONCLUSIONS: Lenvatinib shows no significant difference in response between patients with and without viral infection. Treatment strategies based on the etiology of liver disease may lead to good clinical outcome.

Metabolic syndrome cannot mask the changes of faecal microbiota compositions caused by primary hepatocellular carcinoma.

Both hepatocellular carcinoma (HCC) and metabolic syndrome are closely associated with the composition of the gut microbiota (GM). Although it has been proposed that elements of the GM can be used as biomarkers for the early diagnosis of HCC, whether metabolic syndrome results in a misrepresentation of the results of the early diagnosis of HCC using GM remains unclear. We compared the differences in the faecal microbiota of 10 patients with primary HCC, six patients with type 2 diabetes mellitus (T2DM), seven patients with arterial hypertension, six patients with both HCC and T2DM, and 10 patients with both HCC and arterial hypertension, as well as 10 healthy subjects, using high-throughput sequencing of 16S rRNA gene amplicons. Our results revealed a significant difference in the GM between subjects with and without HCC. The 49 bacterial genera out of the 494 detected genera were significantly different between the groups. These results show that changes in the GM can be used to distinguish between subjects with and without HCC, and can resist interference of T2DM and arterial hypertension with the GM. The results of the present study provide an important basis for the clinical auxiliary diagnosis of HCC by detecting the GM.

Effect of Microbiome on Non-Alcoholic Fatty Liver Disease and the Role of Probiotics, Prebiotics, and Biogenics.

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of liver cirrhosis and hepatocellular carcinoma. NAFLD is associated with metabolic disorders such as obesity, insulin resistance, dyslipidemia, steatohepatitis, and liver fibrosis. Liver-resident (Kupffer cells) and recruited macrophages contribute to low-grade chronic inflammation in various tissues by modulating macrophage polarization, which is implicated in the pathogenesis of metabolic diseases. Abnormalities in the intestinal environment, such as the gut microbiota, metabolites, and immune system, are also involved in the pathogenesis and development of NAFLD. Hepatic macrophage activation is induced by the permeation of antigens, endotoxins, and other proinflammatory substances into the bloodstream as a result of increased intestinal permeability. Therefore, it is important to understand the role of the gut-liver axis in influencing macrophage activity, which is central to the pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH). Not only probiotics but also biogenics (heat-killed lactic acid bacteria) are effective in ameliorating the progression of NASH. Here we review the effect of hepatic macrophages/Kupffer cells, other immune cells, intestinal permeability, and immunity on NAFLD and NASH and the impact of probiotics, prebiotics, and biogenesis on those diseases.

Mechanisms by Which Probiotic Bacteria Attenuate the Risk of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the second leading cause of cancer-related deaths worldwide. Chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV), alcoholic liver disease (ALD), and non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) are the major extrinsic risk factors of HCC development. Genetic background is pivotal in HCC pathogenesis, and both germline mutations and single nucleotide polymorphism (SNP) are intrinsic risk factors of HCC. These HCC risk factors predispose to hepatic injury and subsequent activation of fibrogenesis that progresses into cirrhosis and HCC. Probiotic bacteria can mitigate HCC risk by modulating host gut microbiota (GM) to promote growth of beneficial microbes and inhibit HCC-associated dysbiosis, thus preventing pathogen-associated molecular patterns (PAMPs)-mediated hepatic inflammation. Probiotics have antiviral activities against HBV and HCV infections, ameliorate obesity and risk of NAFLD/NASH, and their antioxidant, anti-proliferative, anti-angiogenic, and anti-metastatic effects can prevent the HCC pathogenesis. Probiotics also upregulate the expression of tumor suppressor genes and downregulate oncogene expression. Moreover, metabolites generated by probiotics through degradation of dietary phytochemicals may mitigate the risk of HCC development. These multiple anticancer mechanisms illustrate the potential of probiotics as an adjuvant strategy for HCC risk management and treatment.

Hepatocellular Carcinoma Immunotherapy and the Potential Influence of Gut Microbiome.

Disruptions in the human gut microbiome have been associated with a cycle of hepatocyte injury and regeneration characteristic of chronic liver disease. Evidence suggests that the gut microbiota can promote the development of hepatocellular carcinoma through the persistence of this inflammation by inducing genetic and epigenetic changes leading to cancer. As the gut microbiome is known for its effect on host metabolism and immune response, it comes as no surprise that the gut microbiome may have a role in the response to therapeutic strategies such as immunotherapy and chemotherapy for liver cancer. Gut microbiota may influence the efficacy of immunotherapy by regulating the responses to immune checkpoint inhibitors in patients with hepatocellular carcinoma. Here, we review the mechanisms by which gut microbiota influences hepatic carcinogenesis, the immune checkpoint inhibitors currently being used to treat hepatocellular carcinoma, as well as summarize the current findings to support the potential critical role of gut microbiome in hepatocellular carcinoma (HCC) immunotherapy.

Gut microbiome in HCC - Mechanisms, diagnosis and therapy.

The microbiome exerts essential functions in health and disease, modulating key processes in metabolism, inflammation and immunity. Recent evidence has revealed a key role of the microbiome in carcinogenesis as well as anti-cancer immune responses in mouse models and patients. Herein, we will review functions of the gut microbiome in hepatocellular carcinoma (HCC), the third leading cause of worldwide cancer mortality. The majority of HCC develops in patients with chronic liver disease, caused by viral hepatitis, non-alcoholic fatty liver disease (NAFLD) and alcohol-related fatty liver disease. In this review, we will discuss mechanisms by which the gut-liver axis promotes the development of HCC in mouse models and patients, including dysbiosis, the leaky gut and bacterial metabolites, with a particular focus on NAFLD as the fastest growing cause of HCC development. Moreover, we will review recent progress in harnessing the gut microbiome as a potential diagnostic tool and novel therapeutic target in patients with HCC, in particular in the setting of immunotherapy.

Long-term risk of hepatocellular carcinoma mortality in 23220 hospitalized patients treated with micafungin or other parenteral antifungals.

BACKGROUND: Liver tumours observed in rats exposed to micafungin led to a black box warning upon approval in Europe in 2008. Micafungin's risk for liver carcinogenicity in humans has not been investigated. We sought to describe the risk of fatal hepatocellular carcinoma (HCC) among persons who received micafungin and other parenteral antifungals (PAFs) with up to 12 years of follow-up. METHODS: We assembled a US multicentre cohort of hospitalized patients who received micafungin or other PAFs between 2005 and 2012. We used propensity score (PS) matching on patient characteristics from electronic medical records to compare rates of HCC mortality identified through the National Death Index though to the end of December 2016. We computed HRs and 95% CIs. RESULTS: A total of 40110 patients who received a PAF were identified; 6903 micafungin recipients (87% of those identified) were successfully matched to 16317 comparator PAF users. Ten incident HCC deaths, one in the micafungin-exposed group and nine among comparator PAF users, occurred in 71285 person-years of follow-up. The HCC mortality rate was 0.05 per 1000 person-years in micafungin patients and 0.17 per 1000 person-years in comparator PAF patients. The PS-matched HR for micafungin versus comparator PAF was 0.29 (95% CI 0.04-2.24). CONCLUSIONS: Both micafungin and comparator PAFs were associated with HCC mortality rates of <0.2 per 1000 person-years. Given the very low event rates, any potential risk for HCC should not play a role in clinical decisions regarding treatment with micafungin or other PAFs investigated in this study.

Hepatocellular Carcinoma Is Associated With Gut Microbiota Profile and Inflammation in Nonalcoholic Fatty Liver Disease.

The gut-liver axis plays a pivotal role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), which is the third leading cause of hepatocellular carcinoma (HCC) worldwide. However, the link between gut microbiota and hepatocarcinogenesis remains to be clarified. The aim of this study was to explore what features of the gut microbiota are associated with HCC in patients with cirrhosis and NAFLD. A consecutive series of patients with NAFLD-related cirrhosis and HCC (group 1, 21 patients), NAFLD-related cirrhosis without HCC (group 2, 20 patients), and healthy controls (group 3, 20 patients) was studied for gut microbiota profile, intestinal permeability, inflammatory status, and circulating mononuclear cells. We finally constructed a model depicting the most relevant correlations among these features, possibly involved in hepatocarcinogenesis. Patients with HCC showed increased levels of fecal calprotectin, while intestinal permeability was similar to patients with cirrhosis but without HCC. Plasma levels of interleukin 8 (IL8), IL13, chemokine (C-C motif) ligand (CCL) 3, CCL4, and CCL5 were higher in the HCC group and associated with an activated status of circulating monocytes. The fecal microbiota of the whole group of patients with cirrhosis showed higher abundance of Enterobacteriaceae and Streptococcus and a reduction in Akkermansia. Bacteroides and Ruminococcaceae were increased in the HCC group, while Bifidobacterium was reduced. Akkermansia and Bifidobacterium were inversely correlated with calprotectin concentration, which in turn was associated with humoral and cellular inflammatory markers. A similar behavior was also observed for Bacteroides. Conclusion: Our results suggest that in patients with cirrhosis and NAFLD the gut microbiota profile and systemic inflammation are significantly correlated and can concur in the process of hepatocarcinogenesis.

Liver tumorigenesis is promoted by a high saturated fat diet specifically in male mice and is associated with hepatic expression of the proto-oncogene Agap2 and enrichment of the intestinal microbiome with Coprococcus.

Liver cancer results in a high degree of mortality, especially among men. As fatty liver disease is a risk factor for development of hepatocellular carcinoma, we investigated the role of dietary fat type in tumor promotion by high-fat diets in mice after initiation with the chemical carcinogen diethyl nitrosamine. Tumor incidence and multiplicity were significantly greater in males than those in females. In males, fat type had complex effects on tumorigenesis. Preneoplastic foci were most prevalent in mice fed a polyunsaturated fat diet enriched in docosahexaenoic acid, whereas carcinomas and large visible liver tumors were significantly greater in mice fed a saturated fat diet made with cocoa butter relative to mice fed mono- or polyunsaturated fats. Different mechanisms thus seemed involved in early and late tumor promotion. The hepatic transcriptome and gut microbiome were assessed for traits associated with tumorigenesis. Hepatic expression of more than 20% of all genes was affected by sex, whereas fat type affected fewer genes. In males, the saturated fat diet induced expression of the proto-oncogene Agap2 and affected the expression of several cytochrome P450 genes, and genes involved in lipid, bile acid and fatty acid metabolism. The gut microbiome had a higher level of genus Akkermansia and a lower level of Firmicutes in females than in males. Males fed saturated fat had an altered microbiome, including an enrichment of the genus Coprococcus. In conclusion, sex and the dietary fat type affect the gut microbiome, the hepatic transcriptome and ultimately hepatic tumor growth.

Overuse of antianaerobic drug is associated with poor postchemotherapy prognosis of patients with hepatocellular carcinoma.

Overuse of antibiotic drugs alters the composition of gut microbiota and has detrimental effects on the host. In our study, we investigated association of gut flora and antibiotics in the prognosis of patients with liver cancer who have undergone chemotherapy by analyzing two independent clinical studies. We retrospectively subanalyzed a previously reported randomized controlled trial (RCT) on hepatic arterial infusion chemotherapy in patients with hepatocellular carcinoma (HCC) to investigate the association between use of antibiotics and prognosis. In the other study, we prospectively determined the abundance of specific bacterial genus in patients with HCC by sequencing 16S ribosomal RNA and assessed its association with survival. Subanalysis of the RCT data showed that, of 26 types of antibiotics used, administration of carbapenem before or during chemotherapy was associated with poor progression-free survival (PFS) and overall survival (OS) of patients with HCC (carbapenem + vs. -; median PFS, 78 days vs. 154 days, p = 0.0053; median OS, 177 days vs. 475 days, p = 0.0003). Multivariate analysis revealed that antianaerobic drug use is an independent predictor of poor prognosis. In the prospective study, the abundance of Blautia in fecal microbiota correlated positively with both PFS and OS of patients with HCC who underwent chemotherapy. Use of antibiotics targeting anaerobes is associated with a poor prognosis in patients with HCC who have undergone chemotherapy, whereas the intestinal anaerobic bacteria, Blautia is associated with a good prognosis. These findings might indicate the need for caution regarding overuse of broad-spectrum antibiotics targeting anaerobes in patients with HCC.

Zn(II)-curcumin solid dispersion impairs hepatocellular carcinoma growth and enhances chemotherapy by modulating gut microbiota-mediated zinc homeostasis.

Zinc(II) complexes of curcumin display moderate cytotoxicity towards cancer cells at low micromolar concentrations. However, the clinical use of zinc(II) complexes is hampered by hydrolytic insolubility and poor bioavailability and their anticancer mechanisms remain unclear. Here, we investigated the efficacy and mechanism of action of a polyvinylpyrrolidone (PVP-k30)-based solid dispersion of Zn(II)-curcumin (ZnCM-SD) against hepatocellular carcinoma (HCC) in vitro and in vivo. In vitro assays revealed ZnCM-SD not only reduced the viability of HepG2 cells and SK-HEP1 cells in a dose-dependent manner, but also potently and synergistically enhanced cell growth inhibition and cell death in response to doxorubicin by regulating cellular zinc homeostasis. ZnCM-SD was internalized into the cells via non-specific endocytosis and degraded to release curcumin and Zn2+ ions within cells. The anticancer effects also occur in vivo in animals following the oral administration of ZnCM-SD, without significantly affecting the weight of the animals. Interestingly, ZnCM-SD did not reduce tumor growth or affect zinc homeostasis in HepG2-bearing mice after gut microbiome depletion. Moreover, administration of ZnCM-SD alone or in combination with doxorubicin significantly attenuated gut dysbiosis and zinc dyshomeostasis in a rat HCC model. Notably, fecal microbiota transplantation revealed the ability of ZnCM-SD to regulate zinc homeostasis and act as a chemosensitizer for doxorubicin were dependent on the gut microbiota. The crucial role of the gut microbiota in the chemosensitizing ability of ZnCM-SD was confirmed by broad-spectrum antibiotic treatment. Collectively, ZnCM-SD could represent a simple, well-tolerated, safe, effective therapy and function as a novel chemosensitizing agent for cancer.

Iron-Oxide Nanocluster Labeling of Clostridium novyi-NT Spores for MR Imaging-Monitored Locoregional Delivery to Liver Tumors in Rat and Rabbit Models.

PURPOSE: To label Clostridium novyi-NT spores (C. novyi-NT) with iron oxide nanoclusters and track distribution of bacteria during magnetic resonance (MR) imaging-monitored locoregional delivery to liver tumors using intratumoral injection or intra-arterial transcatheter infusion. MATERIALS AND METHODS: Vegetative state C. novyi-NT were labeled with iron oxide particles followed by induction of sporulation. Labeling was confirmed with fluorescence microscopy and transmission electron microscopy (TEM). T2 and T2* relaxation times for magnetic clusters and magnetic microspheres were determined using 7T and 1.5T MR imaging scanners. In vitro assays compared labeled bacteria viability and oncolytic potential to unlabeled controls. Labeled spores were either directly injected into N1-S1 rodent liver tumors (n = 24) or selectively infused via the hepatic artery in rabbits with VX2 liver tumors (n = 3). Hematoxylin-eosin, Prussian blue, and gram staining were performed. Statistical comparison methods included paired t-test and ANOVA. RESULTS: Both fluorescence microscopy and TEM studies confirmed presence of iron oxide labels within the bacterial spores. Phantom studies demonstrated that the synthesized nanoclusters produce R2 relaxivities comparable to clinical agents. Labeling had no significant impact on overall growth or oncolytic properties (P >.05). Tumor signal-to-noise ratio (SNR) decreased significantly following intratumoral injection and intra-arterial infusion of labeled spores (P <.05). Prussian blue and gram staining confirmed spore delivery. CONCLUSIONS: C. novyi-NT spores can be internally labeled with iron oxide nanoparticles to visualize distribution with MR imaging during locoregional bacteriolytic therapy involving direct injection or intra-arterial transcatheter infusion.

A different gut microbiome linked to inflammation found in cirrhotic patients with and without hepatocellular carcinoma.

INTRODUCTION AND AIM: A pro-oncogenic intestinal microbiome was observed in murine models; however, no specific microbiome in patients with hepatocellular carcinoma (HCC) has been reported. We aimed to compare the gut microbiome found in cirrhotic patients with or without HCC. MATERIALS AND METHODS: From 407 patients with Child Pugh A/B cirrhosis prospectively followed, 25 with HCC (cases) were matched with 25 without HCC (wo-HCC) in a 1:1 ratio according to age, gender, etiology, Child Pugh and severity of portal hypertension. In addition, results were also compared with 25 healthy subjects. Fecal stool samples were sequenced for the V3-V4 region of the microbial 16S rRNA (Illumina MiSeq Platform). Plasma cytokines were quantified including interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α). RESULTS: We found a differential abundance in family members of Firmicutes with a 3-fold increase of Erysipelotrichaceae and a 5-fold decrease in family Leuconostocaceae in HCC when compared to wo-HCC controls. Genus Fusobacterium was found to be 5-fold decreased in HCC vs wo-HCC. The ratio bacteriodes/prevotella was increased in HCC. Three operational taxonomic units (OTUs), genus Odoribacter and Butyricimonas were more abundant in HCC, whereas a decreased abundance in Lachnospiraceae family genus Dorea was observed in HCC patients. A Random Forest model trained with differential abundant taxa correctly classified HCC individuals. This pattern was associated with an inflammatory milieu with a putative increased activation of NOD-like receptor pathways. CONCLUSION: We found a pattern of microbiome linked to inflammation that could be potentially useful as HCC biomarker after follow-up validation studies.

Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice.

The beneficial roles of probiotics in lowering the gastrointestinal inflammation and preventing colorectal cancer have been frequently demonstrated, but their immunomodulatory effects and mechanism in suppressing the growth of extraintestinal tumors remain unexplored. Here, we adopted a mouse model and metagenome sequencing to investigate the efficacy of probiotic feeding in controlling s.c. hepatocellular carcinoma (HCC) and the underlying mechanism suppressing the tumor progression. Our result demonstrated that Prohep, a novel probiotic mixture, slows down the tumor growth significantly and reduces the tumor size and weight by 40% compared with the control. From a mechanistic point of view the down-regulated IL-17 cytokine and its major producer Th17 cells, whose levels decreased drastically, played critical roles in tumor reduction upon probiotics feeding. Cell staining illustrated that the reduced Th17 cells in the tumor of the probiotic-treated group is mainly caused by the reduced frequency of migratory Th17 cells from the intestine and peripheral blood. In addition, shotgun-metagenome sequencing revealed the crosstalk between gut microbial metabolites and the HCC development. Probiotics shifted the gut microbial community toward certain beneficial bacteria, including Prevotella and Oscillibacter, that are known producers of antiinflammatory metabolites, which subsequently reduced the Th17 polarization and promoted the differentiation of antiinflammatory Treg/Tr1 cells in the gut. Overall, our study offers novel insights into the mechanism by which probiotic treatment modulates the microbiota and influences the regulation of the T-cell differentiation in the gut, which in turn alters the level of the proinflammatory cytokines in the extraintestinal tumor microenvironment.

Gut microbial dysbiosis associates hepatocellular carcinoma via the gut-liver axis.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. Gut microbiota has been demonstrated to play a critical role in liver inflammation, chronic fibrosis, liver cirrhosis, and HCC development through the gut-liver axis. DATA SOURCES: Recently there have been several innovative studies investigating gut microbial dysbiosis-mediated enhancement of HCC through the gut-liver axis. Literatures from January 1998 to January 2018 were searched in the PubMed database using the keywords "gut microbiota" and "hepatocellular carcinoma" or "liver cancer", and the results of experimental and clinical studies were analyzed. RESULTS: Gut microbial dysbiosis accompanies the progression of alcoholic liver disease, non-alcoholic fatty liver disease and liver cirrhosis, and promotes HCC progression in an experimental mouse model. The immune system and key factors such as Toll-like receptor 4 are involved in the process. There is evidence for gut microbial dysbiosis in hepatitis virus-related HCC patients. CONCLUSIONS: Gut microbial dysbiosis is closely associated with hepatic inflammation disease and HCC through the gut-liver axis. With the enhanced understanding of the interactions between gut microbiota and liver through the gut-liver axis, new treatment strategies for HCC are being developed.

Novel association of Streptococcus gallolyticus subspecies pasteurianus and hepatocelluar carcinoma: opening new frontiers.

BACKGROUND: Streptococcus gallolyticus subsp. gallolyticus bacteremia is associated with colorectal malignancies. There is limited data regarding the association of Streptococcus gallolyticus subsp. pasteurianus with malignancies. We aimed to study the pattern of isolation of Streptococcus gallolyticus and analysis of risk factors in patients with hepatobiliary diseases. We also planned to evaluate its association with hepatocellular malignancy. METHODS: We analyzed clinical and laboratory data of 68 cases of Streptococcus gallolyticus infections (77 isolates) from January 2013 to December 2017. These included blood (58), ascitic fluid (15), bile (2) and pleural fluid (2). We analyzed the risk factors in patients developing malignancy with Streptococcus gallolyticus infections. RESULTS: Amongst the 68 patients studied, eight (11.76%) had confirmed malignancies, hepatocellular carcinoma (HCC) (5), rectal adenocarcinoma (1), pancreatic carcinoma (1) and uterine tumors (1). Simultaneous isolation of S. gallolyticus subsp. pasteurianus from blood and ascitic fluid in eight patients (11.8%, p = .01) was significantly associated with the occurrence of HCC. Streptococcus gallolyticus infection with HCC was associated with younger age (median 55 years), lymphocytosis and elevated gamma-glutamyl transferase (GGT). CONCLUSIONS: This study provides a novel insight into the association of Streptococcus gallolyticus subspecies pasteurianus with HCC. The isolation of the organism from blood and ascitic fluid should prompt the clinicians to search for evidence of HCC actively.

Clinical and bacteriological features and prognosis of ascitic fluid infection in Chinese patients with cirrhosis.

BACKGROUND: Spontaneous bacterial peritonitis (SBP) and bacterascites (BA) represent frequent and serious complications in cirrhosis patients with ascites. However, few detailed data are available regarding the clinical and bacteriological feature of SBP or BA patients in China. METHODS: We retrospectively analyzed bacteriological and clinical characteristics of patients with SBP and BA at Beijing 302 Hospital in China from January 2012 to December 2015. RESULTS: A total of 600 patients with SBP (n = 408) or BA (n = 192) were enrolled. Patients with BA appeared to have a less severe clinical manifestation and lower mortality rate than patients with SBP. Gram-negative bacteria formed the majority of pathogens in SBP (73.9%) and BA (55.8%) cases. Higher ascitic fluid polymorphonuclear leucocytes (PMN) count and hepatocellular carcinoma were independent risk factors for BA episode progressing to SBP. The concentration of blood urea nitrogen (BUN) was independent risk factor for 30-day mortality of BA patients. For patients with SBP, the independent risk factors for 30-day mortality were age, Model for End-Stage Liver Disease (MELD) score, septic shock and hepatocellular carcinoma. Patients with third-generation cephalosporin or carbapenems resistant infection had a significantly lower survival probability. There were significant differences in clinical characteristics and outcome among the major bacteria. Multivariate analysis showed that patients infected with Klebsiella spp. had higher hazard ratio of 30-day mortality. CONCLUSION: Our study reported the bacteriological and clinical characteristics of patients with SBP and BA. Higher ascitic fluid PMN count and hepatocellular carcinoma were found to be independent risk factors for BA episode progressed to SBP. Outcome of ascitic fluid infection in patients with cirrhosis was influenced by the type of bacteria and antimicrobial susceptibility.