• FXR/TGR5
• S100A4
• hepatic fibrosis
• liver microenvironment
• vincamine

• Animals
• Mice, Inbred C57BL
• Receptors, Cytoplasmic and Nuclear/metabolism
• Receptors, Cytoplasmic and Nuclear/agonists
• Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors
• Liver Cirrhosis/drug therapy
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/pathology
• Liver Cirrhosis/chemically induced
• S100 Calcium-Binding Protein A4/metabolism
• S100 Calcium-Binding Protein A4/antagonists & inhibitors
• Mice
• Humans
• Male
• Hepatic Stellate Cells/drug effects
• Hepatic Stellate Cells/metabolism
• Thioacetamide
• Receptors, G-Protein-Coupled/metabolism
• Liver/drug effects
• Liver/metabolism
• Liver/pathology

• 81973555 National Natural Science Foundation of China
• YDZJ202501ZYTS270 Natural Science Foundation of Jilin Province

• Gut dysbiosis
• Gut metabolites
• Gut microbiome
• Hedgehog inhibitors
• Hedgehog signaling pathway
• Toll like receptors

• Humans
• Hedgehog Proteins/metabolism
• Dysbiosis/metabolism
• Dysbiosis/complications
• Dysbiosis/microbiology
• Liver Neoplasms/metabolism
• Liver Neoplasms/microbiology
• Liver Neoplasms/pathology
• Signal Transduction
• Gastrointestinal Microbiome/physiology
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/microbiology
• Animals
• Cell Proliferation

• Gut microbiota
• Hepatocellular carcinoma
• Immune modulation
• Metabolic dysfunction-associated steatohepatitis/non-alcoholic steatohepatitis

• Humans
• Gastrointestinal Microbiome/physiology
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/microbiology
• Carcinoma, Hepatocellular/therapy
• Carcinoma, Hepatocellular/etiology
• Carcinoma, Hepatocellular/metabolism
• Liver Neoplasms/microbiology
• Liver Neoplasms/therapy
• Liver Neoplasms/diagnosis
• Liver Neoplasms/etiology
• Liver Neoplasms/metabolism
• Fatty Liver/diagnosis
• Fatty Liver/therapy
• Fatty Liver/microbiology
• Fatty Liver/metabolism
• Fatty Liver/etiology

• Cardiovascular
• Deconditioning
• Gut
• Metabolites
• Microbiota
• Microgravity
• Skeletal muscle

• T cell
• hepatocellular carcinoma
• immune checkpoint inhibitor
• immune system
• immunotherapy
• liver

• Humans
• Carcinoma, Hepatocellular/immunology
• Carcinoma, Hepatocellular/therapy
• Carcinoma, Hepatocellular/pathology
• Liver Neoplasms/immunology
• Liver Neoplasms/pathology
• Liver Neoplasms/therapy
• Immunotherapy
• Gastrointestinal Microbiome/immunology
• Tumor Microenvironment/immunology
• Animals

• chronic liver disease
• clinical trials
• gut microbiota
• liver inflammation
• metabolic regulation
• metabolite

• R01 CA208396 NCI NIH HHS
• R01 CA274959 NCI NIH HHS
• R01 CA250536 NCI NIH HHS
• R01 DK130340 NIDDK NIH HHS
• R01 DK113701 NIDDK NIH HHS

• 16S rRNA
• hepatocellular carcinoma
• metabolic pathways
• microbiota

• Humans
• Carcinoma, Hepatocellular
• RNA, Ribosomal, 16S/genetics
• Liver Neoplasms
• Energy Metabolism

• gut microbes
• mTOR
• metabolites
• therapy

• 5222019 Natural Science Foundation of Beijing

• Chemopreventive
• Hepatocellular carcinoma
• Liver cancer
• Natural products
• Signaling pathways
• Therapeutic targets

• cirrhosis
• gut microbiota
• hepatitis B virus
• liver cancer
• probiotics
• propensity score matching

• T cell immunosuppression
• gut microbiome
• hepatocellular carcinoma
• liver disease
• peripheral immune response

• gut microbiota
• liver disease
• natural product
• therapeutic strategy
• traditional Chinese medicine

Intestinal flora is closely associated with the occurrence and development of hepatocellular carcinoma (HCC). However, gut microbial changes and biological mechanisms in HCC after transarterial chemoembolization (TACE) treatment are rarely reported.

We evaluated changes in intestinal flora after TACE in rabbit HCC models and assessed the impact of these changes on the disease. Twenty-four rabbit VX2 HCC models were established and intestinal flora structures, intestinal barrier function, changes in blood lipopolysaccharide (LPS) levels, Toll-like receptor 4 (TLR4), Cyclooxygenase-2 (COX-2), and p-signal transducer and activator of transcription 3(p-STAT3) protein expression levels were studied after TACE treatment.

Compared with healthy rabbits, the intestinal flora in HCC models exhibited structural changes; intestinal barrier function was decreased, and increased LPS levels entered the circulation. A short-term follow-up after TACE showed the procedure partially reversed the intestinal microflora disorder caused by the tumor: intestinal barrier and liver functions were improved, intestinal LPS levels in the blood were reduced, and liver metabolism toward LPS was enhanced. Correlation analyses of the first 75 significantly changed bacteria with clinical factors showed that harmful bacteria had decreased and beneficial bacteria increased. Blood LPS levels and downstream signaling molecule TLR4, COX-2, and p-STAT3 protein expression levels were reduced, which correlated with tumor drug resistance and invasion capabilities.

We first characterized gut microbiota changes and biological mechanisms in HCC after TACE treatment. Our data provide a theoretical research basis for TACE combined with an intestinal flora intervention and systemic chemotherapy.

This study investigated the therapeutic effects of the phytochemical crocin alone or in combination with sorafenib both in rats chemically induced with hepatocellular carcinoma (HCC) and in human liver cancer cell line (HepG2). Male rats were randomly divided into five groups, namely, control group, HCC induced group, and groups treated with sorafenib, crocin or both crocin and sorafenib. HCC was induced in rats with a single intraperitoneal injection of diethylnitrosamine (DEN), then 2-acetylaminofluorene (2-AAF). The HCC-induced rats showed a significant decrease in body weight compared to animals treated with either or both examined drugs. Serum inflammatory markers (C-reactive protein (CRP); interleukin-6 (IL-6); lactate dehydrogenase (LDH), and oxidative stress markers were significantly increased in the HCC group and were restored upon treatment with either or both of therapeutic molecules. Morphologically, the HCC-induced rats manifested most histopathological features of liver cancer. Treatment with either or both of crocin and sorafenib successfully restored normal liver architecture. The expression of key genes involved in carcinogenesis (TNFα, p53, VEGF and NF-κB) was highly augmented upon HCC induction and was attenuated post-treatment with either or both examined drugs. Treatment with both crocin and sorafenib improved the histopathological and inflammation parameters as compared to single treatments. The in vivo anti-cancer effects of crocin and/or sorafenib were supported by their respective cytotoxicity on HepG2 cells. Crocin and sorafenib displayed an anti-tumor synergetic effect on HepG2 cells. The present findings demonstrated that a treatment regimen with crocin and sorafenib reduced liver toxicity, impeded HCC development, and improved the liver functions.

• Enterococcus faecalis
• bacterial translocation
• chronic liver disease
• liver cirrhosis
• mortality
• rifaximin

• Japan Society for the Promotion of Science
• Japan Agency for Medical Research and Development

• Alcoholic fatty liver disease
• Clinical trials
• Hepatocellular carcinoma
• Non-alcoholic fatty liver disease
• Regulatory T cells
• Treatment

• Carcinogens
• Carcinoma, Hepatocellular/etiology
• Cytokines
• Diabetes Mellitus, Type 2/complications
• Humans
• Liver Cirrhosis/pathology
• Liver Neoplasms/complications
• Non-alcoholic Fatty Liver Disease/epidemiology
• T-Lymphocytes, Regulatory
• Tumor Microenvironment

This study is aimed at investigating the influences of oral administration of probiotics on posthepatectomy recovery in patients in Child-Pugh grade.

100 patients (50 cases in Child-Pugh A grade and 50 cases in Child-Pugh B grade) underwent hepatectomy in our hospital from January 2018 to January 2020 were involved in this study. Subsequently, Child-Pugh A grade and Child-Pugh B grade patients were set as probiotics group (taking Clostridium butyricum, n = 25) and control group (no probiotics, n = 25). The general information, infectious indexes, and liver function indexes on days 1, 3, and 5 after operation were collected.

In Child-Pugh B grade subgroup patients, the procalcitonin, alanine aminotransferase, and prothrombin time of the probiotics group were statistically significantly lower than that of the control group on days 3 (P < 0.05) and 5 (P < 0.05) after surgery. In Child-Pugh A grade subgroup patients, there were no significant differences between probiotics group and control group after operation.

Child-Pugh A grade subgroup patients with hepatectomy could not benefit from oral probiotics. However, Child-Pugh B grade subgroup patients taking probiotics after hepatectomy could reduce postoperative infection and accelerate recovery of liver function.

• Biomarker
• Diagnostic
• Hepatocellular carcinoma
• Prognostics
• TP53 mutant
• UBE2C
• UBE2S
• UBE2T
• Ubiquitin-conjugating enzyme 2

Metabolic diseases such as nonalcoholic fatty liver disease (NAFLD) are rising in incidence and are an increasingly common cause of cirrhosis and hepatocellular carcinoma (HCC). The gut microbiome is closely connected to the liver via the portal vein, and has recently been identified as a predictor of liver disease state. Studies in NAFLD, cirrhosis and HCC have identified certain microbial signatures associated with these diseases, with the disease-associated microbiome changes collectively referred to as dysbiosis. The pathophysiologic underpinnings of these observations are an area of ongoing investigation, with current evidence demonstrating that the gut microbiome can influence liver disease and carcinogenesis via effects on intestinal permeability (leaky gut) and activation of the innate immune system. In the innate immune system, pathogen recognition receptors (Toll like receptors) on resident liver cells and macrophages cause liver inflammation, fibrosis, hepatocyte proliferation and reduced antitumor immunity, leading to chronic liver disease and carcinogenesis. Dysbiosis-associated changes include increase in secondary bile acids and reduced expression of FXR (nuclear receptor), which have also been associated with deleterious effects on lipid and carbohydrate metabolism associated with progressive liver disease. Longitudinal experimental and clinical studies are needed in different populations to examine these questions further. The role of therapeutics that modulate the microbiome is an emerging field with experimental studies showing the potential of diet, probiotics, fecal microbiota transplantation and prebiotics in improving liver disease in experimental models. Clinical studies are ongoing with preliminary evidence showing improvement in liver enzymes and steatosis. The microbial profile is different in responders to cancer immunotherapy including liver cancer, but whether or not manipulation of the microbiome can be utilized to affect response is being investigated.

• Microbiome
• Gut microbiome
• Hepatocellular carcinoma
• Nonalcoholic fatty liver disease
• Pathophysiology
• Treatment

• cardiovascular diseases
• hepatocellular carcinoma
• nonalcoholic fatty liver disease
• obesity
• signaling pathway
• treatment
• type 2 diabetes mellitus

• Biological Products/therapeutic use
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/therapy
• Cardiovascular Diseases/genetics
• Cardiovascular Diseases/metabolism
• Cardiovascular Diseases/therapy
• Diabetes Mellitus, Type 2/genetics
• Diabetes Mellitus, Type 2/metabolism
• Diabetes Mellitus, Type 2/therapy
• Humans
• Inflammation Mediators/antagonists & inhibitors
• Inflammation Mediators/metabolism
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/therapy
• Obesity/genetics
• Obesity/metabolism
• Obesity/therapy
• Risk Reduction Behavior
• Tumor Microenvironment/physiology

• HCC
• NAFLD
• T cell subpopulation
• chemokines
• cytokines
• treatment

• Colorectal liver metastasis
• Gut microbiota
• Immune system
• Liver cancer
• Liver cancer treatment
• Primary liver cancer

• Carcinogenesis
• Dysbiosis
• Hepatocellular carcinoma
• Microbiota

• Oral microbiome
• cancer
• gut microbiome
• radiotherapy

• 20JCJQJC00100 Science Foundation for Distinguished Young Scholars of Tianjin
• 81572969 National Natural Science Foundation of China
• 81730086 National Natural Science Foundation of China
• 81872555 National Natural Science Foundation of China
• 2018ZX09711001-007-008 Drug Innovation Major Project of China
• 2018-1001-04 PUMC Graduate Innovation Fund
• 2019-1001-06 PUMC Graduate Innovation Fund

• clinical trials
• molecules
• nonalcoholic fatty liver disease
• nonalcoholic steatohepatitis
• signaling pathway
• treatment options

• Animals
• Clinical Trials, Phase II as Topic
• Clinical Trials, Phase III as Topic
• Fatty Liver/drug therapy
• Fatty Liver/metabolism
• Fatty Liver/pathology
• Humans
• Non-alcoholic Fatty Liver Disease/drug therapy
• Non-alcoholic Fatty Liver Disease/metabolism
• Non-alcoholic Fatty Liver Disease/pathology
• Randomized Controlled Trials as Topic
• Signal Transduction

• LSECs
• cancer metastasis
• gut microbiota
• liver
• treatment

The gut microbiome (GM), a complex community of bacteria, viruses, protozoa, and fungi located in the gut of humans and animals, plays significant roles in host health and disease. Animal models are widely used to investigate human diseases in biomedical research and the GM within animal models can change due to the impact of many factors, such as the vendor, husbandry, and environment. Notably, variations in GM can contribute to differences in disease model phenotypes, which can result in poor reproducibility in biomedical research. Variation in the gut microbiome can also impact the translatability of animal models. For example, standard lab mice have different pathogen exposure experiences when compared to wild or pet store mice. As humans have antigen experiences that are more similar to the latter, the use of lab mice with more simplified microbiomes may not yield optimally translatable data. Additionally, the literature describes many methods to manipulate the GM and differences between these methods can also result in differing interpretations of outcomes measures. In this review, we focus on the GM as a potential contributor to the poor reproducibility and translatability of mouse models of disease. First, we summarize the important role of GM in host disease and health through different gut–organ axes and the close association between GM and disease susceptibility through colonization resistance, immune response, and metabolic pathways. Then, we focus on the variation in the microbiome in mouse models of disease and address how this variation can potentially impact disease phenotypes and subsequently influence research reproducibility and translatability. We also discuss the variations between genetic substrains as potential factors that cause poor reproducibility via their effects on the microbiome. In addition, we discuss the utility of complex microbiomes in prospective studies and how manipulation of the GM through differing transfer methods can impact model phenotypes. Lastly, we emphasize the need to explore appropriate methods of GM characterization and manipulation.

• gut microbiome
• modulation
• mouse model of disease
• reproducibility
• translatability
• virome

• U42 OD010918 NIH HHS