Various types of liver or hepatic diseases cause the death of about 2 million people worldwide every year, of which 1 million die from the complications of cirrhosis and another million from hepatocellular carcinoma and viral hepatitis. Currently, the second most common solid organ transplant is the liver, and the current rate represents less than 10% of global transplant requests. Hence, finding new approaches to treat and prevent liver diseases is essential. In liver diseases, the interaction between the liver, gut, and immune system is crucial, and probiotics positively affect the human microbiota. Probiotics are a non-toxic and biosafe alternative to synthetic chemical compounds. Health promotion by lowering cholesterol levels, stimulating host immunity, the natural gut microbiota, and other functions are some of the activities of probiotics, and their metabolites, including bacteriocins, can exert antimicrobial effects against a broad range of pathogenic bacteria. The present review discusses the available data on the results of preclinical and clinical studies on the effects of probiotic administration on different types of liver diseases.

Gut microbiota alteration is implicated in the pathogenesis of alcoholic liver disease (ALD) and associated hepatocellular carcinoma (HCC). No study has characterized the dysbiosis associated with ALD by microbial culturomics, which certifies viability and allows pathobiont strain candidates to be characterized.

A case-control study (n = 59) was conducted on patients with ALD without HCC (ALD-NoHCC, n = 16), ALD with HCC (ALD-HCC, n = 19) and controls (n = 24) groups. 16 S rRNA amplicon sequencing and microbial culturomics were used as complementary methods for gut microbiome profiling.

Compared to the control group, Thomasclavelia ramosa and Gemmiger formicilis were significantly increased in the ALD-HCC group and Mediterraneibacter gnavus was significantly increased in the ALD-NoHCC group using 16 S rRNA sequencing. By microbial culturomics, T. ramosa was detected in all ALD samples (100%), and the most enriched since cultivated in only a small proportion of controls (20%, p < 0.001).

T. ramosa, identified by culturomics and 16 rRNA sequencing, may be associated with ALD and ALD-HCC. These results highlight the potential role of T. ramosa in liver cancer, in line with its genotoxic properties and its tumor growth-promoting effect in gnotobiotic mice recently reported.

Intratumoral microbiota has been found to be a crucial component of hepatocellular carcinoma (HCC). Due to insufficient recognition, technical limitations, and low biomass of intratumoral microbiota, it is poorly understood. Intratumoral microbiota exhibit significant diversity in HCC tissues. It is involved in the development of HCC through several mechanisms, such as remodeling the immunosuppressive microenvironment, metabolic reprogramming, and genetic alterations. Moreover, intratumoral microbiota is associated with the metastasis of HCC cells. Herein, we reviewed the history of intratumoral microbiota, applied biotechnology to depict the signatures of intratumoral microbiota, investigated the potential sources of intratumoral microbiota, and assessed their functions, mechanisms, and heterogeneity. Furthermore, in this review, we summarized the development of therapeutics that can be used in the treatment of HCC and proposed future perspectives for research in this field.

Hepatocellular carcinoma (HCC) is closely linked to alterations in the gut microbiota. This dysbiosis is characterized by significant changes in the microbial population, which correlate with the progression of HCC. Gut dysbiosis ultimately promotes HCC development in several ways: it damages the integrity of the gut-vascular barrier (GVB), alters the tumor microenvironment (TME), and even affects the intratumoral microbiota. Subsequently, intratumoral microbiota present a characteristic profile and play an essential role in HCC progression mainly by causing DNA damage, mediating tumor-related signaling pathways, altering the TME, promoting HCC metastasis, or through other mechanisms. Both gut microbiota and intratumoral microbiota have dual effects on HCC progression; a comprehensive understanding of their complex biological roles will provide a theoretical foundation for potential clinical applications in HCC treatment.

The trillions of commensal microorganisms living in the gut lumen profoundly influence the physiology and pathophysiology of the liver through a unique gut-liver axis. Disruptions in the gut microbial communities, arising from environmental and genetic factors, can lead to altered microbial metabolism, impaired intestinal barrier and translocation of microbial components to the liver. These alterations collaboratively contribute to the pathogenesis of liver disease, and their continuous impact throughout the disease course plays a critical role in hepatocarcinogenesis. Persistent inflammatory responses, metabolic rearrangements and suppressed immunosurveillance induced by microbial products underlie the pro-carcinogenic mechanisms of gut microbiota. Meanwhile, intrahepatic microbiota derived from the gut also emerges as a novel player in the development and progression of liver cancer. In this review, we first discuss the causes of gut dysbiosis in liver disease, and then specify the pivotal role of gut microbiota in the malignant progression from chronic liver diseases to hepatobiliary cancers. We also delve into the cellular and molecular interactions between microbes and liver cancer microenvironment, aiming to decipher the underlying mechanism for the malignant transition processes. At last, we summarize the current progress in the clinical implications of gut microbiota for liver cancer, shedding light on microbiota-based strategies for liver cancer prevention, diagnosis and therapy.

Background: Hepatobiliary liver cancers (HBLCs) represent the sixth most common neoplasm in the world. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) constitute the main HBLC types, with alarming epidemiological projections. Methods: In recent decades, alterations in gut microbiota, with mutual implications on the gut-liver axis and gut-biliary axis permeability status, have been massively investigated and proposed as HBLC pathogenetic deus ex machina. Results: In the HCC setting, elevated intestinal levels of Escherichia coli and other Gram-negative bacteria have been demonstrated, resulting in a close association with increased lipopolysaccharide (LPS) serum levels and, consequently, chronic systemic inflammation. In contrast, the intestinal microbiota of HCC individuals feature reduced levels of Lactobacillus spp., Bifidobacterium spp., and Enterococcus spp. In the CC setting, evidence has revealed an increased expression of Lactobacillus spp., with enhanced levels of Actynomices spp. and Alloscardovia spp. Besides impaired strains/species representation, gut-derived metabolites, including bile acids (BAs), short-chain fatty acids (SCFAs), and oxidative-stress-derived products, configure a network severely impacting the progression of HBLC. Conclusions: In the era of Precision Medicine, the clarification of microbiota composition and functioning in HCC and CC settings can contribute to the identification of individual signatures, potentially providing novel diagnostic markers, therapeutic approaches, and prognostic/predictive tools.

Increasing studies have shown that the efficacy of Weizmannia coagulans in treating various cancers. We recently identified W. coagulans MZY531 with potent cell anti-proliferation and exhibiting apoptosis induction activities against the mouse H22 hepatocellular carcinoma cell line.However, the anti-cancer effect of W. coagulans MZY531 against liver cancer in vivo has not been verified. The objective of this study was to assess the anti-hepatoma effect of W. coagulans MZY531 on H22 tumor-bearing mice and the underlying mechanism. The results demonstrated that W. coagulans MZY531 reduced the weight and size of the tumor in comparison to the model group. The levels of serum pro-inflammatory cytokines, including IL-1β, IL-6, IL-2 and TNF-α were suppressed by W. coagulans MZY531 administration. Immunofluorescence and TUNEL analyses demonstrated that W. coagulans MZY531 significantly increased the number of cleaved caspase-3 cells and induced apoptosis in tumor tissues. Importantly, W. coagulans MZY531 activated the AMPK/mTOR autophagy-dependent apoptosis pathway, and regulated the TLR4/MyD88/TRAF-6/NF-κB and JAK2/STAT3 inflammatory signaling pathways through mechanisms. Additionally, Fecal analysis demonstrated the capacity of W. coagulans MZY531 to remodel the gut microbiota of hepatocellular carcinoma-infected mice. Collectively, this experimental finding suggested that W. coagulans MZY531 exhibited prominent anticancer activities in vivo at least partly via reducing inflammation, inducing autophagy-dependent apoptosis, and regulating gut microbiota in H22 tumor-bearing mice.

Macrophages are central to the progression from hepatitis to hepatocellular carcinoma (HCC), with their remarkable plasticity and ability to adapt to the changing liver microenvironment. Chronic inflammation, fibrosis, and ultimately tumorigenesis are driven by macrophage activation, making them key regulators of liver disease progression. This review explores the diverse roles of macrophages in the transition from hepatitis to HCC. In the early stages of hepatitis, macrophages are essential for pathogen clearance and tissue repair. However, chronic activation leads to prolonged inflammation, which exacerbates liver damage and promotes fibrosis. As the disease progresses to liver fibrosis, macrophages interact with hepatic stellate cells, fostering a pro-tumorigenic microenvironment that supports HCC development. In hepatocarcinogenesis, macrophages contribute to tumor initiation, growth, metastasis, immune evasion, cancer stem cell maintenance, and angiogenesis. Their functional plasticity enables them to adapt to the tumor microenvironment, thereby promoting tumor progression and resistance to therapy. Targeting macrophages represents a promising strategy for preventing and treating HCC. Therapeutic approaches, including reprogramming macrophage phenotypes to enhance anti-tumor immunity, blocking macrophage recruitment and activation, and utilizing nanoparticle-based drug delivery systems, may provide new avenues for combating HCC by modulating macrophage functions and tumor microenvironment dynamics.

Incidence of a number of liver diseases has increased. Gut microbiota serves a role in the pathogenesis of hepatitis, cirrhosis and liver cancer. Gut microbiota is considered 'a new virtual metabolic organ'. The interaction between the gut microbiota and liver is termed the gut‑liver axis. The gut‑liver axis provides a novel research direction for mechanism of liver disease development. The present review discusses the role of the gut‑liver axis and how this can be targeted by novel treatments for common liver diseases.

Nucleotide-binding oligomerization domain 1 (NOD1) and NOD2 are involved in carcinogenic processes by recognizing bacterial cell wall components and triggering inflammation. This study explored the association between genetic variations in NOD1 and NOD2 and susceptibility to hepatocellular carcinoma (HCC) and its progression in a Moroccan population.

Genotyping of NOD1 rs2075820 (C>T) and NOD2 rs718226 (A>G) was performed using the TaqMan allelic discrimination assay in 467 Moroccan individuals. The cohort included 156 patients with hepatocellular carcinoma (HCC), 155 patients with liver cirrhosis (LC) diagnosed with HBV, HCV, or MASLD, and 156 controls.

The NOD1 rs2075820 variant showed no association with HCC susceptibility or progression, which is consistent with in silico predictions. However, the NOD2 rs718226 G allele and GG genotype were more common in the HCC group compared to the cirrhosis and control groups. Individuals with the homozygous G variant had a 2-fold higher risk for HCC (ORad = 2.12; CI=1.01-4.44; Pad = 0.04). Those with the GG genotype also had an increased risk of HCC (GG vs. AG+AA ORad = 2.28; CI=1.15-4.54; Pad = 0.016). Furthermore, GG genotype carriers had a significantly higher risk of HCC progression (ORad = 2.58; CI=1.26-5.31; Pad​ = 0.031). Individuals with the rs718226 minor allele had a significantly elevated risk of progressing from LC to HCC (ORad = 1.50; CI=1.07-2.09; Pad = 0.016). Stratification analysis indicated that men had a higher risk of HCC progression compared to women (ORad = 4.63; CI=1.53-14.00 vs. ORad = 2.73; CI=1.05-7.09).

The NOD1 rs2075820 polymorphism does not appear to be a genetic risk factor for susceptibility to HCC. In contrast, the non-coding NOD2 rs718226 variant significantly increases HCC susceptibility and promotes liver cancer progression in the Moroccan population. Further studies involving larger cohorts are warranted to definitively confirm or refute the effects of NOD1 and NOD2 genetic variants on liver cancer susceptibility and progression.

Alcohol drinking and gut microbiota are related to hepatocellular carcinoma (HCC), but the specific relationship between them remains unclear.

We aimed to establish the alcohol drinking-gut microbiota-liver axis and develop machine learning (ML) models in predicting the occurrence of early-stage HCC.

Two hundred sixty-nine patients with early-stage HCC and 278 controls were recruited. Alcohol drinking-gut microbiota-liver axis was established through the mediation/moderation effect analyses. Eight ML algorithms including Classification and Regression Tree (CART), Gradient Boosting Machine (GBM), K-Nearest Neighbor (KNN), Logistic Regression (LR), Neural Network (NN), Random Forest (RF), Support Vector Machine (SVM), and eXtreme Gradient Boosting (XGBoost) were applied.

A total of 160 pairs of individuals were included for analyses. The mediation effects of Genus_Catenibacterium (P = 0.024), Genus_Tyzzerella_4 (P < 0.001), and Species_Tyzzerella_4 (P = 0.020) were discovered. The moderation effects of Family_Enterococcaceae (OR = 0.741, 95%CI:0.160-0.760, P = 0.017), Family_Leuconostocaceae (OR = 0.793, 95%CI:0.486-3.593, P = 0.010), Genus_Enterococcus (OR = 0.744, 95%CI:0.161-0.753, P = 0.017), Genus_Erysipelatoclostridium (OR = 0.693, 95%CI:0.062-0.672, P = 0.032), Genus_Lactobacillus (OR = 0.655, 95%CI:0.098-0.749, P = 0.011), Species_Enterococcus_faecium (OR = 0.692, 95%CI:0.061-0.673, P = 0.013), and Species_Lactobacillus (OR = 0.653, 95%CI:0.086-0.765, P = 0.014) were uncovered. The predictive power of eight ML models was satisfactory (AUCs:0.855-0.932). The XGBoost model had the best predictive ability (AUC = 0.932).

ML models based on the alcohol drinking-gut microbiota-liver axis are valuable in predicting the occurrence of early-stage HCC.

Metabolic dysfunction-associated steatohepatitis (MASH) and progression to hepatocellular carcinoma (HCC) exhibits distinct molecular and immune characteristics. These traits are influenced by multiple factors, including the gut microbiome, which interacts with the liver through the "gut-liver axis". This bidirectional relationship between the gut and its microbiota and the liver plays a key role in driving various liver diseases, with microbial metabolites and immune responses being central to these processes. Our review consolidates the latest research on how gut microbiota contributes to MASH development and its progression to HCC, emphasizing new diagnostic and therapeutic possibilities. We performed a comprehensive literature review across PubMed/MedLine, Scopus, and Web of Science from January 2000 to August 2024, focusing on both preclinical and clinical studies that investigate the gut microbiota's roles in MASH and HCC. This includes research on pathogenesis, as well as diagnostic and therapeutic advancements related to the gut microbiota. This evidence emphasizes the critical role of the gut microbiome in the pathogenesis of MASH and HCC, highlighting the need for further clinical studies and trials. This is to refine diagnostic techniques and develop targeted therapies that exploit the microbiome's capabilities, aiming to enhance patient care in liver diseases.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer with poor prognosis. The available drugs for advanced HCC are limited and substantial therapeutic advances including new drugs and new combination therapies are still in urgent need. In this study, we found that the major metabolite of Lactobacillus reuteri (L. reuteri), reuterin showed great anti-HCC potential and could help in sorafenib treatment. Reuterin treatment impaired mitophagy and caused the aberrant clustering of mitochondrial nucleoids to block mitochondrial DNA (mtDNA) replication and mitochondrial fission, which could promote mtDNA leakage and subsequent STING activation in HCC cells. STING could activate pyroptosis and necroptosis, while reuterin treatment also induced caspase 8 expression to inhibit necroptosis through cleaving RIPK3 in HCC cells. Thus, pyroptosis was the main death form in reuterin-treated HCC cells and STING suppression remarkably rescued the growth inhibitory effect of reuterin and concurrently knockdown caspase 8 synergized to restrain the induction of pyroptosis. In conclusion, our study explains the detailed molecular mechanisms of the antitumor effect of reuterin and reveals its potential to perform as a combinational drug for HCC treatment.

Liver disease represents a significant global health burden, with an increasing prevalence and a lack of efficient treatment options. The microbiota-gut-liver axis involves bidirectional communication between liver function and intestinal microorganisms. A balanced gut flora protects intestinal homeostasis, while imbalances contribute to the development of liver diseases. Distinct alterations in the structure of gut flora during illness are crucial in the management of various liver diseases. Polysaccharides derived from herbal products, fungi, and other sources have been identified to possess diverse biological activities and are well-tolerated in the treatment of liver diseases. This review provides updates on the therapeutic effects of polysaccharides on liver diseases, including fatty liver diseases, acute liver injuries and liver cancers. It also summarizes advancements in understanding the mechanisms involved, particularly from the perspective of gut microbiota and metabolites, by highlighting the changes in the composition of potentially beneficial and harmful bacteria and their correlation with the therapeutic effects of polysaccharides. Additionally, by exploring the structure-activity relationship, our review provides valuable insights for the structural modification of polysaccharides and expanding their applications. In conclusion, this review offers theoretical support and novel perspectives on developing polysaccharides-based therapeutic approaches for the treatment of liver diseases.

Immune checkpoint inhibitors have revolutionised management for a variety of different types of malignancies. However, gastrointestinal adverse effects, in particular colitis and hepatitis, are relatively common with up to 30 % of patients being affected. The gut microbiome has emerged as a potential contributor to both the effectiveness of immune checkpoint inhibitors and their side effects. This review will attempt to examine the impact the microbiome has on adverse effects as a result of immune checkpoint inhibitors as well as the potential for manipulation of the microbiome as a form of management for immune mediated colitis.

Alcohol-associated liver disease (ALD) manifests as a consequence of prolonged and excessive alcohol consumption. This disease is closely associated with the interplay between gut health and liver function, which can lead to complex pathophysiological changes in the body. This review offers a comprehensive exploration of ALD's multifaceted nature, with a keen focus on its pathogenesis and the potential of nutritional and microbiota-based therapies. Insights derived from diverse case studies are utilized to shed light on how interventions can rebalance the gut microbiome and enhance liver function in ALD patients. Furthermore, the feasibility of liver transplantation and stem cell therapy as ultimate measures for ALD has been discussed, with acknowledgment of the inherent risks and challenges accompanying them. ALD's complexity underscores the necessity for a thorough understanding of its etiology and progression to devise effective treatments that mitigate its profound impact on an individual's health.

Tumors present a formidable health risk with limited curability and high mortality; existing treatments face challenges in addressing the unique tumor microenvironment (hypoxia, low pH, and high permeability), necessitating the development of new therapeutic approaches. Under certain circumstances, certain bacteria, especially anaerobes or parthenogenetic anaerobes, accumulate and proliferate in the tumor environment. This phenomenon activates a series of responses in the body that ultimately produce anti-tumor effects. These bacteria can target and colonize the tumor microenvironment, promoting responses aimed at targeting and fighting tumor cells. Understanding and exploiting such interactions holds promise for innovative therapeutic strategies, potentially augmenting existing treatments and contributing to the development of more effective and targeted approaches to fighting tumors. This paper reviews the tumor-promoting mechanisms and anti-tumor effects of the digestive tract microbiome and describes bacterial therapeutic strategies for tumors, including natural and engineered anti-tumor strategies.

Liver cancer, particularly hepatocellular carcinoma (HCC), is a significant gastrointestinal disease with a mortality rate as high as nearly 80% within five years. The disease's pathophysiology involves deranged immune responses and bile acid metabolism, with the gut microbiota (GM) playing a crucial role. Recent research highlights the potential of GM in influencing HCC treatment outcomes, especially regarding immune checkpoint inhibitors (ICIs). However, few patients currently benefit from ICIs due to a lack of effective response biomarkers.

This review aimed to explore the literature on HCC treatment issues, focusing on immune response, bile acid metabolism, and GM dysbiosis. This review included studies from PubMed, Medline, and major gastroenterology and hepatology meetings, using keywords like gut microbiota, immune system, liver cancer, and checkpoint inhibitors.

GM dysbiosis significantly impacts immune response and bile acid metabolism, making it a promising biomarker for ICI response. Modulating GM can enhance ICI treatment efficacy, although more research is needed to confirm its direct therapeutic benefits for HCC.

GM dysbiosis is integral to liver cancer pathogenesis and treatment response. Its modulation offers promising therapeutic avenues for improving HCC prognosis and response to immunotherapy.

Tazobactam/piperacillin and meropenem are commonly used as an empiric treatment in patients with severe bacterial infections. However, few studies have investigated the cause of tazobactam/piperacillin- or meropenem-induced liver injury in them. Our objective was to evaluate the association between tazobactam/piperacillin or meropenem and liver injury in the intensive care unit patients. We evaluated the expression profiles of antibiotics-induced liver injury using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Further, in the retrospective observational study, data of patients who initiated tazobactam/piperacillin or meropenem in the intensive care unit were extracted. In FAERS database, male, age, the fourth-generation cephalosporin, carbapenem, β-lactam and β-lactamase inhibitor combination, and complication of sepsis were associated with liver injury (p < 0.001). In the retrospective observational study, multivariate logistic regression analyses indicated that the risk factors for liver injury included male (p = 0.046), administration period ≥ 7 days (p < 0.001), and alanine aminotransferase (p = 0.031). Not only administration period but also sex and alanine aminotransferase should be considered when clinicians conduct the monitoring of liver function in the patients receiving tazobactam/piperacillin or meropenem.

Hepatocellular carcinoma (HCC) presents a considerable global health burden due to its late diagnosis and high morbidity. The liver's specific anatomical and physiological features expose it to various antigens, requiring precise immune regulation. To the best of our knowledge, this is the first time that a comprehensive overview of the interactions between the immune system and gut microbiota in the development of HCC, as well as the relevant therapeutic approaches are discussed. Dysregulation of immune compartments within the liver microenvironment drives HCC pathogenesis, characterized by elevated regulatory cells such as regulatory T cells (Tregs), myeloid-derived suppressor cells, and M2 macrophages as well as suppressive molecules, alongside reduced number of effector cells like T cells, natural killer cells, and M1 macrophages. Dysbiosis of gut microbiota also contributes to HCC by disrupting intestinal barrier integrity and triggering overactivated immune responses. Immunotherapy approaches, particularly immune checkpoint inhibitors, have exhibited promise in HCC management, yet adoptive cell therapy and cancer vaccination research are in the early steps with relatively less favorable outcomes. Further understanding of immune dysregulation, gut microbiota involvement, and therapeutic combination strategies are essential for advancing precision immunotherapy in HCC.

Hepatitis B virus (HBV) infection playsa significant role in the etiology and progression of liver-relatedpathologies, encompassing chronic hepatitis, fibrosis, cirrhosis, and eventual hepatocellularcarcinoma (HCC). Notably, HBV infection stands as the primary etiologicalfactor driving the development of HCC. Given the significant contribution ofHBV infection to liver diseases, a comprehensive understanding of immunedynamics in the liver microenvironment, spanning chronic HBV infection,fibrosis, cirrhosis, and HCC, is essential. In this review, we focused on thefunctional alterations of CD8+ T cells within the pathogenic livermicroenvironment from HBV infection to HCC. We thoroughly reviewed the roles ofhypoxia, acidic pH, metabolic reprogramming, amino acid deficiency, inhibitory checkpointmolecules, immunosuppressive cytokines, and the gut-liver communication in shapingthe dysfunction of CD8+ T cells in the liver microenvironment. Thesefactors significantly impact the clinical prognosis. Furthermore, we comprehensivelyreviewed CD8+ T cell-based therapy strategies for liver diseases,encompassing HBV infection, fibrosis, cirrhosis, and HCC. Strategies includeimmune checkpoint blockades, metabolic T-cell targeting therapy, therapeuticT-cell vaccination, and adoptive transfer of genetically engineered CD8+ T cells, along with the combined usage of programmed cell death protein-1/programmeddeath ligand-1 (PD-1/PD-L1) inhibitors with mitochondria-targeted antioxidants.Given that targeting CD8+ T cells at various stages of hepatitis Bvirus-induced hepatocellular carcinoma (HBV + HCC) shows promise, we reviewedthe ongoing need for research to elucidate the complex interplay between CD8+ T cells and the liver microenvironment in the progression of HBV infection toHCC. We also discussed personalized treatment regimens, combining therapeuticstrategies and harnessing gut microbiota modulation, which holds potential forenhanced clinical benefits. In conclusion, this review delves into the immunedynamics of CD8+ T cells, microenvironment changes, and therapeuticstrategies within the liver during chronic HBV infection, HCC progression, andrelated liver diseases.

Hepatocellular carcinoma (HCC) is the most frequent among primary liver tumors (90%) and one of the main causes of cancer-related death. It develops usually in a chronically inflamed environment, ranging from compensatory parenchymal regeneration to fibrosis and cirrhosis: carcinogenesis can potentially happen in each of these stages. Inflammation determined by chronic viral infection (hepatitis B, hepatitis C, and hepatitis delta viruses) represents an important risk factor for HCC etiology through both viral direct damage and immune-related mechanisms. The deregulation of the physiological liver immunological network determined by viral infection can lead to carcinogenesis. The recent introduction of immunotherapy as the gold-standard first-line treatment for HCC highlights the role of the immune system and inflammation as a double-edged weapon in both HCC carcinogenesis and treatment. In this review we highlight how the inflammation is the key for the hepatocarcinogenesis in viral, alcohol and metabolic liver diseases.

Recently, research on the human microbiome, especially concerning the bacteria within the digestive system, has substantially advanced. This exploration has unveiled a complex interplay between microbiota and health, particularly in the context of disease. Evidence suggests that the gut microbiome plays vital roles in digestion, immunity and the synthesis of vitamins and neurotransmitters, highlighting its significance in maintaining overall health. Conversely, disruptions in these microbial communities, termed dysbiosis, have been linked to the pathogenesis of various diseases, including digestive system cancers. These bacteria can influence cancer progression through mechanisms such as DNA damage, modulation of the tumour microenvironment, and effects on the host's immune response. Changes in the composition and function within the tumours can also impact inflammation, immune response and cancer therapy effectiveness. These findings offer promising avenues for the clinical application of intratumoral bacteria for digestive system cancer treatment, including the potential use of microbial markers for early cancer detection, prognostication and the development of microbiome-targeted therapies to enhance treatment outcomes. This review aims to provide a comprehensive overview of the pivotal roles played by gut microbiome bacteria in the development of digestive system cancers. Additionally, we delve into the specific contributions of intratumoral bacteria to digestive system cancer development, elucidating potential mechanisms and clinical implications. Ultimately, this review underscores the intricate interplay between intratumoral bacteria and digestive system cancers, underscoring the pivotal role of microbiome research in transforming diagnostic, prognostic and therapeutic paradigms for digestive system cancers.

An increased incidence of liver diseases has been observed in recent years and is associated with gut dysbiosis, which causes bacterial infection, intestinal permeability, and further leads to disease-related complications. Probiotics, active microbial strains, are gaining more clinical importance due to their beneficial effect in the management of many diseases, including liver diseases. Clinical scenarios show strong evidence that probiotics have efficacy in treating liver diseases due to their ability to improve epithelial barrier function, prevent bacterial translocation, and boost the immune system. Moreover, probiotics survive both bile and gastric acid to reach the gut and exert their health benefit. Evidence shows that probiotics are a promising approach to prevent several complications in clinical practice. Herein, we discuss the recent evidence, challenges, and appropriate use of probiotics in managing advanced liver diseases, which may have an impact on future therapeutic strategies. Furthermore, the superior effect of strain-specific probiotics and their efficacy and safety in managing liver diseases are discussed.

Drug-induced liver injury is a prevalent severe adverse event in clinical settings, leading to increased medical burdens for patients and presenting challenges for the development and commercialization of novel pharmaceuticals. Research has revealed a close association between gut microbiota and drug-induced liver injury in recent years. However, there has yet to be a consensus on the specific mechanism by which gut microbiota is involved in drug-induced liver injury. Gut microbiota may contribute to drug-induced liver injury by increasing intestinal permeability, disrupting intestinal metabolite homeostasis, and promoting inflammation and oxidative stress. Alterations in gut microbiota were found in drug-induced liver injury caused by antibiotics, psychotropic drugs, acetaminophen, antituberculosis drugs, and antithyroid drugs. Specific gut microbiota and their abundance are associated closely with the severity of drug-induced liver injury. Therefore, gut microbiota is expected to be a new target for the treatment of drug-induced liver injury. This review focuses on the association of gut microbiota with common hepatotoxic drugs and the potential mechanisms by which gut microbiota may contribute to the pathogenesis of drug-induced liver injury, providing a more comprehensive reference for the interaction between drug-induced liver injury and gut microbiota.

Food ingredients have critical effects on the maturation and development of the immune system, which innate - lymphoid (ILCs) and myeloid - cells play key roles as important regulators of energy storage and hepatic fat accumulation. Therefore, the objective of this study is to define potential links between a dietary immunonutritional induction of the selective functional differentiation of monocytes-derived macrophages, ILCs and lipid homeostasis in hepatocarcinoma (HCC)-developing mice. Hepatic chemically injured (diethylnitrosamine/thiacetamide) Rag2-/- and Rag2-/-Il2-/- mice were administered with serine-type protease inhibitors (SETIs) obtained from Chenopodium quinoa. Early HCC-driven immunometabolic imbalances (infiltrated macrophages, glucose homeostasis, hepatic lipid profile, ILCs expansion, inflammatory conditions, microbiota) in animals put under a high-fat diet for 2 weeks were assessed. It was also approached the potential of SETIs to cause functional adaptations of the bioenergetics of human macrophage-like cells (hMLCs) in vitro conditioning their capacity to accumulate fat. It is showed that Rag2-/-Il2-/- mice, lacking ILCs, are resistant to the SETIs-induced hepatic macrophages (CD68+F4/80+) activation. Feeding SETIs to Rag2-/- mice, carrying ILCs, promoted the expansion towards ILC3s (CD117+Nkp46+CD56+) and reduced that of ILC2s (CD117+KLRG1+) into livers. In vitro studies demonstrate that hMLCs, challenged to SETIs, develop a similar phenotype of that found in mice and bioenergetic adaptations leading to increased lipolysis. It is concluded that SETIs promote liver macrophage activation and ILCs adaptations to ameliorate HCC-driven immunometabolic imbalances.

Gut microbial dysbiosis is implicated in chronic liver disease and hepatocellular carcinoma (HCC), but the role of microbiomes from various body sites remains unexplored. We assessed disease-specific alterations in the urinary microbiome in HCC patients, investigating their potential as diagnostic biomarkers.

We performed cross-sectional analyses of urine samples from 471 HCC patients and 397 healthy controls and validated the results in an independent cohort of 164 HCC patients and 164 healthy controls. Urinary microbiomes were analyzed by 16S rRNA gene sequencing. A microbial marker-based model distinguishing HCC from controls was built based on logistic regression, and its performance was tested.

Microbial diversity was significantly reduced in the HCC patients compared with the controls. There were significant differences in the abundances of various bacteria correlated with HCC, thus defining a urinary microbiome-derived signature of HCC. We developed nine HCC-associated genera-based models with robust diagnostic accuracy (area under the curve [AUC], 0.89; balanced accuracy, 81.2%). In the validation, this model detected HCC with an AUC of 0.94 and an accuracy of 88.4%.

The urinary microbiome might be a potential biomarker for the detection of HCC. Further clinical testing and validation of these results are needed in prospective studies.

The liver has a strong regenerative capacity that ensures patient recovery after hepatectomy and liver transplantation. The portal system plays a crucial role in the dual blood supply to the liver, making it a significant factor in hepatic function. Several surgical strategies, such as portal vein ligation, associating liver partition and portal vein ligation for staged hepatectomy, and dual vein embolization, have highlighted the portal system's importance in liver regeneration. Following hepatectomy or liver transplantation, the hemodynamic properties of the portal system change dramatically, triggering regeneration via shear stress and the induction of hypoxia. However, excessive portal hyperperfusion can harm the liver and negatively affect patient outcomes. Furthermore, as the importance of the gut-liver axis has gradually been revealed, the effect of metabolites and cytokines from gut microbes carried by portal blood on liver regeneration has been acknowledged. From these perspectives, this review outlines the molecular mechanisms of the portal system's role in liver regeneration and summarizes therapeutic strategies based on the portal system intervention to promote liver regeneration.

Background: The modulating effects of probiotics and fecal microbiota transplantation (FMT) on gut flora and their direct antitumor effects remain unclear in dirty rats with established primary liver cancer. Materials & methods: Probiotics (VSL#3), FMT or tap water were administrated to three groups. Fresh fecal samples were collected from all groups for 16S rRNA analysis. Liver cancer tissues were collected to evaluate the tumor response. Results: Significant modulation of β-diversity (p = 0.023) was observed after FMT. VSL#3 and FMT had no inhibitory effect on tumors, but the density of Treg cells decreased (p = 0.031) in the FMT group. Conclusion: FMT is a more attractive alternative to probiotics in dirty rats with liver cancer.

Nonalcoholic fatty liver disease (NAFLD) particularly affects patients with type 2 diabetes and obesity. The incidence of NAFLD has increased significantly over the last decades and is now pandemically across the globe. It is a complex systemic disease comprising hepatic lipid accumulation, inflammation, lipotoxicity, gut dysbiosis, and insulin resistance as main features and with the potential to progress to cirrhosis and hepatocellular carcinoma (HCC). In numerous animal and human studies the gut microbiota plays a key role in the pathogenesis of NAFLD, NAFLD-cirrhosis and NAFLD-associated HCC. Lipotoxicity is the driver of inflammation, insulin resistance, and liver injury. Likewise, western diet, obesity, and metabolic disorders may alter the gut microbiota, which activates innate and adaptive immune responses and fuels hereby hepatic and systemic inflammation. Indigestible carbohydrates are fermented by the gut microbiota to produce important metabolites, such as short-chain fatty acids and succinate. Numerous animal and human studies suggested a pivotal role of these metabolites in the progression of NAFLD and its comorbidities. Though, modification of the gut microbiota and/or the metabolites could even be beneficial in patients with NAFLD, NAFLD-cirrhosis, and NAFLD-associated HCC. In this review we collect the evidence that exogenous and endogenous hits drive liver injury in NAFLD and propel liver fibrosis and the progressing to advanced disease stages. NAFLD can be seen as the product of a complex interplay between gut microbiota, the immune response and metabolism. Thus, the challenge will be to understand its pathogenesis and to develop new therapeutic strategies.

Introduction: Hepatocellular carcinoma (HCC) is the most common primary liver cancer, characterized by high mortality rate. In clinical practice, several makers of liver cancer, such as VEGFR1, FGFR1 and PDGFRα, were identified and their potentials as a therapeutic target were explored. However, the unsatisfied treatment results emphasized the needs of new therapeutic targets. Methods: 112 HCC patients samples were obtained to evaluate the expression of LRRC41, SOX9, CD44, and EPCAM in HCC, combined with prognosis analysis. A DEN-induced HCC rat model was constructed to verify the expression of LRRC41 and SOX9 in HCC and lung metastasis tissues. Immune score evaluation was analysized by bioinformatics methods. Network pharmacology was performed to explored the potential FDA-approved drugs targeting LRRC41. Results: Through analysis of the Timer database and tissue micro-array, we confirmed that LRRC41 was over-expressed in HCC and exhibited a significant positive correlation with recurrence and metastasis. Immunohistochemistry staining of human HCC tissue samples revealed significant upregulation of LRRC41, SOX9, CD44, and EPCAM, with LRRC41 showing a positive correlation with SOX9, CD44, and EPCAM expression. UALCAN database analysis indicated that LRRC41 and SOX9 contribute to poor prognosis whereas CD44 and EPCAM did not demonstrate the same significance. Furthermore, analysis of a DEN-induced HCC rat model confirmed the significantly elevated expression of LRRC41 and SOX9 in HCC and lung metastasis tissues. Drug sensitivity analysis and molecular docking targeting LRRC41 identified several FDA-approved drugs, which may have potential antitumor effects on HCC by targeting LRRC41. Conclusion: Our findings highlight the role of LRRC41 overexpression in promoting HCC progression and its association with a poor prognosis. Drug sensitivity analysis and molecular docking shows several FDA-approved drugs may be potential therapeutic targets for HCC. Targeting LRRC41 may hold promise as a potential therapeutic strategy for HCC.

Hepatocellular carcinoma (HCC) has been linked to the gut microbiota, with recent studies revealing the potential of gut-generated responses to influence several arms of the immune responses relevant to HCC formation. The pro- or anti-tumor effects of specific bacterial strains or gut microbiota-related metabolites, such as bile acids and short-chain fatty acids, have been highlighted in many human and animal studies. The critical role of the gut microbiota in HCC development has spurred interest in modulating the gut microbiota through dietary interventions, probiotics, and fecal microbiota transplantation as a potential strategy to improve liver cancer outcomes. Encouragingly, preclinical and clinical studies have demonstrated that modulation of the gut microbiota can ameliorate liver function, reduce inflammation, and inhibit liver tumor growth, underscoring the potential of this approach to improve HCC outcomes. As research continues to unravel the complex and dynamic mechanisms underlying the gut-liver axis, the development of safe and effective interventions to target this pathway for liver cancer prevention and treatment appears to be on the horizon, heralding a significant advance in our ongoing efforts to combat this devastating disease.

Ginsenosides, the main active pharmacological ingredients of ginseng, have been widely used for the treatment of numerous carcinomas. Hepatocellular carcinoma (HCC) is 3rd leading malignant tumor in terms of mortality worldwide. Accumulating evidence indicates that ginsenosides play a vital role in the prevention and treatment of HCC. Ginsenosides can significantly improve the symptoms of HCC, and their anticancer activity is mainly involved in inhibiting proliferation and migration, inducing cell cycle arrest at the G0/G1 phase, promoting caspase-3 and 8-mediated apoptosis, regulating autophagy related to Atg5, Atg7, Atg12, LC3-II, and PI3K/Akt pathways, and lowering invasion and metastasis associated with decreased nuclear translocation of NF-κB p65 and MMP-2/9, increasing IL-2 and IFN-γ levels to enhance immune function, as well as regulating the gut-liver axis. In addition, ginsenosides can be used as an adjuvant to conventional cancer therapies, enhancing sensitivity to chemotherapy drugs, and improving efficacy and/or reducing adverse reactions through synergistic effects. Therefore, the current manuscript discusses the mechanism and application of ginsenosides in HCC. It is hoped to provide theoretical basis for the treatment of HCC with ginsenosides.

The microbiome is pivotal in maintaining health and influencing disease by modulating essential inflammatory and immune responses. Hepatocellular carcinoma (HCC), ranking as the third most common cause of cancer-related fatalities globally, is influenced by the gut microbiome through bidirectional interactions between the gut and liver, as evidenced in both mouse models and human studies. Consequently, biomarkers based on gut microbiota represent promising non-invasive tools for the early detection of HCC. There is a growing body of evidence suggesting that the composition of the gut microbiota may play a role in the efficacy of immunotherapy in different types of cancer; thus, it could be used as a predictive biomarker. In this review, we will dissect the gut microbiome's role as a potential predictive and diagnostic marker in HCC and evaluate the latest progress in leveraging the gut microbiome as a novel therapeutic avenue for HCC patients, with a special emphasis on immunotherapy.

Hepatocellular carcinoma (HCC), the main primary liver cancer, accounts for 5 % of all incident cases and 8.4 % of all cancer-related deaths worldwide. HCC displays a spectrum of environmental risk factors (viral chronic infections, aflatoxin exposure, alcoholic- and nonalcoholic fatty liver diseases) that result in molecular complexity and heterogeneity, contributing to a rising epidemiological burden, poor prognosis, and non-satisfactory treatment options. The emergence of HCC (i.e., hepatocarcinogenesis) is a multistep and complex process that addresses many (epi)genetic alterations and phenotypic traits, the so-called cancer hallmarks. "Polymorphic microbiomes", "epigenetic reprogramming", "senescent cells" and "unlocking phenotypic plasticity" are trending hallmarks/enabling features in cancer biology. As the main molecular drivers of HCC are still undruggable, chemically induced in vivo models of hepatocarcinogenesis are useful tools in preclinical research. Thus, this narrative review aimed at recapitulating the basic features of chemically induced rodent models of hepatocarcinogenesis, eliciting their permanent translational value regarding the "classic" and the "new" cancer hallmarks/enabling features. We gathered state-of-art preclinical evidence on non-cirrhotic, inflammation-, alcoholic liver disease- and nonalcoholic fatty liver-associated HCC models, demonstrating that these bioassays indeed express the recently added hallmarks, as well as reflect the interplay between classical and new cancer traits. Our review demonstrated that these protocols remain valuable for translational preclinical application, as they recapitulate trending features of cancer science. Further "omics-based" approaches are warranted while multimodel investigations are encouraged in order to avoid "model-biased" responses.

Cancer patients often experience impairments in cognitive function. However, the evidence for tumor-mediated neurological impairment and detailed mechanisms are still lacking. Gut microbiota has been demonstrated to be involved in the immune system homeostasis and brain functions. Here we find that hepatocellular carcinoma (HCC) growth alters the gut microbiota and impedes the cognitive functions. The synaptic tagging and capture (STC), an associative cellular mechanism for the formation of associative memory, is impaired in the tumor-bearing mice. STC expression is rescued after microbiota sterilization. Transplantation of microbiota from HCC tumor-bearing mice induces similar STC impairment in wide type mice. Mechanistic study reveals that HCC growth significantly elevates the serum and hippocampus IL-1β levels. IL-1β depletion in the HCC tumor-bearing mice restores the STC. Taken together, these results demonstrate that gut microbiota plays a crucial role in mediating the tumor-induced impairment of the cognitive function via upregulating IL-1β production.

Differences in the gut microbiota and metabolic processes between males and females may explain differences in the risk of liver injury; however, the sex-specific effects of antibiotics and probiotics on these relationships are not clear. We evaluated differences in the gut microbiota and the risk of liver injury between male and female rats after the oral administration of antibiotics or probiotics followed by a period of diethylnitrosamine treatment to chemically induce liver injuryusing high-throughput sequencing of fecal microbiota combined with histological analyses of liver and colon tissues. Our results suggest that the ratio of gram-positive to gram-negative bacteria in kanamycin-treated rats was significantly higher than that of other groups, and this difference persisted for the duration of the experiment. Antibiotics significantly changed the composition of the gut microbiota of experimental rats. Clindamycin caused more diethylnitrosamine-induced damage to livers of male rats. Probiotics did not influencethe gut microbiota; however, they hadprotective effects against liver injury induced by diethylnitrosamine, especially in female rats. These results strengthen our understanding of sex differences in the indirect effects of antibiotics or probiotics on metabolism and liver injury in hosts via the gut microbiota.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is the third leading cause of tumor-related mortality worldwide. In recent years, the emergency of immune checkpoint inhibitor (ICI) has revolutionized the management of HCC. Especially, the combination of atezolizumab (anti-PD1) and bevacizumab (anti-VEGF) has been approved by the FDA as the first-line treatment for advanced HCC. Despite great breakthrough in systemic therapy, HCC continues to portend a poor prognosis owing to drug resistance and frequent recurrence. The tumor microenvironment (TME) of HCC is a complex and structured mixture characterized by abnormal angiogenesis, chronic inflammation, and dysregulated extracellular matrix (ECM) remodeling, collectively contributing to the immunosuppressive milieu that in turn prompts HCC proliferation, invasion, and metastasis. The tumor microenvironment coexists and interacts with various immune cells to maintain the development of HCC. It is widely accepted that a dysfunctional tumor-immune ecosystem can lead to the failure of immune surveillance. The immunosuppressive TME is an external cause for immune evasion in HCC consisting of 1) immunosuppressive cells; 2) co-inhibitory signals; 3) soluble cytokines and signaling cascades; 4) metabolically hostile tumor microenvironment; 5) the gut microbiota that affects the immune microenvironment. Importantly, the effectiveness of immunotherapy largely depends on the tumor immune microenvironment (TIME). Also, the gut microbiota and metabolism profoundly affect the immune microenvironment. Understanding how TME affects HCC development and progression will contribute to better preventing HCC-specific immune evasion and overcoming resistance to already developed therapies. In this review, we mainly introduce immune evasion of HCC underlying the role of immune microenvironment, describe the dynamic interaction of immune microenvironment with dysfunctional metabolism and the gut microbiome, and propose therapeutic strategies to manipulate the TME in favor of more effective immunotherapy.