The gut microbiota consists of a dynamic multispecies community of bacteria, fungi, archaea, and protozoans, playing a fundamental role in the induction, training, and function of the host immune system. The liver is anatomically and physiologically linked to the gut microbiota via enterohepatic circulation, specifically receiving intestine-derived blood through the portal vein. The gut microbiota is crucial for maintaining immune homeostasis of the gut-liver axis. A shift in gut microbiota composition can result in activation of the mucosal immune response causing homeostasis imbalance. This imbalance results in translocation of bacteria and migration of immune cells to the liver, which is related to inflammation-mediated liver injury and tumor progression. In this review, we outline the role of the gut microbiota in modulating host immunity and summarize novel findings and recent advances in immune-based therapeutics associated with the gut-liver axis. Moving forward, a deep understanding of the microbiome-immune-liver axis will provide insight into the basic mechanisms of gut microbiota dysbiosis affecting liver diseases.

Objectives The discrepancy between supply and demand of organ has led to an increased utilization of steatotic liver for liver transplantation (LT). Hepatic steatosis, however, is a major risk factor for graft failure due to increased susceptibility to ischaemia‐reperfusion (I/R) injury during transplantation. Materials and methods To assess the plasticity and phenotype of immune cells within the microenvironment of steatotic liver graft at single‐cell level, single‐cell RNA‐sequencing (scRNA‐Seq) was carried out on 23 675 cells from transplanted rat livers. Bioinformatic analyses and multiplex immunohistochemistry were performed to assess the functional properties, transcriptional regulation, phenotypic switching and cell‐cell interactions of different cell subtypes. Results We have identified 11 different cell types in transplanted livers and found that the highly complex ecosystem was shaped by myeloid‐derived cell subsets that transit between different states and interact mutually. Notably, a pro‐inflammatory phenotype of Kupffer cells (KCs) with high expression of colony‐stimulating factor 3 (CSF3) that was enriched in transplanted steatotic livers was potentially participated in fatty graft injury. We have also detected a subset of dendritic cells (DCs) with highly expressing XCR1 that was correlated with CD8+ T cells, mediating the severer steatotic liver damage by I/R injury. Conclusions The findings of our study provide new insight into the mechanisms by which steatosis exacerbates liver damage from I/R injury. Interventions based on these observations create opportunities in attenuating fatty liver graft injury and expanding the donor pool.

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Inflammation is crucial to tumorigenesis and the development of metastasis. Hepatic ischemia/reperfusion injury (IRI) is an unresolved problem in liver resection and transplantation which often establishes and remodels the inflammatory microenvironment in liver. More and more experimental and clinical evidence unmasks the role of hepatic IRI and associated inflammation in promoting the recurrence of hepatocellular carcinoma (HCC). Meanwhile, approaches aimed at alleviating hepatic IRI, such as machine perfusion, regulating the gut-liver axis, and targeting key inflammatory components, have been proved to prevent HCC recurrence. This review article highlights the underlying mechanisms and promising therapeutic strategies to reduce tumor recurrence through alleviating inflammation induced by hepatic IRI.

Cytokeratin 19-positive (CK19+) hepatocellular carcinoma (HCC) is an aggressive subtype characterized by early recurrence and chemotherapy tolerance. However, there is no specific therapeutic option for CK19+ HCC. The correlation between tumor recurrence and expression status of CK19 were studied in 206 patients undergoing liver transplantation for HCC. CK19−/+ HCC cells were isolated to screen effective antitumor drugs. The therapeutic effects of regorafenib were evaluated in patient-derived xenograft (PDX) models from 10 HCC patients. The mechanism of regorafenib on CK19+ HCC was investigated. CK19 positiveness indicated aggressiveness of tumor and higher recurrence risk of HCC after liver transplantation. The isolated CK19+ HCC cells had more aggressive behaviors than CK19− cells. Regorafenib preferentially increased the growth inhibition and apoptosis of CK19+ cells in vitro, whereas sorafenib, apatinib, and 5-fluorouracil did not. In PDX models from CK19−/+ HCC patients, the tumor control rate of regorafenib achieved 80% for CK19+ HCCs, whereas 0% for CK19− HCCs. RNA-sequencing revealed that CK19+ cells had elevated expression of mitochondrial ribosomal proteins, which are essential for mitochondrial function. Further experiments confirmed that regorafenib attenuated the mitochondrial respiratory capacity in CK19+ cells. However, the mitochondrial respiration in CK19− cells were faint and hardly repressed by regorafenib. The mitochondrial respiration was regulated by the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which was inhibited by regorafenib in CK19+ cells. Hence, CK19 could be a potential marker of the therapeutic benefit of regorafenib, which facilitates the individualized therapy for HCC. STAT3/mitochondria axis determines the distinct response of CK19+ cells to regorafenib treatment.

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Liver cancer was ranked the sixth most commonly diagnosed cancer with the fourth leading cause of cancer-related deaths worldwide in 2018 (1). Notably, hepatocellular carcinoma (HCC) constitutes 75-85% among all the liver cancer cases, and ranks first morbidity and mortality of malignancies in Chinese males under 60. Due to hypervascularity in liver and high heterogeneity, HCC was regarded as an aggressive disease. Recent clinical trials focusing on resection and transplantation after targeted therapy for advanced HCC show encouraging results. However, the adjuvant therapy for patients with high risk of recurrence after surgery still raises attention. Currently, emerging evidence suggested that the crosstalk between tumor cells and the microenvironment plays a pivotal role in tumorigenesis and metastasis.The tumor microenvironment of HCC provides tumor cells with necessary conditions for their sustained growth, invasion and metastasis. It is typically characterized by dysregulated immune network, sustained injury and regeneration, angiogenesis, inflammation and metabolic reprogramming. These aforementioned characteristics raise attention to the important role of infiltrating immune cell profile and tumor stroma in microenvironmental regulation. According to the immune cell subset and proportion, HCC could be classified into different immune subtypes, for example, Sia's "immune class/ exclusion" and Kurebayashi's "immune high/mid/low". Zhang et al. further identified three novel distinctive HCC subtypes with immunocompetent, immunodeficient, and immunosuppressive features (2).