The portal vein remains the preferred site for pancreatic islet transplantation due to its easy access and low morbidity. However, despite great progress in isolation and transplantation protocols over the past few years, it is still associated with the early loss of some 50-70% of transplanted islets. The complex liver micro-environment itself presumably plays an important role in this loss. The present review focuses on the specifics of the liver micro-environment, notably the localized hepatic ischemia/reperfusion injury following transplantation, the low oxygenation of the portal vein, the instant blood mediated inflammatory reaction (IBMIR), the endogenous liver immune system, and the gut-liver axis, and how they can each have an impact on the transplanted islets. It identifies the potential, or already applied, clinical interventions for improving intraportal islet survival, and pinpoints those promising areas still lacking pre-clinical research. Future interventions on clinical intraportal islet transplantation need to take into account the global context of the liver micro-environment, with multi-point interventions being most likely to improve early islet survival and engraftment.

Kupffer cells represent the first line of defense against tumor cells in the liver. Myeloid-derived suppressor cells (MDSC) have recently been observed in the liver parenchyma of tumor-bearing animals. The present study investigates the function of the MDSC subsets, and their impact on Kupffer cell phenotype and function. RIL-175 mouse hepatocellular carcinoma (HCC) cells were injected into the median liver lobe of C57BL/6 mice. Three weeks later, the median lobe hosting the tumor nodule was removed, and Kupffer cells and MDSCs were sorted from the remaining liver. Mouse livers devoid of HCC served as control. Kupffer cells expressed less co-stimulatory CD86 and MHCII and more co-inhibitory CD274 molecules in HCC-bearing livers than in control livers. Corresponding to this phenotype, Kupffer cells from HCC-bearing mice were less efficient in their function as antigen-presenting cells. Three CD11b⁺ cell populations were identified and sorted from HCC-bearing mice. These cells had various phenotypes with different levels of MDSC-specific surface markers (Ly6G^high cells, Gr1^high cells, and Ly6C^low cells), and may be considered as bonafide MDSCs given their suppression of antigen-specific T cell proliferation. Primary isolated Kupffer cells in co-culture with the three MDSC subsets showed a decrease in CCL2 and IL-18 secretion, and an increase in IL-10 and IL-1β secretion, and an increased expression of CD86, CD274, and MHCII. In conclusion, these data demonstrated the existence of three MDSC subsets in HCC-bearing animals. These cells altered Kupffer cell function and may decrease the migration and activation of anticancer effector cells in the liver.

Introduction: Non-alcoholic fatty liver disease (NAFLD) has the potential to progress to hepatocellular carcinoma (HCC). However, limited therapies are currently available for the treatment of advanced HCC, and one must strive to search for novel strategies. Areas covered: We provide insight on current knowledge related to gut microbiota and NAFLD, summarize the sequence linking obesity to HCC and highlight gut dysbiosis in obesity and its consequences on the liver. We detail the impact of the gut microbiota on immune checkpoint inhibitors, and speculate on the role of fecal microbiota transplantation (FMT) in NAFLD and in improving anti-neoplastic immune response. Expert Opinion: Manipulation of the gut microbiota seems promising in the secondary prevention of NAFLD/NASH and/or in potentiating anti-cancer immune response, notably by a global ‘resetting’ using FMT. However, the composition of a ‘harmful’ gut microbiome in HCC still needs to be characterized, and the impact of FMT on HCC growth needs to be assessed.

The global obesity epidemic particularly affects women of reproductive age. Offspring of obese mothers suffer from an increased risk of liver disease but the molecular mechanisms involved remain unknown. We performed an integrative genomic analysis of datasets that investigated the impact of maternal obesity on the hepatic gene expression profile of the offspring in mice. Furthermore, we developed a murine model of maternal obesity and studied the development of liver disease and the gene expression profile of the top dysregulated genes by quantitative real-time polymerase chain reaction (qPCR). Our data are available for interactive exploration on our companion webpage. We identified five publicly available datasets relevant to our research question. Pathways involved in metabolism, the innate immune system, the clotting cascade, and the cell cycle were consistently dysregulated in the offspring of obese mothers. Concerning genes involved in the development of liver disease, Egfr, Vegfb, Wnt2,Pparg and six other genes were dysregulated in multiple independent datasets. In our own model, we observed a higher tendency towards the development of non-alcoholic liver disease (60 vs. 20%) and higher levels of alanine aminotransferase (41.0 vs. 12.5 IU/l, p = 0.008) in female offspring of obese mothers. Male offspring presented higher levels of liver fibrosis (2.4 vs. 0.6% relative surface area, p = 0.045). In a qPCR gene expression analysis of our own samples, we found Fgf21, Pparg, Ppard, and Casp6 to be dysregulated by maternal obesity. Maternal obesity represents a looming threat to the liver health of future generations. Our comprehensive transcriptomic analysis will help to better understand the mechanisms of the development of liver disease in the offspring of obese mothers and can give rise to further explorations.