Maternal obesity increases the risk of hepatocellular carcinoma through the transmission of an altered gut microbiome.

Background & Aims: Emerging evidence suggests that maternal obesity negatively impacts the health of offspring. Additionally, obesity is a risk factor for hepatocellular carcinoma (HCC). Our study aims to investigate the impact of maternal obesity on the risk for HCC development in offspring and elucidate the underlying transmission mechanisms. Methods: Female mice were fed either a high-fat diet (HFD) or a normal diet (ND). All offspring received a ND after weaning. We studied liver histology and tumor load in a N-diethylnitrosamine (DEN)-induced HCC mouse model. Results: Maternal obesity induced a distinguishable shift in gut microbial composition. At 40 weeks, female offspring of HFD-fed mothers (HFD offspring) were more likely to develop steatosis (9.43% vs. 3.09%, p = 0.0023) and fibrosis (3.75% vs. 2.70%, p = 0.039), as well as exhibiting an increased number of inflammatory infiltrates (4.8 vs. 1.0, p = 0.018) and higher expression of genes involved in fibrosis and inflammation, compared to offspring of ND-fed mothers (ND offspring). A higher proportion of HFD offspring developed liver tumors after DEN induction (79.8% vs. 37.5%, p = 0.0084) with a higher mean tumor volume (234 vs. 3 µm3, p = 0.0041). HFD offspring had a significantly less diverse microbiota than ND offspring (Shannon index 2.56 vs. 2.92, p = 0.0089), which was rescued through co-housing. In the principal component analysis, the microbiota profile of co-housed animals clustered together, regardless of maternal diet. Co-housing of HFD offspring with ND offspring normalized their tumor load. Conclusions: Maternal obesity increases female offspring's susceptibility to HCC. The transmission of an altered gut microbiome plays an important role in this predisposition. Impact and implications: The worldwide incidence of obesity is constantly rising, with more and more children born to obese mothers. In this study, we investigate the impact of maternal diet on gut microbiome composition and its role in liver cancer development in offspring. We found that mice born to mothers with a high-fat diet inherited a less diverse gut microbiome, presented chronic liver injury and an increased risk of developing liver cancer. Co-housing offspring from normal diet- and high-fat diet-fed mothers restored the gut microbiome and, remarkably, normalized the risk of developing liver cancer. The implementation of microbial screening and restoration of microbial diversity holds promise in helping to identify and treat individuals at risk to prevent harm for future generations.

FGF21 negatively affects long-term female fertility in mice.

Objective: Obesity and associated liver disease are a growing public health concern. Pharmacological agents to treat non-alcoholic fatty liver disease are limited. FGF21, a hormone secreted by the liver and potent metabolic modulator, is a promising therapeutic target for this indication with several analogs currently in clinical development. However, concerns about a negative effect of FGF21 on female fertility have not been fully addressed. Methods: After induction of obesity, female C57BL/6N mice received a 7-day course of subcutaneously administered FGF21. Control groups received either high-fat diet (HFD) or a normal diet (ND). The mothers were then mated with lean males for 12 weeks. The estrous cycle was recorded for two weeks after breeding. The metabolic phenotype, liver steatosis and reproductive organs were assessed at sacrifice 14 weeks after treatment. Results: A short-course treatment of FGF21 leads to weight reduction during treatment but has no long-term impact on liver steatosis. A treatment with FGF21 leads to a reduction in the number of pregnancies (0 vs 1, p = 0.019) and no viable pup was born to a mother previously treated with FGF21. The FGF21 treatment affected the number of cycles (1 vs 3, p = 0.048) and amount in diestrus (54 vs 75%, p = 0.008) 12 weeks after the treatment. Additionally, the number of corpora lutea (0.8 vs 3.0, p = 0.016), and mature follicles (0 vs 1, p = 0.037) was reduced compared to the ND group while uterine histology remained unaffected. Conclusion: A short-term treatment with FGF21 has a long-term effect on female fertility in mice. This represents a potential safety concern for FGF21 analogs currently in clinical development. Reproductive health outcomes should be included in upcoming clinical trials.

Artificial Intelligence: Present and Future Potential for Solid Organ Transplantation.

Artificial intelligence (AI) refers to computer algorithms used to complete tasks that usually require human intelligence. Typical examples include complex decision-making and- image or speech analysis. AI application in healthcare is rapidly evolving and it undoubtedly holds an enormous potential for the field of solid organ transplantation. In this review, we provide an overview of AI-based approaches in solid organ transplantation. Particularly, we identified four key areas of transplantation which could be facilitated by AI: organ allocation and donor-recipient pairing, transplant oncology, real-time immunosuppression regimes, and precision transplant pathology. The potential implementations are vast-from improved allocation algorithms, smart donor-recipient matching and dynamic adaptation of immunosuppression to automated analysis of transplant pathology. We are convinced that we are at the beginning of a new digital era in transplantation, and that AI has the potential to improve graft and patient survival. This manuscript provides a glimpse into how AI innovations could shape an exciting future for the transplantation community.

Mapping of etiologies of computed tomography-proven acute colitis: a prospective cohort study.

Our objective was to describe the etiologies of acute colitis and to identify patients who require diagnostic endoscopy. Patients with symptoms of gastrointestinal infection and colonic inflammation on CT were prospectively included. Those immunosuppressed, with history of colorectal cancer or inflammatory bowel disease (IBD), were excluded. Microbiological analysis of the feces was performed using PCR assays BD-Max and FilmArray (GI panel,) and fecal cultures. Fecal calprotectin was determined. Patients with negative BD-Max underwent colonoscopy. One hundred and seventy-nine patients were included. BD-Max was positive in 93 patients (52%) and FilmArray in 108 patients (60.3%). Patients with infectious colitis (n = 103, 57.5%) were positive for Campylobacter spp. (n = 57, 55.3%), Escherichia coli spp. (n = 8, 7.8%), Clostridioides difficile (n = 23, 22.3%), Salmonella spp. (n = 9, 8.7%), viruses (n = 7, 6.8%), Shigella spp. (n = 6, 5.8%), Entamoeba histolytica (n = 2, 1.9%) and others (n = 4, 3.9%). Eighty-six patients underwent colonoscopy, which was compatible with ischemic colitis in 18 patients (10.1%) and IBD in 4 patients (2.2%). Fecal calprotectin was elevated in all patients, with a mean concentration of 1922.1 ± 2895.6 µg/g, and was the highest in patients with IBD (8511 ± 9438 µg/g, p < 0.001). After exclusion of patients with infectious etiology, a fecal calprotectin > 625 µg/g allowed identifying patients with IBD with an area under ROC curve of 85.1%. To conclude, computed tomography-proven colitis was of infectious etiology in 57.5% of patients. The main pathogens identified were Campylobacter spp. (55.3%), Clostridioides difficile (22.3%) and Salmonella spp. (8.7%). Ischemic colitis (10.1%) and IBD (2.2%) were seldom represented. No colorectal cancer was found.

[Hemorrhoidal disease in 2022 : how to select the most appropriate treatment ?] / Maladie hémorroïdaire en 2022 : comment choisir le traitement adapté ?

Hemorrhoidal disease is frequent and can lead to major alteration of quality of life. Conservative treatment, instrumental therapies and surgical approach play a complementary role in the management of hemorrhoidal disease. Understanding all techniques is mandatory to guide the patient and offer the best individualized treatment. Guidelines issued by scientific societies can facilitate the therapeutic decision.

La maladie hémorroïdaire est fréquente et ses répercussions sur la qualité de vie peuvent être majeures. Traitement conservateur, procédés non chirurgicaux et interventions chirurgicales jouent un rôle complémentaire dans le traitement d'une maladie hémorroïdaire symptomatique. Pour guider le patient et lui offrir la prise en charge la plus adaptée à sa situation, une connaissance des différents traitements est indispensable. Les recommandations des sociétés savantes, basées sur des avis d'experts, peuvent faciliter la décision thérapeutique.

Impact of Maternal Obesity on Liver Disease in the Offspring: A Comprehensive Transcriptomic Analysis and Confirmation of Results in a Murine Model.

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.

Changes in the gut bacterial communities in colon cancer surgery patients: an observational study.

BACKGROUND: Colon surgery has been shown to modulate the intestinal microbiota. Our objective was to characterize these changes using state-of-the-art next generation sequencing techniques. METHODS: We performed a single-centre prospective observational cohort study to evaluate the changes in the gut microbiota, i.e., taxon distribution, before and after elective oncologic colon surgery in adult patients with different antimicrobial prophylaxis regimens (standard prophylaxis with cefuroxime/metronidazole versus carbapenems for extended-spectrum beta-lactamase-producing Enterobacterales [ESBL-E] carriers). We obtained rectal samples on the day of surgery, intraoperative luminal samples, and rectal or stoma samples 3 days after surgery. We performed metataxonomic analysis based on sequencing of the bacterial 16S rRNA gene marker. Similarities and differences between bacterial communities were assessed using Bray-Curtis similarity, visualised using principal coordinates analysis and statistically tested by PERMANOVA. Comparison of taxa relative abundance was performed using ANCOM. RESULTS: We included 27 patients between March 27, 2019 and September 17, 2019. The median age was 63.6 years (IQR 56.4-76.3) and 44% were females. Most (81%) patients received standard perioperative prophylaxis as they were not ESBL carriers. There was no significant association between ESBL carriage and differences in gut microbiome. We observed large and significant increases in the genus Enterococcus between the preoperative/intraoperative samples and the postoperative sample, mainly driven by Enterococcus faecalis. There were significant differences in the postoperative microbiome between patients who received standard prophylaxis and carbapenems, specifically in the family Erysipelotrichaceae. CONCLUSION: This hypothesis-generating study showed rapid changes in the rectal microbiota following colon cancer surgery.

PROphylactic MESH (PROMESH) for stoma closure: does it reduce the incidence of incisional hernia? Protocol for a triple-blinded randomised controlled trial.

INTRODUCTION: Application of a prophylactic mesh during stoma closure was shown to reduce the incidence of incisional hernia at the site of stoma closure. Our objective is to provide high quality evidence to validate this finding. METHODS AND ANALYSIS: The study will be a randomised controlled triple-blinded superiority parallel monocentric trial. Patients undergoing elective ileostomy or colostomy closure after surgery for digestive cancer will be eligible for inclusion. Patients allergic to the mesh, immunosuppressed or refusing to participate will be excluded. Randomisation will be performed based on a 1:1 allocation ratio between stoma closure with application of a non-absorbable mesh in the sublay position (intervention) and stoma closure without a mesh (control). The primary outcome will be the 1-year incidence of incisional hernia at the site of stoma closure, determined clinically and by CT. Secondary outcomes will be the 31-day incidence of surgical site infection and the modified Carolinas Comfort Scale. Patients, radiologists and investigators performing the assessment at 1 year will be blinded for the allocated study group. Analysis will be performed in intention-to-treat. The trial will include 68 patients (34 with mesh, 34 without mesh). ETHICS AND DISSEMINATION: The present randomised controlled trial was registered into clinicaltrials.gov (NCT04510558) and was accepted by the local ethic committee (Geneva, Switzerland: CCER 2021-00053). The results will be presented at national and international congresses in the fields of colorectal surgery and general surgery, and published in a peer-reviewed journal.

Comparison of Outcomes between Obese and Non-Obese Patients in a Colorectal Enhanced Recovery After Surgery (ERAS) Program: A Single-Center Cohort Study.

INTRODUCTION: Obese patients are considered at increased risk of postoperative adverse events after colorectal surgery. OBJECTIVE: The objective of the present study was to compare postoperative outcomes between obese and non-obese patients undergoing elective colorectal surgery in an Enhanced Recovery After Surgery (ERAS) program. METHODS: A retrospective analysis of a prospective cohort including patients who underwent elective colorectal surgery and were included in an ERAS protocol between February 2014 and December 2017 at Geneva University Hospital, Geneva, Switzerland, was performed. Postoperative outcomes of obese and non-obese patients were compared. RESULTS: Data of 460 patients were analyzed, including 374 (81%) non-obese and 86 (19%) obese patients. Overall, there was no difference in postoperative outcomes between the 2 groups. Among patients undergoing oncologic surgery, obese subjects had a significantly higher rate of conversion to laparotomy (11.9 vs. 2.1%, p = 0.01) and longer time until return of bowel function (2.38 vs. 1.98 days, p = 0.03), without increased morbidity or longer length of stay. CONCLUSION: Obese and non-obese patients had similar postoperative outcomes after elective colorectal surgery with ERAS management. ERAS can potentially reduce the increased morbidity usually observed in obese patients following elective colorectal surgery.

Antibody-induced NKG2D blockade in a rat model of intraportal islet transplantation leads to a deleterious reaction.

Intraportal islet transplantation is plagued by an acute destruction of transplanted islets. Amongst the first responders, NK cells and macrophages harbour an activating receptor, NKG2D, recognizing ligands expressed by stressed cells. We aimed to determine whether islet NKG2D ligand expression increases with culture time, and to analyse the impact of antibody-induced NKG2D blockade in islet transplantation. NKG2D-ligand expression was analysed in rat and human islets. Syngeneic marginal mass intraportal islet transplantations were performed in rats: control group, recipients transplanted with NKG2D-recombinant-treated islets (recombinant group), and recipients treated with a mouse anti-rat anti-NKG2D antibody and transplanted with recombinant-treated islets (antibody-recombinant group). Islets demonstrated increased gene expression of NKG2D ligands with culture time. Blockade of NKG2D on NK cells decreased in vitro cytotoxicity against islets. Recipients from the control and recombinant groups showed similar metabolic results; conversely, treatment with the antibody resulted in lower diabetes reversal. The antibody depleted circulating and liver NK cells in recipients, who displayed increased macrophage infiltration of recipient origin around the transplanted islets. In vitro blockade of NKG2D ligands had no impact on early graft function. Systemic treatment of recipients with an anti-NKG2D antibody was deleterious to the islet graft, possibly through an antibody-dependent cell-mediated cytotoxicity reaction.

Tolerogenic properties of liver macrophages in non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Our understanding of non-alcoholic fatty liver disease (NAFLD) pathogenesis is improving, but there is still limited data on the function of resident liver macrophages in this context, especially when considering their contribution in dampening liver inflammation. METHODS: Liver macrophages were studied in mouse models of prolonged diet-induced liver steatohepatitis and carbon tetrachloride-induced liver injury. We assessed liver macrophages phenotype and costimulatory/inhibitory properties upon exposure to lipopolysaccharide or interleukin 4. We did phagocytosis and antigen presentation assays to investigate liver macrophages function as scavengers and immune response initiators. Using immunofluorescence staining, we further determined, in human liver tissue of patients with simple steatosis, non-alcoholic steatohepatitis and chronic hepatitis B infection, the expression of the co-inhibitory protein CD274 (Programmed-death ligand 1) and major histocompatibility complex (MHC) class II. RESULTS: Both in humans and mice, within chronically inflamed fatty livers, liver macrophages acquired immunomodulatory properties by reducing the expression of MHC class II, and by enhancing co-inhibitory signalling. Liver macrophages circumscribed endotoxin-mediated inflammatory response by upregulating anti-inflammatory genes arginase 1 and interleukin-10. While hepatic macrophages isolated from mice with normal livers were capable of achieving endotoxin tolerance, our results indicated an impairment of this protective mechanism in the presence NASH-like parenchymal abnormalities. CONCLUSIONS: Liver macrophages can achieve endotoxin tolerance, but in the chronically inflamed fatty liver, while they acquire an immunomodulatory phenotype, liver macrophages fail to dampen immune-mediated damage. Therefore, loss of tolerogenicity induced by ongoing liver insult may be a mechanism contributing to the worsening of NAFLD.

The impact of short-term machine perfusion on the risk of cancer recurrence after rat liver transplantation with donors after circulatory death.

Hypothermic and normothermic ex vivo liver perfusions promote organ recovery after donation after circulatory death (DCD). We tested whether these perfusions can reduce the risk of hepatocellular carcinoma (HCC) recurrence in a 1h-DCD syngeneic transplantation model, using Fischer F344 rats. DCD grafts were machine perfused for 2h with hypothermic perfusion (HOPE) or normothermic perfusion (NORMO), and transplanted. After reperfusion, we injected HCC cells into the vena porta. On day 28 after transplantation, we assessed tumour volumes by MRI. Control rats included transplantations with Fresh and non-perfused DCD livers. We observed apoptotic-necrotic hepatocyte foci in all DCD grafts, which were more visible than in the Fresh liver grafts. Normothermic perfusion allowed a faster post-transplant recovery, with lower day 1 levels of transaminases compared with the other DCD. Overall, survival was similar in all four groups and all animals developed HCCs. Total tumor volume was lower in the Fresh liver recipients compared to the DCD and DCD+HOPE recipients. Volumes in DCD+NORMO recipients were not significantly different from those in the Fresh group. This experiment confirms that ischemia/reperfusion injury promotes HCC cell engraftment/growth after DCD liver transplantation. Using the present extreme 1h ischemia model, both hypothermic and normothermic perfusions were not effective in reducing this risk.

Effects of remote ischaemic preconditioning on intraportal islet transplantation in a rat model.

Remote ischaemic preconditioning (RIPC), which is the intermittent interruption of blood flow to a site distant from the target organ, is known to improve solid organ resistance to ischaemia-reperfusion injury. This procedure could be of interest in islet transplantation to mitigate hypoxia-related loss of islet mass after isolation and transplantation. Islets isolated from control or RIPC donors were analyzed for yield, metabolic activity, gene expression and high mobility group box-1 (HMGB1) content. Syngeneic marginal mass transplantation was performed in four streptozotocin-induced diabetic groups: control, RIPC in donor only, RIPC in recipient only, and RIPC in donor and recipient. Islets isolated from RIPC donors had an increased yield of 20% after 24 h of culture compared to control donors (P = 0.007), linked to less cell death (P = 0.08), decreased expression of hypoxia-related genes (Hif1a P = 0.04; IRP94 P = 0.008), and increased intra-cellular (P = 0.04) and nuclear HMGB1. The use of RIPC in recipients only did not allow for reversal of diabetes, with increased serum HMGB1 at day 1; the three other groups demonstrated significantly better outcomes. Performing RIPC in the donors increases islet yield and resistance to hypoxia. Validation is needed, but this strategy could help to decrease the number of donors per islet recipient.

Fecal microbiota transplantation: a promising strategy in preventing the progression of non-alcoholic steatohepatitis and improving the anti-cancer immune response.

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.

Chimeric liver transplantation reveals interspecific graft remodelling.

BACKGROUND & AIMS: A major limitation in the field of liver transplantation is the shortage of transplantable organs. Chimeric animals carrying human tissue have the potential to solve this problem. However, currently available chimeric organs retain a high level of xenogeneic cells, and the transplantation of impure organs needs to be tested. METHODS: We created chimeric livers by injecting Lewis rat hepatocytes into C57Bl/6Fah-/-Rag2-/-Il2rg-/- mice, and further transplanted them into newly weaned Lewis rats (45 ±â€¯3 g) with or without suboptimal immunosuppression (tacrolimus 0.6 mg/kg/day for 56 or 112 days). Control donors included wild-type C57Bl/6 mice (xenogeneic) and Lewis rats (syngeneic). RESULTS: Without immunosuppression, recipients of chimeric livers experienced acute rejection, and died within 8 to 11 days. With immunosuppression, they all survived for >112 days with normal weight gain compared to syngeneic controls, while all xenogeneic controls died within 98 days due to rejection with Banff scores >6 (p = 0.0014). The chimeric grafts underwent post-transplant remodelling, growing by 670% on average. Rat hepatocytes fully replaced mouse hepatocytes starting from day 56 (absence of detectable mouse serum albumin, histological clearance of mouse hepatocytes). In addition, rat albumin levels reached those of syngeneic recipients. Four months after transplantation of chimeric livers, we observed the development of diffuse mature rat bile ducts through transdifferentiation of hepatocytes (up to 72% of cholangiocytes), and patchy areas of portal endothelium originating from the host (seen in one out of five recipients). CONCLUSIONS: Taken together, these data demonstrate the efficacy of transplanting rat-to-mouse chimeric livers into rats, with a high potential for post-transplant recipient-oriented graft remodelling. Validation in a large animal model is still needed. LAY SUMMARY: Chimeric animals are composed of cells from different species. Chimeric animals carrying human tissue have the potential to increase the availability of transplantable organs. We transplanted rat-to-mouse liver grafts into newly weaned rats. The chimeric grafts underwent post-transplant remodelling with rat hepatocytes replacing all mouse hepatocytes within 56 days. In addition, we observed the post-transplant development of diffuse mature rat bile ducts through the transformation of hepatocytes, and patchy areas of portal endothelium originating from the host. These data demonstrate the efficacy of transplanting rat-to-mouse chimeric livers into rats, with a high potential for post-transplant graft remodelling.

Effects of the gut-liver axis on ischaemia-mediated hepatocellular carcinoma recurrence in the mouse liver.

BACKGROUND & AIMS: There is growing evidence that liver graft ischemia-reperfusion (I/R) is a risk factor for hepatocellular carcinoma (HCC) recurrence, but the mechanisms involved are unclear. Herein, we tested the hypothesis that mesenteric congestion resulting from portal blood flow interruption induces endotoxin-mediated Toll-like receptor 4 (Tlr4) engagement, resulting in elevated liver cancer burden. We also assessed the role of remote ischemic preconditioning (RIPC) in this context. METHODS: C57Bl/6j mice were exposed to standardized models of liver I/R injury and RIPC, induced by occluding the hepatic and femoral blood vessels. HCC was induced by injecting RIL-175 cells into the portal vein. We further evaluated the impact of the gut-liver axis (lipopolysaccharide (LPS)-Tlr4 pathway) in this context by studying mice with enhanced (lipopolysaccharide infusion) or defective (Tlr4-/- mice, gut sterilization, and Tlr4 antagonist) Tlr4 responses. RESULTS: Portal triad clamping provoked upstream mesenteric venous engorgement and increased bacterial translocation, resulting in aggravated tumor burden. RIPC prevented this mechanism by preserving intestinal integrity and reducing bacterial translocation, thereby mitigating HCC recurrence. These observations were linked to the LPS-Tlr4 pathway, as supported by the high and low tumor burden displayed by mice with enhanced or defective Tlr4 responses, respectively. CONCLUSIONS: Modulation of the gut-liver axis and the LPS-Tlr4 response by RIPC, gut sterilization, and Tlr4 antagonism represents a potential therapeutic target to prevent I/R lesions, and to alleviate HCC recurrence after liver transplantation and resection. LAY SUMMARY: Cancer recurrence can occur after liver resection or liver transplantation for hepatocellular carcinoma (HCC). This study suggests that intestinal venous congestion, which often occurs during liver surgery, favors the translocation of gut-derived bacterial products in the portal vein, thereby facilitating cancer recurrence by enhancing the signaling of Toll-like receptor 4 in the liver. Using a mouse model of HCC recurrence, we show that strategies that (i) reduce bacterial translocation (by gut decontamination, or by protecting the intestine from venous ischemia damage) or (ii) inhibit Tlr4 signaling in the liver, could reduce cancer recurrence.

Intraportal islet transplantation: the impact of the liver microenvironment.

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 microenvironment itself presumably plays an important role in this loss. The present review focuses on the specifics of the liver microenvironment, notably the localized hepatic ischemia/reperfusion injury following transplantation, the low oxygenation of the portal vein, the instant blood-mediated inflammatory reaction, 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 preclinical research. Future interventions on clinical intraportal islet transplantation need to take into account the global context of the liver microenvironment, with multi-point interventions being most likely to improve early islet survival and engraftment.

Impact of myeloid-derived suppressor cell on Kupffer cells from mouse livers with hepatocellular carcinoma.

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 (Ly6Ghigh cells, Gr1high cells, and Ly6Clow 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-1ß 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.

Efficient nonarterialized mouse liver transplantation using 3-dimensional-printed instruments.

Because of the wide availability of genetically modified animals, mouse orthotopic liver transplantation is often preferred over rat liver transplantation. We present a simplified mouse liver transplantation technique and compare transplantation outcomes with versus without hepatic artery anastomosis. Instruments for liver implantation were designed and printed with a 3-dimensional (3D) printer. The suprahepatic vena cava anastomosis was performed with a 10-0 running suture. The vena porta and infrahepatic vena cava were joined on extraluminal cuffs, using the 3D-printed device for spatial alignment and stabilization. The hepatic artery was reconstructed in half of the recipients using intraluminal stents. Liver function tests (3, 7, and 28 days) and histology (7 and 28 days) were assessed after transplantation. We performed 22 consecutive syngeneic C57BL/6 mouse orthotopic liver transplantations. The median portal clamping time was 12.5 ± 1.5 minutes. The survival rate at 4 weeks was 100% for both arterialized and nonarterialized recipients (n = 7, 4 recipients of each group being killed for early histology at day 7). Liver function tests at 3, 7, and 28 days were similar between arterialized versus nonarterialized groups. Liver parenchyma demonstrated only irrelevant abnormalities in both groups. The proposed device allows for a shorter clamping time compared with the published literature. Using this technique, the artery does not need to be anastomosed, with no impact on graft and recipient outcomes. The device is available for 3D printing. Liver Transplantation 22 1688-1696 2016 AASLD.