The role of gut-derived microbial antigens on liver fibrosis initiation and progression

Intestinal dysbiosis has recently become known as an important driver of gastrointestinal and liver disease. It remains poorly understood, however, how gastrointestinal microbes bypass the intestinal mucosa and enter systemic circulation to enact an inflammatory immune response. In the context of chronic liver disease (CLD), insults that drive hepatic inflammation and fibrogenesis (alcohol, fat) can drastically increase intestinal permeability, hence flooding the liver with gut-derived microbiota. Consequently, this may result in exacerbated liver inflammation and fibrosis through activation of liver-resident Kupffer and stellate cells by bacterial, viral, and fungal antigens transported to the liver via the portal vein. This review summarizes the current understanding of microbial translocation in CLD, the cell-specific hepatic response to intestinal antigens, and how this drives the development and progression of hepatic inflammation and fibrosis. Further, we reviewed current and future therapies targeting intestinal permeability and the associated, potentially harmful anti-microbial immune response with respect to their potential in terms of limiting the development and progression of liver fibrosis and end-stage cirrhosis

Immune-checkpoint inhibitors for metastatic colorectal cancer : a systematic review of clinical outcomes

Background. Colorectal cancer (CRC) is the fourth most deadly cancer worldwide. Unfortunately, a quarter of the patients are diagnosed at late stages, when surgical options are limited. Targeted therapies, particularly immune-checkpoint inhibitors (ICIs), are the latest addition and have been studied herein regarding their efficacy outcomes. Methods. Clinical studies were identified through the PubMed, Scopus and Cochrane databases. Any trial that evaluated ICIs in patients with metastatic CRC (mCRC) and reported the objective response rate was deemed eligible. Data analysis was performed by employing the random-effects model in STATA v.17. Results. A total of 461 articles were identified; 13 clinical trials were included, encompassing a total cohort of 1209 patients. Our study determined that a single PD-1/PD-L1 checkpoint blockade provides durable clinical response in mCRC patients with high microsatellite instability (MSI-H). The combinatorial therapy of CTLA-4 + PD-1 inhibitors also showed high response rates in pre-treated MSI-H patients. The single-arm REGONIVO trial reported durable clinical response in patients with microsatellite stable (MSS) status. Conclusions. Our study surmises that PD-1/PD-L1 inhibitors as well as combination therapy with CTLA-4 and PD-1 inhibitors show encouraging response rates in mCRC patients, albeit exclusively in patients with cancer that are of MSI-H status. A single study suggests that nivolumab + regorafenib can reach a durable response rate in MSS patients; however, further studies in larger randomized settings are required

Macrophage coordination of the interferon lambda immune response

Lambda interferons (IFN-λs) are a major component of the innate immune defense to viruses, bacteria, and fungi. In human liver, IFN-λ not only drives antiviral responses, but also promotes inflammation and fibrosis in viral and non-viral diseases. Here we demonstrate that macrophages are primary responders to IFN-λ, uniquely positioned to bridge the gap between IFN-λ producing cells and lymphocyte populations that are not intrinsically responsive to IFN-λ. While CD14+ monocytes do not express the IFN-λ receptor, IFNLR1, sensitivity is quickly gained upon differentiation to macrophages in vitro. IFN-λ stimulates macrophage cytotoxicity and phagocytosis as well as the secretion of pro-inflammatory cytokines and interferon stimulated genes that mediate immune cell chemotaxis and effector functions. In particular, IFN-λ induced CCR5 and CXCR3 chemokines, stimulating T and NK cell migration, as well as subsequent NK cell cytotoxicity. Using immunofluorescence and cell sorting techniques, we confirmed that human liver macrophages expressing CD14 and CD68 are highly responsive to IFN-λ ex vivo. Together, these data highlight a novel role for macrophages in shaping IFN-λ dependent immune responses both directly through pro-inflammatory activity and indirectly by recruiting and activating IFN-λ unresponsive lymphocytes

Androgen deprivation in prostate cancer : benefits of home-based resistance training

Introduction: Androgen deprivation therapy (ADT) has detrimental effects on body composition, metabolic health, physical functioning, bone mineral density (BMD) and health-related quality of life (HRQOL) in men with prostate cancer. We investigated whether a 12-month home-based progressive resistance training (PRT) programme, instituted at the start of ADT, could prevent these adverse effects. Methods: Twenty-five patients scheduled to receive at least 12 months of ADT were randomly assigned to either usual care (UC) (n = 12) or PRT (n = 13) starting immediately after their first ADT injection. Body composition, body cell mass (BCM; a functional component of lean body mass), BMD, physical function, insulin sensitivity and HRQOL were measured at 6 weeks and 6 and 12 months. Data were analysed by a linear mixed model. Results: ADT had a negative impact on body composition, BMD, physical function, glucose metabolism and HRQOL. At 12 months, the PRT group had greater reductions in BCM by − 1.9 ± 0.8 % (p = 0.02) and higher gains in fat mass by 3.1 ± 1.0 % (p = 0.002), compared to the UC group. HRQOL domains were maintained or improved in the PRT versus UC group at 6 weeks (general health, p = 0.04), 6 months (vitality, p = 0.02; social functioning, p = 0.03) and 12 months (mental health, p = 0.01; vitality, p = 0.02). A significant increase in the Matsuda Index in the PRT versus UC group was noted at 6 weeks (p = 0.009) but this difference was not maintained at subsequent timepoints. Between-group differences favouring the PRT group were also noted for physical activity levels (step count) (p = 0.02). No differences in measures of BMD or physical function were detected at any time point. Conclusion: A home-based PRT programme instituted at the start of ADT may counteract detrimental changes in body composition, improve physical activity and mental health over 12 months. Trial registration: Australian and New Zealand Clinical Trials Registry, ACTRN1261600131144

Mucosal-associated invariant T (MAIT) cells are activated in the gastrointestinal tissue of patients with combination ipilimumab and nivolumab therapy-related colitis in a pathology distinct from ulcerative colitis

The aim of this study was to investigate the pathogenesis of combination ipilimumab and nivolumab-associated colitis (IN-COL) by measuring gut-derived and peripheral blood mononuclear cell (GMNC; PBMC) profiles. We studied GMNC and PBMC from patients with IN-COL, IN-treated with no adverse-events (IN-NAE), ulcerative colitis (UC) and healthy volunteers using flow cytometry. In the gastrointestinal-derived cells we found high levels of activated CD8+ T cells and mucosal-associated invariant T (MAIT) cells in IN-COL, changes that were not evident in IN-NAE or UC. UC, but not IN-C, was associated with a high proportion of regulatory T cells (Treg). We sought to determine if local tissue responses could be measured in peripheral blood. Peripherally, checkpoint inhibition instigated a rise in activated memory CD4+ and CD8+ T cells, regardless of colitis. Low circulating MAIT cells at baseline was associated with IN-COL patients compared with IN-NAE in one of two cohorts. UC, but not INCOL, was associated with high levels of circulating plasmablasts. In summary, the alterations in T cell subsets measured in IN-COL-affected tissue, characterized by high levels of activated CD8+ T cells and MAIT cells and a low proportion of Treg, reflected a pathology distinct from UC. These tissue changes differed from the periphery, where T cell activation was a widespread on-treatment effect, and circulating MAIT cell count was low but not reliably predictive of colitis

Virus induced inflammation and cancer development

Chronic inflammation as a result of viral infection significantly increases the likelihood of cancer development. A handful of diverse viruses have confirmed roles in cancer development and progression, but the list of suspected oncogenic viruses is continually growing. Viruses induce cancer directly and indirectly, by activating inflammatory signalling pathways and cytokines, stimulating growth of infected cells and inhibiting apoptosis. Although oncogenic viruses induce inflammation by various mechanisms, it is generally mediated by the MAPK, NFκB and STAT3 signalling pathways. This review will explore the unique mechanisms by which different oncogenic viruses induce inflammation to promote cancer initiation and progression

Combination treatment with insulin sensitisers improves the antiviral effect of interferon against hepatitis C virus

Pegylated interferon (IFN) in combination with ribavirin is currently the standard of care for the treatment of hepatitis C virus (HCV) infection, but achieves a sustained viral response in only 50%-60% of patients. Interestingly, patients with HCV genotypes that are more resistant to treatment also demonstrate insulin resistance. Thus we sought to examine the effects of insulin sensitisers on the response of HCV to IFN

Examining the gut-liver axis in liver cancer using organoid models

The World Health Organization predicts that by 2030 liver cancer will cause 1 million deaths annually, thus becoming the third most lethal cancer worldwide. Hepatocellular carcinoma and cholangiocarcinoma are the two major primary cancer subtypes involving the liver. Both are often diagnosed late, and hence response to treatment and survival are poor. It is therefore of utmost importance to understand the mechanisms by which liver cancers initiate and progress. The causes of primary liver cancer are diverse, resulting primarily from obesity, chronic alcohol abuse or viral hepatitis. Importantly, both alcohol and high fat diet can promote intestinal permeability, enabling microbial translocation from the gut into the liver. As a result, these microbial antigens and metabolites exacerbate hepatic inflammation and fibrosis, increasing the risk of primary liver cancer. Organoids are primary, three-dimensional, stem cell derived liver models that can recapitulate many of the disease phenotypes observed in vivo. This review aims to summarize the advantages of organoid culture to examine the gut-liver axis with respect to cancer initiation and progression. In particular, the use of gut and liver organoid mono- and co-cultures together and with immune cell populations to best recapitulate disease mechanisms and develop therapeutic interventions

Hepatitis C virus infection mediates cholesteryl ester synthesis to facilitate infectious particle production

Cholesterol is a critical component of the hepatitis C virus (HCV) life cycle, as demonstrated by its accumulation within infected hepatocytes and lipoviral particles. To cope with excess cholesterol, hepatic enzymes ACAT1 and ACAT2 produce cholesteryl esters (CEs), which are destined for storage in lipid droplets or for secretion as apolipoproteins. Here we demonstrate in vitro that cholesterol accumulation following HCV infection induces upregulation of the ACAT genes and increases CE synthesis. Analysis of human liver biopsy tissue showed increased ACAT2 mRNA expression in liver infected with HCV genotype 3, compared with genotype 1. Inhibiting cholesterol esterification using the potent ACAT inhibitor TMP-153 significantly reduced production of infectious virus, but did not inhibit virus RNA replication. Density gradient analysis showed that TMP-153 treatment caused a significant increase in lipoviral particle density, suggesting reduced lipidation. These data suggest that cholesterol accumulation following HCV infection stimulates the production of CE, a major component of lipoviral particles. Inhibition of CE synthesis reduces HCV particle density and infectivity, suggesting that CEs are required for optimal infection of hepatocytes

The role of zinc in antiviral immunity

Zinc is an essential trace element that is crucial for growth, development, and the maintenance of immune function. Its influence reaches all organs and cell types, representing an integral component of approximately 10% of the human proteome, and encompassing hundreds of key enzymes and transcription factors. Zinc deficiency is strikingly common, affecting up to a quarter of the population in developing countries, but also affecting distinct populations in the developed world as a result of lifestyle, age, and disease-mediated factors. Consequently, zinc status is a critical factor that can influence antiviral immunity, particularly as zinc-deficient populations are often most at risk of acquiring viral infections such as HIV or hepatitis C virus. This review summarizes current basic science and clinical evidence examining zinc as a direct antiviral, as well as a stimulant of antiviral immunity. An abundance of evidence has accumulated over the past 50 y to demonstrate the antiviral activity of zinc against a variety of viruses, and via numerous mechanisms. The therapeutic use of zinc for viral infections such as herpes simplex virus and the common cold has stemmed from these findings; however, there remains much to be learned regarding the antiviral mechanisms and clinical benefit of zinc supplementation as a preventative and therapeutic treatment for viral infections