Gut Microbiota and Infectious Complications in Advanced Chronic Liver Disease: Focus on Spontaneous Bacterial Peritonitis

Liver cirrhosis is a chronic disease that can be complicated by episodes of decompensation such as variceal bleeding, hepatic encephalopathy, ascites, and jaundice, with subsequent increased mortality. Infections are also among the most common complications in cirrhotic patients, mostly due to a defect in immunosurveillance. Among them, one of the most frequent is spontaneous bacterial peritonitis (SBP), defined as the primary infection of ascitic fluid without other abdominal foci. SBP is mainly induced by Gram-negative bacteria living in the intestinal tract, and translocating through the intestinal barrier, which in cirrhotic patients is defective and more permeable. Moreover, in cirrhotic patients, the intestinal microbiota shows an altered composition, poor in beneficial elements and enriched in potentially pathogenic ones. This condition further promotes the development of leaky gut and increases the risk of SBP. The first-line treatment of SBP is antibiotic therapy; however, the antibiotics used have a broad spectrum of action and may adversely affect the composition of the gut microbiota, worsening dysbiosis. For this reason, the future goal is to use new therapeutic agents that act primarily on the gut microbiota, selectively modulating it, or on the intestinal barrier, reducing its permeability. In this review, we aim to describe the reciprocal relationship between gut microbiota and SBP, focusing on pathogenetic aspects but also on new future therapies

Vaccine Responses in Patients with Liver Cirrhosis: From the Immune System to the Gut Microbiota

: Vaccines prevent a significant number of deaths annually. However, certain populations do not respond adequately to vaccination due to impaired immune systems. Cirrhosis, a condition marked by a profound disruption of immunity, impairs the normal immunization process. Critical vaccines for cirrhotic patients, such as the hepatitis A virus (HAV), hepatitis B virus (HBV), influenza, pneumococcal, and coronavirus disease 19 (COVID-19), often elicit suboptimal responses in these individuals. The humoral response, essential for immunization, is less effective in cirrhosis due to a decline in B memory cells and an increase in plasma blasts, which interfere with the creation of a long-lasting response to antigen vaccination. Additionally, some T cell subtypes exhibit reduced activation in cirrhosis. Nonetheless, the persistence of memory T cell activity, while not preventing infections, may help to attenuate the severity of diseases in these patients. Alongside that, the impairment of innate immunity, particularly in dendritic cells (DCs), prevents the normal priming of adaptive immunity, interrupting the immunization process at its onset. Furthermore, cirrhosis disrupts the gut-liver axis balance, causing dysbiosis, reduced production of short-chain fatty acids (SCFAs), increased intestinal permeability, and bacterial translocation. Undermining the physiological activity of the immune system, these alterations could impact the vaccine response. Enhancing the understanding of the molecular and cellular factors contributing to impaired vaccination responses in cirrhotic patients is crucial for improving vaccine efficacy in this population and developing better prevention strategies

Immunotherapy for nonalcoholic fatty liver disease-related hepatocellular carcinoma: Lights and shadows

About one-fourth of adults globally suffer from nonalcoholic fatty liver disease (NAFLD), which is becoming a leading cause of chronic liver disease worldwide. Its prevalence has rapidly increased in recent years, and is projected to increase even more. NAFLD is a leading cause of hepatocellular carcinoma (HCC), the sixth-most prevalent cancer worldwide and the fourth most common cause of cancer-related death. Although the molecular basis of HCC onset in NAFLD is not completely known, inflammation is a key player. The tumor microenvironment (TME) is heterogeneous in patients with HCC, and is characterized by complex interactions between immune system cells, tumor cells and other stromal and resident liver cells. The etiology of liver disease plays a role in controlling the TME and modulating the immune response. Markers of immune suppression in the TME are associated with a poor prognosis in several solid tumors. Immunotherapy with immune checkpoint inhibitors (ICIs) has become the main option for treating cancers, including HCC. However, meta-analyses have shown that patients with NAFLD-related HCC are less likely to benefit from therapy based on ICIs alone. Conversely, the addition of an angiogenesis inhibitor showed better results regarding the objective response rate and progression-free survival. Adjunctive diagnostic and therapeutic strategies, such as the application of novel biomarkers and the modulation of gut microbiota, should be considered in the future to guide personalized medicine and improve the response to ICIs in patients with NAFLD-related HCC

Future Modulation of Gut Microbiota: From Eubiotics to FMT, Engineered Bacteria, and Phage Therapy

The human gut is inhabited by a multitude of bacteria, yeasts, and viruses. A dynamic balance among these microorganisms is associated with the well-being of the human being, and a large body of evidence supports a role of dysbiosis in the pathogenesis of several diseases. Given the importance of the gut microbiota in the preservation of human health, probiotics, prebiotics, synbiotics, and postbiotics have been classically used as strategies to modulate the gut microbiota and achieve beneficial effects for the host. Nonetheless, several molecules not typically included in these categories have demonstrated a role in restoring the equilibrium among the components of the gut microbiota. Among these, rifaximin, as well as other antimicrobial drugs, such as triclosan, or natural compounds (including evodiamine and polyphenols) have common pleiotropic characteristics. On one hand, they suppress the growth of dangerous bacteria while promoting beneficial bacteria in the gut microbiota. On the other hand, they contribute to the regulation of the immune response in the case of dysbiosis by directly influencing the immune system and epithelial cells or by inducing the gut bacteria to produce immune-modulatory compounds, such as short-chain fatty acids. Fecal microbiota transplantation (FMT) has also been investigated as a procedure to restore the equilibrium of the gut microbiota and has shown benefits in many diseases, including inflammatory bowel disease, chronic liver disorders, and extraintestinal autoimmune conditions. One of the most significant limits of the current techniques used to modulate the gut microbiota is the lack of tools that can precisely modulate specific members of complex microbial communities. Novel approaches, including the use of engineered probiotic bacteria or bacteriophage-based therapy, have recently appeared as promising strategies to provide targeted and tailored therapeutic modulation of the gut microbiota, but their role in clinical practice has yet to be clarified. The aim of this review is to discuss the most recently introduced innovations in the field of therapeutic microbiome modulation