Defining the temporal evolution of gut dysbiosis and inflammatory responses leading to hepatocellular carcinoma in Mdr2 −/− mouse model

Abstract

Background Emerging evidence implicates the gut microbiome in liver inflammation and hepatocellular carcinoma (HCC) development. We aimed to characterize the temporal evolution of gut dysbiosis, in relation to the phenotype of systemic and hepatic inflammatory responses leading to HCC development. In the present study, Mdr2 −/− mice were used as a model of inflammation-based HCC. Gut microbiome composition and function, in addition to serum LPS, serum cytokines/chemokines and intrahepatic inflammatory genes were measured throughout the course of liver injury until HCC development. Results Early stages of liver injury, inflammation and cirrhosis, were characterized by dysbiosis. Microbiome functional pathways pertaining to gut barrier dysfunction were enriched during the initial phase of liver inflammation and cirrhosis, whilst those supporting lipopolysaccharide (LPS) biosynthesis increased as cirrhosis and HCC ensued. In parallel, serum LPS progressively increased during the course of liver injury, corresponding to a shift towards a systemic Th1/Th17 proinflammatory phenotype. Alongside, the intrahepatic inflammatory gene profile transitioned from a proinflammatory phenotype in the initial phases of liver injury to an immunosuppressed one in HCC. In established HCC, a switch in microbiome function from carbohydrate to amino acid metabolism occurred. Conclusion In Mdr2 −/− mice, dysbiosis precedes HCC development, with temporal evolution of microbiome function to support gut barrier dysfunction, LPS biosynthesis, and redirection of energy source utilization. A corresponding shift in systemic and intrahepatic inflammatory responses occurred supporting HCC development. These findings support the notion that gut based therapeutic interventions could be beneficial early in the course of liver disease to halt HCC development.

Dynamics in Circulating Proinflammatory Biomarkers for Prognostic Assessment of Patients With Advanced HCC – A Substudy From the SORAMIC Trial

“…Alterations in gut microbiota composition are associated with hepatic inflammatory diseases and may play a contributory role in hepatic carcinogenesis (32). Dysbiotic gut microbiota composition leads to increased hepatic exposure with gutderived microbiota-associated molecular patterns (MAMPs) that include lipopolysaccharides (LPS), a cell wall component of Gram-negative bacteria.…”

“…Bacterial compounds reach the liver via the portal blood flow and are eliminated by Kupffer cells under normal conditions (33). In a mouse model, LPS levels increase during the course of chronic liver disease fostering proinflammatory responses in the periphery and in the liver (32,34). Plasma LPS concentrations correlate with the degree of liver dysfunction (35,36).…”

Crosstalk between Gut Microbiota and Host Immunity: Impact on Inflammation and Immunotherapy

“…While it has long been thought that gut microbiota dysbiosis precedes the development of HCC, this causal relationship has not been explored in depth until more recently. Behary, Raposo et al recently found, before HCC progression, that gut microbiota dysbiosis is in tandem with early onset liver injury that is followed by an LPS-dependent Th1-and Th17-mediated cytokine response [308]. Further investigation should determine whether gut microbiota dysbiosis is a cause or consequence in the liver injury preceding HCC.…”

Inflammasome and pyroptosis in autoimmune liver diseases

“…Bile acids and other regulatory molecules have been shown to induce the activation of the NLRP3 inflammasome ( 153 ). This causes the secretion of IL-1β, thus leading to transinflammatory liver injury and playing a role in reactive cholangiocyte inflammation in patients with PSC ( 154 ). In PSC mouse models fed with 3, 5-dioxy-carboxyl, 1, 4-dihydrogen collidine (DDC) and in human PSC, NLRP3 inflammasomes are increased in reactive bile duct cells, leading to IL-18 secretion and epithelial functional barriers of bile duct cells, thereby affecting the development of bile duct disease ( 155 ).…”