Liver fibrosis is a major public health problem and its burden continues to grow worldwide due to an increase in its main etiological factors: harmful alcohol consumption and non-alcoholic fatty liver disease (NAFLD) (Pimpin L, et al. J. Hepatol, 2018). The liver has a remarkable capacity to regenerate, however, if the healing does not proceed normally, chronic liver inflammation leads to fibrosis, cirrhosis, and the development of liver cancer called hepatocellular carcinoma (Pimpin L, et al. J. Hepatol, 2018). There is no specific treatment for fibrosis other than removing the underlying etiological agent (e.g. alcohol, losing weight), but this is not easily achieved in all the patients. However, among patients exposed to a hepatotoxic injury such as alcohol or metabolic syndrome, as many as 20% will develop liver fibrosis, partly due to host, environmental and genetic factors (EASL, 2018).
The molecular mechanisms leading to liver fibrosis are complex and involve an interplay between multiple cells including immune, vessel (called endothelial), and supporting ( called mesenchymal) cells located within areas of scarring, termed the fibrotic niche. The use of techniques that study the genetic material inside the cells (like single-cell RNA sequencing techniques) has increased our understanding of hepatic homeostasis in fibrosis by identifying different specific cell subpopulations (endothelial cells, macrophages and collagen-producing mesenchymal cells) that interact spatiotemporally to drive fibrosis within the fibrotic niche (Ramachandran P, et al. Nature, 2019).
However, the drivers of these particular cellular phenotypes and why fibrosis develops only in a subset of patients are concepts that are not yet fully understood. In recent years, there has been an increasing body of data suggesting that the microbiome (which encompasses the microorganisms inside the body: bacteria, fungi, and viruses) can modify liver homeostasis. The microorganisms and microbial-derived compounds that reach the liver (as the liver is connected to the gut directly through the portal vein) are rapidly recognized by liver cells. Activation of these cells, leads to hepatic inflammation and hepatocyte damage and in the end to liver fibrosis. This connection is often referred as the gut-liver axis. While normal microbiota prevents liver fibrosis in mice (Mazagova M, et al. FASEB J. 2015), in different liver diseases that develop fibrosis, there are alterations in the composition and function of the gut microbiota and of microbial-derived metabolites, that drive the individual susceptibility to develop liver inflammation (Llopis M, et al. Gut, 2016). Moreover, in animal models, manipulation of the gut microbiota using antibiotics or prebiotics, decreases liver fibrosis, suggesting the existence of fibrosis-associated intestinal microbiota (Seki, E. et al. Nat. Med, 2007, Llorente, C. et al. Nat. Comm., 2017, Kisseleva T, et al. Nat Rev Gastroenterol Hepatol., 2021).
The key objective of my project is to gain a comprehensive understanding of how microbiota modifies liver homeostasis and contributes to liver fibrosis using analysis of the network perturbation in disease, coupled with microbiome experimental techniques.
