The gut-liver-muscle axis in liver cirrhosis

Liver cirrhosis is a silent disease, killing over one million per year worldwide. More than half of the patients suffer from sarcopenia, a progressive loss of muscle mass and function. Sarcopenia impairs prognosis and quality of life in liver cirrhosis. It is not completely understood why so many patients with cirrhosis develop sarcopenia. Better nutrition and physical activity are not enough to prevent sarcopenia. We think that an altered gut flora may cause a leaky gut and allow bacterial products to enter the body. This can the cause inflammation which then impairs muscle cell function. To study this we will do a project consisting of three parts. First, we will study patients with cirrhosis and assess the presence of sarcopenia, leaky gut, bacterial products and inflammation. Furthermore, in this study we will assess the composition and function of the gut flora and the products that are produced by the gut flora. In the second part we will combine these data with modern bioinformatics methods to find out which bacteria or which bacterial products or metabolites are most likely to contribute to the development of sarcopenia. In the third part we will then test the identified metabolites on different cell culture models to understand the underlying mechanisms. With this project we will learn what causes sarcopenia in cirrhosis and we will be able to develop targeted therapies. This will in the future help patients with liver cirrhosis to prevent sarcopenia or to slow down the progression.

Liver cirrhosis is a silent killer of more than 1 million people worldwide each year. More than half of patients with liver cirrhosis suffer from sarcopenia - muscle wasting that is accompanied by loss of muscle strength and physical weakness. Sarcopenia worsens the prognosis and quality of life of people with liver cirrhosis. Why so many people with cirrhosis of the liver develop sarcopenia is not entirely clear. There is no specific treatment for sarcopenia. Healthy eating and exercise alone are not enough to prevent or stop this consequence of cirrhosis. We postulated that changes in the composition of the intestinal microbiome (the bacteria in our intestines) lead to increased intestinal permeability ("leaky gut") and thereby bacterial components enter the circulation and lead to an inflammatory reaction that affects the muscle cells harms. To investigate this, we built a large clinical cohort of patients with and without sarcopenia and with and without liver cirrhosis. We were able to show that sarcopenia is associated with changes in the intestinal microbiome and, above all, also changes the function of the intestinal microbiome. Particularly relevant substances produced by the intestinal microbiome are amino acids, short-chain fatty acids and bile acids. In particular, bile acids produced by the intestinal microbiome can damage muscle function. In addition, our work highlighted weaknesses in the current standard diagnosis of sarcopenia and helps us to understand how relevant the intestinal microbiome and its metabolic products are for the further progression of the disease in cirrhosis. This will allow us to expand our knowledge of sarcopenia in liver cirrhosis and develop targeted therapies that will then benefit patients with liver cirrhosis and sarcopenia to either prevent the development of sarcopenia or slow its progression.