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Cirrhosis is sometimes called end stage liver disease. This simply means that it occurs after other stages of liver damage which can include inflammation (hepatitis), fatty deposits (steatosis), and increased stiffness and mild-scarring of the liver (fibrosis). Such liver damage can be due to alcoholism, infections, unhealthy live style, bad nutrition or eating habits, severe injury, or other causes. That’s why it is so important to avoid any liver damage in the first place and to do everything to keep your liver healthy and functional. Liver means life, and you only have one of each!
Cirrhosis is classified as compensated or decompensated. Compensated cirrhosis is where the liver is coping with the damage and maintaining its important functions. Many people with compensated cirrhosis can feel quite well and live for many years without needing a liver transplant. Until a certain point, the liver can function relatively well even when it is quite severely damaged. Any further damage to the liver may be lethal though. In decompensated cirrhosis, the liver is not able to perform all its functions adequately. People with decompensated cirrhosis often suffer from serious symptoms and complications such as portal hypertension (high blood pressure within the vessel system travelling through the liver), bleeding varices (life-threatening bleeding from blood vessels in the oesophagus or stomach), ascites (accumulation of fluids in the belly, more specifically in the peritoneal cavity), severe infections, encephalopathy (cerebral failure), eventually leading to acute-on-chronic liver failure (ACLF), followed by multi-organ failure and death.
Pathogenesis of decompensated liver cirrhosis and the progression from decompensation to acute-on-chronic liver failure (ACLF).
The gut microbiome represents the largest pool of genetic material in the body with high metabolic activity. Most microbes live in symbiosis with our body, meaning we need them to help us digest and absorb our food properly. Each human being harbours at least 40 billion (4 x 1013) living microbial cells. In healthy conditions, the human (here also called the “host”) tightly regulates the gut microbiome, its distribution, composition, and activity by secretion of bile acids and antibacterial peptides. This ensures that an ideal balance of “just enough microbes” is maintained. By now, there is sufficient evidence that changes in microbiome might modify and even halt the progression of liver disease and that – compared to healthy controls – profound differences in the microbiome are present in liver cirrhosis, the final stage of all chronic liver diseases. However, the dynamics and mechanisms are not yet fully explored.
In cirrhosis, the epithelial barrier of the gut has become quite damaged, resulting in a so called “leaky gut”. This means that bacteria and their metabolites can now enter the portal blood circulation (a process called “bacterial translocation”) to interact with immune cells, interact with vascular cells, reach the liver, and interact with liver cells (hepatocytes). Within cirrhotic patients, a subgroup experience deterioration of their underlying cirrhosis, called decompensation episodes, usually requiring hospital admission. In 30% of these patients, the clinical situation deteriorates further and acute-on-chronic liver failure (ACLF) occurs. The progression from decompensation to ACLF is reflected in an extensive activation of systemic inflammation, affecting many cytokines and inflammatory systems. It is likely that bacterial translocation leads to this burst of inflammation. More often than not decompensation and ACLF develop without identifiable precipitating events, suggesting that endogenous mechanisms, e.g. translocation of detrimental bacteria, are involved.
Currently known and suggested gut-liver interactions in cirrhosis. Impaired epithelial barrier (“leaky gut”) allows bacteria or bacterial products (metabolites) to translocate into the blood circulation and reach the liver. There, they interact with circulating and resident immune cells and liver cells. Concomitantly, bile acids and other molecules (e.g. antibacterial peptides) originating from the liver arbitrate between liver and gut microbiota.
- Integration of existing clinical, laboratory, microbiome and multi-omics data from 12 cohorts, combining more than 200,000 data points from more than 10,000 subjects
- Development of microbiome-based tests for better stratification of cirrhosis patients leading to personalized prediction and prevention of decompensation and ACLF and more personalized allocation to treatment
- Validation of new microbiome-based markers in a clinical trial to enable prediction of response and thereby optimization of Rifaximin or albumin treatment
- Design of modern, effective nanobiosensors as useful clinical tools to set the foundation for personalized therapy
- Involvement of world-leading microbiome specialists, technology leaders and clinical experts for scientific excellence, the European Liver Patients Association (ELPA) and the European Association for the study of the Liver (EASL)
- Improved specificity of diagnostic tools
- Better prediction and thereby prevention of decompensation and ACLF
- Stratifying and personalizing the treatment of decompensated liver cirrhosis and ACLF
- Increasing survival and decreasing health care burden
- Novel diagnostic and therapeutic approaches to stimulate innovation in the European healthcare industry
Diagram of the current disease progression (upper panel) versus personalized medicine applying the results from MICROB-PREDICT (lower panel).