Instead of transplantation
A new method for the treatment of acute liver failure has been proposed
Israeli doctors have found that exposure to certain types of liver cells and bacteria living in the intestine can improve the condition of acute liver failure.
Liver of a mouse with acute liver failure before and after treatment. Figure from the press release of the Weizmann Institute of Science Surprising Players in Acute Liver Failure Point to Potential Treatment – VM.
Acute liver failure is a devastating, rapidly progressing disease. If the patient does not have an emergency liver transplant, in 80% of cases the disease leads to death. In developed countries, the main cause of acute liver failure is a significant overdose of paracetamol.
Researchers from the Department of Immunology at the Weizmann Institute in experiments on mice with acute liver failure identified three groups of liver cells that affect the development of this condition. They also found signals from the intestinal microbiome and from the affected liver activating these cells. Blocking these signals and removing intestinal bacteria led to a marked improvement in liver health and increased survival in mice. Analysis of the liver tissue of patients with acute liver failure revealed a molecular pattern strikingly similar to that found in mice during the study. This gives hope that the results obtained in mice can be used to treat people in the future.
The study was initiated by determining the gene expression profiles of 45,000 individual mouse liver cells in a healthy state and in acute liver failure. Scientists found that three types of cells – stellate, endothelial and Kupfer cells – showed abnormal activity during the development of liver failure. These cells secreted a large amount of substances that attract immune cells to the liver, which contributed to its damage. All three cell subtypes have a characteristic pattern of 77 gene expression controlled by the same regulatory protein, the transcription factor MYC, which indicated that all these cells can be activated using a common program.
The authors of the work suggested that intestinal bacteria can influence the activation of these cells. When they significantly reduced the intestinal microbiome of mice with antibiotics, the symptoms of liver failure weakened. Moreover, when the researchers caused acute liver failure in mice deprived of the microbiome, their condition was much less severe than in normal mice. Further studies of mice with and without an intestinal microbiome have shown that during acute liver failure, individual substances generated by the microbiome accumulate in the liver, where they activate the MYC protein in three subtypes of liver cells that contribute to its damage. In the absence of a microbiome, MYC activation was weakened.
Having studied the activation of the MYC protein at the molecular level, the scientists found that it is caused by exposure to certain membrane receptors of these three cell types. Through the same receptors, the protein is also activated by signals from liver cells affected by paracetamol. In mice with genetically disabled receptors on these cells or when receiving drugs that block the action of the MYC protein, the development of acute liver failure was inhibited.
"Our results were the first step towards achieving a comprehensive understanding of how the microbiome interacts with the host, contributing to acute liver failure," the authors say. "This knowledge may lead to a new way of helping with this incurable and devastating disorder."
The study was published in the journal Nature Medicine (Kolodziejczyk et al., Acute liver failure is regulated by MYC- and microbiome-dependent programs).
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