Wednesday , November 25 2020

Scientists uncover unexpected players in acute liver failure

Acute liver failure is a rapidly developing, devastating disease that results in death in 80% of cases, unless an urgent liver transplant is performed. In the developed world, its main cause is a significant overdose of acetaminophen, also known as paracetamol.

In a study published in Nature Medicine, researchers from Profs labs. Eran Elinav and Ido Amit in the Weizmann Institute of Science Institute of Immunology, using mouse models of acute liver failure, have discovered three new subsets of liver cells that orchestrate the development of this condition.

The scientists also revealed signals – from the gut microbiome as well as the infected liver – that collectively activate these cells, and show that selective blocking of these signals and depletion of the microbiome led to a marked improvement in liver function and prolonged survival in mice. Analysis of liver tissue from human patients with acute liver failure revealed a striking molecular pattern similar to that reported in mice in the study, raising hopes that future findings in mice will be replicated. convert to human treatment.

Aleksandra Kolodziejczyk, a postdoctoral fellow in the Elinav laboratory, led this project in collaboration with other scientists at the Weizmann and Dr. Science Institute. Amir Shlomai of the Liver Institute, Rabin Medical Center.

Kolodziejczyk and her colleagues began their exploration by creating gene expression profiles of 45,000 individual mouse liver cells, ultimately producing a comprehensive liver cell atlas under conditions of health and acute liver failure. The scientists identified 49 cell subsets, of which three new subsets – among stellate, endothelial and Kupffer cells – became abnormally activated as the acute liver failure progressed in the rat. These previously described cell subsets secreted a large variety of substances that attracted immune cells from outside the liver, which subsequently contributed to its damage. The three new cell subtypes shared a typical expression pattern of 77 genes – a pattern regulated by the same regulatory protein, the transcription factor MYC – that suggested that these cells might be activated through a common program.

The researchers suspected that the newly revealed activation pathway might be regulated by signals from the gut microbiome. This makes anatomical sense, as the gastrointestinal tract drains to the liver through a large network of veins, exposing the liver directly to substances produced in the gut and by its microbes. When the scientists exhausted the mouse microbiome by administering broad-spectrum antibiotics, the symptoms of liver failure eased. Moreover, when they induced acute liver failure in germ-free, non-microbial mice, the condition was much less severe than in regular mice. Further studies of mice with and without gut microbiome revealed that, during acute liver failure, specific molecules produced by the microbiome accumulate in the liver, where they activate the MYC protein in the three contributing stem cell subtypes to liver damage. In the absence of a microbiome, MYC activation was weakened, leading to reduced liver damage.

Kolodziejczyk then worked out the molecular details of MYC activation. She found that the molecules coming from the microbiome activate the MYC program through surface receptors on the three cell subtypes she had earlier identified as exacerbating liver failure. It also found that the MYC program was similarly activated – that is, through the same receptors on all three cell subtypes – by signals coming from paracetamol-damaged liver cells.

When mice were genetically depleted of active receptors, given that drugs that blocked MYC or otherwise interrupted the signals between these receptors and MYC, they no longer developed acute liver failure and extended their survival . Gene expression analysis of individual cells showed that the three newly identified cell subtypes were no longer abnormally activated in the treated mice, and this reduced immune cell infiltration and damage to the liver as a result.

Finally, the researchers joined Dr. Shlomai to analyze liver samples from patients with acute liver failure and compare them with samples from healthy liver donors. Those were characterized by the patients – but not by healthy donors – activating a robust MYC that was similar to that seen in mice. These results raise the possibility that blocking the MYC program by drugs, together with microbiome modulation, may be a potential treatment for acute liver failure.

Our findings provide a first step toward achieving a comprehensive understanding of how the microbiome interacts with the host while contributing to acute liver failure. Such information could lead to a new treatment option for this debilitating and destructive disorder. “

Professor Eran Elinav, Department of Immunology, Weizmann Institute of Science


Weizmann Institute of Science

Journal reference:

Kolodziejczyk, AA, et al. (2020) Acute liver failure is regulated by MYC- and microbe-dependent programs. Nature Medicine.

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