Abstract
Persistent liver injury can drive asymptomatic stable cirrhosis to symptomatic acute decompensated cirrhosis (AD) or acute-on-chronic liver failure (ALCF). This progression to decompensated cirrhosis is defined by the development of ascites, gastrointestinal haemorrhage, hepatic encephalopathy, and/or bacterial infections, with acute hepatic and extrahepatic organ failure for ACLF. The progression to decompensated cirrhosis significantly increases the mortality rates, with a 28-day mortality rate of 33.9% for ACLF. Importantly, AD and ACLF remain clinically unmet needs with lack of targetable therapeutic options and there is an urgent need to understand the pathophysiology to identify and develop treatments. The progression from stable cirrhosis to AD and ACLF is multi-facted, complex and the molecular pathways responsible are not fully understood. However, clinically, progression to AD and ACLF is characterised under the umbrella of the PIRO definition, where predisposing factors (Predisposition) can contribute to precipitating events of AD and ACLF (Injury) and elicit a systemic inflammatory host response (Response), leading to multi-organ failure (Organ failure).Many PIRO factors are associated with increased bacterial translocation from the intestine, due to the impaired intestinal barrier and gut dysbiosis associated with cirrhosis. Translocating bacteria from the intestine can induce hepatic inflammation and concomitant immunoparesis with an increased susceptibility to the bacterial infections, these not only drive progression, but also contribute directly to systemic inflammation that is a hallmark of AD and ACLF. However, the mechanisms that facilitate increased intestinal permeability and consequent bacterial translocation in these patients remains unknown.
The aim of this PhD project was to investigate the mechanisms underpinning intestinal epithelial injury and response that may contribute to increased permeability, bacterial translocation, and progression of cirrhosis. The chapters described herein delineate the role of intestinal endoplasmic reticulum (ER) stress mediated inflammasome activation on epithelial cell death in cirrhosis, report on the development of a permeability assay for mouse intestinal organoids and assess the impact of intestine epithelial stem cell and cell death disruption that promotes intestinal permeability in cirrhosis.
Firstly, I showed no ER stress or inflammasome activation in cirrhosis and no ER stress sensitised pyroptosis via the non-canonical inflammasome pathway in intestine epithelial cells. Secondly, I showed that luminal propidium iodide-stained dead cells in intestinal organoids can be analysed to measure intestinal organoid permeability. And lastly, I showed reduced stemness and increased intestine epithelial cell death in cirrhosis. Taken together this work contributes to our understanding of the molecular mechanisms of barrier failure and identifies pathways that maybe modulated for better outcomes in patients with liver cirrhosis.
| Date of Award | 1 Feb 2024 |
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| Original language | English |
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| Supervisor | Ugo Soffientini (Supervisor), Shilpa Chokshi (Supervisor) & Gautam Mehta (Supervisor) |