Macnaughtan, JS; (2017) Modulation of the Gut-Liver Axis in Cirrhosis with Activated Carbon. Doctoral thesis , UCL (University College London).

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Abstract

Abstract Introduction A substantial body of evidence now exists to implicate bacterial products such as endotoxin in the pathogenesis of cirrhosis and determinants of outcome, most markedly in advanced disease. Strategies to modulate this process clinically are currently limited to antibiotics with the attendant risk of superinfection and resistance. Yaq-001, a new, synthetic non-absorbable carbon, has been shown to exhibit a high adsorptive capacity for bacterial toxins and thus represent a novel strategy to modulate the gut-liver axis. Methods Neutrophil function, cytokine profile and endotoxin concentrations were determined in the splanchnic circulation of cirrhotic patients. Gut barrier integrity, innate immune function and microbiome analysis was performed in bile duct ligated (BDL) rats treated with or without oral Yaq-001. Ob/ob and MCD mice were treated with or without Yaq-001. Effects on liver injury, immune function and metabolomic profile were determined. Results Portal compartmentalisation of neutrophil dysfunction and endotoxaemia was observed and associated with an anti-inflammatory cytokine profile. In vitro Yaq-001 exhibited a high adsorptive capacity for endotoxin and acetaldehyde without any effect on bacterial growth kinetics. Yaq-001 administration in BDL rats significantly improved organ injury, portal pressure and innate immune profile along the gut-liver axis. In vivo and in vitro endotoxin sensitivity was improved. Oral Yaq-001 was found to significantly improve liver injury, Kupffer cell function and metabolomic profile in NASH models. Conclusions Defects at the gut barrier interface play a key role in driving bacterial translocation rates with preserved integrity of hepatic immune surveillance despite advanced disease. Oral administration of Yaq-001 in models of cirrhosis and NASH is safe and associated with a significant improvement in organ injury, portal pressure, innate immune function and endotoxin sensitivity. These studies suggest Yaq-001 represents a promising new strategy for the management of liver disease.

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