Tabibian et al. report the efficacy of vancomycin and metronidazole in the treatment of primary sclerosing cholangitis (PSC). The use of antibiotics to target enteric Gram-negative organisms is an established approach in the treatment of infective liver disease, portal hypertension and chronic liver disease. In PSC, there are a paucity of therapeutic agents to halt progression to cirrhosis and hepatic failure. This study is the first double-blind, pilot study to demonstrate a link between antibiotic use and improvement in liver function tests in PSC and ratifies data from previous case reports and small number studies.
Disruption of the host–gut microbiota homeostasis can lead to disease development, and has been appreciated in inflammatory bowel diseases where functional changes, specifically decreasing microbiota diversity, may drive pathogenesis.[3, 4] Increasingly, attention is being focused upon this contribution in the development of liver disease.
The respective effects of vancomycin and metronidazole on Gram-positive and anaerobic populations, and the impact this has upon the bacterial species and products translocating from the gut to the portal circulation, which shapes the innate immune response via pattern recognition receptors (PRRs) such as toll-like receptors (TLR), are of specific interest. The interplay between TLR-4, whose signalling pathway is associated with increased pro-inflammatory cytokine production, which promotes pro-fibrotic states, and TLR-3, which attenuates these effects via immunoregulatory cytokines, e.g. interleukin-10, is an appealing starting point, given the known activation of TLR-4 by lipopolysaccharide.[5-8]
The data presented by Tabibian and colleagues highlight a number of avenues for future research. As discussed by the authors, in the first instance, a larger multicentre randomised controlled trial is essential, but the opportunities of investigating the influence upon the immune response and potential manipulation to minimise pathophysiology remain a tantalising possibility.