The Time is Ripe for a Randomized Controlled Trial of Oral Vancomycin in Primary Sclerosing Cholangitis

We read with interest the recent publication by Zigmond et al1Zigmond E. et al.Clin Gastroenterol Hepatol. 2023; 21: 1223-1232.e3Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar titled “Bile Duct Colonization With Enterococcus sp. Associates With Disease Progression in Primary Sclerosing Cholangitis.” Primary sclerosing cholangitis (PSC) is a chronic, often progressive biliary disease, which can lead to end-stage liver disease and liver transplantation.2Karlsen T.H. et al.J Hepatol. 2017; 67: 1298-1323Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar The pathogenesis of PSC remains incompletely defined; however, the gut microbiota is increasingly recognized as a key player in PSC development.3Little R. et al.World J Gastroenterol. 2020; 26: 2768-2780Crossref PubMed Google Scholar In this study, the authors have described that colonization of biliary fluid with Enterococci sp in patients with PSC undergoing endoscopic retrograde cholangiopancreatography is associated with increased risk of disease progression, defined as decompensated cirrhosis, liver transplantation, or death. These findings might fit with the data on the role of Enterococci in the gut microbiota in murine and human PSC models, their association with bile acids metabolism, and with disease progression in PSC.4Awoniyi M. et al.Gut. 2022 Jun 15; (gutjnl-2021-326500)PubMed Google Scholar,5Nakamoto N. et al.Nat Microbiol. 2019; 4: 492-503Crossref PubMed Scopus (220) Google Scholar We applaud the authors for adding another piece of the puzzle in the relationship between gut microbes and PSC. Zigmond et al,1Zigmond E. et al.Clin Gastroenterol Hepatol. 2023; 21: 1223-1232.e3Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar while reinforcing the rationale for testing antibiotics in PSC, particularly oral vancomycin (OV) therapy, underscored that how this affects the biliary microbiome remains unknown. Authors concluded that further research is necessary to investigate the functional implications of Enterococci for mucosal immune responses and that “if [their] results are confirmed by independent studies, specific therapies targeting Enterococci, e.g., by using bacteriophages, may represent a promising novel therapeutic strategy for PSC.” We agree that additional studies of specific bacteriophage targeting may prove beneficial in the treatment of PSC; however, the pharmaceutical development of such agents is years in the making. In the interim, patients with PSC continue to experience disease progression and liver failure. It is likely that manipulation of the bacterial species in the colon by antibiotics will prove to be of benefit in the treatment of PSC. We acknowledge that OV might not work for all patients with PSC,6Deneau M.R. et al.Hepatology. 2021; 73: 1061-1073Crossref PubMed Scopus (39) Google Scholar but there is substantial evidence that some patients with PSC taking OV will experience improvement in liver function tests, biliary strictures, and gut symptoms.7Ali A.H. et al.Scand J Gastroenterol. 2020; 55: 941-950Crossref PubMed Scopus (22) Google Scholar, 8Shah A. et al.Semin Liver Dis. 2019; 39: 432-441Crossref PubMed Scopus (42) Google Scholar, 9Rahimpour S. et al.J Gastrointestin Liver Dis. 2016; 25: 457-464Crossref PubMed Scopus (68) Google Scholar Based on the published experience of OV in PSC, and in view of its potentially attractive properties by acting as an immune modulator in the gut and as an antimicrobial against gram-positive bacteria, larger long-term randomized controlled trials of OV versus placebo are needed. Two randomized controlled trials using OV in PSC are already recruiting in the United States (Mayo Clinic, NCT03710122) and in United Kingdom (University of Birmingham, NCT05376228), and another will start at the beginning of 2023 in Italy (University of Milano-Bicocca, EudraCT number 2022-00875-37) led by our group. The aim of our randomized controlled trial will be to ascertain the efficacy and the safety of OV in PSC, with the accepted limitations on available surrogate end points. Moreover, the trial through a multiomics investigation on blood, urine, and stool affords newfound analytical opportunities to understand how these microbes and their metabolites operate before and after OV therapy, hopefully shedding light on pathogenetic mechanisms in PSC. Novel disease-modifying therapies targeting bile acid homeostasis, fibrosis, and gut inflammation are under development; but one can mitigate the delay to patients with PSC now, by repurposing OV, which can control bile duct and gut inflammation and relieve symptoms in patients with inflammatory bowel disease. Bile Duct Colonization With Enterococcus sp. Associates With Disease Progression in Primary Sclerosing CholangitisClinical Gastroenterology and HepatologyVol. 21Issue 5PreviewPrimary sclerosing cholangitis (PSC) is characterized by chronic inflammation of the biliary mucosa. Bile ducts in PSC are often colonized with bacteria. Although accumulating evidence demonstrates the importance of microbiota for mucosal immunity, little is known about the impact of bile duct colonization with bacteria on the clinical course of PSC. Full-Text PDF Open AccessReplyClinical Gastroenterology and HepatologyVol. 21Issue 10PreviewWe thank Drs Halma, Cristoferi, and Carbone for their interest in our paper1 in which we have shown that bile duct colonization with Enterococcus sp, and not with other bacterial species, is associated with disease progression in primary sclerosing cholangitis (PSC). Full-Text PDF