Rifaximin as a Therapeutic Agent for Reducing Endotoxemia and Fibrosis in Neonatal Cholestasis

PROJECT SUMMARY Biliary atresia (BA) is a neonatal cholestatic liver disease and the leading cause of pediatric liver transplants. The primary treatment, known as the Kasai procedure, aims to promote bile flow by creating a direct connection between the liver and the intestine. However, the success of this procedure varies, and many children still require liver transplants within two years. The progression of fibrosis, driven by hepatocyte injury, bile duct obstruction, ductular reaction, and hepatic stellate cell (HSC) activation, is a key factor leading to liver transplant necessity. Identifying approaches to reduce fibrosis progression is a potential mechanism to reduce the need for liver transplant in BA patients. Bile acids are often considered key factors in initiating liver inflammation and promoting fibrosis development. However, in addition to elevated bile acids, infants with BA have elevated blood endotoxin levels, originating from gut bacteria translocation. Endotoxin is known to activate hepatic stellate cells, promoting hepatic collagen deposition, even without elevated bile acids. Our preliminary results in bile duct-ligated neonatal piglets demonstrate that oral antibiotic treatment reduces fibrosis development without preventing increased bile acid concentrations or ductular reaction over a two-week period. This finding suggests that fibrosis progression can be suppressed by reducing endotoxin load from gut bacteria. This study will investigate the use of a clinically relevant, non-absorbable antibiotic to reduce bacterial-derived inflammation and subsequent fibrosis in neonatal cholestasis, potentially offering a safer alternative to high-potency, absorbable antibiotics that pose a risk of drug- induced liver injury during BA. We hypothesize that suppression of bacteria-derived inflammation using non- absorbable antibiotics will reduce fibrosis development during obstructive cholestasis in the neonatal period. To research this hypothesis, we will: 1) determine if a non-absorbable antibiotic suppresses the development of liver fibrosis and injury, and 2) determine whether high concentrations of bile acids enhance fibrosis activation induced by endotoxin in a novel 3D spheroid cell culture model.