A phase 1/2 trial of Bifidobacterium breve supplementation in infants with cholestasis and suspected biliary atresia

About This Grant

PROJECT SUMMARY/ABSTRACT: Biliary atresia (BA), the most common potentially fatal cause of neonatal cholestasis in the U.S., is a progressive fibrostenotic disorder of the extrahepatic biliary system that leads to bile accumulation, severe liver damage, and ultimately rapid liver failure in the first year of life if untreated. The only non-liver transplant treatment is the Kasai portoenterostomy (KP), a surgical procedure to restore bile flow. Two-year native liver survival after KP is predicted by clearance of jaundice (COJ; serum total bilirubin <2mg/dL by 3 months after KP). Yet, 50% of infants will not obtain COJ after KP, leading to liver transplantation within two years. Critically, no interventions currently improve COJ after KP because the factors influencing this crucial outcome remain poorly understood. Our recent K23-funded, multicenter fecal microbiome studies (the STOol Microbiome in Infants with Cholestasis, STOMIC, n=172 infants from 8 sites over 8 years) pilot (n=8) and preliminary data (n=20) revealed that infants who achieved COJ had significantly different gut microbiome compositions compared to those who did not, with these differences evident even before KP. In particular, the abundance of Bifidobacterium, specifically B. breve at early time points, strongly associated with improved bile flow outcomes after KP. Neither pre-KP therapeutics nor Bifidobacterium have been investigated in BA. B. breve M16V strain, combined with prebiotics oligofructose and inulin, is commercially available in Neocate Syneo formula with demonstrated safety in both healthy infants and those with milk protein allergies. While Neocate Syneo effectively increases B. breve abundance in stool of healthy infants, suggesting it could successfully modify the gut microbiome in BA patients, it is not known how this formula may impact neonates with BA. Thus, we propose a single-center phase 1/2 trial with 8 infants to evaluate B. breve supplementation in infants with cholestasis to address our central hypothesis that supplementation of B. breve via Neocate Syneo in infants with biliary atresia will be well tolerated while increasing abundance of B. breve in the fecal microbiome. A phase 1/2 trial will test this hypothesis in 2 aims: In aim 1, we will assess the safety and tolerability of Bifidobacterium breve supplementation in infants with cholestasis. In aim 2, we will determine the effects of Bifidobacterium breve intake on stool microbiome in infants with cholestasis. We expect to establish a favorable safety profile with minimal GI symptoms, providing the first evidence for B. breve tolerability in cholestatic infants and creating a foundation for efficacy testing. Additionally, we anticipate a significant increase in B. breve abundance post-supplementation, establishing proof-of-concept for microbiome modulation in BA and identifying key targets for intervention in future R01-funded studies. Successful completion of this award will continue to build the strong foundation for the PI’s career as an independent PI performing clinical trials, supporting the long-term goal of becoming an expert in the microbiome in cholestatic diseases of infancy and childhood.