Claudin-3, Lipopolysaccharide Binding Protein, and Jaundice Clearance in Infants with Biliary Atresia

Vandana Jain; Jessica Nulty; Emma C Alexander; Charlotte Burford; Mark Davenport; Shilpa Chokshi; Antonio Riva; Matthew J Dalby; Anita Verma; Lindsay J Hall; Muhammed Yuksel; Anil Dhawan

doi:10.1016/j.jpeds.2025.114703

Claudin-3, Lipopolysaccharide Binding Protein, and Jaundice Clearance in Infants with Biliary Atresia

J Pediatr. 2025 Jun 23:114703. doi: 10.1016/j.jpeds.2025.114703. Online ahead of print.

Authors

Affiliations

¹ Paediatric Liver, GI and Nutrition Centre and Mowatlabs, Kings College Hospital, London, UK. Electronic address: vjain@nhs.net.
² Paediatric Liver, GI and Nutrition Centre and Mowatlabs, Kings College Hospital, London, UK.
³ Department of Paediatric Surgery, Kings College Hospital, London, UK.
⁴ Roger Williams Institute of Hepatology, Foundation for Liver Research, London, UK; School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.
⁵ Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK.
⁶ Department of Infection Science, Paediatric Liver, GI and Nutrition Centre and Mowatlabs, King's College Hospital, London, UK.
⁷ Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK; Food, Microbiomes and Health, Quadram Institute Bioscience, Norwich Research Park, Norwich, UK; Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, UK.
⁸ Department of Biochemical Sciences, University of Westminster, London, UK.
⁹ Paediatric Liver, GI and Nutrition Centre and Mowatlabs, Kings College Hospital, London, UK. Electronic address: anil.dhawan@nhs.net.

PMID: 40562300
DOI: 10.1016/j.jpeds.2025.114703

Abstract

Objective: To explore the relationship between bacterial translocation, intestinal barrier integrity, and systemic inflammation in early biliary atresia (BA).

Study design: Newly diagnosed Infants with BA were assessed longitudinally before as well as 6, 12, and 24 weeks after undergoing Kasai portoenterostomy. Plasma immune marker measurement included interleukin (IL)-2, interferon-gamma (IFNγ), IL-4, IL-10, tumor necrosis factor alpha (TNFα), IL-6, IL-8, IL-1β, IL-17, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Bacterial translocation (lipopolysaccharide binding protein, LBP; D-lactate), intestinal barrier (claudin-3; intestinal fatty acid binding protein[IFABP], fecal calprotectin) biomarkers, and fecal microbiota genus abundance were analyzed.

Results: 55 infants were included, of whom 60% cleared their jaundice. Early post-Kasai, upregulation of plasma adhesion molecules and pro-inflammatory cytokines were associated with poorer jaundice clearance and liver fibrosis and correlated with jaundice severity. Elevated claudin-3 early post-Kasai was associated with poor jaundice clearance [OR 1.02 (1.00, 1.04); p=0.02] and jaundice severity [p<0.01]. On multivariable analysis, early ICAM-1 elevation (OR 1.008 [1.002, 1.014]; p=0.01) and claudin-3 (OR 1.038 [1.009, 1.068]; p=0.02), represented independent prognostic markers for persistent jaundice. Increased longitudinal trends of LBP (OR 0.79 [0.71, 0.89];p<0.01) and IFABP (OR <0.01 [2.4E-43,0.24];p=0.04) were associated with poor jaundice clearance. LBP positively correlated with pro-inflammatory-cytokines (IL-6, p<0.01: TNFα, P<0.01) and ICAM-1 (p<0.01) early post-Kasai. Fecal calprotectin positively correlated with jaundice severity (p<0.01) by 24 weeks post-Kasai. No correlation between fecal microbiota abundance and bacterial translocation/intestinal integrity markers was demonstrated.

Conclusions: Bacterial translocation may be linked to post-Kasai BA-immune pathways. Claudin-3 could represent a novel biomarker of early intestinal permeability in BA; links to the gut microbiota need further exploration.

Keywords: Claudin-3; Cytokine; Gut Microbiota; Intercellular adhesion molecule 1; Lipopolysaccaride-binding protein.