Multi-omics analysis of pediatric short bowel syndrome induced intestinal failure and associated liver disease:...

Compromised bowel function and altered gut microbiota may disrupt gut-liver axis in short bowel syndrome (SBS), contributing to the development of intestinal failure-associated liver disease (IFALD). We conducted a multi-omics study integrating data from gut microbiota and liver transcriptomes with serum bile acids and clinical data in pediatric SBS-IF.

Fifty-nine pediatric SBS-IF patients provided 177 fecal samples, 100 during parenteral nutrition (PN) and 77 after weaning off PN. Gut microbiota was analysed using 16 S rRNA amplicon sequencing and sequence-based prediction of functional profiles, liver transcriptome using bulk RNA sequencing of selected liver biopsies (n = 31), and serum bile acids with mass spectrometry and surrogates of intestinal integrity with ELISA (n = 67). Results were related to liver histopathology and clinical outcomes and compared to healthy controls.

Besides markedly reduced richness and diversity of intestinal microbiota, unsupervised clustering on pathway abundances revealed five principal clusters dominated by Escherichia, Klebsiella, Lactobacillus, Veillonella, and Faecalibacterium spp. that are associated with different metabolic processes. Clusters were segregated by residual bowel length, serum citrulline, PN dependency, and intestinal anatomy. Faecalibacterium predominated (67%) after achieving enteral autonomy, whereas PN dependency, short remaining bowel, and low citrulline levels were linked to the Lactobacillus-dominant cluster. End-enterostomy was associated with the Klebsiella and Escherichia dominant clusters. The Lactobacillus-dominant cluster was characterized by overexpression of bile acid metabolism pathway genes, and associated with elevated serum unconjugated chenodeoxycholic acid, which correlated inversely with histological cholestasis (r = -0.435, P = 0.003) and portal inflammation (r = -0.507, P < 0.001). SBS-IF livers showed activation of bile acid metabolism including CYP7A1, alongside increased serum C4.

Pediatric SBS-IF is characterized by distinct microbiota clusters linked to clinical phenotype and bile acid metabolism, highlighting contribution of gut-liver crosstalk to IFALD pathogenesis and providing avenues for early diagnostics.

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