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Parenteral nutrition (PN) is a lifesaving nutritional intervention in premature infants with delayed tolerance of oral or enteral feeds. PN-associated liver disease or cholestasis (PNAC) is a frequent complication of PN, with high morbidity and associated healthcare costs. The central theme of this proposal is to leverage the microbiome and metabolome to predict–versus simply react to–PNAC, thereby setting the stage to prevent PNAC in high risk children. To that end, we propose pilot studies to elucidate the role of the gut microbiome in PNAC and identify microbiome signatures predictive of PNAC, building on prior collaborative work.

Hence, our goals are two-fold:

1. Establish a microbiome-based prediction algorithm for PNAC to facilitate early intervention,
2. Determine the degree to which transplantation of PNAC-associated microbiota from infants to germ-free mice confers susceptibility to PNAC.

If successful, these pilot studies will provide compelling preliminary data for comprehensive collaborative project proposals between the Departments of Pediatrics at UVa, Inova, Carillion, and VCU and UVA Biomedical Engineering.

Specific Aims:

1. Develop a microbiome-based prediction tool for PNAC in neonates. We hypothesize blooms of gram-negative taxa in the stool and subsequent metabolites produced are a robust predictor of PNAC in NICU patients when combined with other clinical predictors.
2. Determine the extent to which the stool microbiota of infants with PNAC confers greater susceptibility to PNAC in gnotobiotic mice. We hypothesize a higher abundance of gut gram-negative taxa is a driver of PNAC.

1. Hourigan SK, Moutinho TJ Jr, Berenz A, Papin J, Guha P, Bangiolo L, Oliphant S, Provenzano M, Baveja R, Baker R, Vilboux T, Levy S, Deopujari V, Nataro JP, Niederhuber JE, Moore SR. Gram-negative Microbiota Blooms in Premature Twins Discordant for Parenteral Nutrition-associated Cholestasis. J Pediatr Gastroenterol Nutr. 2020 May;70(5):640-644. doi: 10.1097/MPG.0000000000002617. PMID: 31939866; PMCID: PMC7699457.
2. Moutinho TJ, Powers DA, Hanson GF, Levy S, Baveja R, Hefner I, Mohamed M, Abdelghani A, Baker RL, Papin JA, Moore SR, Hourigan SK. Fecal sphingolipids predict parenteral nutrition-associated cholestasis in the neonatal intensive care unit. JPEN J Parenter Enteral Nutr. 2022 Nov;46(8):1903-1913. doi: 10.1002/jpen.2374. Epub 2022 Apr 7. PMID: 35285019; PMCID: PMC9468188
3. Moutinho TJ, Powers DA, Hanson GF, Levy S, Baveja R, Hefner I, Mohamed M, Abdelghani A, Baker RL, Papin JA, Moore SR, Hourigan SK. Fecal sphingolipids predict parenteral nutrition-associated cholestasis in the neonatal intensive care unit. JPEN J Parenter Enteral Nutr. 2022 Nov;46(8):1903-1913. doi: 10.1002/jpen.2374. Epub 2022 Apr 7. PMID: 35285019; PMCID: PMC9468188