Sepsis As a Confounding Factor in Assessing Liver Dysfunction in Parenterally Fed Piglets: a Model for Human Infants with Intestinal Failure

Abstract Background Sepsis is a common complication of parenteral nutrition therapy for infants with intestinal failure, due to the presence of a central venous catheter and impairment of gut barrier function. Intestinal failure-associated liver disease (IFALD) is another complication, often attributed to the type of intravenous lipid emulsion delivered and this is commonly studied in pre-clinical animal models. Animal studies frequently overlook sepsis as a confounding factor, potentially biasing the results. We retrospectively reviewed 14-day studies of total parenteral nutrition (TPN) in piglets in our laboratory from 2011 to 2025, to determine if sepsis is an independent predictor of key liver outcomes relevant to IFALD research. Sepsis was defined as positive blood culture. Results A total of 86 piglets (76 male; aged 2–5 days) were eligible for inclusion across four experimental studies. In total, 44 (51%) were suspected to have sepsis on the basis of clinical signs, 4 had missing blood cultures, and of these 28/40 (70%) had a positive blood culture. Septic piglets had higher mortality compared to those not suspected to be septic or having a negative blood culture (43% vs. 9%, p < 0.001). Septic piglets showed significantly lower bile flow (p < 0.001) and higher serum total bilirubin (p < 0.001) compared to non-septic piglets. The risk of developing sepsis was reduced in piglets with older age (OR = 0.42, p = 0.007) and increased when given a pure soy-oil compared to pure fish-oil emulsion (OR = 10.77, p = 0.05). Multivariate analysis showed the independent predictors of bile flow were both sepsis (negative) and higher body weight at study entry (positive) (R2 = 0.42, p < 0.001), while sepsis and use of a soy-based lipid emulsion were independent positive predictors of total bilirubin (R2 = 0.34, p < 0.001). Conclusions Sepsis is associated with reduced bile flow, elevated total bilirubin and increased mortality in PN fed neonatal piglets. As sepsis can be a confounding factor in liver outcomes, researchers should both introduce refinements to mitigate sepsis as well as consistently report on the number of animals with sepsis within treatment groups and their outcomes.