Pharmacokinetics and Efficacy of the FimH Inhibitor Sibofimloc in Preventing Necrotizing Enterocolitis in Preterm Piglets
- 1USDA/ARS Children's Nutrition Research Center
Abstract
Necrotizing enterocolitis (NEC) is a disease in preterm infants associated with an increased abundance of Enterobacteriaceae. FimH, a mannose-binding adhesin on Enterobacteriaceae type 1 fimbriae, mediates mucosal attachment and TLR4-dependent inflammatory cascades. We evaluated the safety, pharmacokinetics, and efficacy of an oral FimH inhibitor (Sibofimloc) to reduce Enterobacteriaceae colonization and prevent NEC in preterm piglets. We performed a 9-d dose-escalation safety study (10, 25, 50 mg/kg BID) assessing absorption and tolerability and a 10-d randomized efficacy study. Piglets in the efficacy study received an infant formula diet with or without oral sibofimloc (40 mg/kg BID), or donor human milk (DHM) as a healthy control. NEC incidence, tissue histopathology, and gut microbiota composition via metagenomic whole-genome sequencing (WGS) were evaluated. Systemic exposure data reveal that sibofimloc was dose-dependently absorbed, while plasma levels decreased from postnatal day 2 to day 8, indicating reduced drug absorption with maturation of the intestinal barrier. Treatment with sibofimloc did not reduce NEC incidence (100% in sibofimloc in formula controls) or severity, whereas DHM-fed piglets experienced 0% NEC. Sibofimloc-treated animals exhibited significantly reduced crypt depths, demonstrating heightened mucosal injury and impaired regenerative capacity. WGS revealed that sibofimloc-treated animals maintained a gut luminal microbiota composition similar to untreated formula controls, dominated by Clostridium perfringens (C. perfringens). Selective targeting of FimH-expressing Enterobacteriaceae was insufficient to prevent NEC or alter the gut microbiota in this preterm piglet model, underscoring the complexity of NEC-associated microbial communities and suggesting that additional microbial targets and other colonization mechanisms may contribute to disease development.
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BibTeX
@misc{hebib2026pharmacokinetics,
title = {{Pharmacokinetics and Efficacy of the FimH Inhibitor Sibofimloc in Preventing Necrotizing Enterocolitis in Preterm Piglets}},
author = {V. Melendez Hebib and B. Earls and B. Stoll and C. Vonderohe and G. Guthrie and H. J. Haiser and M. Paton and S. Balani and M. Hesse and D. Burrin},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.12.758546},
url = {https://www.biorxiv.org/content/10.64898/2026.10.12.758546v1},
note = {CC0},
}
RIS
TY - UNPB
TI - Pharmacokinetics and Efficacy of the FimH Inhibitor Sibofimloc in Preventing Necrotizing Enterocolitis in Preterm Piglets
AU - V. Melendez Hebib
AU - B. Earls
AU - B. Stoll
AU - C. Vonderohe
AU - G. Guthrie
AU - H. J. Haiser
AU - M. Paton
AU - S. Balani
AU - M. Hesse
AU - D. Burrin
PY - 2026
DA - 2026/10/12
PB - bioRxiv
DO - 10.64898/2026.10.12.758546
UR - https://www.biorxiv.org/content/10.64898/2026.10.12.758546v1
AB - Necrotizing enterocolitis (NEC) is a disease in preterm infants associated with an increased abundance of Enterobacteriaceae. FimH, a mannose-binding adhesin on Enterobacteriaceae type 1 fimbriae, mediates mucosal attachment and TLR4-dependent inflammatory cascades. We evaluated the safety, pharmacokinetics, and efficacy of an oral FimH inhibitor (Sibofimloc) to reduce Enterobacteriaceae colonization and prevent NEC in preterm piglets. We performed a 9-d dose-escalation safety study (10, 25, 50 mg/kg BID) assessing absorption and tolerability and a 10-d randomized efficacy study. Piglets in the efficacy study received an infant formula diet with or without oral sibofimloc (40 mg/kg BID), or donor human milk (DHM) as a healthy control. NEC incidence, tissue histopathology, and gut microbiota composition via metagenomic whole-genome sequencing (WGS) were evaluated. Systemic exposure data reveal that sibofimloc was dose-dependently absorbed, while plasma levels decreased from postnatal day 2 to day 8, indicating reduced drug absorption with maturation of the intestinal barrier. Treatment with sibofimloc did not reduce NEC incidence (100% in sibofimloc in formula controls) or severity, whereas DHM-fed piglets experienced 0% NEC. Sibofimloc-treated animals exhibited significantly reduced crypt depths, demonstrating heightened mucosal injury and impaired regenerative capacity. WGS revealed that sibofimloc-treated animals maintained a gut luminal microbiota composition similar to untreated formula controls, dominated by Clostridium perfringens (C. perfringens). Selective targeting of FimH-expressing Enterobacteriaceae was insufficient to prevent NEC or alter the gut microbiota in this preterm piglet model, underscoring the complexity of NEC-associated microbial communities and suggesting that additional microbial targets and other colonization mechanisms may contribute to disease development.
ER -