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This study tested whether Sibofimloc, an oral drug that blocks bacterial adhesion by inhibiting FimH on Enterobacteriaceae, could prevent necrotizing enterocolitis (NEC) in preterm piglets. Despite dose-dependent absorption of the drug, Sibofimloc treatment failed to reduce NEC incidence or severity compared to formula-fed controls, and treated animals showed increased intestinal injury with reduced crypt depths. The drug did not significantly alter gut microbiota composition, which remained dominated by Clostridium perfringens rather than Enterobacteriaceae, suggesting that targeting FimH alone is insufficient to prevent NEC.
Why it matters
These findings indicate that preventing NEC in preterm infants requires approaches beyond blocking a single bacterial adhesion mechanism, as the disease involves complex microbial communities and multiple colonization pathways. The results highlight the continued superiority of donor human milk in preventing NEC and suggest that future therapeutic strategies may need to target multiple bacterial species or mechanisms simultaneously.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
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.