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Background and hypothesis <p>Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease in preterm infants, characterized by exaggerated inflammation and poorly understood pathogenesis. Aryl hydrocarbon receptor (AhR) signaling has been shown to reduce intestinal inflammation in colitis models. In these models, a microbial-derived AhR ligand, Urolithin A (UroA), has demonstrated anti-inflammatory properties and improved gut barrier function. We hypothesize that UroA attenuates inflammation and enhances epithelial barrier integrity in an in vitro NEC-in-a-Dish model.</p> Methods <p>Enteroids derived from human neonatal intestinal tissue were pretreated with 100 µM UroA or 0.1% DMSO (vehicle) before a 6-h incubation with dysbiotic enteric bacteria cultured from an infant with NEC totalis (NEC-in-a-Dish). RNA sequencing was performed and analyzed for pro-inflammatory cytokine expression and pathway enrichment. Epithelial barrier integrity was evaluated using a fluorescein-isothiocyanate-dextran permeability assay on two-dimensional monolayers.</p> Results <p>UroA pretreatment decreased pro-inflammatory cytokine expression and enhanced barrier integrity. Transcriptomic analysis showed downregulation of NOD-like receptor, IL-17/Th17, NF-κB, and TLR signaling, and upregulation of AhR-dependent genes involved in antioxidant responses.</p> Conclusion <p>UroA reduces inflammation and strengthens epithelial barrier integrity in a NEC-in-a-Dish model through a variety of mechanisms. These findings support further investigation of dietary-derived metabolites as potential preventative strategies for NEC in preterm infants.</p> Impact <p><UnorderedList Mark="Bullet"> <ItemContent> <p>Urolithin A (UroA), a microbiota-derived metabolite, reduces inflammation and enhances epithelial barrier integrity in a human neonatal in vitro model of necrotizing enterocolitis (NEC).</p> </ItemContent> <ItemContent> <p>This study is the first to demonstrate the protective effects of UroA in the neonatal small intestinal epithelium using a NEC-in-a-Dish model system. It also expands on the current understanding of the mechanism of action of UroA by revealing modulation of key inflammatory and oxidative stress pathways in neonatal tissue.</p> </ItemContent> <ItemContent> <p>These findings identify UroA as a promising candidate for dietary-based prevention strategies targeting epithelial injury in NEC.</p> </ItemContent> </UnorderedList></p>

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Urolithin A attenuates inflammation and enhances barrier integrity in an experimental NEC-in-a-Dish model

  • 期刊论文

  • 发表日期：

    2026年5月27日

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  • Ahmad Salah Sami,
  • Gergely Mozes,
  • Corey M. Jania,
  • Erika Maldonado-Rosado,
  • Austin J. Hepperla,
  • Nadia Ghetie,
  • Vikram Puri,
  • Lauren Bolzan,
  • Yukihiro Yamaguchi,
  • Lauren C. Frazer,
  • Stephen Mackay,
  • Venkatakrishna Jala,
  • Natalia S. Akopyants,
  • Misty Good

摘要

Background and hypothesis

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease in preterm infants, characterized by exaggerated inflammation and poorly understood pathogenesis. Aryl hydrocarbon receptor (AhR) signaling has been shown to reduce intestinal inflammation in colitis models. In these models, a microbial-derived AhR ligand, Urolithin A (UroA), has demonstrated anti-inflammatory properties and improved gut barrier function. We hypothesize that UroA attenuates inflammation and enhances epithelial barrier integrity in an in vitro NEC-in-a-Dish model.

Methods

Enteroids derived from human neonatal intestinal tissue were pretreated with 100 µM UroA or 0.1% DMSO (vehicle) before a 6-h incubation with dysbiotic enteric bacteria cultured from an infant with NEC totalis (NEC-in-a-Dish). RNA sequencing was performed and analyzed for pro-inflammatory cytokine expression and pathway enrichment. Epithelial barrier integrity was evaluated using a fluorescein-isothiocyanate-dextran permeability assay on two-dimensional monolayers.

Results

UroA pretreatment decreased pro-inflammatory cytokine expression and enhanced barrier integrity. Transcriptomic analysis showed downregulation of NOD-like receptor, IL-17/Th17, NF-κB, and TLR signaling, and upregulation of AhR-dependent genes involved in antioxidant responses.

Conclusion

UroA reduces inflammation and strengthens epithelial barrier integrity in a NEC-in-a-Dish model through a variety of mechanisms. These findings support further investigation of dietary-derived metabolites as potential preventative strategies for NEC in preterm infants.

Impact

Urolithin A (UroA), a microbiota-derived metabolite, reduces inflammation and enhances epithelial barrier integrity in a human neonatal in vitro model of necrotizing enterocolitis (NEC).

This study is the first to demonstrate the protective effects of UroA in the neonatal small intestinal epithelium using a NEC-in-a-Dish model system. It also expands on the current understanding of the mechanism of action of UroA by revealing modulation of key inflammatory and oxidative stress pathways in neonatal tissue.

These findings identify UroA as a promising candidate for dietary-based prevention strategies targeting epithelial injury in NEC.