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Background <p>Necrotizing enterocolitis (NEC) is mediated by toll-like receptor 4 (TLR4)-induced inflammation and is preceded by reduced intestinal motility. Human milk oligosaccharides (HMOs) are non-digestible components of breast milk that prevent NEC in preclinical models. We now hypothesize that HMOs can reduce the risk of NEC through restoration of intestinal motility and reduced TLR4-mediated inflammation.</p> Methods <p>NEC was induced in C57-BL/6 mice through the combination of formula gavage, hypoxia, and oral administration of NEC stool. Mice were administered either 2’-FL (5 g/L), 6’-SL (5 g/L), or a blend of 5 specific HMOs (5 g/L) containing 2’-FL (2.606 g/L), 3’-FL (0.652 g/L), LNT (1.304 g/L), 3’-SL (0.174 g/L), and 6’-SL (0.260 g/L). Gastrointestinal motility was assessed by 70 Kd FITC-dextran transit time. Enteric glia were quantified by immunohistochemistry and qRT-PCR expression.</p> Results <p>Administration of either 2’-FL, 6’-SL, or HMO blend significantly attenuated NEC severity and reversed intestinal hypomotility. HMOs prevented enteric glia loss and regulated key genes critical for enteric glia maintenance, attenuated pro-apoptotic genes, and increased anti-apoptotic genes in vitro, resulting in a reduction in apoptosis. Strikingly, HMOs reduced LPS-TLR4-induced NFκB signaling and ROS generation in enteric glia.</p> Conclusions <p>HMOs protect against NEC at least in part through protective effects on inflammation and the enteric nervous system.</p> Impact <p><UnorderedList Mark="Bullet"> <ItemContent> <p>This study sheds light on the role of certain human milk oligosaccharides in a clinically relevant mouse model of NEC and adds additional insights into their underlying mechanism of action by revealing a protective effect on the enteric nervous system.</p> </ItemContent> <ItemContent> <p>These results reveal that HMOs prevent the loss of enteric glia in NEC and influence the expression of genes that regulate enteric glia maintenance.</p> </ItemContent> <ItemContent> <p>HMOs also limit TLR4-NFkB signaling, providing an additional mechanism of enteric glia maintenance.</p> </ItemContent> </UnorderedList></p>

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Necrotizing enterocolitis: specific human milk oligosaccharides prevent enteric glia loss and hypomotility

  • 期刊论文

  • 发表日期：

    2025年5月10日

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  • Chhinder P. Sodhi,
  • Daniel J. Scheese,
  • Cody Tragesser,
  • William B. Fulton,
  • Johannes W. Duess,
  • Koichi Tsuboi,
  • Maame Efua S. Sampah,
  • Rachael H. Buck,
  • David R. Hill,
  • Anice Sabag-Daigle,
  • Thomas Prindle,
  • Sanxia Wang,
  • Menghan Wang,
  • David J. Hackam

摘要

Background

Necrotizing enterocolitis (NEC) is mediated by toll-like receptor 4 (TLR4)-induced inflammation and is preceded by reduced intestinal motility. Human milk oligosaccharides (HMOs) are non-digestible components of breast milk that prevent NEC in preclinical models. We now hypothesize that HMOs can reduce the risk of NEC through restoration of intestinal motility and reduced TLR4-mediated inflammation.

Methods

NEC was induced in C57-BL/6 mice through the combination of formula gavage, hypoxia, and oral administration of NEC stool. Mice were administered either 2’-FL (5 g/L), 6’-SL (5 g/L), or a blend of 5 specific HMOs (5 g/L) containing 2’-FL (2.606 g/L), 3’-FL (0.652 g/L), LNT (1.304 g/L), 3’-SL (0.174 g/L), and 6’-SL (0.260 g/L). Gastrointestinal motility was assessed by 70 Kd FITC-dextran transit time. Enteric glia were quantified by immunohistochemistry and qRT-PCR expression.

Results

Administration of either 2’-FL, 6’-SL, or HMO blend significantly attenuated NEC severity and reversed intestinal hypomotility. HMOs prevented enteric glia loss and regulated key genes critical for enteric glia maintenance, attenuated pro-apoptotic genes, and increased anti-apoptotic genes in vitro, resulting in a reduction in apoptosis. Strikingly, HMOs reduced LPS-TLR4-induced NFκB signaling and ROS generation in enteric glia.

Conclusions

HMOs protect against NEC at least in part through protective effects on inflammation and the enteric nervous system.

Impact

This study sheds light on the role of certain human milk oligosaccharides in a clinically relevant mouse model of NEC and adds additional insights into their underlying mechanism of action by revealing a protective effect on the enteric nervous system.

These results reveal that HMOs prevent the loss of enteric glia in NEC and influence the expression of genes that regulate enteric glia maintenance.

HMOs also limit TLR4-NFkB signaling, providing an additional mechanism of enteric glia maintenance.