Abstract
Background
The accumulation of short-chain fatty acids (SCFAs) from bacterial fermentation may adversely affect the under-developed gut as observed in premature newborns at risk for necrotizing enterocolitis (NEC). This study explores the mechanism by which specific SCFA fermentation products may injure the premature newborn intestine mucosa leading to NEC-like intestinal cell injury.
Methods
Intraluminal injections of sodium butyrate were administered to 14- and 28-day-old mice, whose small intestine and stool were harvested for analysis. Human intestinal epithelial stem cells (hIESCs) and differentiated enterocytes from preterm and term infants were treated with sodium butyrate at varying concentrations. Necrosulfonamide (NSA) and necrostatin-1 (Nec-1) were used to determine the protective effects of necroptosis inhibitors on butyrate-induced cell injury.
Results
The more severe intestinal epithelial injury was observed in younger mice upon exposure to butyrate (p = 0.02). Enterocytes from preterm newborns demonstrated a significant increase in sensitivity to butyrate-induced cell injury compared to term newborn enterocytes (p = 0.068, hIESCs; p = 0.038, differentiated cells). NSA and Nec-1 significantly inhibited the cell death induced by butyrate.
Conclusions
Butyrate induces developmental stage-dependent intestinal injury that resembles NEC. A primary mechanism of cell injury in NEC is necroptosis. Necroptosis inhibition may represent a potential preventive or therapeutic strategy for NEC.
Impact
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Butyrate induces developmental stage-dependent intestinal injury that resembles NEC.
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A primary mechanism of cell injury caused by butyrate in NEC is necroptosis.
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Necroptosis inhibitors proved effective at significantly ameliorating the enteral toxicity of butyrate and thereby suggest a novel mechanism and approach to the prevention and treatment of NEC in premature newborns.
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Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
We are grateful to Dr. Teri A. Longacre for acquisition of IHC images.
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K.G.S. and J.D. conceived the study. K.W. and G.-Z.T. contributed to the study design. K.W. drafted the manuscript. K.W., G.-Z.T., P.-Y.L., Z.S., B.L., and M.M. contributed to experiments and data acquisition. K.W., G.-Z.T., P.-Y.L., F.S.-J., T.S., J.D., and K.G.S. contributed to data analysis. F.S.-J. and K.G.S. edited the draft and contributed to the final submitted version. All the authors have read and approved the final manuscript.
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Wang, K., Tao, GZ., Salimi-Jazi, F. et al. Butyrate induces development-dependent necrotizing enterocolitis-like intestinal epithelial injury via necroptosis. Pediatr Res 93, 801–809 (2023). https://doi.org/10.1038/s41390-022-02333-z
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DOI: https://doi.org/10.1038/s41390-022-02333-z
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