Abstract
Background
Necrotizing enterocolitis (NEC), a necrotic inflammation of the intestine, represents a major health problem in the very premature infant. Although prevention is difficult, the combination of ingestion of maternal-expressed breastmilk in conjunction with a probiotic provides the best protection. In this study, we establish a mechanism for breastmilk/probiotic protection.
Methods
Ultra-high-performance liquid chromatography-tandem mass spectrometry of Bifidobacterium longum subsp. infantis (B. infantis) secretions was used to identify an anti-inflammatory molecule. Indole-3-lactic acid (ILA) was then tested in an established human immature small intestinal cell line, necrotizing colitis enterocytes, and other immature human enteroids for anti-inflammatory effects and to establish developmental function. ILA was also examined in immature and mature enterocytes.
Results
We have identified ILA, a metabolite of breastmilk tryptophan, as the anti-inflammatory molecule. This molecule is developmentally functional in immature but not mature intestinal enterocytes; ILA reduces the interleukin-8 (IL-8) response after IL-1β stimulus. It interacts with the transcription factor aryl hydrocarbon receptor (AHR) and prevents transcription of the inflammatory cytokine IL-8.
Conclusions
This molecule produced by B. infantis (ATCC No. 15697) interaction with ingested breastmilk functions in a complementary manner and could become useful in the treatment of all at-risk premature infants for NEC if safety and clinical studies are performed.
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Acknowledgements
This study was supported by the following grants: NIDDK (P01-DK033506) “Barrier function of the GI tract in health and disease” PI W.A.W.; Family Larsson-Rosenquist Foundation “The impact of breastmilk microbiome and protective factors on development of human intestinal disease” PI W.A.W.; Beth Israel/Deaconess Medical Center (Award #01027741) “Impact of breastmilk in premature intestinal colonization” PI W.A.W.
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D.M. oversaw all experiments; E.S., P.C. and E.S. analyzed the B. infantis fractions and identified ILA; K.G., K.D. and W.Z. contributed to ELISA and LDH assay analysis, cell line maintenance, and mouse experiments; W.A.W. conceived of the research plan and analyzed experimental data.
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Meng, D., Sommella, E., Salviati, E. et al. Indole-3-lactic acid, a metabolite of tryptophan, secreted by Bifidobacterium longum subspecies infantis is anti-inflammatory in the immature intestine. Pediatr Res 88, 209–217 (2020). https://doi.org/10.1038/s41390-019-0740-x
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DOI: https://doi.org/10.1038/s41390-019-0740-x
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