Antimicrobial Peptides Modify Gut Microbiota to Reduce Pulmonary Damage

Antimicrobial Peptides Modify Gut Microbiota to Reduce Pulmonary Damage
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Lung development begins in the womb at low oxygen tension, but following a very premature birth, the partially developed lungs of the tiny infants experience significantly greater oxygen tensions even without the lengthy supplemental oxygen that is frequently necessary. This has been shown to have devastating effects on the structure and function of the neonatal lung, resulting in the deadly lung disorder bronchopulmonary dysplasia in high-risk preterm infants. Using a neonatal mouse model, researchers at the University of Alabama at Birmingham discovered that changes in the gut flora lead to this potentially fatal lung injury. The changes arise because supraphysiologic oxygen exposure — 85 percent oxygen vs the normal 21 percent oxygen given to newborn mice between the third and fourteenth days of life — decreases expression of normal host-derived antimicrobial peptides in the small intestine.

Antimicrobial peptides have been shown to have an important role in the regulation of gut microbiota via host defense against microorganisms. These tiny proteins produced by intestinal cells have wide antimicrobial activity, including the ability to kill or prevent the growth of bacteria, fungi, and viruses.

The discovery of a reduction in antimicrobial peptides after neonatal mice were exposed to supraphysiologic oxygen resulted in an altered composition of the intestinal microbiota, including an increase in the abundance of bacteria in the genus Staphylococcus, as measured in the terminal ileum of the small intestine, where preterm infants are uniquely vulnerable to microbiome-mediated necrotizing enterocolitis.

Significantly, when the UAB researchers, led by Kent Willis, M.D., and Tamás Jilling, M.D., UAB Department of Pediatrics Division of Neonatology, gave supplemental lysozyme to neonatal mice exposed to supraphysiologic oxygen, the augmented dietary lysozyme significantly altered the ileal microbiome, alleviating the increase in Staphylococcus seen after hyperoxia exposure. The most prevalent antimicrobial peptide produced by the gut is lysozyme, which is also extensively expressed in human breast milk.

This enhanced dietary lysozyme resulted in decreased lung harm, including improved lung shape and function after hyperoxia exposure in neonatal mice. Through an apparent feed-forward mechanism, dietary lysozyme enhanced gene expression of several antimicrobial peptides in the ileum, including a 2.4-fold increase in expression of the mouse lysozyme Lyz1 gene.

To see if supraphysiologic oxygen directly suppresses antimicrobial peptide production by intestinal epithelial cells, researchers at Boston Children’s Hospital, Harvard Medical School, led by Amy O’Connell, M.D., Ph.D., grew intestinal organoids and exposed them to either hyperoxia (95 percent oxygen) or normal oxygen tension (21 percent) for 24 hours. Intestinal organoids are three-dimensional structures formed by self-organizing intestinal cells and developed in vitro to mimic the activity of the natural intestine tissue.

These intestinal organoids demonstrated inhibition of antimicrobial peptide genes after exposure to supraphysiologic oxygen, which was identical to the alterations reported in hyperoxia-exposed mice’s intestines.

“In summary, we have described a gut-lung axis driven by intestinal antimicrobial peptide expression and mediated by the intestinal microbiota that influences hyperoxia-induced lung injury,” Willis went on to say. These murine and organoid studies suggest that antimicrobial peptide expression could be used as a therapeutic target to modulate the intestinal microbiota and the response to lung injury.” These findings have significance for the clinical management of premature infants in neonatal care who are at high risk of developing bronchopulmonary dysplasia.

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