Asthma-protective Fecal Protoporphyrin IX Inhibits NFkB-mediated Inflammation and Basophil Activation

Document Type

Conference Proceeding

Publication Date

2-1-2025

Publication Title

J Allergy Clin Immunol

Abstract

Rationale: Gut microbial metabolites promote allergic asthma. Mechanisms by microbial-derived products promote protection against asthma remain elusive. Methods: Comparative analysis of fecal metabolomic profiles from 1 month old infants in the Wayne County Health, Environment, Allergy and Asthma Longitudinal Study (WHEALS) who did (n=23; A+) or did not (n=72; A-) have current atopic (2+ allergic sensitizations) asthma at 10 years was performed. Metabolites associated with asthma protection were assessed for their capacity to inhibit allergic inflammation. Results: Thirty-five fecal metabolites associated with asthma protection were screened for their capacity to inhibit macrophage NFκB-mediated inflammation; the heme precursor, Protoporphyrin IX (PPIX) exhibited the greatest inhibitory capacity. Bulk RNAseq analysis of PBMCs from 3 donors exposed to PPIX exhibited significant transcriptional reprogramming, including increased expression of the heme oxygenase-1 gene (HO-1), which is known to suppress basophil maturation. Human basophil KU812 cells exposed to PPIX exhibited significantly fewer CD31 + CD123 + cells and increased CD31 + CCR3 + and CD31 + CD203c + cells, consistent with the effect of known inhibitors of basophil maturation/activation. Infant fecal metagenomic data indicated a difference in microbiome functional capacity of one-month old A+ and A- infants (PERMAONOVA; p = 0.018, R2=0.03). Weighted gene correlation network analysis of identified two microbial gene modules enriched in A- infants, both of which included bacterial genes involved in porphyrin biosynthesis. ShortBRED analysis indicated that fecal Escherichia coli encoded these genes. Conclusions: Intestinal E. coli capable of PPIX production in the infant gut may prevent atopic asthma by suppressing macrophage-derived inflammation and maintaining basophils in an immature state.

Volume

155

Issue

2

First Page

AB315

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