Strain-Level microbial signatures and inferred functional alterations in infants with Food Protein-Induced Allergic Proctocolitis.

The complex relationship between the gut microbiome and immune system development during infancy is thought to be a key factor in the rising rates of pediatric allergic diseases. Food protein-induced allergic proctocolitis (AP), the earliest identified form of non-IgE-mediated food allergy in infants, occurs at the mucosal surface where dietary proteins, intestinal microbes, and immune cells directly interact, and increases the risk for life threatening IgE-mediated food allergy, making it an important model for understanding early food allergic disease development. The question of how specific microbial compositions and functional pathways contribute to AP development and progression remains poorly understood. Here we show that infants with AP exhibit microbial compositions that differ from unaffected controls, characterized by enrichment of and during early life, including pre-symptomatic stages, while protective species like Bifidobacterium breve and species are more abundant in unaffected controls. Strain-level analyses uncovered additional disease-linked patterns, particularly strains showed strong association with probiotic use and predominantly found in infants with AP. These findings reveal disease-associated microbial signatures that can sometimes be detectable before clinical symptoms emerge, and demonstrate that strain-level differences within populations may represent AP-specific lineages with distinct gene content profiles that were not previously recognized. Genes for biofilm formation and cell adhesion in , for example, were particularly enriched in AP-associated clades. Short chain fatty acid (SCFA) and other functional pathways were also associated with AP, including reduced SCFA production during the symptomatic phase, and then a potentially compensatory increased production following AP resolution. Our results provide the first comprehensive strain-level characterization of the gut microbiome in AP, and functional implications, and establish a foundation for future efforts to identify early microbial biomarkers and potential interventional targets for AP. This work advances our understanding of how specific microbial taxa and functional pathways may contribute to non-IgE-mediated food allergies and opens new avenues for microbiome-targeted therapeutic approaches as well as novel prevention targets for IgE-mediated food allergies.