Oral and Gut Microbial Hubs Associated With Reaction Threshold Interact With Circulating Immune Factors in Peanut Allergy

Background: Among peanut-allergic individuals, there is high variability in the amount of peanut that triggers reactions (i.e., reaction threshold) that is not predictable or well-understood. We conducted this study to characterize relationships between the oral and gut microbiomes and systemic processes associated with reaction threshold in peanut allergy (PA). Methods: In a cohort of 120 children with suspected PA who underwent double-blind, placebo-controlled food challenges, we generated and analyzed parallel profiles of the oral microbiome, gut microbiome, peripheral blood transcriptome, peripheral blood cytometry, and serum antibody levels to identify threshold-associated markers and their inter-relationships. Results: The 120 participants included 23 children with no PA, 74 with high-threshold PA (reacting to ≥ 443 mg cumulative peanut protein), and 23 with low-threshold PA (reacting to < 443 mg cumulative peanut protein). Ten hub microbes were each identified in saliva and stool microbiome networks that were constructed, including the hub microbes Rothia aeria in saliva and Bacteroides sp. in stool that were associated with reaction threshold. These hub microbes were also associated with peripheral blood transcript levels for threshold-associated key drivers of FcγR-mediated phagocytosis and TLR signaling. Correlation network construction with additional data on threshold-associated peripheral blood neutrophil abundance and peanut-specific serum IgE and Ara h 2 antibody levels revealed central roles for saliva Rothia aeria and stool Bacteroides sp. in local-systemic networks for IgE- and IgG-mediated peanut allergy. Conclusions: This integrated study of oral and stool microbiomes, blood transcriptome, cellular profiles, and peanut-specific serum antibodies revealed new relationships between local microbiota and systemic measures associated with reaction threshold in peanut allergy.