Coordinated changes in oral propionate, oral microbiota, and peripheral blood inflammatory processes during peanut...

Peanut allergy is an increasingly prevalent condition without curative treatment. Oral immunotherapy (OIT) can induce desensitization, but its mechanisms are not fully understood. Administration of oral short-chain fatty acids (SCFAs) in murine models induces favorable immunomodulation that overlaps with processes observed in OIT. We hypothesized that in human populations, oral SCFA levels change during OIT and are associated with systemic downregulation of Type 2 processes.

Within a clinical trial of children age 4-14 years with high-threshold peanut allergy randomized to OIT or avoidance, we profiled oral SCFA levels, the oral microbiome, and peripheral blood transcriptome over the course of OIT or avoidance. Statistical and network analyses were carried out to test our hypotheses.

Among the 56 children in the clinical trial with complete multi-omic profiles over the trial duration, 29 were randomized to OIT and 27 to avoidance. 100% of the participants in the OIT group achieved desensitization compared to 18.5% in the avoidance group. Oral levels of the SCFA propionate increased with OIT but not avoidance (FDR=0.042) and remained elevated with sustained unresponsiveness. Oral propionate levels positively correlated with the relative abundances of several oral microbes, including known propionate producers Prevotella spp. (r=0.47, FDR 3.75x 10-3) and Veillonella (r=0.39, FDR 1.45x10-2). Oral propionate levels negatively correlated with peripheral blood transcript expression of OIT-associated Fcγ receptors (FDR≤ 0.05), IL-4 & IL-13 signaling (FDR≤ 0.05), and neutrophil degranulation pathways (FDR≤ 0.05).

This study raises the intriguing possibility of oral propionate serving as an important immunoregulatory bridge between local and systemic processes in peanut OIT.

ClinicalTrials.gov NCT03907397.