Gut Microbiome Membrane Lipids and Bile Acids Relate to Peanut Oral Immunotherapy Outcomes

The Peanut Oral Immunotherapy in Children (IMPACT) trial, a randomized, double-blinded, placebo-controlled study achieved the primary endpoints of desensitisation (D+) in 71% or desensitization and remission (D+R+) in 21% of children treated with peanut oral immunotherapy (POIT). Variance in the gut microbiome relates to allergy and asthma status in childhood. We sought to identify functional and metabolic features of the gut microbiome that relate to the primary clinical endpoints in the IMPACT trial. One hundred forty-six children (12-48 months) were randomly assigned to receive POIT (n=96) or placebo (n=50) for 134 weeks, followed by 26 weeks of avoidance. Stool samples were collected pre-treatment, end of maintenance, and at the end of the avoidance period. Microbiota profiling using 16S rRNA sequencing (n=388), shotgun metagenomics (n=184) and untargeted metabolomics (n=174), of fecal samples was performed. Variance in pre-treatment fecal microbiota composition (R2=0.06 p=0.033), microbial gene content (R2=0.04 p=0.03) and metabolism (R2=0.046 p=0.049) related with desensitization and remission outcomes. Children who responded to treatment exhibited a phylogenetically distinct fecal microbiota throughout the course of the trial (p=8.9x10-4). Those in the D+R+ group had a distinct pre-treatment metagenomic profile, characterized by a network of microbial pathways involved in phospholipid, cholesterol, hydrogen, peptidoglycan and lipopolysaccharide biosynthesis. In parallel, pre-treatment metabolic modules comprised of membrane lipids or secondary bile acid metabolites also associated with D+R+. These data implicate gut microbial composition, function and metabolic activity, specifically membrane lipid biosynthesis and bile acid metabolism in POIT efficacy.