LAUSR

BACKGROUND AND AIMS Few studies, even those with cohort designs, test the mediating effects of infant gut microbes and metabolites on the onset of disease. We undertook such a study. METHODS Using SEM path analysis, we tested directional relationships between first pregnancy, birth mode, prolonged labour and breastfeeding; infant gut microbiota, metabolites and Immunoglobulin A; and childhood BMI and atopy in 1667 infants. RESULTS Following both cesarean birth, and prolonged labour with a first pregnancy, a higher Enterobacteriaceae/Bacteroidaceae (E/B) ratio at 3 months was the dominant path to overweight; higher E/B ratios and Clostridiodes difficile colonization at 12 months were the main pathway to atopic sensitization. Depletion of Bifidobacterium following prolonged labour was a secondary pathway to overweight. Influenced by C. difficile colonization at 3 months, metabolites propionate and formate were secondary pathways to child outcomes, with a key finding that formate was at the intersection of several paths. CONCLUSION Pathways from cesarean section and first pregnancy to child overweight and atopy share many common mediators of the infant gut microbiome, notably C. difficile colonization.