Personalized modeling of gut microbiome metabolism throughout the first year of life

•Background: Early-life exposures including diet, and the gut microbiome have been proposed to predispose infants towards multifactorial diseases later in life. Delivery via Cesarian section disrupts the establishment of the gut microbiome and has been associated with negative long-term outcomes. Here, we hypothesize that Cesarian section delivery alters not only the composition of the developing infant gut microbiome but also its metabolic capabilities. To test this, we developed a metabolic modeling workflow targeting the infant gut microbiome. •Methods: The AGORA2 resource of human microbial genome-scale reconstructions was expanded with a human milk oligosaccharide degradation module. Personalized metabolic modeling of the gut microbiome was performed for a cohort of 20 infants at four time points during the first year of life as well as for 13 maternal gut microbiome samples. •Results: Here we show that at the earliest stages, the gut microbiomes of infants delivered through Cesarian section are depleted in their metabolic capabilities compared with vaginal delivery. Various metabolites such as fermentation products, human milk oligosaccharide degradation products, and amino acids are depleted in Cesarian section delivery gut microbiomes. Compared with maternal gut microbiomes, infant gut microbiomes produce less butyrate but more L-lactate and are enriched in the potential to synthesize B-vitamins. •Conclusions: Our simulations elucidate the metabolic capabilities of the infant gut microbiome demonstrating they are altered in Cesarian section delivery at the earliest time points. Our workflow can be readily applied to other cohorts to evaluate the effect of feeding type, or maternal factors such as diet on host-gut microbiome inactions in early life.