Association of maternal gut microbiota and plasma metabolism with congenital heart disease in offspring: a multi-omic analysis

Congenital heart disease (CHD) is the most common congenital disorder diagnosed in newborns. Although lots of related studies have been published, yet the pathogenesis has not been fully elucidated. A growing body of evidence indicates perturbations of the gut microbiota may contribute in a significant way to the development of obesity and diabetes. Given that maternal obesity and diabetes are well-known risk factors for CHD, maternal gut microbiota may be considered as one of the environmental factors involved in the pathogenesis of CHD. The object of this study is to explore the association between maternal gut microbiota and risk of congenital heart disease (CHD) in offspring, as well as the possible mechanisms linking gut microbiota and disease risk. A case–control study was conducted in mothers of infants with CHD (n = 101) and mothers of infants without CHD (n = 95). By applying 16S rRNA gene sequencing and metabolic approaches to 196 stool and plasma samples, we determined microbiome and metabolome profiles in mothers of infants with CHD and controls, and their association with risk of CHD in offspring. The gut microbiome of mothers of infants with CHD was characterized with lower alpha-diversity and distinct overall microbial composition compared with mothers of infants without CHD. A distinct different metabolic profile was found between mothers of infants with CHD and controls. After controlling for the possible confounders, thirty-four bacterial genera and fifty-three plasma metabolites showed distinct abundances between the two groups. The results of the Spearman correlation analyses revealed a great number of significant correlations between the abundant bacterial genera and differentially expressed metabolites. In particular, the genus Bifidobacterium and Streptococcus showed comparable moderate positive correlations with a range of metabolites that involved in lipid metabolism pathway. Our findings suggest that perturbations of maternal gut microbiota and plasma metabolites may be associated with risk of CHD in offspring, and co-variation between microbiota and metabolites may play a part in the linkage between gut microbiota and risk of CHD in offspring.