Mapping the early life gut microbiome in neonates with critical congenital heart disease: multiomics insights and implications for host metabolic and immunological health

Background The early life gut microbiome is crucial in maintaining host metabolic and immune homeostasis. Though neonates with critical congenital heart disease (CCHD) are at substantial risks of malnutrition and immune imbalance, the microbial links to CCHD pathophysiology remain poorly understood. In this study, we aimed to investigate the gut microbiome in neonates with CCHD in association with metabolomic traits. Moreover, we explored the clinical implications of the host-microbe interactions in CCHD. Methods Deep metagenomic sequencing and metabolomic profiling of paired fecal samples from 45 neonates with CCHD and 50 healthy controls were performed. The characteristics of gut microbiome were investigated in three dimensions (microbial abundance, functionality, and genetic variation). An in-depth analysis of gut virome was conducted to elucidate the ecological interaction between gut viral and bacterial communities. Correlations between multilevel microbial features and fecal metabolites were determined using integrated association analysis. Finally, we conducted a subgroup analysis to examine whether the interactions between gut microbiota and metabolites could mediate inflammatory responses and poor surgical prognosis. Results Gut microbiota dysbiosis was observed in neonates with CCHD, characterized by the depletion of Bifidobacterium and overgrowth of Enterococcus , which was highly correlated with metabolomic perturbations. Genetic variations of Bifidobacterium and Enterococcus orchestrate the metabolomic perturbations in CCHD. A temperate core virome represented by Siphoviridae was identified to be implicated in shaping the gut bacterial composition by modifying microbial adaptation. The overgrowth of Enterococcus was correlated with systemic inflammation and poor surgical prognosis in subgroup analysis. Mediation analysis indicated that the overgrowth of Enterococcus could mediate gut barrier impairment and inflammatory responses in CCHD. Conclusions We demonstrate for the first time that an aberrant gut microbiome associated with metabolomic perturbations is implicated in immune imbalance and adverse clinical outcomes in neonates with CCHD. Our data support the importance of reconstituting optimal gut microbiome in maintaining host metabolic and immunological homeostasis in CCHD. 4pXZJ27nHYVeyd4JvNJWQd Video Abstract