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

Abstract

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.

Human milk feeding and direct breastfeeding improve outcomes for infants with single ventricle congenital heart disease: Propensity score matched analysis of the NPC-QIC registry

“…12 We also speculate that, as the underlying cause of cardiac NEC may be different than in preterm infants, some providers might assume that HM is not similarly protective for infants with CHD. Both Huang et al's 64 novel research demonstrating similarities between the gut microbiome of preterm infants and those with critical CHD and our findings of strong associations between HM and reduced NEC would discount this assumption. Furthermore, in animal studies focused on the mechanistic relationship between HM and preterm NEC, a common method of NEC-induction involves subjecting mice to hypoxia, infant formula, and introduction of lipopolysaccharide to induce inflammation 73 a process with clear analogies to the SV CHD clinical course.…”

“…Knowledge about the gut microbiome of infants with CHD is only beginning to emerge, [64][65][66][67][68][69] and there has been no investigation into HM composition in the context of CHD. A 2022 study by Huang et al.…”

“…A 2022 study by Huang et al. 64 provides the first comprehensive evidence on the gut microbiome of neonates with critical CHD, reporting dysbiosis characterized by increased pathogens (eg, Enterococcaceae, Enterobacteriaceae) and decreased beneficial organisms (eg, Bifidobacterium, Lactobacillus)a profile that shares similarities with the gut microbiome of very-low-birth-weight infants 60 with consequent inflammatory and immune imbalances potentially contributing to poor clinical outcomes, including NEC. Huang and colleagues note the key role of HM/BF (eg, human milk oligosaccharides) in establishing normal gut Bifidobacterium colonization and reducing pathogenic activity, and speculate that low HM/BF prevalence could contribute to gut dysbiosis in the context of CHD.…”

“…Huang and colleagues note the key role of HM/BF (eg, human milk oligosaccharides) in establishing normal gut Bifidobacterium colonization and reducing pathogenic activity, and speculate that low HM/BF prevalence could contribute to gut dysbiosis in the context of CHD. 64 The authors propose Bifidobacterium and oligosaccharide supplementation for infants with critical CHD, but stop short of recommending improved lactation support for these infants and their families as a mechanism to promote intestinal homeostasis. Of the remaining abstracts, 69 studies, 65,67,68 or reviews 66 identified on the topic of the gut microbiome in patients with CHD, only one briefly mentions HM/BF 68 and none discuss HM/BF as a therapeutic intervention for gut dysbiosis.…”

Lactobacillus plantarum 24-7 improves postoperative bloating and hard stools by modulating intestinal microbiota in patients with congenital heart disease: a randomized controlled trial

“…A growing body of research suggests a strong relationship between gut microbiota and a variety of cardiovascular diseases, such as coronary heart disease, aneurysms, and congenital heart disease. [9][10][11] In a clinical trial, Yuan Huang performed metagenomic sequencing on fecal samples from neonates with CHD compared to healthy controls. The results showed that the CHD group had significant gut microbiota disruption, impaired intestinal barriers, and increased systemic inflammation.…”