Approximately 40,000 infants are born each year in the United States with congenital heart defects (CHD), and heart defects are the leading cause of birth defect-related deaths in the United States(1). While advances in surgical treatment and post-operative care have reduced in-hospital mortality for children born with CHD, 1/3 of infants continue to suffer morbidity from post-operative multiple organ dysfunction syndrome (MODS)(2, 3). Emerging data suggests a role for intestinal dysbiosis and a pro-inflammatory metabolome in the pathogenesis of post-operative MODS(4, 5). In two case reports of adult ICU patients with MODS, fecal microbiome transplantation to correct dysbiosis resulted in resolution of MODS. A multi-omics approach may provide insight into host-microbe interactions contributing to MODS. In children with CHD, intestinal microbiome dysbiosis is prevalent pre-operatively, and in pilot data from Dr. Typpo's NIDDK K23 award project, we found that post-operative MODS was associated with a pattern of dysbiosis previously reported in adult ICU patients: decreased relative abundance of Firmicutes and Actinobacteria and an increased relative abundance of Bacteroidetes and Proteobacteria(5). Through PICRUSt analysis to predict functional composition of the dysbiotic metagenome(6), we identified twenty-five metabolic pathways associated with MODS and one protective pathway. The goal of this R03 proposal is to complement and expand Dr. Typpo's K23 program of research from pure structural analysis (what microbes are present) of intestinal microbial populations to functional analysis (what they are doing) of microbial populations via the following 3 specific aims.
Specific Aim 1 : Characterize the pre- and post-operative fecal microbiome in infants with and without post-operative MODS using whole genome shotgun metagenomics sequencing to identify if pre-operative microbiome is associated with post-operative MODS.
Specific Aim 2 Identify differentially abundant fecal and urinary metabolites of infants with and without post-operative MODS to identify associations between the pre-operative metabolome and post-operative MODS.
Specific Aim 3 : Derive mechanistic models to explain how observed pre-operative dysbiosis and host-microbe interactions contribute to the development of post-operative MODS by combining clinical metadata, metagenomics (Aim1), and metabolomics (Aim2) output. This proposal is significant, because we will address gaps in knowledge regarding the functional consequences of intestinal dysbiosis in children who develop MODS after surgical correction of CHD. This proposal is innovative, through use of combined metagenomics and metabolomics approaches to derive mechanistic pathways which contribute to MODS. We may identify novel microbial targets to reduce the incidence or severity of post- operative MODS. This proposal, in combination with Dr Typpo's career development award (K23) will provide her with the training, experience, and preliminary data to test interventions designed to target host-microbe interactions and prevent post-operative MODS in a successful future R01 proposal.
Approximately 40,000 infants are born each year in the United States with congenital heart defects (CHD), and heart defects are the leading cause of birth defect-related deaths in the United States. While advances in surgical treatment and cardiopulmonary bypass have improved survival for children born with CHD, these infants continue to suffer morbidity from post-operative multiple organ dysfunction (MODS). The proposed studies have the potential to discover new host-microbial interactions and novel strategies for the prevention of MODS in children with CHD.
