Polymorphic toxin secretion systems mediate interbacterial antagonism to shape the intestinal microbiome. We have developed a marker sequence approach to profile polymorphic toxin secretion system genes from microbiome shotgun metagenomic data, called PolyProf. Preliminary studies using publicly available data indicate that PolyProf are distinct in 15 disease states, and that there is strong maternal - infant vertical transmission of PolyProf, influenced by the delivery mode. We propose to use this dataset for two aims: 1) validate disease associations with PolyProf and 2) test the hypothesis that polymorphic toxin-related genes are transmitted by close contact, resulting in families with similar PolyProf. The proposed timeline is 1 year. The approach will be to apply PolyProf to all shotgun metagenomes in the dataset using Iowa’s high performance computing cluster (Argon) and a pipeline established in preliminary studies. We will link each PolyProf with the available disease state, family relation, and infant exposure metadata. To address aim 1, we will apply decision tree predictors for disease states (cardiovascular disease, IBD, osteoarthritis, type 2 diabetes, rheumatoid arthritis, and others) that were developed with independent, publicly available datasets and measure their performance. We will also derive disease-distinguishing PolyProf signatures from the DMP cohort and test diagnostic accuracy on the preliminary datasets. In Aim 2 we will assess correlation of PolyProf similarity (e.g. alpha diversity and Bray-Curtis dissimilarity) with family relationships, particularly mother-child pairs. We will stratify these data by birth delivery mode to test our preliminary finding that vaginal delivery confers stronger vertical transmission of polymorphic toxin-related genes. We will use the available genotyping data to ask whether familial PolyProf patterns are detectable in more distantly related populations.
Metagenomic polymorphic toxin effector and immunity profiling predicts microbiome development and disease-related dysbiosis
Year of approval
2024
Institute
University of Iowa
Primary applicant
Bosch, D.