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Metagenomic polymorphic toxin effector and immunity profiling predicts microbiome development and disease-related dysbiosis
Journal article   Peer reviewed

Metagenomic polymorphic toxin effector and immunity profiling predicts microbiome development and disease-related dysbiosis

Hunter W. Schroer, Francesco Beghini, Juan Antonio Raygoza Garay, Nicholas A. Christakis and Dustin E. Bosch
mSystems, e0030526
05/22/2026
DOI: 10.1128/msystems.00305-26
PMID: 42171373

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Abstract

Bacteria use antagonistic interbacterial weapons, such as polymorphic toxin secretion systems (TSS), to compete for niches in the human gut microbiome. We hypothesized that TSS influence gut microbiome development and disease-related dysbiosis. We developed a bioinformatic marker gene approach (PolyProf) to quantify TSS including ~200 effector and immunity genes and applied it to ~15,000 publicly available human metagenomes. PolyProf alpha and beta diversity readily distinguished 12 different human disease states and enabled the construction of highly accurate linear regression classifier machine learning models. Elastic net machine learning models integrating bacterial taxonomy with PolyProf had strong predictive value for 12 disease states, outperforming models utilizing taxonomy alone. During microbiome development in the first year of life, PolyProf alpha diversity increases, and beta diversity becomes increasingly like the maternal microbiome, influenced by vertical transfer, delivery mode, and breastfeeding. PolyProf is related to strain sharing among adults through social interactions. In summary, TSS genes strongly correlate with microbiome development and interpersonal strain sharing, suggesting roles for interbacterial antagonism. Since PolyProf distinguishes diverse adult disease statuses, these dynamics may contribute to non-genetic inheritance.IMPORTANCEPrevious research has demonstrated that bacteria compete within the gut microbiome using toxin secretion systems (TSS). How TSS contribute to human microbiome development and the microbiome alterations observed in human diseases is not known. This study develops a new bioinformatic tool for profiling TSS-related genes in metagenomic data. Application of this approach to large-scale human fecal metagenomic data demonstrates the dynamic association of TSS during microbiome development, including the exchange of strains among social contacts. TSS gene abundance patterns are highly predictive of 12 disease states. This study advances the field by enabling TSS profiling in metagenomes and by identifying disease and microbiome development biomarkers that provide hypotheses for future mechanistic studies and may be useful for disease diagnosis.
 Bacterial Genomics Host Interactions Host-Associated Microbiomes Host-Microbiome Interactions Human Microbiome Human Microbiota Microbial Communities Microbial Genomics Microbial Physiology and Genetics Microbiome Analysis Microbiome and Disease Susceptibility Microbiome Applications Microbiome Dynamics Microbiome Research Microbiome-Based Diagnostics Microbiome-Host Interactions Research Article

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