Cross-cohort single-nucleotide-variant profiling of gut microbiota suggests a novel gut-health assessment approach

Abstract

<p>Introduction: Adaptive evolutionary changes can precede the ecological changes in the gut microbial communities under constant host selection pressure, yet their association with host diseased status was underexplored. </p><p>Objectives: Explore shared disease-associated single nucleotide variants (SNVs) in gut microbes spanning diverse human diseases.</p><p>Methods: We performed a meta-analysis of 1711 gut metagenomic samples from 16 case-control studies spanning 12 human diseases, and included an additional 446-member cohort for validation.</p><p>Results: Overall, healthy individuals carried more mutated resident gut microbes, and more SNVs, mainly involving the short-chain fatty acids (SCFAs) producing bacteria. Furthermore, the widespread differences in base mutation bias of gut microbes were observed between health and nonhealthy subjects suggesting divergent gut microbial evolutionary directions under different host medical conditions. We further found that nonsynonymous SNVs can lead to functional inactivation of four SCFA-production genes in non-healthy populations, among of which two genes (i.e., ack, and scpC) from Faecalibacterium prausnitzii C, and Bacteroides stercoris respectively were externally validated. Subsequently, we developed a novel gut microbiome health index (GMHI) based on the SNV rate of all mutated strains, classifying host health states with 74.23% accuracy, validated with high accuracy (AUROC=69.28%). Conclusion: Our study highlights the importance of employing the genetic variability in gut microbiome to characterize the gut microbial adaptation that can also predict human chronic diseases.</p>