Pangenomes of Human Gut Microbiota Uncover Links Between Genetic Diversity and Stress Response

Abstract

The human gut microbiota has been the subject of many studies, establishing its central role in host health and disease. Interplay between mutations, horizontal gene transfer, natural selection, and genetic drift, lead to genetic diversity within these species, resulting in different phenotypes and effects on the host. Pangenome represents the collective gene pool of different strains of the same species. Here, we created pangenomes for 728 human gut prokaryotic species, holding four times more genes than the highest quality individual genome, showcasing the genetic diversity inherent in the human gut population. We find these species have a core set of about a thousand genes that defines them, distinct even between closely related species, and an accessory set of genes that are unique to the different strains. Furthermore, we show a spectrum of microbial behavior, while some species exhibit a saturated or "closed" pangenome, suggesting a limited set of genetic capabilities, others maintain an "open" pangenome, indicating elevated adaptability through genetic diversity. We discover that high strain variability is associated with the capacity of species to undergo sporulation, whereas low strain variability is associated with carrying genes that facilitate antibiotic resistances, suggesting different evolutionary strategies for survival taken by these microbes. We further map the landscape of antibiotic resistance genes across the human gut population, and find 237 cases of extreme resistance, predominantly of Enterobacteriaceae species, even to last resort antibiotics kept for cases where traditional treatments have failed. Lastly, we associate microbial strain level differences with human age and sex, exemplifying how the presence of specific genes in Akkermansia muciniphila and Phocaeicola vulgatus relate to host characteristics. Overall, our research provides a comprehensive overview of the evolution, genetic complexity and functional potential of the human gut microbiota, emphasizing its significant implications for human health and disease. The pangenomes and the antibiotic resistances map constitute a valuable resource for further scientific research and therapeutic advancements.