Intra-species variations in global, host, and familial microbiomes

The microbiomes within and around us have gained increasing attention over the past few decades. Now, the microbiome in any ecosystem is considered a crucial component of its health status. Compositional microbiome differences between healthy and diseased states have been identified, and methods to manipulate microbiomes for beneficial outcomes are emerging.

Advancements in the field of metagenomics is now allowing for higher resolution investigations of of microbiome variations. In this thesis, I employed Metagenome-Assembled Genomes (MAGs) to investigate intra-species differences on a global scale in sewage metagenomes, among hominid hosts from Tanzania, and following Fecal Microbiota Transplantation (FMT). These investigations, presented in four manuscripts, each contribute to the understanding of microbiome intra-species variation.

In manuscript 1, we investigated global differences in multiple bacterial species using 757 sewage metagenomes from 101 countries. We performed genome reconstructions and gene-focused analyses to determine intra-species variations. We recovered 3353 near-complete MAGs covering 1439 different species. In this study, we found species showing genomic variation coherent with regional separation. Moreover, variation in organelle gene was less correlated with geography compared to metabolic and membrane genes, proposing that regional environmental selection drives global differences in these species.

In manuscript 2 and 3, we studied 546 Tanzanian hominid metagenomes, including samples from indigenous Hadza and wild chimpanzees, to explore the relationship between hosts and their microbiomes. From these metagenomes we identified 15,146 MAGs and found that Tanzanian hominids have higher bacterial richness and diversity than that of westernized host populations. While most bacterial species were either prevalent in chimpanzee or human populations, several bacterial species have adapted to their specific human host populations. When expanding the investigation to structural levels, we found a xyloglucanase gene that was highly specialized to the Hadza population, suggesting an important function related to their diet. Collectively, these findings suggest that microbiome host adaptations have led to both taxonomic and within-species variations, potentially driven by selective adaptation to host diets.

In manuscript 4, we investigated the cross-generational transmission of bacterial strains following FMT in a pregnant woman with a Clostridioides difficile infection (CDI). Upon the FMT treatment, the woman gave birth to a healthy infant. Fecal samples from the donor, mother, and infant were analyzed using metagenomic sequencing. The results showed that FMT successfully resolved the CDI and normalized the mother’s gut microbiota. Notably, specific bacterial strains from the donor were transmitted to the mother and subsequently to the infant, demonstrating microbial transfer across generations. This finding provides new insights into the dynamics and long-term engraftment of bacterial strains from healthy donors.

Collectively, the findings of this PhD demonstrate global differences in metagenomes from both sewage and human gut, underscoring the importance of investigating understudied microbiomes. Furthermore, the identified intra-species variations highlight the potential for a deeper understanding of microbiome dynamics through highresolution studies. A more comprehensive understanding of microbiome variations can support the development of strategies to maintain healthy microbiomes.