Impact of Microbial Transfer on the Human Gut Microbiome

Abstract

The gut microbiome has become an attractive target for therapeutic manipulation because of its connection with a wide range of human phenotypes and disease. A variety of microbial intervention strategies have been developed to alter its composition and function. These strategies range from the administration of compositionally defined single- or multi-strain microorganisms (probiotics) to the transfer of undefined microbial communities derived from healthy donors (e.g., faecal microbiota transplantation) or maternal sources (e.g., vaginal seeding). Yet how the gut microbiome responds to these microbial interventions remains poorly understood. In this thesis, I interrogated the structural and functional impact of microbial transfer on the human gut microbiome using high-resolution shotgun metagenomic sequencing data obtained from three randomised placebo-controlled clinical trials. This approach enabled me to identify specific patterns of donor strain engraftment and monitor the persistence of these strains over time. In the Gut Bugs study, transplantation of faecal microbiota derived from multiple healthy lean donors led to durable shifts in the composition and functional potential of the gut microbiome in adolescents with obesity. Strain engraftment varied considerably between recipients and was biased towards donors with high microbial diversity and a Prevotella-dominant enterotype. Engraftment of strains from these ‘super-donors’ enriched the microbial gene pool leading to increased representation of metabolic pathways involved in energy metabolism (e.g., NAD biosynthesis). In the PROFAST study, daily supplementation with the probiotic Lactobacillus rhamnosus HN001 in combination with a 12-week 5:2 intermittent fasting regime did not alter the gut microbiome of adults with prediabetes. The relative abundance of Lactobacillus rhamnosus within participant stool samples was extremely low, suggesting proliferation of the probiotic strain was inhibited or restricted by members of the resident gut microbiome. Despite this, the abundance of several microbial species at baseline (e.g., Faecalibacterium prausnitzii and Streptococcus salivarius) were correlated with greater amounts of weight loss, suggesting these species might play a significant role in metabolic health. In the ECOBABe study, oral administration of maternal vaginal microbes at birth failed to normalise the gut microbiome of babies born by caesarean section (CS). Compared with vaginally born babies, the gut microbiome of CS babies had lower abundances of Bacteroides species and reduced representation of microbial pathways involved in the biosynthesis of B vitamins and peptidoglycan – a potent immune stimulator. Engraftment of maternal vaginal strains within the infant gut was minimal, suggesting these strains do not have a dominant role in seeding the infant gut microbiome. Collectively, the results of these studies demonstrate that alteration of the gut microbiome in response to microbial administration is highly context-specific. The degree of microbiome modification likely depends on the fitness of the microbes being transmitted, their biological interactions with the residing gut microbiome, and the environmental conditions supplied by the host. A greater mechanistic understanding of these interactions will assist in developing effective microbial therapeutics that are individually tailored to the specific microbiome perturbations driving disease aetiology.