Metagenomic analyses of the human gut microbiome reveal connections to the immune system

Abstract

Mounting evidence shows that the gut microbiome has an important role in human health. This thesis utilizes metagenomic sequencing data to examine the role of the gut microbiota in human health, specifically in juvenile autoimmune disorders such as type 1 diabetes (T1D). Numerous studies suggest that the intestinal microbes contribute to many immunological disorders and other conditions such as obesity. According to the hygiene hypothesis, lack of certain microbial exposures are central in development of autoimmunity in early childhood. However, a clear distinction between beneficial and harmful bacteria as well as mechanistic understanding of how the microbiome leads to aberrations in immune development are lacking. We aimed to elucidate the mechanisms behind the hygiene hypothesis by studying the gut microbiome of infants at risk for autoimmune disorders in Northern Europe. We also investigated the gut microbiome of 1135 healthy Dutch adults for connections with various intrinsic and extrinsic factors, and conducted a fecal microbial transplantation study in active Crohn's disease (CD). We used whole metagenome shotgun (WMS) and 16S rRNA gene sequencing, and computational analysis methods to taxonomically and functionally profile the gut microbial communities in three separate cohorts. By investigating the gut microbiome of 294 infants from Finland, Estonia and Russian Karelia, we characterized the developing infant gut microbiome and identified the immunogenicity of lipopolysaccharide (LPS) produced by Bacteroides species as a novel factor contributing to the higher incidence of T1D in Finland and Estonia compared to Russian Karelia. LPS derived from Bacteroides dorei, a species that has been previously linked to T1D pathogenesis, harbored tetra- and penta-acylated LPS structures which failed to induce immune stimulation in human cells and inhibited immune stimulation and endotoxin tolerance by Escherichia coli-derived LPS. We also found that recurrent antibiotic treatments lead to decrease in microbial diversity and increase in antibiotic resistance genes. Using WMS sequencing data from healthy adults, we identified chromogranin A as a novel biomarker for gut health. By investigating the gut microbiome of 19 CD patients before and after colonoscopic fecal microbial transplantation (FMT), we concluded that the FMT was safe and resulted in a shift towards the donor microbiota. This thesis contributes to novel functional and mechanistic understanding of the human gut microbiome in infancy and adulthood, health and disease. I provide new computational methodologies for analysing microbiome on strain level and connecting its functionalities with human health. The findings of this thesis pave way towards therapeutic interventions modifying the gut microbiome to prevent immune mediated and other disorders in humans.