The interaction of genetics, inflammation and the microbiome in the human metaorganism

The evolutionary relationship between animals, from sponges to mammals, and their associated assemblages of microorganism – the microbiome – created biological entities that should not and cannot be considered without one another: the metaorganism. Especially the existence and development of the human as a metaorganism has shifted into the focus of scientific research, as the human-associated microbial communities are thought to have great impact on the host’s constitution and health. Here especially the intestinal microbiota, the largest reservoir of microorganisms associated with the human body, has gained large interest in a wide range of medical fields, from gastrointestinal to neurological disorders. Host-microbe interactions with these commensal microbes – bacteria, archaea, fungi, unicellular eukaryotes and viruses – are expected to integrate into and modulate a wide range of the host’s metabolic processes. As the forces shaping the human-associated microbial communities and the extent of these interactions are still largely unknown, this doctoral thesis aimed to contribute to a deeper understanding of the human metaorganism. The first chapter introduces major concepts, technologies and diseases discussed in this thesis. Chapter 2 discusses how technological aspects of 16S rRNA gene amplicon-based surveys of microbial communities and shotgun metagenomic sequencing influence the outcome of microbiome studies. Using a wide range of microbial communities associated with model and non-model organisms investigated in the framework of the ‘Collaborative Reseach Centre 1182-Origin and Function of Metaorganisms’, the study shows that amplicon-based and metagenomic approaches are capable of complementing each other, and that the choice of technology always depends on the community under investigation. In addition, the study demonstrates that the transition from aquatic to terrestrial lifestyle in the evolutionary history of animals had major impact on the community composition of the host-associated microbiome. Chapter 3 investigates the effect of host-genetic variation on the community composition and the presence and abundance of individual members and taxonomic groups of the human intestinal microbiota. In two genome-wide association studies, one involving 1,767 individuals from Norther Germany and the other an additional 7,275 individuals from North-Eastern and Southern Germany, four and 32 human genomic loci with influence on microbial traits were identified, respectively. In addition, the second study reveals specific ABO histo-blood group related changes in members of Bacteroides, and causative effects of microbial features on inflammatory bowel disease as well as other inflammatory and non-inflammatory disorders using Mendelian randomization. Chapter 4 summarizes findings on disease-associated changes in different parts of the human microbiome. Marked changes were found in the bacterial microbiota in connection with primary sclerosing cholangitis (PSC) and ulcerative colitis in comparison with healthy control individuals from Germany and Norway. Especially an increase in the relative abundance of Veillonella and a decrease abundance of Coprococcus, a bacterium generally associated with intestinal health, were found to be robust in connection with PSC, together with a wide-ranging loss of diversity. In addition, bacterial signatures that are useful as diagnostic markers for the discrimination of PSC patients and healthy controls were obtained (AUC = 0.88). Also, the intestinal mycobiota exhibits clear differences between healthy individuals and PSC patients, displayed by disease-associated increases in relative abundances of the genera Candida and Humicola/Trichocladium. Lastly, disease-associated changes were found in the skin microbiota of individuals with atopic dermatitis (AD) at sites with acute and chronic lesions, as well as non-lesional skin across all sampled body sites. Lesions were associated with increased relative abundances of Staphylococcus aureus and changes of other Staphylococcus spp. In addition, epidermal lipid composition and mutations in the filaggrin gene, a major known risk factor for AD, were found to be influencing skin microbiome composition. In summary, the findings presented in this thesis suggest a strong impact of host-genetics on the abundance of individual members of the microbiome and the community composition as a whole. The disease associated changes in different parts of the host microbiota imply metabolic interactions of host and microbes. Whether these are causal for or consequence of disease remains uncertain, however, the results of Mendelian randomization suggest that members of the intestinal microbiota actively contribute to the modulation of complex disease phenotypes. These results may lead to an in-depth investigation of candidate microorganisms, such as Bacteroides and Trichocladium, for potential treatment targets of chronic inflammatory diseases.


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