Systems and Synthetic Biology: ​“Mining human gut microbial metabolism through in vitro and in silico approaches”

Doktorsavhandling, 2019

The human gut microbiome is a succession of microorganisms living inside the human colon. They act as a signaling hub by transmitting signals to the human host in various ways based on the environmental and dietary inputs. Host cells can sense these microbial species and their metabolic products and translate into a physiological response. This bilateral co-evolutionary interaction between the eukaryotic and prokaryotic parts of the mammalian holobiont is crucial in contributing to the health and complex diseases. Any disturbances in the process of communication between the host system and the gut microbiota could alter the balance of the crosstalk.

For the evaluation of human gut microbiome, fecal samples are reasonable proxies among otherwise invasive procedures. In the past decade, large-scale efforts of culture-independent characterization of gut microbiome realized the microbial composition of a community. Current studies reveal that at a functional level, gut microbiota entails valuable resource of metabolic enzymes which are complementary to host capabilities. With the help of experimental characterization of gut microbial species, computational modeling, and bioinformatics approaches, multi-faceted datasets could be analyzed to extract biological message crucial in sustaining the host-microbiome mutualism.

From a systems biology perspective, this thesis focuses on the interplay between the host and bacterial microbiome. As a model system, fecal metagenomes from subjects with Malnutrition, Inflammatory bowel disease, and Type 2 diabetes were investigated for microbial metabolic potential as they integrate all aspects of host immunology at the interface between bacterial colonization and innate-immune-system activation. It also highlights the co-occurrence patterns between the commensal bacteria, how variation in microbiota’s metabolite production potential (such as short-chain fatty acids, amino acids, secondary bile acids, and vitamins) could contribute to multifactorial disorders.

Research findings in this thesis report three concurrent themes: first, environmental factors are pivotal drivers of species co-existence in a community; second, the metabolic potential of a community is country- and context-dependent; third, a combination and integration of in vitro multi-layered information is valuable in strengthening the computational in silico predictions.