Systems and Synthetic Biology: “Mining human gut microbial metabolism through in vitro and in silico approaches”
Doctoral thesis, 2019
The human gut microbiome is a consequence of mutual co-evolutionary interaction between the eukaryotic and prokaryotic parts of the mammalian holobiont. Based on the environmental and dietary inputs, there is a succession of microorganisms living inside the human colon. They have evolved to perform metabolic tasks that are not possible by the human host — for example, they breakdown complex polysaccharides and produce bioactive molecules such as short-chain fatty acids. They have the potential to transform human generated metabolites (e.g., primary bile acids) to signaling compounds such as secondary bile acids. They also produce several of B-vitamins, which otherwise human host derive through dietary means. Cognate receptors in various host cells could sense these bioactive metabolites and contribute to a wide variety of physiological function through signaling system in the host. An imbalance between the microbial activity and their effect on the host system could lead to the development of metabolic diseases.
Provided the critical role of gut microbial metabolism, this thesis presents the evaluation of metabolic genes of gut microbiota such as bile acid, vitamin, and short-chain fatty acid metabolism using metabolic reconstructions and bioinformatics analysis in different states of health. Fecal metagenomes of subjects with inflammatory bowel diseases, type 2 diabetes and malnutrition were analyzed for such functional analyses. Furthermore, abundant gut microbial species were characterized to study their growth and metabolism in in vitro co-cultures using network analysis. The findings explained here show the gut microbial metabolic diversity in various cohorts and conditions. It also includes a discussion on the challenges and future perspectives in a broader context of its potential application. The efforts undertaken in this work aims to inspire how the interplay between gut microbial metabolism and the host health status could contribute to the overall well-being of an individual.
Provided the critical role of gut microbial metabolism, this thesis presents the evaluation of metabolic genes of gut microbiota such as bile acid, vitamin, and short-chain fatty acid metabolism using metabolic reconstructions and bioinformatics analysis in different states of health. Fecal metagenomes of subjects with inflammatory bowel diseases, type 2 diabetes and malnutrition were analyzed for such functional analyses. Furthermore, abundant gut microbial species were characterized to study their growth and metabolism in in vitro co-cultures using network analysis. The findings explained here show the gut microbial metabolic diversity in various cohorts and conditions. It also includes a discussion on the challenges and future perspectives in a broader context of its potential application. The efforts undertaken in this work aims to inspire how the interplay between gut microbial metabolism and the host health status could contribute to the overall well-being of an individual.
gut
bile acids
metatranscriptomics
in vitro co-cultures
metagenomics
co-occurrence network
short chain fatty acids
metabolomics
metabolism
vitamins
Lecture Hall KC, Kemihuset, Kemigården 4
Opponent: Prof. Susanne Brix Pedersen, Technical University of Denmark (DTU), Denmark
Author
Promi Das
Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology
Metagenomic analysis of microbe-mediated vitamin metabolism in the human gut microbiome
BMC Genomics,;Vol. 20(2019)
Journal article
Gut microbiota dysbiosis is associated with malnutrition and reduced plasma amino acid levels: Lessons from genome-scale metabolic modeling
Metabolic Engineering,;Vol. 49(2018)p. 128-142
Journal article
In vitro co-cultures of human gut bacterial species as predicted from co-occurrence network analysis
PLoS ONE,;Vol. 13(2018)
Journal article
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.
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.
Subject Categories
Microbiology
Bioinformatics and Systems Biology
ISBN
978-91-7597-875-8
Doktorsavhandlingar vid Chalmers tekniska högskola. Ny serie: 4556
Publisher
Chalmers
Lecture Hall KC, Kemihuset, Kemigården 4
Opponent: Prof. Susanne Brix Pedersen, Technical University of Denmark (DTU), Denmark