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Studying the metabolic functionality of the intestinal microbiota in vitro
S12
Abstracts / Toxicology Letters 280S (2017) S11–S12
S02-03 Systems biology: Prediction of health-relevant human-microbial co-metabolism through a computational framework Almut Heinken Luxembourg Centre for Systems Biomedicine, Université du Luxembourg, Esch-sur-Alzette, Luxembourg The human gut microbiota performs important functions for host health and wellbeing. Disturbances in host-microbe co-metabolism have been linked to complex diseases. To further our understanding of human-gut microbiota interactions, an integrative computational systems biology approach is necessary. Constraint-based Reconstruction and Analysis (COBRA) is useful tool for detailed, mechanistic large-scale modeling of host-microbe metabolic interactions. COBRA uses genome-scale metabolic reconstructions (GENREs) that represent a knowledge base of the reconstructed organism. We constructed the first genome-scale model of a human gut microbe community, consisting of 11 manually curated and validated gut microbe reconstructions spanning three phyla. To predict the model gut community’s impact on human metabolism, it was joined with the global human reconstruction, Recon2. The effects of the different microbes on host metabolic tasks were systematically explored while simulating four different dietary regimes. A variety of human body fluid metabolites were predicted to be influenced by microbial presence, including many that have been measured in vivo and found to be affected by the microbiota. Moreover, we recently published AGORA, a resource of curated genome-scale metabolic reconstructions for 773 common gut microbial strains. AGORA captures the metabolic diversity of the human gut microbiota and can be contextualized with metagenomic data to generate individual-specific microbiota models. In summary, we demonstrate the applicability of constraintbased modeling for predicting host-microbiota co-metabolism. Future applications include the prediction of individual-specific metabolism of dietary components or xenobiotics by joining the human reconstruction with personalized gut microbiota models. http://dx.doi.org/10.1016/j.toxlet.2017.07.017 S02-04 Studying the metabolic functionality of the intestinal microbiota in vitro Karsten Beekmann Division of Toxicology, Wageningen University, Wageningen, Netherlands The human organism is host to a huge number and variety of microorganisms. In normal homeostasis, the host lives in a symbiotic relationship with these microorganisms that are considered to play a significant role in the health of the host. The intestinal microbiota influences the host’s health among others through metabolism of indigestible food components, production of essential vitamins, and protection against opportunistic pathogens. Increasing evidence shows that the intestinal microbiota can affect
the ultimate bioactivity of various xenobiotics through a wide range of biochemical and metabolic activities. This can lead to the formation of metabolites with often uncharacterized toxicokinetics and toxicodynamics. Especially in modern, mode-of-action driven safety assessments, the potential intestinal microbial metabolism is easily overlooked, indicating that there is a need for in vitro models that can be used to identify the formation of relevant intestinal microbial metabolites. We utilize anaerobic incubations of fecal samples from different species (e.g. rat and human) and different individuals to study the intestinal microbial metabolism of different types of xenobiotics. This presentation will show preliminary results on the time-dependent formation of intestinal microbial metabolites of xenobiotics, such as the phytochemical daidzein, obtained from anaerobic incubations of fecal samples from rat and human. It will be further demonstrated that this technique can be used for the biosynthesis of sufficient amounts of these metabolites for subsequent toxicokinetic and toxicodynamic studies. The data show that anaerobic incubations of fecal samples are a valuable tool to study the intestinal microbial metabolism of xenobiotics. http://dx.doi.org/10.1016/j.toxlet.2017.07.018 S02-05 Towards affordable diagnosis based on human gut microbiome: Colorectal cancer as a case study Manimozhiyan Arumugam NNF Metabolism Center, University of Copenhagen, Copenhagen, Denmark The trillions of microorganisms living in the human body, collectively known as the human microbiota, have a tremendous influence on human health and diseases. Although it was virtually impossible to study them until a few years ago, next generation sequencing technologies have enabled us to access and characterize these microbiota in a culture-free manner using metagenomic sequencing. Thanks to these developments, a new family of studies known as metagenome-wide association studies (MGWAS) have reported significant associations between the human microbiome and diseases such as type 2 diabetes. Establishing catalogues of human gut microbial genes (Li et al., Nature Biotechnology 2014) was instrumental in performing such studies. This is only the beginning of a new trend to elucidate the role of host-associated microbiome in diseases, and developing scalable bioinformatics tools is becoming increasingly important in this endeavor. Moreover, establishing a role of gut microbiome in the pathogenesis of complex diseases requires carefully designed experiments in animal models. Recently we reported significant changes in the gut microbiome associated with colorectal carcinoma in a Chinese cohort (Yu et al., Gut 2015). We identified microbial gene biomarkers from fecal microbiome and validated them in multiple cohorts from Europe. Quantitative PCR measurements of some of these markers show promising potential for affordable diagnosis of colorectal cancer using fecal microbiome. In this talk, our published and ongoing research on understanding the role of the gut microbiome in diseases will be discussed. http://dx.doi.org/10.1016/j.toxlet.2017.07.019
Abstracts / Toxicology Letters 280S (2017) S11–S12
S02-03 Systems biology: Prediction of health-relevant human-microbial co-metabolism through a computational framework Almut Heinken Luxembourg Centre for Systems Biomedicine, Université du Luxembourg, Esch-sur-Alzette, Luxembourg The human gut microbiota performs important functions for host health and wellbeing. Disturbances in host-microbe co-metabolism have been linked to complex diseases. To further our understanding of human-gut microbiota interactions, an integrative computational systems biology approach is necessary. Constraint-based Reconstruction and Analysis (COBRA) is useful tool for detailed, mechanistic large-scale modeling of host-microbe metabolic interactions. COBRA uses genome-scale metabolic reconstructions (GENREs) that represent a knowledge base of the reconstructed organism. We constructed the first genome-scale model of a human gut microbe community, consisting of 11 manually curated and validated gut microbe reconstructions spanning three phyla. To predict the model gut community’s impact on human metabolism, it was joined with the global human reconstruction, Recon2. The effects of the different microbes on host metabolic tasks were systematically explored while simulating four different dietary regimes. A variety of human body fluid metabolites were predicted to be influenced by microbial presence, including many that have been measured in vivo and found to be affected by the microbiota. Moreover, we recently published AGORA, a resource of curated genome-scale metabolic reconstructions for 773 common gut microbial strains. AGORA captures the metabolic diversity of the human gut microbiota and can be contextualized with metagenomic data to generate individual-specific microbiota models. In summary, we demonstrate the applicability of constraintbased modeling for predicting host-microbiota co-metabolism. Future applications include the prediction of individual-specific metabolism of dietary components or xenobiotics by joining the human reconstruction with personalized gut microbiota models. http://dx.doi.org/10.1016/j.toxlet.2017.07.017 S02-04 Studying the metabolic functionality of the intestinal microbiota in vitro Karsten Beekmann Division of Toxicology, Wageningen University, Wageningen, Netherlands The human organism is host to a huge number and variety of microorganisms. In normal homeostasis, the host lives in a symbiotic relationship with these microorganisms that are considered to play a significant role in the health of the host. The intestinal microbiota influences the host’s health among others through metabolism of indigestible food components, production of essential vitamins, and protection against opportunistic pathogens. Increasing evidence shows that the intestinal microbiota can affect
the ultimate bioactivity of various xenobiotics through a wide range of biochemical and metabolic activities. This can lead to the formation of metabolites with often uncharacterized toxicokinetics and toxicodynamics. Especially in modern, mode-of-action driven safety assessments, the potential intestinal microbial metabolism is easily overlooked, indicating that there is a need for in vitro models that can be used to identify the formation of relevant intestinal microbial metabolites. We utilize anaerobic incubations of fecal samples from different species (e.g. rat and human) and different individuals to study the intestinal microbial metabolism of different types of xenobiotics. This presentation will show preliminary results on the time-dependent formation of intestinal microbial metabolites of xenobiotics, such as the phytochemical daidzein, obtained from anaerobic incubations of fecal samples from rat and human. It will be further demonstrated that this technique can be used for the biosynthesis of sufficient amounts of these metabolites for subsequent toxicokinetic and toxicodynamic studies. The data show that anaerobic incubations of fecal samples are a valuable tool to study the intestinal microbial metabolism of xenobiotics. http://dx.doi.org/10.1016/j.toxlet.2017.07.018 S02-05 Towards affordable diagnosis based on human gut microbiome: Colorectal cancer as a case study Manimozhiyan Arumugam NNF Metabolism Center, University of Copenhagen, Copenhagen, Denmark The trillions of microorganisms living in the human body, collectively known as the human microbiota, have a tremendous influence on human health and diseases. Although it was virtually impossible to study them until a few years ago, next generation sequencing technologies have enabled us to access and characterize these microbiota in a culture-free manner using metagenomic sequencing. Thanks to these developments, a new family of studies known as metagenome-wide association studies (MGWAS) have reported significant associations between the human microbiome and diseases such as type 2 diabetes. Establishing catalogues of human gut microbial genes (Li et al., Nature Biotechnology 2014) was instrumental in performing such studies. This is only the beginning of a new trend to elucidate the role of host-associated microbiome in diseases, and developing scalable bioinformatics tools is becoming increasingly important in this endeavor. Moreover, establishing a role of gut microbiome in the pathogenesis of complex diseases requires carefully designed experiments in animal models. Recently we reported significant changes in the gut microbiome associated with colorectal carcinoma in a Chinese cohort (Yu et al., Gut 2015). We identified microbial gene biomarkers from fecal microbiome and validated them in multiple cohorts from Europe. Quantitative PCR measurements of some of these markers show promising potential for affordable diagnosis of colorectal cancer using fecal microbiome. In this talk, our published and ongoing research on understanding the role of the gut microbiome in diseases will be discussed. http://dx.doi.org/10.1016/j.toxlet.2017.07.019