Reference number : GC-2017-Q1-01769, amendment number : , agreement type : G, recipient legal name : Shearer, Jane (University of Calgary), recipient country : CA, recipient province : nan, recipient city : Alberta, recipient postal code : nan, program name english : Discovery Grants Program - Individual, program name french : Programme de subventions à la découverte - individuelles, program purpose english : SYNOPSIS. Despite an abundance of evidence showing the gut microbiome to influence metabolism, our understanding of the mechanisms by which differential gut microbiota contribute to metabolism is incomplete. In this respect, recent studies have revealed that the host and the microbiota are involved in several complex interactions resulting in so-called &ldquo;host-microbiome metabolic axes&rdquo;. These metabolic axes result in the combinatorial metabolism of substrates by the microbiome and host genome, exemplified by the production of bile acids, choline metabolites and short-chain fatty acids. The production of these metabolites contributes not only to the host metabolic phenotype, but also to glucose and fatty acid metabolism. 
 
SPECIFIC AIMS. The overarching hypothesis is that it might be more suitable to examine the host-microbiome metabolic axes compared to the phylogenetic composition of a bacterial community. Thus, for the host-microbiome interactions, it might not be that important what defined bacterial species are present in the gut but rather the overall metabolic activity of the whole microbiome which is referred to as the &ldquo; metabotype &rdquo;. The short-term objectives are to: 
 
i) Uncover the signatures of various bacterial metabotypes by examining the metabolism of specific polyphenols. 
ii) Determine the contribution of fermented food products in modulating the host gut microbiome, metabolism and whether observed changes are metabotype dependent. 
iii) To examine the impact of micronutrient supplementation, specifically iron, copper and zinc on host microbiota, metabolism and metabotype profiles. 
iv) Employ data from Aims 1-3 to model gut host-microbiome interactions. 
 
APPROACHES AND METHODOLOGIES. Our scientific approach will capitalize on our well-established NSERC-funded rodent models of gut-microbiome interactions. Specifically, we will take advantage of expertise developed in the laboratory over the past six years that concentrates on detailed microbiome, metabolomic and bioinformatics analyses as well as tools to infer nutrition &ndash; microbiome &ndash; serum metabolite interactions. The experimental model that will be used is the well-characterized, chronically catheterized (portal, arterial, venous), conscious rat. Sequencing will assess the microbiome at a functional rather than a taxonomical level. Extensive serum and fecal metabolomic profiling will be conducted by GC-MS, ICP-MS and 1H-NMR. Assessment of circulating inflammatory markers, key regulators (mRNA, protein, activity) and gut peptides will provide further insight. 
 
 IMPACT AND RELEVANCE. This grant will gain insight into gut microbiome-nutrient interactions by examining the capacity of varied metabotypes. Describing the mechanisms by which gut microbiota can affect metabolism is the next frontier in our understanding of the microbiome and its impact on host physiology., program purpose french : SYNOPSIS. Despite an abundance of evidence showing the gut microbiome to influence metabolism, our understanding of the mechanisms by which differential gut microbiota contribute to metabolism is incomplete. In this respect, recent studies have revealed that the host and the microbiota are involved in several complex interactions resulting in so-called &ldquo;host-microbiome metabolic axes&rdquo;. These metabolic axes result in the combinatorial metabolism of substrates by the microbiome and host genome, exemplified by the production of bile acids, choline metabolites and short-chain fatty acids. The production of these metabolites contributes not only to the host metabolic phenotype, but also to glucose and fatty acid metabolism. 
 
SPECIFIC AIMS. The overarching hypothesis is that it might be more suitable to examine the host-microbiome metabolic axes compared to the phylogenetic composition of a bacterial community. Thus, for the host-microbiome interactions, it might not be that important what defined bacterial species are present in the gut but rather the overall metabolic activity of the whole microbiome which is referred to as the &ldquo; metabotype &rdquo;. The short-term objectives are to: 
 
i) Uncover the signatures of various bacterial metabotypes by examining the metabolism of specific polyphenols. 
ii) Determine the contribution of fermented food products in modulating the host gut microbiome, metabolism and whether observed changes are metabotype dependent. 
iii) To examine the impact of micronutrient supplementation, specifically iron, copper and zinc on host microbiota, metabolism and metabotype profiles. 
iv) Employ data from Aims 1-3 to model gut host-microbiome interactions. 
 
APPROACHES AND METHODOLOGIES. Our scientific approach will capitalize on our well-established NSERC-funded rodent models of gut-microbiome interactions. Specifically, we will take advantage of expertise developed in the laboratory over the past six years that concentrates on detailed microbiome, metabolomic and bioinformatics analyses as well as tools to infer nutrition &ndash; microbiome &ndash; serum metabolite interactions. The experimental model that will be used is the well-characterized, chronically catheterized (portal, arterial, venous), conscious rat. Sequencing will assess the microbiome at a functional rather than a taxonomical level. Extensive serum and fecal metabolomic profiling will be conducted by GC-MS, ICP-MS and 1H-NMR. Assessment of circulating inflammatory markers, key regulators (mRNA, protein, activity) and gut peptides will provide further insight. 
 
 IMPACT AND RELEVANCE. This grant will gain insight into gut microbiome-nutrient interactions by examining the capacity of varied metabotypes. Describing the mechanisms by which gut microbiota can affect metabolism is the next frontier in our understanding of the microbiome and its impact on host physiology., agreement title english : Gut Based Modulators of Metabolism, agreement title french : Gut Based Modulators of Metabolism, agreement number : RGPIN, agreement value : 28000.0, agreement start date : 2017-05-10, agreement end date : nan, description english : nan, description french : nan, expected results english : nan, expected results french : nan, additional information english : Grant or Award spanning more than one fiscal year. (2017-2018 to 2018-2019), additional information french : Subvention ou bourse octroyée s'appliquant à plus d'un exercice financier. (2017-2018 à 2018-2019), owner organization : nserc-crsng, owner organization title : Natural Sciences and Engineering Research Council of Canada | Conseil de recherches en sciences naturelles et en génie du Canada