Integrated Biology of the GI Tract
The Gut Microbiota
Primary Objectives
- What is the extent, basis and function of the metabolic activity of the microbiota?
- How do intestinal microbes interact with and modulate the mucus layer that coats intestinal epithelial cells and is an integral part of its barrier function?
- Can we establish a model microbiota that is representative of the diversity found in the human colon that can be used to investigate its function and how it interacts with the host
Bacteria dominate the human gut ecosystem. The majority belong to just two phyla: the Firmicutes and the Bacteroidetes. On the other hand, there is great diversity at lower taxonomic levels and considerable interpersonal variation in the bacterial species and strains present in the gut microbiota. Detailed characterisation of the human microbiota faces the considerable obstacle of unculturability. Despite this, great advances have been made through the development of culture-independent technologies and in particular, metagenomics. Metagenomic surveys have revealed unprecedented microbial biodiversity in the human intestine. Upwards of 40,000 bacterial species are estimated to comprise the collective gastrointestinal microbiome, most of which have yet to be characterised by culture.
Diverse disorders such as antibiotic-associated diarrhoea, Crohn's disease, ulcerative colitis, obesity, and pouchitis have been correlated with large-scale imbalances in the gastrointestinal microbiota, or 'dysbiosis', demonstrating the importance of commensal microorganisms in maintaining gastrointestinal health.
We will explore the metabolic diversity and the molecular basis of its interactions with the host. One approach will be to develop, as an enabling technology, a model microbiota that is representative of the taxonomic and metabolic diversity of the human colonic microbiota that can be used to probe in more detail than ever before its function and the nature of inter-species and -kingdom interactions and how it contributes to preserving GIT health.
Collectively, our research should open avenues to developing new bioactive compounds, targeting in particular immunomodulation and cell proliferation in relation with work on Gut Immunity and the Gut Epithelium, and also rational modulation of the microbiota.
Understanding the extent, basis and function of metabolic diversity in GI tract commensal and pathogenic species by exploiting sequenced genomes and metagenomes and producing a "gold standard" set of characterised pathways within the gut microbiota.
This work has evolved from pioneering studies at IFR. Focusing on the initial targets of polyamine and carbohydrate metabolism, essential metabolic pathways in both prokaryotic and eukaryotic organisms have been defined through the use of functional genomics and biochemistry coupled with exploitation of sequenced genomes and transcriptomes to define metabolic diversity. Of direct relevance is the development of methodologies for analysing the functions of metabolic pathways and the consequences of metabolic dysfunction.
The 10 trillion or so microbial cells living in the gut, exceed the number of human cells by 10 to 1, thus harbouring millions of genes, compared with the 28,000 estimated in the human genome. Large metagenomic datasets are being generated by a number of sequencing projects across the world (the NIH's 5-year Human Microbiome Project, the European Commision;'s 4 year Metagenomics of Human Intestinal Tract - MetaHIT, being the largest ones), which includes the sequencing of 1000 specific human microbiome species. The enormous amounts of data from sequenced genomes and metagenomes are difficult to interpret due to the fact that most metabolic pathways have been characterised in Escherichia coli and therefore annotation of genomic sequences is poorly supported by experimental data, if at all. The aim is to investigate the biochemical function in key core metabolic pathways. We will focus on the polyamine biosynthetic pathway because it is an essential core pathway and it is one of the shortest biosynthetic pathways consisting of a diamine and triamine (putrescine and spermidine in E. coli).
Defining how intestinal microbes, particularly mucus-resident commensal bacteria, regulate and modulate the development and maintenance of the mucin barrier.
Nathalie Juge
We have considerable strength in structure/function studies of carbohydrate-active enzymes to explore the diversity of the glycobiome in gut bacteria species. From this pioneering work, bioinformatics, molecular and enzymology approaches have been developed that are central to the proposed focus on the degradation of complex polysaccharides.
The overlying mucus gel layer of the intestinal epithelium is the anatomical site at which the host first encounters gut bacteria. Bacterial attachment to the mucus is fundamental to the establishment of a stable commensal microflora, and relevant to the progress of infection by important pathogenic bacteria. However to date there has been little attention paid to the interaction of bacteria with the complex mucus gel that overlay epithelial surfaces.
We will be examining the differential transcriptional response of commensal bacterial species to mucins; investigating the structure and function of the complex bacteria-mucin interactions; identifying glycan binding proteins, adhesins/lectins and receptors in host-microbe interaction; determining the role of gut bacteria in mucin-degradation; and investigating the impact of intestinal microbiota (Firmicutes/Bacteroidetes) on mucin and mucin composition.
This work involves collaboration with teams working on Gut Immunity (Simon Carding), Foodborne Bacterial Pathogens (Arnoud van Vliet) and Food Structure and Health (Clare Mills).
Development of a new enabling technology - the establishment of a model GI tract microbiota representative of the taxonomic and metabolic diversity found in the human colon.
Arjan Narbad
The complexity and diversity of the gut microbiota pose significant challenges to studying its biology. Whilst progress has been made in understanding and defining the properties of individual members, how the microbiota functions is the product of communities of bacteria and interactions between multiple species. New paradigms and approaches are needed therefore in order to begin to study the ecology of the human gut microbiota. We propose to address this by developing a model microbiota that is representative of the taxonomic and metabolic diversity found in the human colon. This will provide a powerful and tractable experimental system to address fundamental questions concerning the molecular and biochemical nature of inter-species and -kingdom interactions. It can also be used to investigate affects of diet and metabolic stress, and how complex microbial communities interact with the host in preserving gut health and, the role they play in the pathogenesis of chronic inflammation and intestinal disease.
Understanding how bacteria adapt to the intestinal environment and become stable residents of the gut microbiota
Sacha Lucchini
The gut microbiota is a complex and diverse community of microorganisms that plays an important role in gut homeostasis. Recent experiments in both humans and animals have provided strong evidence that the composition of the microbiota can have a significant impact on different aspects of host health such as metabolism or susceptibility to bacterial pathogens. Strategies aimed at maintaining an appropriate gut microbiota composition could therefore be beneficial. However, this requires a better understanding of the genetic and environmental factors which determine the abundance of the various microbial species within the gut microbiota.
We are taking advantage of recent advances in high-throughput sequencing technologies to identify which bacterial genes are expressed in the gut. Because the bacterial transcriptome closely reflects the conditions where the bacteria reside, this approach will help identifying bacterial functions that are important for the colonisation of the gut and also provide information about the gut microenvironment as sensed by the bacteria.
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