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Mechanistic studies to develop a polysaccharide degradation signature (PDS) and its application in improving host health

开发多糖降解特征（PDS）的机制研究及其在改善宿主健康中的应用

基本信息

批准号：
10260593
负责人：
ISAAC CANN
金额：
$ 51.12万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10260593
关键词：
Adult Aminoglycoside Antibiotics Anaerobic Bacteria Antioxidants Avena sativa Bacteria Bacteriodetes Bacteroides Bacteroidetes Barley Biochemical Bioinformatics Biological Biological Assay Biological Availability Cells Chemopreventive Agent Cisplatin Colon Communities Complex Cytoprotection Data Databases Deposition Development Diet Dietary Component Dietary Fiber Dietary Polysaccharide Distal Environment Enzymes Family Fermentation Fiber Firmicutes Gene Cluster Gene Expression Genes Genome Genomics Germ-Free Gnotobiotic Goals Growth Hair Hair Cells Harvest Health Health Benefit Health Promotion Human Hydrolysis Individual Link Mediating Metabolism Microbe Modeling Molecular Molecular Profiling Mucins Noise Nutritional Oligosaccharides Pectins Pharmaceutical Preparations Pharmacology Phenols Phylogenetic Analysis Phytochemical Plants Polysaccharides Prevotella Proteins Proxy Reporting Rice Sensory Hair Structure System Trees Volatile Fatty Acids Wheat X-Ray Crystallography Zebrafish base colon microbiome ferulic acid improved in vivo member microbial microbiome microorganism multiple omics nutrition polypeptide predictive signature protein complex response search engine sensor sugar transcriptomics yeast two hybrid system

项目摘要

PROJECT SUMMARY/ABSTRACT The human colon harbors a large number of microorganisms that collectively are referred to as the colonic microbiome. The microbes in the colonic microbiome are dominated by bacteria of the phyla Bacteroidetes and Firmicutes. Among the Bacteriodetes, Prevotella spp. and Bacteroides spp. abound in the colonic environment and have evolved a complex protein machinery that allows them to harvest energy from both host undegradable polysaccharides in the diet and host derived-glycans, such as mucin. Central to the mechanism underlying polysaccharide degradation by the Bacteroidetes is the Polysaccharide Degradation Locus (PUL) or Loci (PULs) present on their genomes. The PULs are composed of gene clusters that encode proteins that enable the Bacteroidetes to sense, transport, and degrade diverse polysaccharides to their unit sugars for fermentation. A large protein, known as the Hybrid Two Component System (HTCS), is conserved in the PULs of the Bacteroidetes and functions by sensing either a polysaccharide or its oligosaccharides to turn on the expression of the hydrolytic enzymes and their associated transporters. In this proposal, we demonstrate that indeed the Bacteroidetes HTCS contain sensor modules that sense unique polysaccharides or their degradative products in the colonic environment. Thus, we hypothesized that the diverse sensors in the HTCS polypeptides collectively can serve as a proxy for polysaccharide sensing in the colon of an individual. We have designated this proxy as the Polysaccharide Degradation Signature or PDS. By using more than 3000 HTCS sequences in the publicly available databases, we constructed a phylogenetic tree that appeared to cluster the sensor modules into different branches. Among host undegradable polysaccharides found in human diets, such as wheat, barley, rice and oats, is arabinoxylan. We, therefore, used growth on arabinoxylan and transcriptomic analysis to determine the PULs that target soluble arabinoxylan and insoluble arabinoxylan degradation, respectively, in three members of the human colonic Bacteroidetes. Our data showed that clusters in our phylogenetic tree or PDS can be matched to arabinoxylan sensing and metabolism. Interestingly, we also discovered that the Bacteroides spp that metabolize complex arabinoxylan release the plant phenolic compound ferulic acid and that the compound accumulates in the spent medium. Ferulic acid is known to have antioxidant effects and also to protect against mechanosensory hair loss. We will, therefore, determine whether a synbiotic of complex arabinoxylan and arabinoxylan-metabolizing Bacteroidetes has the capacity to confer protection against mechanosensory hair loss in germ-free zebrafish. Confirmation of this observation will allow us, through transcriptomics analysis, to determine the underlying molecular mechanisms for this protection. Furthermore, we will use biochemical and structural analyses to completely characterize the mechanism of arabinoxylan degradation by the human colonic Bacteroidetes. We also anticipate that our development of the PDS will allow rational manipulation of the polysaccharides sensed by an individual’s microbiome for health and nutritional benefits.

项目总结/文摘