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Harnessing the gut microbiome to detect and quantify glycans

利用肠道微生物组来检测和量化聚糖

基本信息

批准号：
10501753
负责人：
Guy Edmund Townsend
金额：
$ 45.3万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10501753
关键词：
Affinity Affinity Chromatography Animals Automobile Driving Bacteroides Bacteroides thetaiotaomicron Binding Proteins Biological Biological Process Carbohydrates Complement Complex Complex Mixtures Detection Disease Dose Engineering Environment Genes Glycosides Goals Harvest Health Human In Vitro Individual Intestinal Content Intestines Libraries Life Mass Spectrum Analysis Measurement Measures Metabolic Metabolism Methods Microbe Modeling Modification Natural regeneration Nuclear Magnetic Resonance Nucleic Acids Nutrient Oligonucleotides Organism Output Plants Polymers Polysaccharides Proteins Recombinants Reporter Reporting Resources Sampling Sensitivity and Specificity Source Specificity Standardization Structure Surveys System Therapeutic clinically relevant cost detection method detection platform gut bacteria gut microbes gut microbiome gut microbiota interest member microbial microbiome composition novel predictive tools response therapeutic target tool tool development

项目摘要

Project Summary Detecting various compositionally similar but structurally distinct glycans present in heterogenous mixtures has traditionally been challenging due to the limitations facing current glycomics approaches. These limitations have hindered our understanding of the availability and abundance of individual glycans in the mammalian gut environment, which is replete with diverse mixtures of microbial, mammalian, and plant-derived oligo- and polysaccharides. Moreover, the intestinal glycan composition is a primary driver of gut microbiome composition and metabolism, which represents an increasingly important human health determinant, and necessitates a deep understanding of the glycomic-microbial interface to identify important biological interactions and putatively develop glycan-derived therapeutics to target specific microbial activities. Therefore, new tools are necessary to detect and measure the relative abundance of individual glycan substrates present in the heterogenous mixtures prepared from biological sources such as mammalian intestinal contents. We have harnessed the glycan detection machinery employed by dominant members of the gut microbiota to detect, measure and isolate individual glycan substrates present in heterogenous mixtures extracted from the mammalian intestine. Herein, we demonstrate robust, specific, and scalable approaches by which engineered microbes report the presence of individual glycan substrates with incredible sensitivity. Furthermore, we demonstrate that this approach can accurately measure the abundance of individual glycans present in mixtures across wide linear ranges and that the specificity and sensitivity of these measurements can be tuned by modifying particular microbial glycan utilization genes. Finally, we demonstrate that microbially-encoded glycan-binding proteins can be used to isolate individual target glycans from mixtures for downstream compositional and structural determination. We propose to 1.) develop arrayed libraries of distinct gut microbial species, each engineered to report the presence of unique target glycans, 2.) develop a rapid glycan isolation pipeline to purify individual substrates of interest for downstream structural and functional characterization, and 3.) develop genetically modified microbial strains with enhanced sensitivity or target specificity. In addition to offering a rapid and inexpensive alternative to quantifying known glycans, we believe that further development of these tools will reveal the presence and abundance of previously undetectable glycans and dramatically enhance our understanding of the interactions between gut microbes and their mammalian hosts.

项目总结