Gastro-intestinal microbes degrading dietary gluten

胃肠道微生物降解膳食麸质

基本信息

批准号：
8662167
负责人：
Eva Josephine Helmerhorst
金额：
$ 40.73万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8662167
关键词：
Adenocarcinoma Adherence Allergic Amino Acids Anemia Bacteria Biological Assay Biological Models Biology CD4 Positive T Lymphocytes Carbohydrates Celiac Disease Cleaved cell Clinical Cloning Complex Dental Plaque Diet Digestion Disease Drug Metabolic Detoxication Environment Enzymes Eukaryotic Cell Feces Fluorescence Resonance Energy Transfer Food Gastrointestinal tract structure Genes Gliadin Glutamine Gluten Glycoside Hydrolases Habitats Health High Pressure Liquid Chromatography Human Immune System Diseases Immunologics In Vitro Intestines Investigation Laboratories Life Liquid substance Lower Gastrointestinal Tract Lymphoma Malignant Neoplasms Malnutrition Measurement Metabolic Metabolism Microbe Nutrient Oral Oral cavity Organ Osteoporosis Pancreas Patients Peptide Hydrolases Peptides Preparation Prevalence Probiotics Proline Protein Family Proteins Reaction Recombinants Recovery Ribosomal RNA Risk Role Saliva Salivary Site Source Specificity Specimen Stomach Structure Symbiosis T-Cell Proliferation Time Toxic effect Work base combat cytotoxic dietary restriction gastrointestinal glutenin immunogenic in vivo in vivo Model interest microbial microbial colonization microorganism mouse model novel proline-rich proteins response

项目摘要

DESCRIPTION (provided by applicant): The gastrointestinal tract is a major reservoir of a wide variety of microorganisms. The role of the colonizing microorganisms in contributing to host metabolic processes and overall gastrointestinal health is becoming more widely recognized. Recent work in our laboratory has revealed that bacteria residing in the oral cavity, the entrance to the gastrointestinal tract, are able to degrade dietary gluten. Glutens elicit immunologic reactions and serious clinical conditions in patients suffering from celiac disease. The basis of this disease is an auto-immune disorder in which a host-anti-self response is triggered by gluten-derived cytotoxic peptides. Patients with overt celiac disease suffer from gastroenteropathy and are at risk for malnutrition, anemia, osteoporosis and gastrointestinal malignancies such as lymphoma and adenocarcinoma. To avoid gluten toxicity, patients are required to adherence to a strict gluten-free diet, which is currently the only treatment option available. However, the dietary restriction approach requires a life-long commitment and represents a significant burden to the patient. The discovery of natural gluten degrading microorganisms from the oral cavity opens a promising new avenue in the quest to neutralize the deleterious effects of glutens. The current application seeks to explore the proteolytic activities of resident gastrointestinal microorganisms and study their potential to fragment gluten proteins into non-toxic peptides. The specific aims are: (1) To identify gluten-degrading microorganism(s) in dental plaque and fecal specimens; (2) To define protease cleavage site specificity and assess the abolishment of immunogenic gliadin regions, and to determine pH activity profiles; (3) To assess gliadin detoxification by selected microbes and purified enzyme preparations in a T-cell proliferation assay and in an in vivo model for celiac disease; (4) To characterize, clone and recombinantly express the gene(s) of the most promising enzyme(s). Reduction of gluten toxicity by natural colonizers of the gastrointestinal tract would offer novel treatment perspectives in the form of probiotics or applications of pure gluten-degrading enzymes.

描述（由申请人提供）：胃肠道是多种微生物的主要储层。定殖微生物在促进宿主代谢过程和整体胃肠道健康方面的作用变得越来越广泛地认识到。我们实验室的最新工作表明，居住在胃肠道的口腔中的细菌能够降解饮食面筋。麸质引起患有乳糜泻的患者的免疫反应和严重的临床状况。该疾病的基础是一种自身免疫性疾病，其中宿主抗自身反应是由麸质衍生的细胞毒性肽触发的。患有肠胃病的明显腹腔疾病的患者有营养不良，贫血，骨质疏松和胃肠道恶性肿瘤的风险，例如淋巴瘤和腺癌。为了避免麸质毒性，需要患者遵守严格的无麸质饮食，这是目前唯一可用的治疗选择。但是，饮食限制方法需要终身承诺，并为患者带来了重大负担。从口腔中发现天然面筋降解的微生物的发现为中和面筋的有害作用而开辟了一个有希望的新途径。当前的应用程序旨在探索居民胃肠道微生物的蛋白水解活性，并研究其将麸质蛋白分解为无毒肽的潜力。具体目的是：（1）识别牙齿斑块和粪便标本中降解麸质微生物；（2）定义蛋白酶裂解位点特异性并评估免疫原性的麦醇溶蛋白区域，并确定pH活性谱；（3）在T细胞增殖测定法和腹腔疾病的体内模型中，通过选定的微生物和纯化的酶制剂评估麦醇溶蛋白排毒；（4）表征，克隆和重组表达最有前途的酶的基因。胃肠道的天然殖民者减少麸质毒性将以益生菌或纯麸质降解酶的应用形式提供新的治疗观点。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Identification of Pseudolysin (lasB) as an Aciduric Gluten-Degrading Enzyme with High Therapeutic Potential for Celiac Disease.

DOI：
10.1038/ajg.2015.97
发表时间：
2015-06
期刊：
AMERICAN JOURNAL OF GASTROENTEROLOGY
影响因子：
9.8
作者：
Wei, Guoxian;Tian, Na;Valery, Adriana C.;Zhong, Yi;Schuppan, Detlef;Helmerhorst, Eva J.
通讯作者：
Helmerhorst, Eva J.

Commensal Bacterium Rothia aeria Degrades and Detoxifies Gluten via a Highly Effective Subtilisin Enzyme.

DOI：
10.3390/nu12123724
发表时间：
2020-12-02
期刊：
Nutrients
影响因子：
5.9
作者：
Wei G;Darwish G;Oppenheim FG;Schuppan D;Helmerhorst EJ
通讯作者：
Helmerhorst EJ

Effect of Rothia mucilaginosa enzymes on gliadin (gluten) structure, deamidation, and immunogenic epitopes relevant to celiac disease.

Rothia mucilaginosa 酶对与乳糜泻相关的麦醇溶蛋白（麸质）结构、脱酰胺和免疫原性表位的影响。

DOI：
10.1152/ajpgi.00144.2014
发表时间：
2014
期刊：
American journal of physiology. Gastrointestinal and liver physiology
影响因子：
0
作者：
Tian,Na;Wei,Guoxian;Schuppan,Detlef;Helmerhorst,EvaJ
通讯作者：
Helmerhorst,EvaJ

Despite sequence homologies to gluten, salivary proline-rich proteins do not elicit immune responses central to the pathogenesis of celiac disease.

尽管与麸质具有序列同源性，但唾液中富含脯氨酸的蛋白质不会引发乳糜泻发病机制中的核心免疫反应。

DOI：
10.1152/ajpgi.00157.2015
发表时间：
2015
期刊：
American journal of physiology. Gastrointestinal and liver physiology
影响因子：
0
作者：
Tian,Na;Leffler,DanielA;Kelly,CiaranP;Hansen,Joshua;Marietta,EricV;Murray,JosephA;Schuppan,Detlef;Helmerhorst,EvaJ
通讯作者：
Helmerhorst,EvaJ

Salivary proline-rich proteins and gluten: Do structural similarities suggest a role in celiac disease?

DOI：
10.1002/prca.201400170
发表时间：
2015-10
期刊：
Proteomics. Clinical applications
影响因子：
0
作者：
Tian N;Messana I;Leffler DA;Kelly CP;Hansen J;Cabras T;D'Alessandro A;Schuppan D;Castagnola M;Helmerhorst EJ
通讯作者：
Helmerhorst EJ