Dietary strategies for rational manipulation of the gut microbiome in inflammatory bowel disease

合理调控炎症性肠病肠道微生物组的饮食策略

• 批准号: 10630312
• 负责人: Long H Nguyen
• 金额: $ 19.98万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630312
• 关键词: Address; Affect; Area; Bacteria; Biochemical Pathway; Calories; Cataloging; Chemicals; Chronic; Clinical Trials Design; Colitis; Collection; Communities; Complex; Control Groups; Crohn' s disease; Data; Development; Diet; Diet Modification; Dietary Assessment; Dietary Intervention; Dietary Sulfur; Dietary intake; Disease; Disease remission; Disparity; Disulfides; Eating; Ecology; Enzymes; Epithelium; Equipment and supply inventories; Expert Opinion; Feces; Food; Friends; Funding; Gastrointestinal Diseases; Gastrointestinal tract structure; General Hospitals; Genes; Genetic Transcription; Genomics; Goals; Health Transition; Homeostasis; Human; Human Microbiome; Hydrogen Sulfide; Immune; Immune response; Individual; Inflammatory Bowel Diseases; Inflammatory Response; Informatics; Intervention; Lead; Leukocyte L1 Antigen Complex; Link; Literature; Manuals; Massachusetts; Measures; Mediating; Mentors; Metabolic; Metagenomics; Methodology; Methods; Microbe; Mucous body substance; Nutritional; Outcome; Pathogenesis; Pathway Analysis; Patients; Phylogenetic Analysis; Physicians; Population; Process; Processed Meats; Proteins; Randomized, Controlled Trials; Recommendation; Relapse; Reporting; Research; Research Personnel; Research Project Grants; Resolution; Role; Sampling; Severity of illness; Starvation; Sulfoxide; Sulfur; Sulfur Metabolism Pathway; Sulfur-Reducing Bacteria; Taxonomy; Testing; Therapeutic; Training; Ulcerative Colitis; candidate identification; cohort; colorectal cancer risk; comparative; computer framework; design; dietary; distilled alcoholic beverage; disulfide bond; dysbiosis; food avoidance; genetic variant; gut bacteria; gut inflammation; gut microbiome; gut microbiota; improved; indexing; innovation; insight; member; metabolomics; metagenome; metatranscriptomics; microbial; microbiome; microbiome research; multidisciplinary; novel; open source; treatment guidelines; treatment strategy

PROJECT ABSTRACT Despite now conclusive evidence that alterations in gut microbial communities precede and contribute to the etiopathogenesis of inflammatory bowel disease (IBD), the promise of therapeutic strategies to favorably influence this ecology is still largely unrealized. In sharp contrast to the widely understood importance of well- characterized taxonomic changes that occur during transitions from health to disease, comparatively little is known about the specific microbially-mediated processes that contribute to this loss of homeostasis. This disparity is largely due to the fact that even in well-studied communities, such as the human gastrointestinal (GI) tract, only a small fraction of the genomic content of a sample, the metagenome, can be functionally annotated. To address this glaring deficiency, we propose to develop a novel computational framework to infer a microbial gene’s metabolic function using quantitative metagenomics and sequence similarity network analysis. We will then apply this method to more comprehensively evaluate the role of sulfur-metabolizing bacteria in IBD. Sulfur- metabolizing bacteria are a phylogenetically diverse group of microbes defined by their ability to process dietary sulfur, often generating hydrogen sulfide (H2S) as a harmful byproduct. H2S in the GI tract can compromise gut barrier integrity by causing a breach in the protective mucus bilayer, a necessary precursor to intestinal inflammation. Our central hypothesis is that higher abundance of sulfur-metabolizing bacteria is associated with greater disease activity, and this community will prove amenable to selective depletion through food avoidance. Our overall objective is to comprehensively identify the bacterial species and strains participating in sulfur metabolism by first cataloging which of them encode known or novel sulfur metabolizing enzymes. We will then determine how these bacteria, their transcriptional activities, and the metabolites they generate influence disease severity in a cohort of densely sampled IBD patients who provided stool at up to 24 timepoints over one year along with short- and long-term assessments of dietary intake. Finally, we will develop and implement a rational dietary avoidance strategy designed to specifically target these bacteria and starve them of the foods that fuel this process, concluding with a randomized controlled trial testing this intervention in IBD patients. The scientific rationale to pursue this line of inquiry is rigorously supported by a body of literature demonstrating that: 1) both diet and the presence of select sulfur-metabolizing bacteria influence IBD severity and 2) preliminary efforts led by the candidate reveal that diet may modulate the relative abundance and functional activities of these bacteria. The approach requires innovative scaling solutions to apply homology-based methods to fully characterize an entire biochemical pathway—microbial sulfur metabolism—in humans. Anticipated outcomes from this multidisciplinary effort include the development of an open-sourced methodological framework for hypothesis- driven microbiome research and the creation of a patient-friendly IBD treatment based on dietary avoidance.

项目摘要 尽管现在有确凿的证据表明，肠道微生物群落的改变先于并有助于 炎症性肠病（IBD）的病毒作用，治疗策略有利的希望 影响这种生态仍然是未实现的。与广泛理解良好的重要性形成鲜明对比 从健康到疾病过渡期间发生的分类学变化的特征，相对较少 知道有助于这种体内稳态丧失的特定微生物介导的过程。这 差异很大程度上是由于以下事实：即使在诸如人类胃肠道（GI）之类的经过良好的社区中 可以在功能上注释样品的基因组含量的一小部分，即元基因组。 为了解决这种明显的缺陷，我们建议开发一个新颖的计算框架来推断微生物 Gene的代谢功能使用定量宏基因组学和序列相似性网络分析。我们将 然后，将此方法应用于更全面地评估IBD中硫代谢细菌的作用。硫- 代谢细菌是一种系统发育多样的微生物，其定义是由它们处理饮食的能力 硫，通常会产生硫化氢（H2S）作为有害副产品。胃肠道中的H2S会损害肠道 通过在受保护的粘液双层中造成破坏，这是肠道的必要前体 炎。我们的核心假设是，硫属代谢细菌的较高抽象与 疾病活动更大，这个社区将被证明可以通过避免食物来选择性耗尽。 我们的总体目标是全面识别参与硫的细菌和菌株 首先分类的代谢编码已知或新颖的硫代谢酶。然后我们会 确定这些细菌，它们的转录活性和它们产生影响疾病的代谢产物的方式 在一系列需要采样的IBD患者队列中的严重性 以及对饮食摄入量的短期和长期评估。最后，我们将发展并实施合理的 旨在专门针对这些细菌的饮食回避策略，并使它们饿死了燃料的食物 该过程以随机对照试验进行了对IBD患者的干预测试。科学 购买此询问线的理由是由文学机构严格支持：1） 饮食和精选的硫代生物化细菌的存在会影响IBD的严重性和2）初步努力LED 候选人表明，饮食可以调节这些细菌的相对抽象和功能活性。 该方法需要创新的缩放解决方案来应用基于同源的方法来充分表征 整个生化途径 - 菌硫代谢 - 在人类中。预期的结果 多学科的工作包括开发假设的开源方法学框架 - 驱动的微生物组研究和基于饮食避免的患者友好型IBD治疗的创建。

项目成果

Antibiotic Therapy and Risk of Early-Onset Colorectal Cancer: A National Case-Control Study.

• DOI: 10.14309/ctg.0000000000000437
• 发表时间: 2022-01-13
• 期刊: Clinical and translational gastroenterology
• 影响因子: 3.6
• 作者: Nguyen LH;Cao Y;Batyrbekova N;Roelstraete B;Ma W;Khalili H;Song M;Chan AT;Ludvigsson JF
• 通讯作者: Ludvigsson JF

The mental health burden of racial and ethnic minorities during the COVID-19 pandemic.

• DOI: 10.1371/journal.pone.0271661
• 发表时间: 2022
• 期刊: PLOS ONE
• 影响因子: 3.7
• 作者: Nguyen, Long H.;Anyane-Yeboa, Adjoa;Klaser, Kerstin;Merino, Jordi;Drew, David A.;Ma, Wenjie;Mehta, Raaj S.;Kim, Daniel Y.;Warner, Erica T.;Joshi, Amit D.;Graham, Mark S.;Sudre, Carole H.;Thompson, Ellen J.;May, Anna;Hu, Christina;Jorgensen, Solveig;Selvachandran, Somesh;Berry, Sarah E.;David, Sean P.;Martinez, Maria Elena;Figueiredo, Jane C.;Murray, Anne M.;Sanders, Alan R.;Koenen, Karestan C.;Wolf, Jonathan;Ourselin, Sebastien;Spector, Tim D.;Steves, Claire J.;Chan, Andrew T. T.
• 通讯作者: Chan, Andrew T. T.

Microbiome connections with host metabolism and habitual diet from 1,098 deeply phenotyped individuals.

• DOI: 10.1038/s41591-020-01183-8
• 发表时间: 2021-03
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Asnicar F;Berry SE;Valdes AM;Nguyen LH;Piccinno G;Drew DA;Leeming E;Gibson R;Le Roy C;Khatib HA;Francis L;Mazidi M;Mompeo O;Valles-Colomer M;Tett A;Beghini F;Dubois L;Bazzani D;Thomas AM;Mirzayi C;Khleborodova A;Oh S;Hine R;Bonnett C;Capdevila J;Danzanvilliers S;Giordano F;Geistlinger L;Waldron L;Davies R;Hadjigeorgiou G;Wolf J;Ordovás JM;Gardner C;Franks PW;Chan AT;Huttenhower C;Spector TD;Segata N
• 通讯作者: Segata N

Self-reported COVID-19 vaccine hesitancy and uptake among participants from different racial and ethnic groups in the United States and United Kingdom.

• DOI: 10.1038/s41467-022-28200-3
• 发表时间: 2022-02-01
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Nguyen LH;Joshi AD;Drew DA;Merino J;Ma W;Lo CH;Kwon S;Wang K;Graham MS;Polidori L;Menni C;Sudre CH;Anyane-Yeboa A;Astley CM;Warner ET;Hu CY;Selvachandran S;Davies R;Nash D;Franks PW;Wolf J;Ourselin S;Steves CJ;Spector TD;Chan AT;COPE Consortium
• 通讯作者: COPE Consortium

Symptom clusters in COVID-19: A potential clinical prediction tool from the COVID Symptom Study app.

• DOI: 10.1126/sciadv.abd4177
• 发表时间: 2021-03
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Sudre CH;Lee KA;Lochlainn MN;Varsavsky T;Murray B;Graham MS;Menni C;Modat M;Bowyer RCE;Nguyen LH;Drew DA;Joshi AD;Ma W;Guo CG;Lo CH;Ganesh S;Buwe A;Pujol JC;du Cadet JL;Visconti A;Freidin MB;El-Sayed Moustafa JS;Falchi M;Davies R;Gomez MF;Fall T;Cardoso MJ;Wolf J;Franks PW;Chan AT;Spector TD;Steves CJ;Ourselin S
• 通讯作者: Ourselin S