Commensal fungal communities in the regulation of immunity and intestinal inflammation

共生真菌群落调节免疫和肠道炎症

基本信息

批准号：
10659752
负责人：
ILIYAN Dimitrov ILIEV
金额：
$ 58.57万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659752
关键词：
Affect Antibody Repertoire Antifungal Agents Bacteria Candida Candida albicans Categories Cells Characteristics Chronic Clinical Clonal Expansion Clustered Regularly Interspaced Short Palindromic Repeats Colitis Collection Colon Communities Controlled Clinical Trials Data Disease Distal Event Evolution Fungal DNA Fungal Genome Genetic Genetic Polymorphism Genome Grant Home Human IL1R1 gene Immune Immune response Immunity In Vitro Individual Inflammation Inflammatory Inflammatory Bowel Diseases Integration Host Factors Interleukin-1 Interleukin-1 beta Interleukin-10 Intestinal Diseases Intestines Laboratories Lead Light Maps Mediating Methodology Modeling Mononuclear Mucous Membrane Mus Organism Pathogenicity Pathway interactions Patients Phagocytes Phenotype Placebo Control Play Process Production Property Regulation Research Resolution Role Severity of illness Shapes Symbiosis T-Lymphocyte TNF gene Therapeutic Therapeutic Intervention Treatment Efficacy Ulcerative Colitis Virulence Virulence Factors Virus Work acrosome stabilizing factor cell injury fecal transplantation fungal microbiota fungus genome sequencing genome wide association study gut colonization gut inflammation immune activation immunomodulatory therapies imprint in vivo insight intestinal homeostasis mouse model murine colitis new therapeutic target novel prednisolone response treatment response

项目摘要

Abstract Decades of research have revealed that intestinal bacteria are critical for regulating homeostatic and protective immune responses. However, recent studies suggest that additional players such as fungi and viruses have high potential to influence these processes. While important trans-kingdom relationships between gut fungi (mycobiota) and bacteria have been recently unveiled, how fungi influence intestinal homeostasis, states of inflammation and responses to therapeutic interventions for Inflammatory Bowel Disease (IBD) is still less clear. In prior works, we defined profound effects of gut mycobiota on local and gut distal immunity through interaction with CX3CR1+ mononuclear phagocyte or by shaping host antibody repertoires that influence fungal commensalism. We defined that these processes are affected in IBD. In a multicenter placebo-controlled clinical trial of fecal microbiota transplantation (FMT) in Ulcerative colitis (UC) we recently determined that fungal clearance and blunted immune activation against Candida albicans correlates with a response to therapy. These findings suggest a possible role of gut mycobiota in efficacy of and response to therapeutic interventions. In preliminary studies we demonstrate the presence of rich genetic and phenotypic diversity of opportunistic Candida strains that dominated the colonic mucosa of IBD patients. We found that these isolates differ by their ability to cause host cell damage and are functionally diverse across individuals. In this competitive renewal we propose studies aiming to decipher the processes on inflammation caused by patient-associated strains. We hypothesize that these organisms influence inflammation and response to therapy through the production of factors that are regulated at strain-specific level. The results of this study will map the human gut mycobiota functionally and might provide a basis for targeted novel therapies and co-therapies for inflammatory diseases.

抽象的数十年的研究表明，肠道细菌对于调节体内平衡和保护性至关重要免疫反应。然而，最近的研究表明真菌和病毒等其他参与者具有很高的影响这些过程的潜力。虽然肠道真菌之间存在重要的跨界关系（真菌群）和细菌最近被揭示，真菌如何影响肠道稳态，炎症和炎症性肠病（IBD）治疗干预的反应仍不太清楚。在之前的工作中，我们通过相互作用定义了肠道菌群对局部和肠道远端免疫的深远影响与 CX3CR1+ 单核吞噬细胞或通过塑造影响真菌的宿主抗体库共栖主义。我们定义这些过程在 IBD 中受到影响。在一项多中心安慰剂对照临床中粪便微生物群移植（FMT）治疗溃疡性结肠炎（UC）的试验我们最近确定真菌针对白色念珠菌的清除和免疫激活减弱与治疗反应相关。这些研究结果表明肠道菌群在治疗干预的功效和反应中可能发挥作用。在初步研究表明，机会主义物种存在丰富的遗传和表型多样性 IBD 患者结肠粘膜中占主导地位的念珠菌菌株。我们发现这些分离株的不同之处在于导致宿主细胞损伤的能力，并且在个体之间功能多样。在这场竞争更新中，我们提出旨在破译患者相关菌株引起的炎症过程的研究。我们假设这些生物体通过产生在菌株特异性水平上受到调节的因素。这项研究的结果将绘制人类肠道菌群图功能上，可能为炎症性疾病的靶向新疗法和联合疗法提供基础。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Laboratory mice born to wild mice have natural microbiota and model human immune responses.

野生小鼠所生的实验室小鼠具有天然微生物群，可以模拟人类免疫反应。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Rosshart, Stephan P;Herz, Jasmin;Vassallo, Brian G;Hunter, Ashli;Wall, Morgan K;Badger, Jonathan H;McCulloch, John A;Anastasakis, Dimitrios G;Sarshad, Aishe A;Leonardi, Irina;Collins, Nicholas;Blatter, Joshua A;Han, Seong;Tamoutounour, Sam
通讯作者：
Tamoutounour, Sam

Gut epithelium modulates fungal pathogenesis.

肠道上皮调节真菌发病机制。

DOI：
发表时间：
2023-08-04
期刊：
影响因子：
0
作者：
Lin, Woan;Iliev, Iliyan D
通讯作者：
Iliev, Iliyan D

Mycobiota-induced IgA antibodies regulate fungal commensalism in the gut and are dysregulated in Crohn's disease.

菌群诱导的 IgA 抗体调节肠道内的真菌共生，并且在克罗恩病中失调。

DOI：
发表时间：
2021-12
期刊：
影响因子：
28.3
作者：
Doron, Itai;Mesko, Marissa;Li, Xin V;Kusakabe, Takato;Leonardi, Irina;Shaw, Dustin G;Fiers, William D;Lin, Woan;Bialt;Román, Elvira;Longman, Randy S;Pla, Jesus;Wilson, Patrick C;Iliev, Iliyan D
通讯作者：
Iliev, Iliyan D

Immune regulation by fungal strain diversity in inflammatory bowel disease.

炎症性肠病中真菌菌株多样性的免疫调节。

DOI：
发表时间：
2022-03
期刊：
影响因子：
64.8
作者：
Li, Xin V;Leonardi, Irina;Putzel, Gregory G;Semon, Alexa;Fiers, William D;Kusakabe, Takato;Lin, Woan;Gao, Iris H;Doron, Itai;Gutierrez;DeCelie, Meghan B;Carriche, Guilhermina M;Mesko, Marissa;Yang, Chen;Naglik, Julian
通讯作者：
Naglik, Julian

Gut mycobiota under scrutiny: fungal symbionts or environmental transients?

肠道菌群受到密切关注：真菌共生体还是环境瞬变？