Modulation of microbiome function by host-derived noncoding small RNA

宿主来源的非编码小 RNA 调节微生物组功能

基本信息

  • 批准号:
    10415206
  • 负责人:
  • 金额:
    $ 18.84万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-06-01 至 2023-11-30
  • 项目状态:
    已结题

项目摘要

Summary: A number of studies have reported changes in the composition of microbiota in diseases such as metabolic syndrome, inflammatory bowel diseases, hypertension, Asthma, cardiovascular diseases, rheumatoid arthritis, cancer and infection. Some of these links have been shown to be causative of diseases by using specific bacteria introduced into pre-clinical models. For example, we showed that the human clinical isolate C. jejuni (C. jejuni) 81-176 promote development of colitis-associated colorectal cancer through the production of cytolethal distending toxin (cdt) (He Z et al. Gut. 2019; 68(2) 289-300). Importantly, mice colonized with C. jejuni 81-176 had a significantly different microbial gene expression profile compared to C. jejuni lacking the toxin cdtB group, and different microbial communities as measured by 16S rDNA sequencing (He Z et al. Gut. 2019; 68(2):289-300). In addition, we demonstrated that the intestinal microbiota prevents C. jejuni-induced intestinal inflammation in ex-GF Il10-/- mice, through bile acid metabolism (Sun X et al. Gastroenterology. 2018;154(6):1751-1763). Thus, disruption of microbial composition and function may be an important aspect of disease mediated by enteropathogenic microorganisms. The mechanism implicated in maintaining a healthy host-microbiota balance is complex and included production of host-derived anti-microbial peptides, mucus barrier and immunoglobulin secretion among others. Recent findings from our laboratory suggest that human intestinal microbiota obtained from healthy or colorectal tissues altered expression of mammalian-derived fecal small RNAs such as miRNA, with some miRNAs preferentially targeting bacteria genes as predicted by bioinformatic approach (Tomkovich S et al. mSystems. 2020; 5(1)). Many of these miRNAs were predicted to target bacterial genes implicated in regulating motility, secretion, outer membrane proteins, stress response, iron acquisition, and carbohydrate utilization/transport. Thus, host-derived production of small non-coding RNA may represent another mean by which the host regulate microbiota function. This exciting concept is supported by our preliminary data demonstrating gene knockdown in bacteria using mammalian extracellular vesicles (EVs) loaded with siRNA targeting prokaryotic genes. These findings suggest that bacteria differentially impact host- derived miRNA, which in turn could influence bacterial composition and gene expression. From these observations, we hypothesize that bacteria influence the production of miRNA, which in turn modified microbiota community function and consequently disease phenotype. We plan to test this hypothesis with the following two specific aims: Aim 1. Define the role of EV in bacteria-induced miRNA in Il10-/- mice. Aim 2. Define the impact of EV-mediated siRNA on microbial gene expression. This study will establish a proof of principal that enteric pathogens triggers selective EV-containing miRNA differently affecting microbiota. Our approach using microbial genomics, transcriptomic, genetic manipulation, and gnotobiotic technology represents a unique opportunity to address the interplay between host, microbiota activities, host response and inflammation. The findings generated from this project will provide a firm support for the existence of an interkingdom communication through small non-coding RNA and open new possibilities to exploit this discovery for microbial gene manipulation and therapeutic purpose.
简介:

项目成果

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Christian Jobin其他文献

Christian Jobin的其他文献

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{{ truncateString('Christian Jobin', 18)}}的其他基金

Cancer Therapeutics and Host Response Research Program
癌症治疗和宿主反应研究计划
  • 批准号:
    10625756
  • 财政年份:
    2023
  • 资助金额:
    $ 18.84万
  • 项目类别:
Microbiota-mediated enhancement of the anti-tumor effect of natural killer cells
微生物介导的自然杀伤细胞抗肿瘤作用的增强
  • 批准号:
    10654555
  • 财政年份:
    2022
  • 资助金额:
    $ 18.84万
  • 项目类别:
Microbiota-mediated enhancement of the anti-tumor effect of natural killer cells
微生物介导的自然杀伤细胞抗肿瘤作用的增强
  • 批准号:
    10435626
  • 财政年份:
    2022
  • 资助金额:
    $ 18.84万
  • 项目类别:
Microbiota, Metabolites, and Colon Neoplasia
微生物群、代谢物和结肠肿瘤
  • 批准号:
    10616669
  • 财政年份:
    2021
  • 资助金额:
    $ 18.84万
  • 项目类别:
Modulation of microbiome function by host-derived noncoding small RNA
宿主来源的非编码小 RNA 调节微生物组功能
  • 批准号:
    10317154
  • 财政年份:
    2021
  • 资助金额:
    $ 18.84万
  • 项目类别:
Impact of microbiota-mediated biotransformation of black tea polyphenols
微生物介导的红茶多酚生物转化的影响
  • 批准号:
    9208104
  • 财政年份:
    2015
  • 资助金额:
    $ 18.84万
  • 项目类别:
Impact of microbiota-mediated biotransformation of black tea polyphenols
微生物介导的红茶多酚生物转化的影响
  • 批准号:
    9398095
  • 财政年份:
    2015
  • 资助金额:
    $ 18.84万
  • 项目类别:
Impact of microbiota-mediated biotransformation of black tea polyphenols
微生物介导的红茶多酚生物转化的影响
  • 批准号:
    8825636
  • 财政年份:
    2015
  • 资助金额:
    $ 18.84万
  • 项目类别:
Mechanism by which H2S-producing bacteria influence development of colorectal cancer
产H2S细菌影响结直肠癌发生的机制
  • 批准号:
    9024941
  • 财政年份:
    2015
  • 资助金额:
    $ 18.84万
  • 项目类别:
Molecular Mechanisms of Campylobacter Jejuni-induced Pathogenesis
空肠弯曲菌诱发发病的分子机制
  • 批准号:
    8135463
  • 财政年份:
    2010
  • 资助金额:
    $ 18.84万
  • 项目类别:

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