Cannabinoid signaling via the host CB1 receptor promotes intestinal dysbiosis
通过宿主 CB1 受体的大麻素信号传导促进肠道菌群失调
基本信息
- 批准号:10534724
- 负责人:
- 金额:$ 15.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-09-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:2-arachidonylglycerolAgonistAntiinflammatory EffectAttenuatedCNR1 geneCNR2 geneCannabinoidsChronicColitisDevelopmentDiseaseEndocannabinoidsEnvironmental Risk FactorEnzymesEscherichia coliGeneticGenetic ModelsHormonesHumanImmuneImmunityInflammationInflammatory Bowel DiseasesIntestinesKnockout MiceLipidsMediatingMediator of activation proteinModelingMusPhasePhysiologyReceptor SignalingRelapseReportingSeverity of illnessSignal TransductionSymbiosisTherapeuticTissuescannabinoid receptorchemically induced colitisdietary supplementsdysbiosisendogenous cannabinoid systemgut dysbiosisgut inflammationgut microbiotametabolomemicrobiotamouse modelmurine colitisnoveltherapeutic target
项目摘要
Inflammatory bowel diseases (IBD) are chronic, relapsing, immune-mediated diseases influenced by host genetics,
environmental factors and the gut microbiota. Intestinal inflammation alters gut microbiota composition and function to
disrupt its symbiosis with the host (dysbiosis). Increased Escherichia coli is a common signature of gut dysbiosis in
human IBD and murine colitis models and is thought to contribute to colitis development. The endocannabinoid (EC)
system has emerged as a promising therapeutic target for human IBD because of its reported anti-inflammatory effects.
ECs are lipid hormones that activate host cannabinoid receptors to modulate gut physiology and immunity. Host EC
activity is regulated by biosynthetic and degradative enzymes that modulate tissue EC levels and by signaling at host
cannabinoid receptors (e.g. CB1, CB2) . Inhibiting EC degradation, or agonism of CB1 or CB2, attenuates disease in
chemically-induced colitis models. The host EC system also influences microbiota composition and directly modulates
bacterial functions. However, it remains unknown whether cannabinoid modulation of the gut microbiota occurs in IBD
and whether these interactions impact disease severity. Moreover, the therapeutic potential of cannabinoids in genetic
models of IBD remains understudied. Using the Il10 KO mouse model of IBD, our initial studies demonstrate that
inhibiting degradation of the EC 2-AG exacerbates colitis and and promotes dysbiosis as characterized by the
expansion of intestinal E. coli. Moreover, we show that inhibiting 2-AG degradation increases gut E. coli in non-inflamed
WT mice, which is counteracted with CB1 receptor blockade Our central hypothesis is that cannabinoid signaling at the
host CB1 receptor promotes the outgrowth of intestinal E. coli, thus exacerbating inflammation in IBD-susceptible hosts.
The objective of this proposal is to establish host cannabinoid signaling as a novel mediator of intestinal dysbiosis by
completing the following Aims.
Aim 1: Determine the contribution of the host CB1 and CB2 receptors in promoting the outgrowth of intestinal E. coli.
Aim 2: Evaluate the effects of host cannabinoid signaling on intestinal dysbiosis and consequent inflammation in IBDsusceptible
Il10 KO mice.
Aim 3: Characterize the effects of host CB1 receptor signaling on the intestinal metabolome.
炎症性肠病(IBD)是受宿主遗传因素影响的慢性、复发性、免疫介导性疾病。
环境因素和肠道微生物区系。肠道炎症改变肠道微生物区系组成和功能
破坏其与寄主的共生关系(生物失调)。大肠埃希氏菌增多是肠道菌群失调的常见标志
人类IBD和小鼠结肠炎模型,被认为有助于结肠炎的发展。内源性大麻素(EC)
由于其抗炎作用的报道,该系统已成为治疗人类IBD的有前途的靶点。
ECs是一种脂类激素,能激活宿主大麻素受体,调节肠道生理和免疫。东道主欧共体
活性受生物合成和降解酶的调节,这些酶调节组织EC水平和宿主的信号
大麻素受体(如CB1、CB2)。抑制EC的降解,或CB1或CB2的激活,可减轻疾病
化学性结肠炎模型。宿主EC系统也影响微生物区系组成,并直接调节
细菌的功能。然而,目前尚不清楚IBD是否存在肠道微生物区系的大麻素调节。
以及这些相互作用是否会影响疾病的严重性。此外,大麻素在遗传疾病中的治疗潜力
IBD的模型仍未得到充分研究。使用IBD的Il10 KO小鼠模型,我们的初步研究表明
抑制EC2-AG的降解加剧了结肠炎,并促进了生态失调,其特征是
肠道大肠杆菌的扩张。此外,我们还表明,抑制2-AG的降解可增加非炎症性肠炎患者的肠道大肠杆菌数量。
被CB1受体拮抗的WT小鼠我们的中心假设是大麻素信号在
宿主CB1受体促进肠道大肠杆菌的生长,从而加剧IBD易感宿主的炎症。
这项建议的目的是建立宿主大麻素信号作为肠道生物失调的新媒介,通过
完成以下目标。
目的1:确定宿主CB1和CB2受体在促进肠道大肠杆菌生长中的作用。
目的2:评价宿主大麻素信号对IBD易感人群肠道生态失调及炎症反应的影响
I10 KO小鼠。
目的3:研究宿主CB1受体信号对肠道代谢的影响。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Melissa Ellermann的其他文献
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{{ truncateString('Melissa Ellermann', 18)}}的其他基金
Cannabinoid signaling via the host CB1 receptor promotes intestinal dysbiosis
通过宿主 CB1 受体的大麻素信号传导促进肠道菌群失调
- 批准号:
10531040 - 财政年份:2021
- 资助金额:
$ 15.98万 - 项目类别:
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