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
• 负责人: Melissa Ellermann
• 金额: $ 17.93万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-11 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10531040
• 关键词: Cannabinoid; signaling; via; host; CB1

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）是受宿主遗传学影响的慢性、复发性、免疫介导的疾病， 环境因素和肠道微生物群。肠道炎症改变肠道微生物群组成和功能， 破坏其与宿主的共生关系（生态失调）。大肠杆菌的增加是肠道生态失调的常见标志， 人IBD和鼠结肠炎模型，并被认为有助于结肠炎的发展。内源性大麻素（EC） 系统已经成为一个有前途的治疗目标，人类IBD，因为其报道的抗炎作用。 EC是激活宿主大麻素受体以调节肠道生理和免疫的脂质激素。主机EC 活性受调节组织EC水平的生物合成和降解酶以及宿主的信号传导调节 大麻素受体（如CB 1、CB 2）。抑制EC降解或CB 1或CB 2的激动作用， 化学诱导的结肠炎模型。宿主EC系统也影响微生物群组成，并直接调节 细菌功能然而，大麻素对肠道微生物群的调节是否发生在IBD中仍然是未知的。 以及这些相互作用是否影响疾病的严重程度。此外，大麻素在遗传学上的治疗潜力 IBD的模型仍然研究不足。使用IBD的Il 10 KO小鼠模型，我们的初步研究表明， 抑制EC 2-AG的降解会加剧结肠炎并促进生态失调， 肠扩张E.杆菌此外，我们发现，抑制2-AG降解增加肠道E。非炎症性大肠杆菌 WT小鼠，这是抵消与CB 1受体阻断我们的中心假设是，大麻素信号在 宿主CB 1受体促进肠E.大肠杆菌，从而加重IBD易感宿主的炎症。 该提案的目的是通过以下方式建立宿主大麻素信号传导作为肠道生态失调的新介质： 完成以下目标。 目的1：探讨宿主细胞CB 1和CB 2受体在促进肠上皮细胞生长中的作用。杆菌 目的2：评估宿主大麻素信号传导对IBD易感者肠道生态失调和随后的炎症的影响。 IllO KO小鼠。 目的3：研究宿主CB 1受体信号对肠道代谢组的影响。