Does the parasitic worm product ES-62 resolve aberrant chronic inflammation by sensing and normalising the gut microbiome and intestinal integrity?

寄生虫产品 ES-62 是否可以通过感知肠道微生物组和肠道完整性并使之正常化来解决异常的慢性炎症？

• 批准号: BB/V001027/1
• 负责人: Margaret Harnett
• 金额: $ 57.79万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV001027%2F1
• 关键词: Does; parasitic; worm; product; ES

People are now living much longer, mainly due to better disease control, greater access to food, and improved sanitation such that by 2050, 25% of the UK population will be over 65. However, our increasing lifespan is causing major socio-economic issues, because it is not accompanied by an equivalent extension of well-being ("healthspan"). Although this disconnect reflects natural "wear and tear" on our bodies, current life-styles, combining a high calorie diet (HCD) with sedentary behavior, are promoting alarming increases in age-associated ailments such as obesity, type-2 diabetes, stroke and heart disease. In addition, obesity is a reciprocal risk factor for development of autoimmunity, a group of diseases including, for example, rheumatoid arthritis (RA) that arise when the body's immune system, which normally protects against infectious agents, begins to attack its own tissues.Increasing evidence suggests that development of both ageing-associated conditions and autoimmunity can be avoided by infection with parasitic worms or products that they secrete. Indeed, using mice in which the conditions can be modelled, we showed that an anti-inflammatory worm product called ES-62 was highly effective in suppressing development of a range of diseases including both atherosclerosis and RA. Furthermore, we have found that administering ES-62 weekly throughout the life of HCD-fed mice improves multiple aspects of their health and even makes male mice live longer. While attempting to discover ES-62's mechanism of action, a key observation to emerge from both our ageing and RA studies was that the worm product maintains gut health, which is disrupted by both HCD and arthritis. Specifically, ES-62 reduces damage to the gut barrier that protects against infection and prevents changes in the composition of bacteria (the microbiome) in the bowel, meaning that species that promote good health are maintained.The normal maintenance of gut health and consequently, immune responses that target infectious agents rather than host tissues relies on a complex network of different cells of the immune system, located within the gut microenvironment to coordinate bidirectional interactions with the microbiome. Our previous studies indicate that ES-62 can directly modify the activities of some of these cell types when isolated from other organs in the mouse, e.g., B cells recovered from the spleen. We therefore now wish to determine whether effects on any of these cell types present within the intestinal microenvironment are responsible for maintaining gut health, thereby in turn preventing inflammation and promoting wellbeing. Thus, we plan to:1. Comprehensively examine the effect of ES-62 on gut health, focusing on the different cells in the local environment. Based on supportive data from previous studies, we particularly anticipate a role for ES-62 targeting of interactions between two types, called CD1d+ regulatory B cells and invariant NKT cells, in countering inflammation and normalising the composition of the microbiome. 2. Identify how key target cells of ES-62 are modified to effect protection and examine whether their transfer into recipient mice functionally recapitulates the actions of ES-62. 3. Define whether in addition to ES-62 acting directly on target cells, it has any indirect effects, e.g., by promoting enrichment of bacteria species that produce molecules such as butyrate that are known to support a healthy gut.To achieve our objectives, we plan to employ a combination of approaches, first exploiting tissue from biobanks that we generated during our recently completed obesity-accelerated ageing and arthritis experiments and then undertaking new studies making use of our mouse models of HCD-induced ageing and RA.

人们现在的寿命要长得多，这主要是因为疾病控制得更好，更容易获得食物，以及卫生条件的改善，到2050年，25%的英国人口将超过65岁。然而，我们日益增长的寿命正在造成重大的社会经济问题，因为它并没有伴随着福祉(“健康寿命”)的相应延长。尽管这种脱节反映了我们身体的自然“磨损”，但目前的生活方式，结合了高卡路里饮食(HCD)和久坐不动的行为，正在推动肥胖、2型糖尿病、中风和心脏病等与年龄相关的疾病的惊人增加。此外，肥胖是发展自身免疫的一个相互的风险因素，这是一组疾病，包括类风湿性关节炎(RA)，它是当身体的免疫系统开始攻击自己的组织时出现的，通常情况下，它可以保护身体免受感染。越来越多的证据表明，与衰老相关的疾病和自身免疫的发展都可以通过感染寄生虫或它们分泌的产品来避免。事实上，在可以模拟条件的小鼠身上，我们证明了一种名为ES-62的抗炎蠕虫产品在抑制包括动脉粥样硬化和类风湿性关节炎在内的一系列疾病的发展方面非常有效。此外，我们还发现，在喂食HCD的小鼠的整个生命过程中，每周服用ES-62可以改善它们的健康状况，甚至可以延长雄性小鼠的寿命。在试图发现ES-62的S作用机制的同时，我们的老化和RA研究中出现的一个关键观察结果是，这种蠕虫产品保持肠道健康，而肠道健康会受到HCD和关节炎的破坏。具体地说，ES-62减少了对肠道屏障的破坏，肠道屏障防止感染，并防止肠道细菌(微生物群)组成的变化，这意味着促进良好健康的物种得以维持。肠道健康的正常维持以及因此针对感染源而不是宿主组织的免疫反应依赖于位于肠道微环境中的免疫系统不同细胞的复杂网络，以协调与微生物群的双向相互作用。我们以前的研究表明，当ES-62从小鼠的其他器官中分离出来时，可以直接改变其中一些细胞类型的活性，例如从脾中恢复的B细胞。因此，我们现在希望确定对肠道微环境中存在的这些细胞类型中的任何一种的影响是否负责维持肠道健康，从而反过来预防炎症和促进健康。因此，我们计划：1.全面检测ES-62对肠道健康的影响，重点研究局部环境中的不同细胞。基于以前研究的支持性数据，我们特别预期ES-62靶向两种类型的CD1d+调节性B细胞和不变的NKT细胞之间的相互作用，在抗炎和使微生物组组成正常化方面发挥作用。2.确定ES-62的关键靶细胞如何被修饰以起到保护作用，并检查它们转移到受体小鼠体内是否在功能上概括了ES-62的作用。3.确定除了ES-62直接作用于靶细胞外，它是否还有任何间接影响，例如，通过促进产生丁酸盐等已知支持健康肠道的分子的细菌物种的丰富。为了实现我们的目标，我们计划使用多种方法的组合，首先利用我们在最近完成的肥胖加速老化和关节炎实验中从生物库中产生的组织，然后利用我们的HCD诱导衰老和RA的小鼠模型进行新的研究。

项目成果

The parasitic worm product ES-62 protects the osteoimmunology axis in a mouse model of obesity-accelerated ageing.

• DOI: 10.3389/fimmu.2022.953053
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3

The parasitic worm product ES-62 protects against collagen-induced arthritis by resetting the gut-bone marrow axis in a microbiome-dependent manner

• DOI: 10.3389/fitd.2023.1334705
• 发表时间: 2024-01
• 期刊: Frontiers in tropical diseases
• 作者: M. Harnett;J. Doonan;Anuradha Tarafdar;M. Pineda;Josephine Duncombe-Moore;Geraldine Buitrago;Piaopiao Pan;P. Hoskisson;Colin Selman;W. Harnett

Conquering rheumatic diseases: are parasitic worms the answer?

• DOI: 10.1016/j.pt.2023.06.010
• 发表时间: 2023-08-09
• 期刊: TRENDS IN PARASITOLOGY
• 影响因子: 9.6
• 作者: Buitrago，Geraldine;Harnett，Margaret M.;Harnett，William
• 通讯作者: Harnett，William