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

人们现在的寿命更长，主要是由于更好的疾病控制，更容易获得食物和改善卫生条件，到2050年，25%的英国人口将超过65岁。然而，我们寿命的延长正在造成重大的社会经济问题，因为它没有伴随着福祉的同等延长（“健康寿命”）。虽然这种脱节反映了我们身体的自然“磨损”，但目前的生活方式，结合高热量饮食（HCD）和久坐不动的行为，正在促进与年龄相关的疾病，如肥胖，2型糖尿病，中风和心脏病的惊人增长。此外，肥胖是自身免疫发展的相互风险因素，自身免疫是一组疾病，包括例如类风湿性关节炎（RA），当身体的免疫系统（其通常保护免受感染因子的侵害），开始攻击自己的组织。越来越多的证据表明，相关的病症和自身免疫可以通过感染寄生蠕虫或它们分泌的产物来避免。事实上，使用可以模拟条件的小鼠，我们发现一种名为ES-62的抗炎蠕虫产品在抑制一系列疾病（包括动脉粥样硬化和RA）的发展方面非常有效。此外，我们发现，在喂食HCD的小鼠的整个生命周期中每周给予ES-62可以改善其健康的多个方面，甚至使雄性小鼠寿命更长。在试图发现ES-62的作用机制时，我们的衰老和RA研究中出现的一个关键观察结果是，蠕虫产品保持肠道健康，这是由HCD和关节炎破坏的。具体来说，ES-62减少了对肠道屏障的损害，从而防止感染并防止细菌组成的变化。肠道健康的正常维持以及因此针对感染因子而不是宿主组织的免疫反应依赖于免疫系统不同细胞的复杂网络，位于肠道微环境内，以协调与微生物组的双向相互作用。我们以前的研究表明，ES-62可以直接改变这些细胞类型中的一些细胞类型的活性，当从小鼠的其他器官分离时，例如，从脾脏回收的B细胞。因此，我们现在希望确定对肠道微环境中存在的任何这些细胞类型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.全面检查ES-62对肠道健康的影响，重点关注局部环境中的不同细胞。基于先前研究的支持性数据，我们特别预期ES-62靶向两种类型（称为CD 1d+调节性B细胞和不变NKT细胞）之间的相互作用在对抗炎症和使微生物组的组成正常化方面的作用。2.确定ES-62的关键靶细胞如何被修饰以实现保护，并检查它们转移到受体小鼠中是否在功能上重演ES-62的作用。3.确定除了ES-62直接作用于靶细胞外，它是否具有任何间接作用，例如，为了实现我们的目标，我们计划采用多种方法相结合，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产生的生物库中的组织，然后利用我们的HCD诱导老化和RA小鼠模型进行新的研究。

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.