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

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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.