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

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

During parasitism, helminths secrete molecules to modulate host inflammatory responses. Consistent with the potential for employing such molecules therapeutically, we have reported that ES-62, a phosphorylcholine (PC)-containing glycoprotein secreted by Acanthocheilonema viteae, protects mice against both collagen-induced arthritis (CIA) and ill health associated with life-long consumption of a high calorie diet (HCD). In both models of inflammation-driven morbidity, ES-62-protection correlates with its ability to normalise disease-induced changes in the microbiome, maintain gut homeostasis and via restoration of IL-10+ regulatory B cells, reset immunoregulatory networks. Our aim is thus to establish how ES-62 resolves chronic inflammatory responses by sensing and normalising the gut microbiome and promoting gut barrier integrity.

The gut has evolved a complex cellular network, comprising epithelial cells, B cells, dendritic cells, gammadelta T cells, innate lymphoid cells and NKT cells, that coordinates bidirectional signalling with the microbiota to train immune responses and maintain gut homeostasis. This becomes defective during infection, autoimmunity, obesity and ageing and we specifically plan to elucidate how ES-62 counters this. In particular, we will define which cell types ES-62 targets in promoting gut health, establish how they are reprogrammed, and validate their health-endorsing roles by investigating whether their transfer to recipient mice functionally recapitulates ES-62-actions. We will also assess whether in addition to directly rewiring these cells, ES-62 fosters gut health indirectly, via induction of immunomodulatory anti-PC antibodies or enrichment of microbiota metabolites such as butyrate that support barrier integrity. To achieve these objectives, we will exploit biobanked tissue from completed HCD-accelerated ageing and CIA studies in addition to undertaking further experiments employing these two models of chronic inflammation.

The research to be undertaken could have academic impact on:

1. Young researcher development: the post-doctoral research assistant (PDRA), Dr Felicity Lumb, will receive further multidisciplinary research training focusing on the impact of ES-62 on microbiome dysbiosis and failure of gut barrier integrity driving the chronic inflammation underpinning the debilitating conditions associated with ageing. This will additionally allow her to increase her skills in assessment of potential targets for therapeutic intervention for future ES-62-based drug development. At the same time, she will further expand her expertise in both project management of collaborative research and oral and written presentation, all of which will promote her development as an independent scientist, thereby facilitating future employability.

2. Knowledge exchange: in addition to providing added value to related ES-62 projects on countering inflammatory disease, microbiota-host interactions and the impact of dietary restriction on heath- and lifespan, our unique ageing biobank and data set resources will benefit collaborators and the wider research community working on the biology of ageing and microbiome-regulated inflammatory disease. Moreover, greater understanding of the mechanism of action of ES-62 will interest scientists considering the broad therapeutic potential of helminth-derived molecules that modulate the immune response as well as those working on immune system evasion and anthelmintic therapies. With respect to the latter, helminths infect around one quarter of the global population and also represent a huge economic burden on animal and plant farming.

Impacts could also relate to:
1. Fostering the economic competitiveness of the UK and global biopharma industry: The proposal seeks to increase our fundamental understanding of how ES-62 impacts on the gut sensory mechanisms bidirectionally regulating the microbiota and shaping of immune responses across the lifecourse. As ageing-associated dysfunction of these processes underlies susceptibility to infection and drives development of the autoimmune, metabolic and cardiovascular complications that are accelerated by the chronic inflammation resulting from obesity, our data could also identify potential novel sites of therapeutic intervention. Given the global major health challenges presented by our ageing and increasingly obese population, these could be exploited by Biopharma. Moreover, as we have already patent-protected small molecule analogues (SMAs) that mimic the immunomodulatory actions of ES-62, these new studies could help facilitate their development as novel drugs. Any licensing agreement/spin-out company arising out of the IP generated by the project would raise the global profile and economy of our universities.

2. Public Services and Policy: Identification of biomarkers, novel sites of intervention and the development of ES-62-based SMAs as drugs could ultimately impact on regulatory bodies such as the Medicines and Healthcare Products Regulatory Agency and the National Institute for Biological Standards and Control in the UK and also globally, for example, via the USA Federal Drug Agency in terms of drug licensing and patient treatment guidelines.

3. Patients: Autoimmunity, age- and life style-associated disorders are of dramatically increasing prevalence and currently, there are no entirely effective therapeutic strategies. Of note, as our already generated SMAs exhibit good ADMET/pharmacokinetic properties, their successful development could be short/mid- rather than long-term. This could have potential major socio-economic impacts for these ageing-associated inflammatory conditions, which pose a daunting scenario, not only of large-scale poor quality of life and disability but also of consequent reduced economic performance and dramatically increased health costs.