Abstract
The human immune system has evolved in the context of our colonisation by bacteria, viruses, fungi and parasitic helminths. Reflecting this, the rapid eradication of pathogens appears to have resulted in reduced microbiome diversity and generation of chronically activated immune systems, presaging the recent rise of allergic, autoimmune and metabolic disorders. Certainly, gastrointestinal helminths can protect against gut and lung mucosa inflammatory conditions by modulating the microbiome and suppressing the chronic inflammation associated with dysbiosis. Here, we employ ES-62, an immunomodulator secreted by tissue-dwelling Acanthocheilonema viteae to show that helminth-modulation of the gut microbiome does not require live infection with gastrointestinal-based worms nor is protection restricted to mucosal diseases. Specifically, subcutaneous administration of this defined immunomodulator affords protection against joint disease in collagen-induced arthritis, a mouse model of rheumatoid arthritis, which is associated with normalisation of gut microbiota and prevention of loss of intestinal barrier integrity.
Highlights
The human immune system has evolved in the context of our colonisation by bacteria, viruses, fungi and parasitic helminths
Commensal bacteria have increasingly been proposed to contribute to rheumatoid arthritis (RA) pathogenesis[9,10] and decline in grip strength during ageing has been associated with changes in the gut microbiome[23]
Initiation of RA pathogenesis is associated with disruption of the balance of effector:regulatory immune cells and so we characterised the bacterial changes pertaining during established arthritis in the ileum and colon; intestinal sites where the microbiome and the metabolic microenvironment play key roles in shaping Th17 and regulatory immune responses[22,27,28]
Summary
The human immune system has evolved in the context of our colonisation by bacteria, viruses, fungi and parasitic helminths. Genetic studies have identified gene variants associated with various inflammatory diseases, these alone do not appear to be strong risk factors, integration with environmental factors being required to trigger disease Recognition of this has focused interest on the role of the microbiota[3,5] and on how helminths may regulate this in health and disease[6,7]. Helminth-mediated protection against autoimmune disease is not limited to GI-tract parasites, with striking examples of this involving filarial nematodes preventing development of RA13 and SLE14. It is unclear whether tissue-resident or blood-borne parasitic worms can mediate these effects via modulation of the host microbiome and if so, which mechanisms they utilise. Amongst the best characterised ES products is ES-62, a phosphorylcholine (PC)-containing glycoprotein secreted by the filarial nematode
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