The parasitic worm product ES-62 normalises the gut microbiota bone marrow axis in inflammatory arthritis

Doonan, James; Tarafdar, Anuradha; Pineda, Miguel A.; Lumb, Felicity E.; Crowe, Jenny; Khan, Aneesah; Hoskisson, Paul A.; Harnett, Margaret M.; Harnett, William

doi:10.1038/s41467-019-09361-0

Cited by 49 publications

(91 citation statements)

References 78 publications

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“…Changes in the microbiome contribute to the loss of intestinal barrier integrity 46,47,58 during ageing and impact directly on obesity and longevity 48,49 . We have recently shown that the protection afforded by ES-62 against inflammatory arthritis is associated with normalisation of the gut microbiome and stabilisation of gut barrier integrity that prevents generation of pathogenic TH17-mediated inflammation and allows homeostatic resolution of inflammation by IL-10 + Bregs in the collageninduced arthritis model of rheumatoid arthritis in male mice 16 . Thus, we investigated whether ES-62 acted to normalise the ageing microbiota and prevent the dysbiosis resulting in loss of barrier integrity by metagenomic analysis of faecal (ileum plus colon) material, with samples from individual mice pooled to generate a representative cohort phenotype.…”

Section: Es-62 Maintains Gut Microbiota Homeostasis During Hcd-inducementioning

confidence: 99%

“…Paraffin embedded tissues were sectioned at 5-6 µm and OCT tissues were cryosectioned (Thermoscientific, UK) at 8-10 µm thickness between -14 to -30°C. All tissues were haematoxylin and eosin (H&E) stained, gut and liver tissue sections were also stained with Gömöri's Trichrome using previously described methods 16 .…”

Section: Tissue Processing Histology and Immunofluorescencementioning

confidence: 99%

“…The overall pathology score was calculated (average of cellular infiltration-spatial, epithelial erosion and villus/crypt atrophy). to select for live cells and, for analysis of IL-10 + regulatory B cells (Bregs), lymphocytes were stimulated with PMA, ionomycin, Brefeldin A and LPS (Sigma, UK) as described previously 16 . Data were acquired using a BD LSRII flow cytometer and populations were gated using isotype and fluorescence minus one (FMO) controls using FlowJo, LLC analysis software (Tree Star/ BD) as described previously 16 .…”

Section: Image Quantification and Analysismentioning

confidence: 99%

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Parasitic worm-derived ES-62 promotes health- and life-span in high calorie diet-fed mice

Crowe

Doonan

et al. 2019

Preprint

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The recent extension of human lifespan has not been matched by equivalent improvements in late-life health due to the corresponding increase in ageingassociated comorbidities and obesity, conditions exacerbated by the widespread adoption of the high calorie Western diet (HCD). Chronic low-grade inflammation underpins ageing-induced ill-health and thus we have focused on ES-62, an immunomodulator secreted by the parasitic worm Acanthocheilonema viteae that we have previously shown to have potent anti-inflammatory properties, as a novel therapeutic strategy. ES-62 was tested in a mouse model of HCD-accelerated ageing and found to ameliorate pathophysiological, inflammatory and metabolic parameters, when administered at only 1 µg/week. Strikingly, ES-62 also substantially increased the median survival of male HCD-mice. This extension was not observed with female mice and indeed, ES-62 treatment resulted in distinct gender-specific healthspan signatures. Combined with a machine learning approach, such signatures signpost candidate parameters key to promoting both healthspan and lifespan.Adoption of the modern Western diet (high fat and high sugar) has significantly contributed to a global pandemic in metabolic syndrome, obesity, type-2 diabetes and cardiovascular disease; ageing-associated conditions that impact on both wellbeing (healthspan) and lifespan 1,2 . This increasing major public health problem reflects, at least in part, that such a high calorie diet (HCD) disrupts the gut microbiome, with the consequent intestinal inflammation and loss of barrier integrity driving chronic systemic inflammation that appears to dysregulate immunometabolic pathways, accelerating the ageing process and reducing lifespan 1,3-7 . Interestingly, epidemiological data suggest that Western diet-associated diseases are rising fastest in in the developing world 2,8 , regions where parasitic worms (helminths) and other infectious agents are being eradicated 9 . Helminths promote their survival by releasing excretory-secretory (ES) products that, by dampening inflammation and promoting tissue repair, act to prevent worm expulsion but also limit host pathology 10 . Thus, the relatively rapid eradication of these parasites appears to have resulted in hyper-active host immune systems, characterised by chronic low-grade inflammation that may (further) contribute to development of obesity and associated metabolic syndrome co-morbidities, as well as allergic and autoimmune inflammatory disorders, in developing and urbanised countries 10 . Whilst this has questioned the wisdom of current mass parasite eradication programs, it has emphasised the potential of utilising worm infections or ES to treat a wide range of noncommunicable diseases that are characterised by chronic inflammation [11][12][13] . Indeed, we have shown that a single, defined ES protein, ES-62, can suppress pathology in mouse models of allergic and autoimmune inflammatory diseases 9,10,14-16 . ES-62 achieves this by virtue of immunomodulatory phosphorylcholine groups attached...

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Section: Es-62 Maintains Gut Microbiota Homeostasis During Hcd-inducementioning

confidence: 99%

Section: Tissue Processing Histology and Immunofluorescencementioning

confidence: 99%

Section: Image Quantification and Analysismentioning

confidence: 99%

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Parasitic worm-derived ES-62 promotes health- and life-span in high calorie diet-fed mice

Crowe

Doonan

et al. 2019

Preprint

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“…We have previously shown that a single, defined ES protein, ES-62, can resolve chronic inflammation by normalising aberrant MyD88 signalling to homeostatically restore immunoregulation, irrespective of the inflammatory phenotype [4,5,[10][11][12]. MyD88 is increasingly recognized not only as a key innate immune system receptor transducer but also as an integrator of dysregulated inflammatory and metabolic pathways [7,[13][14][15].…”

Section: Introductionmentioning

confidence: 99%

“…Critically, these HCD-TLR4/ MyD88-induced effects are exacerbated by ageing [18]. Thus, based on ES-62's targeting of MyD88 and demonstrable ability to protect against chronic inflammatory allergic and autoimmune conditions [4,5,[10][11][12], we investigated whether it could safeguard against the impact of HCD-associated ageing in C57BL/6J mice. Our approach of combining longitudinal (survival) and cross-sectional (intervention) studies has revealed that ES-62 improves healthspan in both male and female HCD-fed mice and substantially extends median lifespan of male HCD-fed mice.…”

Section: Introductionmentioning

confidence: 99%

The parasitic worm product ES-62 promotes health- and life-span in a high calorie diet-accelerated mouse model of ageing

et al. 2020

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Improvements in hygiene and health management have driven significant increases in human lifespan over the last 50 years. Frustratingly however, this extension of lifespan has not been matched by equivalent improvements in late-life health, not least due to the global pandemic in type-2 diabetes, obesity and cardiovascular disease, all ageing-associated conditions exacerbated and accelerated by widespread adoption of the high calorie Western diet (HCD). Recently, evidence has begun to emerge that parasitic worm infection might protect against such ageing-associated co-morbidities, as a serendipitous side-effect of their evolution of pro-survival, anti-inflammatory mechanisms. As a novel therapeutic strategy, we have therefore investigated the potential of ES-62, an anti-inflammatory secreted product of the filarial nematode Acanthocheilonema viteae, to improve healthspan (the period of life before diseases of ageing appear) by targeting the chronic inflammation that drives metabolic dysregulation underpinning ageing-induced ill-health. We administered ES-62 subcutaneously (at a dose of 1 μg/week) to C57BL/6J mice undergoing HCD-accelerated ageing throughout their lifespan, while subjecting the animals to analysis of 120 immunometabolic responses at various time-points. ES-62 improved a number of inflammatory parameters, but markedly, a range of pathophysiological, metabolic and microbiome parameters of ageing were also successfully targeted. Notably, ES-62-mediated promotion of healthspan in male and female HCD-mice was associated with different mechanisms and reflecting this, machine learning modelling identified sex-specific signatures predictive of ES-62 action against HCD-accelerated ageing. Remarkably, ES-62 substantially increased the median survival of male HCD-mice. This was not the case with female animals and unexpectedly, this difference between the two sexes could not be explained in terms of suppression of the chronic inflammation driving ageing, as ES-62 tended to be more effective in reducing this in female mice. Rather, the difference appeared to be associated with ES-62's

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Can the Study of Parasitic Helminths Be Fruitful for Human Diseases?

Rzepecka

Harnett

2022

Helminth Infections and Their Impact on Global Public Health

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The parasitic worm product ES-62 normalises the gut microbiota bone marrow axis in inflammatory arthritis

Cited by 49 publications

References 78 publications

Parasitic worm-derived ES-62 promotes health- and life-span in high calorie diet-fed mice

Parasitic worm-derived ES-62 promotes health- and life-span in high calorie diet-fed mice

The parasitic worm product ES-62 promotes health- and life-span in a high calorie diet-accelerated mouse model of ageing

Can the Study of Parasitic Helminths Be Fruitful for Human Diseases?

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