Hookworm-derived metabolites suppress pathology in a mouse model of colitis and inhibit secretion of key inflammatory cytokines in primary human leukocytes

Wangchuk, Phurpa, Shepherd, Catherine, Constantinoiu, Constantin, Ryan, Rachael Y.M., Kouremenos, Konstantinos A., Becker, Luke, Jones, Linda, Buitrago, Geraldine, Giacomin, Paul, Wilson, David, Daly, Norelle, Mcconville, Malcolm J., Miles, John J., and Loukas, Alex (2019) Hookworm-derived metabolites suppress pathology in a mouse model of colitis and inhibit secretion of key inflammatory cytokines in primary human leukocytes. Infection and Immunity, 87 (4). e00851-18.

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Abstract

Iatrogenic hookworm therapy shows promise for treating disorders that result from a dysregulated immune system, including inflammatory bowel disease (IBD). Using a murine model of trinitrobenzenesulfonic acid-induced colitis and human peripheral blood mononuclear cells, we demonstrate that low molecular weight metabolites derived from both somatic extracts (LMWM-SE) and excretory-secretory products (LMWM-ESP) of the hookworm, Ancylostoma caninum, display anti-inflammatory properties. Administration to mice of LMWM-ESP as well as sequentially extracted fractions of LMWM-SE using both methanol (SE-MeOH) and hexane: dichloromethane: acetonitrile (SE-HDA) resulted in significant protection against T cell-mediated immunopathology, clinical signs of colitis and impaired histological colon architecture. To assess bioactivity in human cells, we stimulated primary human leukocytes with lipopolysaccharide in the presence of hookworm extracts and showed that SE-HDA suppressed ex vivo production of inflammatory cytokines. Gas chromatography-mass spectrometry (MS) and liquid chromatography-MS analysis revealed the presence of 46 polar metabolites, 22 fatty acids and five short-chain fatty acids (SCFAs) in the LMWM-SE fraction, and 29 polar metabolites, 13 fatty acids and six SCFAs in the LMWM-ESP fraction. Several of these small metabolites, notably the SCFAs, have been previously reported to have anti-inflammatory properties in various disease settings, including IBD. This is the first report showing that hookworms secrete small molecules with both ex vivo and in vivo anti-inflammatory bioactivity, and warrant further exploration as a novel approach to the development of anti-inflammatory drugs inspired by coevolution of gut-dwelling hookworms with their vertebrate hosts.

Item ID: 57198
Item Type: Article (Research - C1)
ISSN: 1098-5522
Keywords: ancylostoma caninum; excretory-secretory product; hookworm metabolomics; small molecule; helminths
Copyright Information: Copyright © 2019 American Society for Microbiology.
Funders: National Health and Medical Research Council (NHMRC), Australian Institute of Tropical Health and Medicine (AITHM)
Projects and Grants: NHMRC Peter Doherty Early Career Fellowship Grant APP1091011, AITHM Capacity Development Grant, NHMRC program grant APP1037304, NHMRC Senior Principal Research Fellowship APP1117504, NHMRC Career Development Fellowship APP1131732
Date Deposited: 27 Feb 2019 04:32
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110799 Immunology not elsewhere classified @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920199 Clinical Health (Organs, Diseases and Abnormal Conditions) not elsewhere classified @ 100%
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