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

Wangchuk, P.; Constantinoiu, C.; Kouremenos, K. A.; Becker, L.; Jones, L.; Shepherd, C.; Buitrago, G.; Giacomin, P.; Daly, N. L.; McConville, M. J.; Ryan, R.; Miles, J.; Loukas, A.

doi:10.1101/316885

bioRxiv · 10.1101/316885

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

Wangchuk, P.·Constantinoiu, C.·Kouremenos, K. A.·Becker, L.·Jones, L.·Shepherd, C.·Buitrago, G.·Giacomin, P.·Daly, N. L.·McConville, M. J.·Ryan, R.·Miles, J.·Loukas, A.

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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). Here we use a metabolomics approach to characterize the non-protein small molecule complement of hookworms. Gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry analyses of somatic tissue extracts revealed the presence of 52 polar metabolites and 22 non-polar components including short chain fatty acids (SCFA). Several of these small metabolites, notably the SCFA, have been shown to have anti-inflammatory properties in various diseases, including IBD. Using a murine model of colitis and human peripheral blood mononuclear cells, we demonstrate that somatic tissue extracts of the hookworm Ancylostoma caninum contain small molecules with anti-inflammatory activities. Of the five extracts tested, two of them significantly protected mice against T cell-mediated immunopathology and weight loss in a chemically-induced colitis model. Moreover, one of the anti-colitic extracts suppressed ex vivo production of inflammatory cytokines from primary human leukocytes. While the origin of the SCFA (parasite or host microbiota-derived) present in the hookworm somatic tissue extracts cannot be ascertained from this study, it is possible that A. caninum may be actively promoting an anti-inflammatory host microbiome by facilitating immune crosstalk through SCFA production.

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Wangchuk, P., Constantinoiu, C., Kouremenos, K. A., Becker, L., Jones, L., Shepherd, C., Buitrago, G., Giacomin, P., Daly, N. L., McConville, M. J., Ryan, R., Miles, J., Loukas, A.. 2018-05-08. Hookworm-derived small molecule extracts suppress pathology in a mouse model of colitis and inhibit secretion of key inflammatory cytokines in primary human leukocytes. https://doi.org/10.1101/316885

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