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

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.