Helminth Regulation of the Colonic Microbiome: Implications for the Control of Colitis
AdvisorMcKay, Derek Mark
Buret, André Gerald
Committee MemberSharkey, Keith A.
SubjectMicrobiota, Helminth, Immune, Short Chain Fatty Acids, IL-10, IL-10 receptor
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AbstractThe mammalian gut is a dynamic and complex organ composed of host cells, bacteria, fungi and viruses; while parasitic protozoa and helminths can be transient residents in the intestine. Through the advancements in high throughput sequencing, an increasing number of studies have catalogued taxonomic compositional changes in the gut microbiota following infection with parasitic helminths. However, the functional implications of such helminth-microbiota interactions on the host are not well understood, especially in the context of controlling inflammation. The McKay laboratory continuously demonstrates that mice infected with the rat tapeworm, Hymenolepis diminuta, are protected from dinitrobenzene sulfonic acid (DNBS)-induced colitis. My thesis seeks to determine if H. diminuta is dependent on the intestinal microbiota to protect from colonic inflammation and to determine the underlying mechanisms that are responsible for this anti-inflammatory event. Although H. diminuta does not require the microbiota to infect or be recognized/expelled by the murine host’s immune system, distinct compositional changes to the colonic microbiota occur during infection with H. diminuta. Removing microbes by using germ-free mice or disrupting the intestinal microbiota through broad-spectrum antibiotic use inhibits the anti-inflammatory mechanism of H. diminuta towards DNBS-colitis. In addition to characterizing the compositional shift in the intestinal microbiota of mice infected with H. diminuta, we demonstrated a significant increase in fecal short chain fatty acids (SCFA), in particular acetate and butyrate. Infecting free fatty receptor 2 (ffar2)-knockout mice with H. diminuta inhibited the beneficial effect towards DNBS, and in parallel to this, treating mice with neutralizing IL-10 antibodies also blocked the protective effect of H. diminuta when challenged with DNBS. Immunostaining for IL-10Rα demonstrated increased reactivity in colonic tissues of mice that were either treated with butyrate enemas or infected with H. diminuta, as compared to tissue from naive mice. The data in this thesis provides proof-of-principle evidence that H. diminuta modulates both the gut microbiota and the immune system of its host to protect from chemically induced colitis. Where the removal of these constituents, inhibits H. diminuta’s ability to protect the host from colitis.
CitationShute, A. (2020). Helminth Regulation of the Colonic Microbiome: Implications for the Control of Colitis (Unpublished doctoral thesis). University of Calgary, Calgary, AB.
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