Browsing by Author "McKay, Derek M."

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    Cooperation between host immunity and the gut bacteria is essential for helminth-evoked suppression of colitis
    (2021-09-13) Shute, Adam; Callejas, Blanca E.; Li, ShuHua; Wang, Arthur; Jayme, Timothy S.; Ohland, Christina; Lewis, Ian A.; Layden, Brian T.; Buret, André G.; McKay, Derek M.
    Abstract Background Studies on the inhibition of inflammation by infection with helminth parasites have, until recently, overlooked a key determinant of health: the gut microbiota. Infection with helminths evokes changes in the composition of their host’s microbiota: one outcome of which is an altered metabolome (e.g., levels of short-chain fatty acids (SCFAs)) in the gut lumen. The functional implications of helminth-evoked changes in the enteric microbiome (composition and metabolites) are poorly understood and are explored with respect to controlling enteric inflammation. Methods Antibiotic-treated wild-type, germ-free (GF) and free fatty-acid receptor-2 (ffar2) deficient mice were infected with the tapeworm Hymenolepis diminuta, then challenged with DNBS-colitis and disease severity and gut expression of the il-10 receptor-α and SCFA receptors/transporters assessed 3 days later. Gut bacteria composition was assessed by 16 s rRNA sequencing and SCFAs were measured. Other studies assessed the ability of feces or a bacteria-free fecal filtrate from H. diminuta-infected mice to inhibit colitis. Results Protection against disease by infection with H. diminuta was abrogated by antibiotic treatment and was not observed in GF-mice. Bacterial community profiling revealed an increase in variants belonging to the families Lachnospiraceae and Clostridium cluster XIVa in mice 8 days post-infection with H. diminuta, and the transfer of feces from these mice suppressed DNBS-colitis in GF-mice. Mice treated with a bacteria-free filtrate of feces from H. diminuta-infected mice were protected from DNBS-colitis. Metabolomic analysis revealed increased acetate and butyrate (both or which can reduce colitis) in feces from H. diminuta-infected mice, but not from antibiotic-treated H. diminuta-infected mice. H. diminuta-induced protection against DNBS-colitis was not observed in ffar2−/− mice. Immunologically, anti-il-10 antibodies inhibited the anti-colitic effect of H. diminuta-infection. Analyses of epithelial cell lines, colonoids, and colon segments uncovered reciprocity between butyrate and il-10 in the induction of the il-10-receptor and butyrate transporters. Conclusion Having defined a feed-forward signaling loop between il-10 and butyrate following infection with H. diminuta, this study identifies the gut microbiome as a critical component of the anti-colitic effect of this helminth therapy. We suggest that any intention-to-treat with helminth therapy should be based on the characterization of the patient’s immunological and microbiological response to the helminth.
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    Helminth Parasites and the Modulation of Joint Inflammation
    (2011-04-18) Matisz, Chelsea E.; McDougall, Jason J.; Sharkey, Keith A.; McKay, Derek M.
    There is an urgent need to develop better therapeutics for autoimmune and autoinflammatory diseases, of which musculoskeletal disorders such as rheumatoid arthritis are particularly prevalent and debilitating. Helminth parasites are accomplished masters at modifying their hosts' immune activity, and so attention has focused on rodent-helminth model systems to uncover the workings of the mammalian immune response to metazoan parasites, with the hope of revealing molecules and/or mechanisms that can be translated into better treatments for human autoimmune and idiopathic disorders. Substantial proof-of-principal data supporting the concept that infection with helminth parasites can reduce the severity of concomitant disease has been amassed from models of mucosal inflammation. Indeed, infection with helminth parasites has been tried as a therapy in inflammatory bowel disease, and there are case reports relating to other conditions (e.g., autism); however, the impact of infection with parasitic helminths on musculoskeletal diseases has not been extensively studied. Here, we present the view that such a strategy should be applied to the amelioration of joint inflammation and review the literature that supports this contention.
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    Infection with Hymenolepis diminuta Is More Effective than Daily Corticosteroids in Blocking Chemically Induced Colitis in Mice
    (2009-11-30) Melon, Alexandra; Wang, Arthur; Phan, Van; McKay, Derek M.
    Purpose. To compare infection with the tapeworm, Hymenolepis diminuta, with steroid (dexamethasone) administration in the inhibition of dinitrobenzene sulfonic acid- (DNBS-) induced colitis in mice. Procedures. Mice were treated with DNBS ± infected with H. diminuta or treated with daily dexamethasone (2 mg/Kg, ip.) and were assessed 72 hours post-DNBS by the calculation of disease activity and histological damage scores, and spleen cell cytokine production. Results. H. diminuta-infected mice showed increased IL-4 and IL-10 production by spleen cells compared to other groups and were protected from DNBS-induced colitis. In contrast, there was little benefit of dexamethasone in the treatment of colitis. Collagen deposition in the colon was not different between the groups. Conclusions. H. diminuta was superior to dexamethasone in the prevention of DNBS-induced colitis and did not result in additional side effects (i.e., collagen deposition). Comparisons with current therapeutics and long-term followup to studies are essential if “helminth therapy” is to become a viable treatment for specific inflammatory diseases in the gut or other tissues.
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    Lipid mediators and the regulation of macrophage function and colitis
    (2012) Prescott, David Charles; McKay, Derek M.
    The maintenance of balanced immune responses is vital to the health of an individual. This is of particular importance in the intestine, as it represents a vast immunological challenge due to the enormous antigenic potential of the commensal microbiota. The body has therefore developed a number of homeostatic strategies to ensure that inflammatory reactions are freely able to clear foreign material such as bacteria in a manner that is self-limiting. The dysregulation of these processes, however, can lead to the development of chronic diseases such as inflammatory bowel disease (IBO). A cell type that plays a vital role in maintaining this homeostasis is the macrophage. In this thesis, I have demonstrated how the phagocytosis of bacteria is enhanced in these cells by lipoxins, a family of lipid mediators that are involved in inducing the resolution of inflammation. This phenomenon was associated with a concomitant decrease in pro-inflammatory mediator production, suggesting that lipoxins are able to induce a macrophage phenotype that is geared towards eliminating any residual infections at the end stages of inflammation, and return tissues to sterile homeostasis. The functions of lipoxin were also found to be dependent on the signalling molecule phosphoinositide 3-kinase pl l0y (PI3Ky). This enzyme has previously been shown to be involved in the recruitment of leukocytes to inflamed tissues, and thus its inhibition or genetic knock-out has been shown to effectively treat a number of mouse models of inflammatory disease. We show here that mice deficient in PB Ky are initially protected from acute experimental colitis induced by the haptenizing agent trinitrobenzene sulfonic acid (TNBS), but fail to heal properly due to an inability to clear bacteria that have infected the colonic tissue. Taken together, these studies highlight the importance of bacterial clearance from inflamed tissues, and suggest that the development of novel anti-inflammatory therapies that promote, rather than hinder the antimicrobial functions of phagocytes such as macrophages could be of use in the treatment of IBD.
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    Neuropeptide y regulation of mouse colon epithelial ion transport in health and colitis
    (2009) Klompus, Matthew; McKay, Derek M.; Sharkey, Keith A.
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