Browsing by Author "Sharkey, Keith Alexander"

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    Characterization of Bacterial Depletion and Colitis-Associated Changes in the Gut Microbiota on Behaviour and Intestinal Physiology
    (2021-05-10) Vicentini, Fernando Augusto; Sharkey, Keith Alexander; Hirota, Simon Andrew; Pittman, Quentin Jerome; McCafferty, Donna-Marie; DeVinney, Rebekah; Gareau, Melanie
    The role of the microbiota in modulating host physiology is now widely accepted. Acting via the microbiota-gut-brain (MGB) axis, intestinal bacteria have been associated with the regulation of gastrointestinal tract and the central nervous system function, in both physiological and pathophysiological conditions, such as in inflammatory bowel disease (IBD). Patients with IBD have an increased incidence of anxiety and depression, which is accompanied by alterations in the microbiota composition. However, the link between changes in microbiota composition and behavioural abnormalities in the context of intestinal inflammation is unknown. Mechanisms that mediate the MGB axis in homeostasis have emerged but are still incomplete. We sought to characterize the effects of bacterial depletion on intestinal physiology and animal behaviour, and the role of colitis-associated microbiota in the modulation of behavioural abnormalities. Using mouse models of bacterial depletion (antibiotic treatment) and colitis (administration of dextran sulfate sodium), we investigated the role of the microbiota in intestinal physiology and behavioural outputs, and the potential mechanisms of these interactions. The major findings were: (1) bacterial depletion induced a reduction in despair behaviour in a sex-specific manner. The altered behaviour observed in male mice was normalized by activation of the Aryl hydrocarbon receptor, suggesting that this receptor is involved in modulation of behaviour via host-microbe interactions. (2) Bacterial depletion was linked to sex-independent changes in intestinal physiology, including reduced motility, altered secretion, and increased permeability. These changes were accompanied by a reduction in the numbers of enteric neurons, suggesting that microbiota influences the enteric nervous system integrity. Administration of bacterial-derived molecules, lipopolysaccharide and short-chain fatty acids, was associated with neuronal survival and neurogenesis, respectively. (3) Colitis induced changes in the intestinal bacteria composition, which was associated with behavioural abnormalities. Microbiota transfer of colitis-associated microbiota into recipient healthy mice was sufficient to induce behavioural alterations. Remarkably, no intestinal or neuroinflammation were observed in recipient mice. Collectively, these findings provide support to expand our understanding of the MGB axis under homeostatic and intestinal inflammatory conditions. Thus, a better understanding of this integrated network provides a rationale for the development of microbiota-centred therapeutic approaches for the improvement of health.
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    Prion protein distribution and function in the Enteric Nervous System of the Gastrointestinal Tract of Mice
    (2013-05-01) Alvarez Veronesi, Ana Laura; Sharkey, Keith Alexander; Jirik, Frank Robert
    The prion protein (PrPC) is a membrane bound copper binding protein widely expressed throughout the body. Although the pathophysiological role of PrPC in prion diseases has been well established, its physiological function remains poorly understood. This study was designed to characterize the distribution of PrPC in the gastrointestinal tract, more specifically the enteric nervous system (ENS), and to establish a functional role of PrPC in the gut. We have shown that PrPC is expressed in the ENS of mice, both in neurons and enteric glial cells. In addition, Ussing chambers studies showed that PrPC is involved in neuronal and epithelial control of electrolyte transport; PrPC-deficient mice had decreased responses to electric field stimulation, bethanechol, and forskolin, compared to controls. However, this was not due to PrPC’s ability to bind copper. These studies show that PrPC is widely distributed in the ENS and has a physiological role in gastrointestinal function.
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    The Role of Intestinal Tuft Cells in the Murine Response to Infection with the Cestode, Hymenolepis diminuta
    (2023-12-21) Rajeev, Sruthi; McKay, Derek Mark; MacNaughton, Wallace Keith; Sharkey, Keith Alexander; McCafferty, Donna-Marie; Reynolds, Lisa
    The small intestinal tuft cell has garnered considerable interest in the field of parasitic immunology over the past few years for being a sentinel cell in the host response against nematode, trematode, and protist parasites. The tuft cell displays versatility in its capacity to respond to various luminal stimuli and in the mediators it produces. Whether the tuft cell is involved in the host response to enteric cestodes has not been previously explored. My thesis seeks to determine if enteric tuft cells coordinate host anti-helminthic immunity against cestode parasites using murine infection with Hymenolepis diminuta as a model system. H. diminuta-infection induced tuft cell hyperplasia in mice which is dependent on IL-4R𝛼 signalling and the adaptive immune system. Tuft cell hyperplasia still occurs in germ free mice, indicating that the parasite and host responses to the parasite and not microbial factors drive tuft cell hyperplasia. Using pou2f3-/- tuft cell-deficient mice, our study reveals that enteric tuft cells modulate local host responses to H. diminuta that are ultimately important in quicker worm expulsion from the mouse. At the same time, tuft cell deficiency does not abrogate the development of systemic immunity against H. diminuta, nor the ultimate (albeit delayed) expulsion of the worms. We further show that although infection with H. diminuta induces both tuft cell hyperplasia as well as protection from subsequent parasitic infection with H. bakeri, the tuft cell is not solely responsible for mediating systemic and other local Th2 responses against H. diminuta. This work reveals that while tuft cells play subtle roles in fine tuning the host response against the parasite H. diminuta, tuft cell deficiency is overcome by redundancies that exist in host’s mucosal immune arsenal leading to ultimate expulsion of the parasite.