ORCID Profile
0000-0002-6688-0595
Current Organisation
University of Oxford
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Publisher: Wiley
Date: 12-01-2022
DOI: 10.1002/GLIA.24139
Abstract: Fecal‐oral contamination promotes malnutrition pathology. Lasting consequences of early life malnutrition include cognitive impairment, but the underlying pathology and influence of gut microbes remain largely unknown. Here, we utilize an established murine model combining malnutrition and iterative exposure to fecal commensals (MAL‐BG). The MAL‐BG model was analyzed in comparison to malnourished (MAL mice) and healthy (CON mice) controls. Malnourished mice display poor spatial memory and learning plasticity, as well as altered microglia, non‐neuronal CNS cells that regulate neuroimmune responses and brain plasticity. Chronic fecal‐oral exposures shaped microglial morphology and transcriptional profile, promoting phagocytic features in MAL‐BG mice. Unexpectedly, these changes occurred independently from significant cytokine‐induced inflammation or blood–brain barrier (BBB) disruption, key gut‐brain pathways. Metabolomic profiling of the MAL‐BG cortex revealed altered polyunsaturated fatty acid (PUFA) profiles and systemic lipoxidative stress. In contrast, supplementation with an ω3 PUFA/antioxidant‐associated diet (PAO) mitigated cognitive deficits within the MAL‐BG model. These findings provide valued insight into the malnourished gut microbiota‐brain axis, highlighting PUFA metabolism as a potential therapeutic target.
Publisher: Wiley
Date: 11-02-2019
DOI: 10.1111/MMI.14182
Abstract: Envelope-localized proteins, such as adhesins and secretion systems, play critical roles in host infection by Gram-negative pathogens. As such, their folding is monitored by envelope stress response systems. Previous studies demonstrated that the Cpx envelope stress response is required for virulence of Citrobacter rodentium, a murine pathogen used to model infections by the human pathogens enteropathogenic and enterohemorrhagic Escherichia coli however, the mechanisms by which the Cpx response promotes host infection were previously unknown. Here, we characterized the C. rodentium Cpx regulon in order to identify genes required for host infection. Using transcriptomic and proteomic approaches, we found that the Cpx response upregulates envelope-localized protein folding and degrading factors but downregulates pilus genes and type III secretion effectors. Mouse infections with C. rodentium strains lacking in idual Cpx-regulated genes showed that the chaperone rotease DegP and the disulfide bond oxidoreductase DsbA were essential for infection, but Cpx regulation of these genes did not fully account for attenuation of C. rodentium ΔcpxRA. Both deletion of dsbA and treatment with the reducing agent dithiothreitol activated the C. rodentium Cpx response, suggesting that it may sense disruption of disulfide bonding. Our results highlight the importance of envelope protein folding in host infection by Gram-negative pathogens.
Publisher: eLife Sciences Publications, Ltd
Date: 20-04-2021
DOI: 10.7554/ELIFE.67740
Abstract: Bacterial members of the infant gut microbiota and bacterial-derived short-chain fatty acids (SCFAs) have been shown to be protective against childhood asthma, but a role for the fungal microbiota in asthma etiology remains poorly defined. We recently reported an association between overgrowth of the yeast Pichia kudriavzevii in the gut microbiota of Ecuadorian infants and increased asthma risk. In the present study, we replicated these findings in Canadian infants and investigated a causal association between early life gut fungal dysbiosis and later allergic airway disease (AAD). In a mouse model, we demonstrate that overgrowth of P. kudriavzevii within the neonatal gut exacerbates features of type-2 and -17 inflammation during AAD later in life. We further show that P. kudriavzevii growth and adherence to gut epithelial cells are altered by SCFAs. Collectively, our results underscore the potential for leveraging inter-kingdom interactions when designing putative microbiota-based asthma therapeutics.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Sarah E Woodward.