Giardia duodenalis stabilizes HIF-1α and induces glycolytic alterations in intestinal epithelial cells
Abstract The gastrointestinal epithelium relies on activation of the hypoxia-inducible factor (HIF) to promote cell survival and maintain bioenergetic homeostasis during hypoxia. While many pathogens can activate HIF, the effects of enteric protozoa on HIF activation in gastrointestinal epithelial c...
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Nature Portfolio
2025-08-01
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| Online Access: | https://doi.org/10.1038/s41598-025-13635-7 |
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| author | Emily DeMichele Olivia Sosnowski Darragh Flood Cormac T. Taylor Ian A. Lewis Thibault Allain Andre G. Buret |
| author_facet | Emily DeMichele Olivia Sosnowski Darragh Flood Cormac T. Taylor Ian A. Lewis Thibault Allain Andre G. Buret |
| author_sort | Emily DeMichele |
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| description | Abstract The gastrointestinal epithelium relies on activation of the hypoxia-inducible factor (HIF) to promote cell survival and maintain bioenergetic homeostasis during hypoxia. While many pathogens can activate HIF, the effects of enteric protozoa on HIF activation in gastrointestinal epithelial cells remain unclear. Giardia duodenalis, a prevalent protozoan enteropathogen, causes intestinal barrier dysfunction characterized by epithelial malabsorption, mucus depletion, altered mucin glycosylation, and microbiota dysbiosis. Findings from the present study reveal an epithelial hypoxic signature upon Giardia infection. Human intestinal epithelial cells were exposed to vehicle or Giardia duodenalis isolate GS/M under normoxic (21% O2) or hypoxic (1% O2) conditions. In normoxia, infected cells displayed a time-dependent increase in HIF-1α protein expression, the oxygen-dependent subunit of HIF-1. In normoxia, Giardia infection upregulated HIF-1 target genes involved in cellular stress (i.e., VEGFA, ANKRD37, GADD45A) and glycolysis (i.e., HK2, LDHA). This was accompanied by changes in the abundance of glycolytic intermediates (i.e., glucose-6-phosphate, pyruvate, lactate). Although infection in hypoxia failed to augment the hypoxia-induced HIF-1α stabilization, HIF-1 target genes were still upregulated, albeit to a lesser degree. These findings indicate that Giardia induces a transient epithelial hypoxic response in normoxic conditions, revealing a hitherto unrecognized epithelial rescue response to this intestinal parasite. |
| format | Article |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-08-01 |
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| spelling | doaj-art-f70eb49e07ba45d085ff67f46b48acf92025-08-20T03:42:38ZengNature PortfolioScientific Reports2045-23222025-08-0115111210.1038/s41598-025-13635-7Giardia duodenalis stabilizes HIF-1α and induces glycolytic alterations in intestinal epithelial cellsEmily DeMichele0Olivia Sosnowski1Darragh Flood2Cormac T. Taylor3Ian A. Lewis4Thibault Allain5Andre G. Buret6Department of Biological Sciences, University of CalgaryDepartment of Biological Sciences, University of CalgaryThe Conway Institute, School of Medicine and Systems Biology Ireland, University College DublinThe Conway Institute, School of Medicine and Systems Biology Ireland, University College DublinDepartment of Biological Sciences, University of CalgaryDepartment of Biological Sciences, University of CalgaryDepartment of Biological Sciences, University of CalgaryAbstract The gastrointestinal epithelium relies on activation of the hypoxia-inducible factor (HIF) to promote cell survival and maintain bioenergetic homeostasis during hypoxia. While many pathogens can activate HIF, the effects of enteric protozoa on HIF activation in gastrointestinal epithelial cells remain unclear. Giardia duodenalis, a prevalent protozoan enteropathogen, causes intestinal barrier dysfunction characterized by epithelial malabsorption, mucus depletion, altered mucin glycosylation, and microbiota dysbiosis. Findings from the present study reveal an epithelial hypoxic signature upon Giardia infection. Human intestinal epithelial cells were exposed to vehicle or Giardia duodenalis isolate GS/M under normoxic (21% O2) or hypoxic (1% O2) conditions. In normoxia, infected cells displayed a time-dependent increase in HIF-1α protein expression, the oxygen-dependent subunit of HIF-1. In normoxia, Giardia infection upregulated HIF-1 target genes involved in cellular stress (i.e., VEGFA, ANKRD37, GADD45A) and glycolysis (i.e., HK2, LDHA). This was accompanied by changes in the abundance of glycolytic intermediates (i.e., glucose-6-phosphate, pyruvate, lactate). Although infection in hypoxia failed to augment the hypoxia-induced HIF-1α stabilization, HIF-1 target genes were still upregulated, albeit to a lesser degree. These findings indicate that Giardia induces a transient epithelial hypoxic response in normoxic conditions, revealing a hitherto unrecognized epithelial rescue response to this intestinal parasite.https://doi.org/10.1038/s41598-025-13635-7GiardiaGiardiasisIntestinal epithelial cellsHypoxiaHIF-1αGlycolysis |
| spellingShingle | Emily DeMichele Olivia Sosnowski Darragh Flood Cormac T. Taylor Ian A. Lewis Thibault Allain Andre G. Buret Giardia duodenalis stabilizes HIF-1α and induces glycolytic alterations in intestinal epithelial cells Scientific Reports Giardia Giardiasis Intestinal epithelial cells Hypoxia HIF-1α Glycolysis |
| title | Giardia duodenalis stabilizes HIF-1α and induces glycolytic alterations in intestinal epithelial cells |
| title_full | Giardia duodenalis stabilizes HIF-1α and induces glycolytic alterations in intestinal epithelial cells |
| title_fullStr | Giardia duodenalis stabilizes HIF-1α and induces glycolytic alterations in intestinal epithelial cells |
| title_full_unstemmed | Giardia duodenalis stabilizes HIF-1α and induces glycolytic alterations in intestinal epithelial cells |
| title_short | Giardia duodenalis stabilizes HIF-1α and induces glycolytic alterations in intestinal epithelial cells |
| title_sort | giardia duodenalis stabilizes hif 1α and induces glycolytic alterations in intestinal epithelial cells |
| topic | Giardia Giardiasis Intestinal epithelial cells Hypoxia HIF-1α Glycolysis |
| url | https://doi.org/10.1038/s41598-025-13635-7 |
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