Objectives: This study aimed to evaluate the intestinal mucosal alterations in lambs naturally infected with Giardia duodenalis at both histopathological and molecular levels, focusing on the relationship between infection severity and gene expression. Materials and Methods: A total of 24 lambs were categorized into four groups (control, mild, moderate, and severe) based on histopathological assessment of intestinal tissue sections. The tissues were examined for villus morphology, epithelial integrity, inflammatory cell infiltration, crypt morphology, and hyperemia. Additionally, the expression levels of FABP2, TFF3, ALPI, CLDN3, and ACTG2 genes were quantified using real-time PCR (qPCR). Results: Histopathological examination revealed progressive villus atrophy, epithelial degeneration, crypt hyperplasia, and lymphoplasmacytic infiltration in the lamina propria, which intensified with infection severity. Molecular analysis showed significant upregulation of FABP2 and TFF3 in the mild and moderate groups, suggesting early activation of mucosal repair. In contrast, ALPI expression decreased in the moderate and severe groups, indicating impaired epithelial detoxification. CLDN3 expression was significantly elevated across all infected groups, reflecting a compensatory response to tight junction disruption, while ACTG2 expression remained unchanged. Conclusions: Giardia duodenalis infection in lambs induces complex mucosal pathogenesis. The results demonstrate that the disease involves a simultaneous activation of destructive and regenerative molecular mechanisms, with distinct gene expression patterns correlating with the severity of intestinal damage.
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