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Vitamin A and D deficiencies are associated with immune modulatory effects and intestinal barrier impairment. However, the underlying mechanisms remain unclear. C57BL/6J mice were fed either a diet lacking in vitamin A (VAd), vitamin D (VDd) or a control diet (CD) for 12 weeks. Gut barrier function, antimicrobial peptide (AMP) defense and regulatory pathways were assessed. VAd mice compared to CD mice showed a reduced villus length in the ileum (<i>p</i> < 0.01) and decreased crypt depth in the colon (<i>p</i> < 0.05). In both VAd- and VDd-fed mice, ileal α-defensin 5 (<i>p</i> < 0.05/<i>p</i> < 0.0001 for VAd/VDd) and lysozyme protein levels (<i>p</i> < 0.001/<i>p</i> < 0.0001) were decreased. Moreover, mRNA expression of lysozyme (<i>p</i> < 0.05/<i>p</i> < 0.05) and total cryptdins (<i>p</i> < 0.001/<i>p</i> < 0.01) were reduced compared to controls. Furthermore, matrix metalloproteinase-7 (Mmp7) mRNA (<i>p</i> < 0.0001/<i>p</i> < 0.001) as well as components of the Wnt signaling pathway were decreased. VAd- and VDd-fed mice, compared to control mice, exhibited increased expression of pro-inflammatory markers and β-defensins in the colon. Organoid cell culture confirmed that vitamins A and D regulate AMP expression, likely through the Jak/STAT5 signaling pathway. In conclusion, our data show that vitamin A and D regulate intestinal antimicrobial peptide defense through Wnt and STAT5 signaling pathways.