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Background RNA splicing is a key post-transcriptional mechanism that generates protein diversity and contributes to the fine-tuning of gene expression, which may facilitate adaptation to environmental challenges. Here, we employ a systems approach to study alternative splicing changes upon enteric infection in females from classical Drosophila melanogaster strains as well as 38 inbred lines. Results We find that infection leads to extensive differences in isoform ratios, which results in a more diverse transcriptome with longer 5 ' untranslated regions (5 ' UTRs). We establish a role for genetic variation in mediating inter-individual splicing differences, with local splicing quantitative trait loci (local-sQTLs) being preferentially located at the 5 ' end of transcripts and directly upstream of splice donor sites. Moreover, local-sQTLs are more numerous in the infected state, indicating that acute stress unmasks a substantial number of silent genetic variants. We observe a general increase in intron retention concentrated at the 5 ' end of transcripts across multiple strains, whose prevalence scales with the degree of pathogen virulence. The length, GC content, and RNA polymerase II occupancy of these introns with increased retention suggest that they have exon-like characteristics. We further uncover that retained intron sequences are enriched for the Lark/RBM4 RNA binding motif. Interestingly, we find that lark is induced by infection in wild-type flies, its overexpression and knockdown alter survival, and tissue-specific overexpression mimics infection-induced intron retention. Conclusion Our collective findings point to pervasive and consistent RNA splicing changes, partly mediated by Lark/RBM4, as being an important aspect of the gut response to infection.