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Somatostatin is a neuropeptide and a key regulator of the growth axis. Six Sst encoding genes (sst1 to sst6) have been identified in teleost fish genomes but little is known about their function. The present study aimed at replicating the context of the inflammatory bowel disease (IBD) and clarifying the involvement of sst3 in the intestine innate defence barrier in zebrafish larvae. We first established a CRISP/Cas9 sst3 deficient line (MT) and analysed the morphological and transcriptomic response to 0.4% dextran sulfate sodium (DSS). Alcian blue staining of larval sections 6 days post fertilization showed an increased in acidic mucins in the intestinal bulb and mid-intestine, with a much stronger response in the MT compared to wild type (WT). The transcriptomic analysis revealed that WT and MT shared enriched gene ontology (GO) terms and pathways linked to catabolism, chondrocyte development, innate immune system, xenobiotic metabolism and oxidative stress. In contrast, the WT specific response to DSS was enriched in GO terms and pathways linked to transcription and translation, various developmental processes, regulation of biosynthetic processes, apelin signalling and apoptosis while the MT specific response included terms and pathways linked to protein metabolism and catabolic processes, extracellular matrix – receptor interaction and proteasome and chondrocyte development. Overall, this study demonstrated that Sst3 deficiency impairs insulin growth factor and adipocytokine signalling exacerbating the inflammatory response to DSS.