Colorectal cancer (CRC) is the fourth and the third most common and deadlycancer, respectively, worldwide. Even with alternative therapies, some patients do notrespond to treatment. Identifying modulations in the tumor microenvironment (TME) ofCRC is indeed a challenge due to the complex and dynamic nature of the TME. Theintestinal epithelial cells (IECs) are composed by different types of secretory-lineagecells, such as goblet, tuft, paneth and enteroendocrine cells (EECs). Yet, the relevanceof each subtype of secretory IEC in the tumor microenvironment is still a matter of debate.This study investigated the involvement of IECs in CRC through an integrativebioinformatics analysis using publicly available datasets from National Center forBiotechnology Information (NCBI) and The Cancer Genome Atlas Program (TCGA),encompassing both human and mouse CRC samples. Our findings reveal a CRC TMEfeatured by elevated expression levels of genes associated with WNT pathway activity.Remarkably, there was an increased expression of Paneth cell-associated markers andtranscription factors, such as WISP1, LYZ, SOX9, and DEFA1 while enteroendocrinecells-specific gene markers, such as GCG (encoding Glucagon like Peptide-1) andCHGA exhibited a significant downregulation in CRC tissue compared with health tissue.Gene ontology (GO) analysis showed a species-conserved downregulation inhormone/peptide secretion-related pathways of CRC in mouse and human. Of note,lower levels of GCG and CHGA correlated with reduced overall survival andchemotherapy-unresponsive patients. These results suggest that disruption of EECsignaling is a hallmark of CRC development and may hold prognostic and therapeuticvalue for treating CRC patients.