Prior studies in IBS-D patients showed immune activation, secretion and barrier dysfunction in jejunal or colorectal mucosa. We measured mRNA expression by RT-PCR of 91 genes reflecting tight junction proteins, chemokines, innate immunity, ion channels, transmitters, housekeeping genes, and controls for DNA contamination and PCR efficiency in small intestinal mucosa from 15 IBS-D and 7 controls (biopsies negative for celiac disease). Fold change was calculated using 2(-, CT) formula. Nominal p values (p<0.05) were interpreted with FDR correction (q value). Cluster analysis with LENS explored connectivity of mechanisms. Upregulated genes (uncorrected p<0.05) were related to ion transport (INADL, MAGI1 and SONS1), barrier (TJP1, 2, 3 and CLDN) or immune functions (TLR3, IL15, MAPKAPK5), or histamine metabolism (HNMT); downregulated genes were related to immune function (IL-1β, TGF β 1 and CCL20) or antigen detection (TLR1 and 8). The following genes were significantly upregulated (q<0.05) in IBS-D: INADL, MAGI1, PPP2R5C, MAPKAPK5, TLR3, IL-15. Among the 14 nominally upregulated genes, there was clustering of barrier and PDZ domains (TJP1, TJP2, TJP3, CLDN4, INADL, MAGI1) and clustering of downregulated genes (CCL20, TLR1, IL1B, and TLR8). Protein expression of PPP2R5C in nuclear lysates was greater in patients with IBS-D and controls. There was increase in INADL protein (median 9.4ng/mL) in patients with IBS-D relative to controls (median 5.8ng/mL, p>0.05). In conclusion, altered transcriptome (and to lesser extent protein) expression of ion transport, barrier, immune and mast cell mechanisms in small bowel may reflect different alterations in function and deserves further study in IBS-D.