Ameliorative Effects of Casein Peptides on Constipation-Predominant Irritable Bowel Syndrome: Involvement of the GC-C/cGMP Signaling Pathway

Abstract This study investigated the effects of casein peptides on constipation-predominant irritable bowel syndrome (IBS-C) in mice. Results revealed that oral administration of casein hydrolyzate significantly attenuated constipation symptoms, reduced visceral hypersensitivity, improved intestinal barrier integrity, suppressed inflammatory responses, and restored serum neurotransmitter balance in IBS-C mice. Casein hydrolyzate did not alter guanylyl cyclase C (GC-C) mRNA levels but significantly increased cyclic guanosine-3‘,5′-monophosphate (cGMP) levels in the colon of IBS-C mice, suggesting the possible involvement of the GC-C/cGMP signaling pathway in the above effects. Additionally, nine casein peptides with potential GC-C agonistic activity were identified through an integrated in silico screening and ex vivo functional evaluation, among which PFPGPIPN showed the highest activity. Moreover, in vivo experiments confirmed that PFPGPIPN significantly ameliorated IBS-C symptoms and elevated colonic cGMP levels in mice. These findings highlight the potential of casein peptides as bioactive ingredients in functional foods for the management of IBS-C.