Molecular mechanisms by which casein glycomacropeptide maintains internal homeostasis in mice with experimental ulcerative colitis

Abstract

ObjectivesThe aim of this study was to elucidate the molecular mechanisms by which food-derived casein glycomacropeptide (CGMP) maintains internal homeostasis in the intestinal mucosa and to investigate the effects of CGMP on the intestinal mucosal immunological barrier and related signal transduction pathways.MethodsIn this study, a famoxadone (OXZ)-induced mouse experimental ulcerative colitis (UC) model was built. The experimental UC mice were intragastrically administered milk-derived CGMP for four consecutive days. The molecular mechanisms by which milk-derived CGMP improved and restored the inflammatory status in UC symptoms were elucidated by H&E staining, immunohistochemical staining and western blotting.ResultsThe results indicated that CGMP (50 mg/(kg bw·d)) could significantly improve morphological injury to intestinal mucosa in OXZ-induced UC mice to the same extent that did sulfasalazine (SASP, 40 mg/(kg bw·d)), a medicine used to treat UC, in the control group. The study found that CGMP could significantly reduce the expression of Human mucosal addressin cell adhesion molecule-1 (MAdCAM-1), Cluster of differentiation 4 (CD4) and Cluster of differentiation 8 (CD8) in the lamina propria of the intestinal mucosa and significantly stimulate the secretion of sIgA to increase intestinal immunity. Furthermore, CGMP was found to be directly involved in inhibiting the MAPK pathway and activating the TGF-β1/Smad signal transduction cascade, which could maintain immunological regulation of the intestinal mucosa and protect the functions of the intestinal mucosal barrier.ConclusionsThis study elucidated the molecular mechanisms by which CGMP maintained homeostasis of the intestinal mucosa and further confirmed its pharmaceutical value as a food-derived functional component with promising potential for further exploration/utilization.

Protective Effect of Glycomacropeptide on Food Allergy with Gastrointestinal Manifestations in a Rat Model through Down-Regulation of Type 2 Immune Response

“…Although we did not perform permeability assays, we believe that the inhibitory effect of GMP on IL-1β and TNF-α expression and the up-regulation of TGF-β at the intestine of FA animals may prevent an impaired intestinal barrier function, as it has been demonstrated with in vitro studies using cell lines of enterocytes and goblet cells [ 81 , 82 ]. This suggestion is supported by studies showing that GMP is able to inhibit signaling pathways involved in TNF-α and IL-1β gene expression, such as NF-κB and MAPK pathways, in the intestinal mucosa of mice with ulcerative colitis [ 83 ], as well as in cell lines of goblet cells [ 81 ], mature enterocytes [ 84 ], and macrophages [ 85 ]. Future research in this field will be necessary to demonstrate it.…”

“…IgA expression in intestinal tissue of FA animals administered with GMP showed a strong tendency to increase. Accordingly, in an experimental model of ulcerative colitis, GMP intake recovers the levels of secretory IgA in intestinal mucosa of mice and potentiates the anti-inflammatory signal transduction mediated by TGF-β [ 83 ]. GMP administration also results in an increased number of IgA-positive plasma cells in the intestinal lamina propria of healthy animals [ 109 ].…”

Protective effect of Gloeostereum�incarnatum on ulcerative colitis via modulation of Nrf2/NF‑κB signaling in C57BL/6 mice

“…Cluster of differentiation 1a acts as an inflammatory mediator of UC, inducing T cell activation to elicit an immune response in the body ( 52 ). As a central factor in immune mediation, the elevated levels of secretory IgA in the colon help to prevent intestinal damage and restore mucosal barrier function ( 53 ). IgG exerts important protective and regulatory effects in the placental barrier ( 54 ) and IgM serves an important role in its own immune regulation ( 55 ).…”

Glycomacropeptide Bioactivity and Health: A Review Highlighting Action Mechanisms and Signaling Pathways

“…In this sense, a recent study demonstrated that oral GMP administration to mice resulted in a greater number of IgA-positive plasma cells in the intestinal lamina propria [74]. Accordingly, other work showed that GMP intake recovers the levels of secretory IgA in intestinal mucosa of mice with experimental ulcerative colitis [75]. Altogether, these results suggest an immuno-suppressing activity of GMP on systemic humoral response, but an immuno-stimulating activity on humoral mucosal immunity.…”

“…Authors concluded that the intestinal anti-inflammatory action of GMP is probably mediated by the direct modulation of monocyte or splenocyte activity, especially by hampering the activation of T helper 1 (Th1) cells while favoring the differentiation of regulatory T (Treg) cells [68]. In the same way, in a mice model of famoxadone-induced colitis, orally GMP induced body weight restoration and intestinal injury reduction, in association with a decrease in CD4, CD8, mucosal addressin cell adhesion molecule-1 (MAdCAM), mitogen extracellular-signal-regulated kinase kinase-1 (MEKK1), and Smad7 (a molecule that transduces TGF-β signaling) intestinal expression [75]. Thus, GMP protection in colitis might be due to a decrease in T-lymphocyte gut infiltration, and to an upregulation of TGF-β and a downregulation of mitogen activation protein (MAP) kinase and NF-κB signaling pathways.…”