Bovine glycomacropeptide ameliorates experimental rat ileitis by mechanisms involving downregulation of interleukin 17

Abstract

Background and purpose: Bovine glycomacropeptide (BGMP) is an inexpensive, non-toxic milk peptide with antiinflammatory effects in rat experimental colitis but its mechanism of action is unclear. It is also unknown whether BGMP can ameliorate inflammation in proximal regions of the intestine. Our aim was therefore two-fold: first, to determine the antiinflammatory activity of BGMP in the ileum; second, to characterise its mechanism of action. Experimental approach: We used a model of ileitis induced by trinitrobenzenesulphonic acid in rats. Rats were treated orally with BGMP and its efficacy compared with that of oral 5-aminosalicylic acid or vehicle, starting 2 days before ileitis induction. Key results: BGMP pretreatment (500 mg kg À1 day À1 ) resulted in marked reduction of inflammatory injury, as assessed by lower extension of necrosis and damage score, myeloperoxidase, alkaline phosphatase, inducible nitric oxide synthase, interleukin 1b, tumour necrosis factor and interleukin 17. These effects were generally comparable to those of 5-aminosalicylic acid (200 mg kg À1 day À1 ). Neither compound affected the production of interferon g, tumour necrosis factor and interleukin 2 by mesenteric lymph node cells isolated from animals with ileitis. The expression of Foxp3 was increased in ileitis and not reduced significantly by BGMP or aminosalicylate treatment. Conclusions and implications:These results demonstrate that BGMP has anti-inflammatory activity in the ileum with similar efficacy to 5-aminosalicylic acid. The mechanism of action may involve Th17 and regulatory T cells and perhaps macrophages but probably not Th1 lymphocytes. Patients with Crohn's ileitis may benefit from treatment with BGMP.

Glycomacropeptide, a low-phenylalanine protein isolated from cheese whey, supports growth and attenuates metabolic stress in the murine model of phenylketonuria

“…Moreover, oral gavage of GMP shows significant anti-inflammatory effects in rat models of colitis and ileitis, resulting in normalization of spleen mass and reduced expression of IL-1␤ in ileum and colon (29,46), similar to our observations in PKU mice. GMP inhibits the induction of IFN-␥, and, to a lesser extent TNF-␣, in concanavalin A-stimulated rat splenocytes (47), also consistent with our observation that the GMP diet normalized the elevated plasma levels of IFN-␥ noted in PKU mice fed casein or AA diets.…”

“…In vitro studies indicate that GMP binds cholera and E. coli enterotoxins and inhibits bacterial and viral adhesions (36), inhibits adhesion of cariogenic bacteria with usage in toothpaste (2), and modulates immune response (27,47). In vivo studies indicate that oral administration of GMP shows substantial anti-inflammatory effects in rat models of colitis and ileitis (29,46), increases zinc absorption in rhesus monkeys (22), and may promote satiety in humans (9,26,30,56). The mechanisms underlying these observations of GMP action are largely unknown, although thought to be linked with the unique chemical structure of GMP.…”

Identification of dairy fractions with anti-inflammatory properties in models of acute gout

“…Both GMP and G600 milk fat extract showed consistent inhibition of cytokine gene and protein expression in the MSU crystal-stimulated THP-1 cell assay, and also a reduction in cellular influx in the urate peritonitis model following oral feeding. GMP is the 64-amino acid carboxy-terminal fragment of κ-casein with a number of documented immunomodulatory effects including enterotoxin neutralisation, inhibition of microbial adhesion and local anti-inflammatory responses involving Th17 lymphocytes 12–14. G600 milk fat extract is a complex lipid fraction in which the phospholipids and gangliosides, particularly GD3 (di-sialo ganglioside 3), are enriched.…”

Novel Mechanisms Underlying the Therapeutic Effect of Glycomacropeptide on Allergy: Change in Gut Microbiota, Upregulation of TGF-β, and Inhibition of Mast Cells

“…TGF-β induces the expression of FOXP3 in naïve CD4+ T cells and is essential for in vivo expansion and immunosuppressive capacity of inducible regulatory T cells [8]. Besides, anti-inflammatory activity of GMP in experimental rat ileitis has been associated with increased levels of FOXP3 expression [9]. Therefore, it would be important to analyze the effect of GMP on systemic TGF-β production in allergen-sensitized animals.…”