EARLY SUPPLEMENTATION OF HUMAN MILK OLIGOSACCHARIDES SUPPRESSES SPONTANEOUS AUTOIMMUNE DIABETES IN NON-OBESE DIABETIC MICE LATER IN LIFE
Folkerts G., Xiao L., Vos A., Nato A., Bastiaans J., Leusink-Muis A.
Division of Pharmacology, Department of Pharmaceutical Sciences, Utrecht University, The Netherlands
Early life nutrition such as breast milk plays a crucial role in the development of type 1 diabetes. Human milk oligosaccharides (HMOS) are important bioactive components of human milk. We evaluated the effect of early supplementation with HMOS on the autoimmune diabetes incidence in Non-obese diabetic (NOD/ShiLtJ) mice, and correlated the protective effect with regulation of immune system and modulation of gut microbiota. Methods: NOD mice were fed with HMOS containing diet from week 4 to 10 or normal diet. Diabetes incidence was determined by urine glucose tests. Pancreatic insulitis was characterized histologically. Naturally occurring regulatory T cell and T helper cell frequencies in the spleen were analyzed by flow cytometry. Cytokines profile in serum were evaluated by Luminex assays. Intestinal microbiome composition was analyzed by 16S rRNA amplicons derived from fecal sample. Short chain fatty acids (SCFAs) were measured in cecal and fecal samples by HPLC. Results: Early supplementation with HMOS significantly reduced the incidence of diabetes up to the age of 30 weeks (p=0.03). Suppressive effects were corroborated by lower pancreatic insulitis and decreased T-cell activation markers (CD25 and CD69) expression in the spleen, although the ratio of Th1/Th2 as well as Th17 cells remained unchanged. Spleen regulatory T cells (CD4+CD25+FOXP3+) were reduced in the HMOS group as well. Reduction in serum concentrations of IL-17 was observed, no significant differences were observed in other cytokines. Total cecal SCFAs were relatively elevated by HMOS diet. Moreover, Furthermore, bacteriological examination of the gut microbiota composition revealed that HMOS diet significantly changed the gut microbiota composition compared with control diet. Particularly, a decreased ratio of Bacteriodes/Firmicutes was observed in HMOS group.
Temporary dietary exposure of NOD mice to HMOS in early life reduced the incidence of autoimmune diabetes beyond the intervention period. This immunomodulatory effect is assisted via directly interacting on immune system, and dependent on the positive alterations of gut microbiota, which may in turn influence mucosal immune system.
Early life nutrition, Human milk oligosaccharides, Probiotics, Autoimmune diabetes, Non-Obese Diabetic Mice
Folkerts G., et al. (2016). Early supplementation of human milk oligosaccharides suppresses spontaneous autoimmune diabetes in non-obese diabetic mice later in life. Conference Proceedings of IPC2016. Paper presented at the International Scientific Conference on Probiotics and Prebiotics, Budapest (p. 24.). IPC2016