T1D is an autoimmune disease characterized by lymphocytic infiltration of the pancreatic islets, culminating in specific destruction of insulin-producing β cells. This immunological process unfolds over a variable number of years, resulting in clinically detectable hyperglycemia and, ultimately, diagnosis of diabetes. In vitro, vitamin D acts as an immunosuppressive agent, reducing lymphocyte proliferation and cytokine production. Furthermore, in animals, the oral administration of biologically active vitamin D3 metabolite (1,25[OH]2D3) seems to prevent development of type 1 diabetes.
The first prospective study of vitamin D3 supplementation in infants and type 1 diabetes was published in 2001 by Hyppönen et al. Among infants who were given supplements regularly, diabetes risk was lower at doses of over 50 µg/d or 2000 IU/d (relative risk 0.14) and exactly 50 µg/d (relative risk 0.22) compared with doses under 50 µg/d. This quite large, well-designed, prospective study provided compelling evidence that vitamin D3 supplementation of 50 µg/d (2000 IU/d) or more during infancy may reduce the risk for type 1 diabetes, at least in very northern parts of the world where sunlight is severely limited during a greater part of the year. In 2001 the recommended daily allowance of vitamin D3 in Finland for infants was about one tenth of what it was in the 1960s.
According to a systematic review and meta-analysis from 2008 vitamin D3 supplementation in early childhood may offer protection against the development of type 1 diabetes. The evidence for this is based on observational studies. While we are waiting randomised controlled trials with long enough periods of follow-up for possible causality we can address this interesting issue from another direction, through the GI tract.
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As we've learnt earlier environmental factors seem to be behind increased prevalence of T1D and dietary and microbial factors may be partly responsible for this increase. Evidence suggesting that gut immune disruptions may trigger type 1 diabetes originated from studies that showed correlations between a high prevalence of cow-milk antibodies, brief breastfeeding in infancy, and an increased risk of type 1 diabetes. This hypothesis gained further support from the discovery that lymphocytes accumulating in the islets share homing characteristics with gut-associated lymphocytes.
The development of the postnatal immune system is guided by the interactions of lymphocytes with self-MHC/peptide ligands derived from our body's own tissues and those from the environment, such as the commensal microbial flora of the gastrointestinal tract and the diet.The intestinal mucosa is constantly exposed to these factors, and it is therefore important to thoroughly understand how these factors affect the intestinal immune system.
The way in which antigenic stimulation guides the development and maintenance of a healthy immune system is of fundamental importance to our understanding of immunological tolerance. In the non-obese diabetic (NOD) mouse strain, the target pancreatic insulin producing beta cells are attacked and destroyed by activated immune cells, leading to type-1 diabetes. Several infectious, and non-infectious agents are known to prevent type-1 diabetes in NOD mice. Stimulation with adjuvant containing bacterial extracts in the neonatal period is known to prevent diabetes and imparts qualitative and quantitative changes in the immune cell compartments that lasts throughout adulthood. There has been a number of hypotheses presented that could account for the protective effect of immunostimulation such as a change in the cytokine milieu and the increase in T cell numbers or populations of regulatory T cells.
The development of the postnatal immune system is guided by the interactions of lymphocytes with self-MHC/peptide ligands derived from our body's own tissues and those from the environment, such as the commensal microbial flora of the gastrointestinal tract and the diet.The intestinal mucosa is constantly exposed to these factors, and it is therefore important to thoroughly understand how these factors affect the intestinal immune system.
The way in which antigenic stimulation guides the development and maintenance of a healthy immune system is of fundamental importance to our understanding of immunological tolerance. In the non-obese diabetic (NOD) mouse strain, the target pancreatic insulin producing beta cells are attacked and destroyed by activated immune cells, leading to type-1 diabetes. Several infectious, and non-infectious agents are known to prevent type-1 diabetes in NOD mice. Stimulation with adjuvant containing bacterial extracts in the neonatal period is known to prevent diabetes and imparts qualitative and quantitative changes in the immune cell compartments that lasts throughout adulthood. There has been a number of hypotheses presented that could account for the protective effect of immunostimulation such as a change in the cytokine milieu and the increase in T cell numbers or populations of regulatory T cells.
The incidence of type-1 diabetes in NOD mice is thought to reflect the degree of cleanliness of the colony. A widely accepted extrapolation from these data has been that NOD mice maintained under germ-free conditions have an increased incidence of diabetes. New studies has confirmed that idea wrong and instead support the notion that modulation of intestinal microbiota can have beneficial effects on the development of autoimmune diabetes.
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In 2011 Alam et al from the University of Turku presented evidence that young NOD mice suffer from a mild level of colitis, which disrupts the immune homeostasis of the large intestine. Intolerance to autologous microbiota, colonic hyperplasia, increased numbers of dendritic cells, and increased levels of IL-17 and IL-23 in the NOD colon are all indicative of colonic inflammatory activity. Remarkably, this condition is alleviated if the standard mouse diet is changed to an antidiabetogenic diet (ProSobee) from the time of weaning. It is thought that the intestinal immune system of newly weaned individuals may be particularly sensitive to immune disruption due to the yet immature immune system, higher permeability of the intestinal wall, and lower numbers of IgA positive B-cells in infancy.
The evidence brought forward in Alam et al emphasizes the importance of the colonic immune system and the role of microbial prevalence in the development of type 1 diabetes in the NOD model. They suggested that the antidiabetogenic effects of the ProSobee diet derive, at least in part, from its capacity to restore colonic immune homeostasis in NOD, where a proinflammatory bias otherwise prevails. The anti-inflammatory effects of the ProSobee diet also have implications outside of the gastrointestinal immune system, because it changes the properties of the peritoneal B-cells. It was proposed that the colonic immune imbalance in NOD mice reflects on the peritoneal immune cells, which subsequently aid in initiating an autoimmune response in the pancreatic lymph nodes, triggering type 1 diabetes development which was alleviated by diet.
How does this intestinal inflammation connect to first stone in the wall, vitamin D3, and the T1D protection seen in the animal studies?
Vitamin D receptor (VDR) is a nuclear receptor that mediates most known functions of 1,25-dihydroxyvitamin D3 (1,25[OH]2D3), the hormonal form of vitamin D. In recent study it was demonstrated that commensal and pathogenic bacteria directly regulate colonic epithelial VDR expression and location in vivo. VDR negatively regulates bacterial-induced intestinal NF-κB activation and attenuates response to infection. Therefore, VDR is an important contributor to intestinal homeostasis and host protection from bacterial invasion and infection.
So there it is for chewing. Could vitamin D3 be a brick in a wall or is it just giving some ideas what may be going on?
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