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http://blogs.discovermagazine.com/gnxp/2010/07/daily-data-dump-wednesday-9/&http://nephropal.blogspot.com/2010/07/vitamin-d-and-colon.htmlWednesday, July 7, 2010Vitamin D and the ColonThe GUT is the entry point between the environment and the human body. What more critical barrier to protect? In our GI system, there dwells billions of "friendly" bacterial whom without we would not survive. And yet, a colon that is inflamed will cause havoc on the rest of the body. Celiac Disease is associated with many various autoimmune disease orders. Also Inflammatory Bowel Disorders (like Crohn's Disease and Ulcerative Colitis) are also associated with vitamin and mineral deficiencies.Exactly how does the GI tract maintain such a barrier against bacterial pathogens and yet create an environment friendly enough to host natural, pro-health bacterial flora? One of the answers is yet again Vitamin D or to be more specific the Vitamin D Receptor (VDR).As I have stated in the past (in my post the Leaky Gut), like all cells in the body, there are proteins called tight junctions which seal the barrier between cell walls. (see cartoon). In this previous post - Leaky Gut (click), a study noted that Vitamin D supplementation strengthened the tight junctions making it more difficult for pathogens to enter the circulatory system. But what is the mechanism?All modern disease is based on one simple issue - inflammation. One of the main proteins of inflammation is NF-kB - which I have written about many times. The level of activity of NF-kB is decreased with green tea, anthocyanins (like blueberries), resveratrol, omega 3 fatty acid, curcumin (curry), cacao, coffee......and yes.....Vitamin D.A study this month in the American Journal of Pathology looks at the Vitamin D Receptor (VDR) and inflammation in the colon with mice models. Comically, the last name of the lead author is Dr. SUN. The team looked at intestinal inflammation in the presence of a Salmonella infection. Mice which lacked VDRs had higher states of colonic inflammation and worse outcomes than controls. They had higher concentrations of the inflammatory cytokine IL-6.Mice with the intact VDR had greater protection against colonic Salmonella colonization and invasion.The mechanism by which VDR works is suppressing the translocation of the NF-kB protein from the cytoplasm of the cell to the nucleus. Once in the nucleus, NF-kB can bind to the genes causing gene transcription and thus an inflammatory state. There is a NF-kB inhibitor called IkB which maintains NF-kB in the cytoplasm. The VDR has somewhat the same effect as IkB. VDR interacts with a subunit of NF-kB called p65. This binding of VDR/p65 inhibits NF-kB's translocation into the nucleus. Interestingly in the article, the authors noted that VDR can be stimulated without active Vitamin D (1,25 Vitamin D).Ultimately, the study results showed the the presence of an intact VDR led to less inflammation in the presence of a Salmonella infection.How does this related through an evolutionary means? It was about a change in diet. Humans were eating meat and being exposed to bacteria like Salmonella. Without the effects of the VDR, they would have had severe inflammatory bowel disease and possibly higher rates of colon cancers. Hey wait! That is what we have as modern humans!Now this was a study on mice. The question is do humans have a higher concentration of VDR in the colon than other mammalian species?With Vitamin D and the VDR, the tight junctions between the colonic cells are less prone to having a "leak gut" due to inflammation. A leaky pathway between the cellular walls will allow foreign pathogens like bacteria to enter the circulatory system. Obviously, the immune system will counteract these pathogens. However, the antibody production of the immune system may cross react with native proteins of the body which will lead to autoimmune disease. This is exactly what happens with Celiac Disease. There is a higher incidence of autoimmune disorders like thyroid and adrenal. Chronic inflammation on the body is BAD! The metabolic syndrome is a chronic inflammatory state. And thus the risk of cancer and heart disease increases.1) Wu S, Liao AP, Xia Y, Li YC, Li JD, Sartor RB, Sun J: Vitamin D Receptor Negatively Regulates Bacterial-Stimulated NF-{kappa}B Activity in Intestine. Am J Pathol. 2010 Jun 21.Abstract Vitamin D receptor (VDR) plays an essential role in gastrointestinal inflammation. Most investigations have focused on the immune response; however, how bacteria regulate VDR and how VDR modulates the nuclear factor (NF)-kappaB pathway in intestinal epithelial cells remain unexplored. This study investigated the effects of VDR ablation on NF-kappaB activation in intestinal epithelia and the role of enteric bacteria on VDR expression. We found that VDR(-/-) mice exhibited a pro-inflammatory bias. After Salmonella infection, VDR(-/-) mice had increased bacterial burden and mortality. Serum interleukin-6 in noninfected VDR(+/+) mice was undetectable, but was easily detectable in VDR(-/-) mice. NF-kappaB p65 formed a complex with VDR in noninfected wild-type mouse intestine. In contrast, deletion of VDR abolished VDR/P65 binding. P65 nuclear translocation occurred in colonic epithelial cells of untreated VDR(-/-) mice. VDR deletion also elevated NF-kappaB activity in intestinal epithelia. VDR was localized to the surface epithelia of germ-free mice, but to crypt epithelial cells in conventionalized mice. VDR expression, distribution, transcriptional activity, and target genes were regulated by Salmonella stimulation, independent of 1,25-dihydroxyvitamin D3. Our study demonstrates that commensal and pathogenic bacteria directly regulate colonic epithelial VDR expression and location in vivo. VDR negatively regulates bacterial-induced intestinal NF-kappaB activation and attenuates response to infection. Therefore, VDR is an important contributor to intestinal homeostasis and host protection from bacterial invasion and infection.
 
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