Does vitamin A supplementation improve Crohn's symptoms?

Vitamin A from Wikipedia

Vitamin A from CyberLipids Center

Vitamin A is important to vitamin D supplementation.  See my post entitled "Does increasing vitamin D improve Crohn's symptoms?"

Vitamin E recycles vitamin A.

Zinc is a cofactor for vitamin A.

"Plasma zinc levels have been found to be dependent upon vitamins A and D. This suggests that a Vitamin A or D deficiency could cause a secondary zinc deficiency and that for treatment of zinc deficiency one should ensure adequate vitamin A and D intake" from Zinc Deficiency on Wikipedia

"From the diet to the nucleus: Vitamin A and TGF-β join efforts at the mucosal interface of the intestine" from Seminars in Immunology, The Roles of Retinoic Acid in Lymphocyte Differentiation (2009)

"The vitamin A metabolites, including retinoic acid (RA), form ligands for retinoic acid-related nuclear receptors and together they play pleiotropic roles in various biological processes. Recently, we described that RA also functions as a key modulator of transforming growth factor-beta (TGF-β)-driven immune deviation, capable of suppressing the differentiation of interleukin-17 secreting T helper cells (TH17) and conversely promoting the generation of Foxp3+ T regulatory (Treg) cells. This review will focus on the role of RA in the reciprocal TGF-β-driven differentiation of TH17 and Treg and on the importance of such regulatory mechanism to control a functional immune system, in particular at the mucosal interface of the intestine."

"Environmental influences on T regulatory cells in inflammatory bowel disease" from Review, Seminars in Immunology, Gene-environment Interaction in Induction of Autoimmunity (2011)
"In this review we will discuss environmental factors, including cytokines, vitamins A and D, and commensal bacteria, which influence the phenotype and function of regulatory [CD4] T cells and thereby alter the course of IBD. We will also discuss how these environmental signals can be manipulated therapeutically in order to improve the function of regulatory T cells and ultimately restore mucosal homeostasis in patients with IBD.

...
Impact of environmental factors on CD4+T cell differentiation in IBD. Environmental factors such as vitamins A and D, cytokines and specific microbiota are able to skew the differentiation of naïve CD4+ T cells and alter the balance between Treg and/or Th1/Th17 cells. The shift from a Treg dominated response to a Th1/Th17 response is implicated in the gut inflammatory process and the development of IBD. Manipulation of these environmental factors could be used therapeutically to shift the balance towards Tregs."

Primal Body, Primal Mind: Beyond the Paleo Diet for Total Health and a Longer Life by Nora T. Gedgaudas (2011)
"... with vitamin A in its true state, as found in beef liver, grass-fed butter and ghee, and what is called "high vitamin" cod-liver oil (rich in both vitamins A and D)--not simply beta-carotene."


"Vitamins A & D Inhibit the Growth of Mycobacteria in Radiometric Culture" in PLoS ONE (2011)
"Vitamins A and D cause dose-dependent inhibition of all three mycobacterial species studied. Vitamin A is consistently more inhibitory than vitamin D. The vitamin A precursor, β-carotene, is not inhibitory, whereas three vitamin A metabolites cause inhibition."

"Effects of Carotenoids and Retinoids on Immune-Mediated Chronic Inflammation in Inflammatory Bowel Disease" in Functional Foods, Nutraceuticals, and Degenerative Disease Prevention (2011)
"Inflammation is the body's reaction to physiological interference from several external factors and internal abnormalities of the immune system. Chronic states of inflammation can lead to other complications such as the development of cardio-vascular diseases and cancer. Inflammatory intestinal diseases such as Crohn's and Colitis result from abnormalities in immune function. Carotenoids are strong antioxidants, and carotenoids derived retinoids such as vitamin A can down-regulate inflammation by biochemical and molecular mechanisms. This could be achieved by the modulation in the levels of pro-inflammatory and anti-inflammatory cytokines."

"Food intake in patients with Inflammatory Bowel Disease" in ABCD Arq Bras Cir Dig (2011) [full article]

"There was deficiency in food intake in both CD and UC in active and in remission. These deficiencies
are mainly related to the intake of macronutrients, energy and fiber and micronutrients, including ... retinol...."

Will suppression of IL 17 cytokines reduce the symptoms of CD in anti-TNF-resistant patients?

"Cytokine Regulation of Gut Inflammation in IBD" in Int J Clin Rev (2010)
"Anti-cytokine therapies, such as the three licensed anti-tumor necrosis factor-a (anti-TNF-a) antibodies, have transformed the management of difficult-to-treat IBD patients. However, only 40–50% of patients respond to these agents, there are side effects, and efficacy wanes with time. Consequently, great interest remains in new agents that may be more effective than anti-TNF-a antibodies. Here, we argue that no single agent will ever be clinically better than anti-TNF-a antibodies, and that there is no “Holy Grail” anti-cytokine biological therapy that will be clinically effective in all patients. Instead, work in this area should be focused on identifying new drugs targeting other cytokines (here, we concentrate on the interleukin-17 [IL-17] family and IL-21), which can be used logically in individual patients based on biomarker studies, as well as after failure of a first, second, or third biological treatment." [emphasis mine]

What are Th17 cells and why might they be important in Crohn's?

T helper 17 cell on Wikipedia
"T helper 17 cells (Th17) are a newly discovered subset of T helper cells producing interleukin 17 (IL-17). They are considered developmentally distinct from Th1 and Th2 cells and excessive amounts of the cell are thought to play a key role in autoimmune disease such as multiple sclerosis (which was previously thought to be caused by Th1 cells), but also psoriasis, autoimmune uveitis, juvenile diabetes, rheumatoid arthritis, and Crohn's disease.
More specifically, they are thought to play a role in inflammation and tissue injury in these conditions. Th17 cells can cause severe autoimmune diseases, however they serve a very important function in anti-microbial immunity at epithelial /mucosal barriers. They produce cytokines (such as interleukin 22) which stimulates epithelial cells to produce anti-microbial proteins to clear out certain types of microbe (such as Candida and Staphylococcus). Thus, a severe lack of Th17 cells may leave the host susceptible to opportunistic infections."

"Autoimmune diseases in the TH17 era" in Braz J Med Biol Res (2009)

"A new subtype of CD4+ T lymphocytes characterized by the production of interleukin 17, i.e., TH17 cells, has been recently described. This novel T cell subset is distinct from type 1 and type 2 T helper cells. The major feature of this subpopulation is to generate significant amounts of pro-inflammatory cytokines, therefore appearing to be critically involved in protection against infection caused by extracellular microorganisms, and in the pathogenesis of autoimmune diseases and allergy. The dynamic balance among subsets of T cells is important for the modulation of several steps of the immune response. Disturbances in this balance may cause a shift from normal immunologic physiology to the development of immune-mediated disorders. In autoimmune diseases, the fine balance between the proportion and degree of activation of the various T lymphocyte subsets can contribute to persistent undesirable inflammatory responses and tissue replacement by fibrosis. This review highlights the importance of TH17 cells in this process by providing an update on the biology of these cells and focusing on their biology and differentiation processes in the context of immune-mediated chronic inflammatory diseases."

"Phenotypic and functional features of human Th17 cells" in J Exp Med (2007)
"T helper (Th) 17 cells represent a novel subset of CD4+ T cells that are protective against extracellular microbes, but are responsible for autoimmune disorders in mice. However, their properties in humans are only partially known. We demonstrate the presence of Th17 cells, some of which produce both interleukin (IL)-17 and interferon (IFN)-γ (Th17/Th1), in the gut of patients with Crohn's disease. Both Th17 and Th17/Th1 clones showed selective expression of IL-23R, CCR6, and the transcription factor RORγt, and they exhibited similar functional features, such as the ability to help B cells, low cytotoxicity, and poor susceptibility to regulation by autologous regulatory T cells. Interestingly, these subsets also expressed the Th1-transcription factor T-bet, and stimulation of these cells in the presence of IL-12 down-regulated the expression of RORγt and the production of IL-17, but induced IFN-γ. These effects were partially inhibited in presence of IL-23. Similar receptor expression and functional capabilities were observed in freshly derived IL-17–producing peripheral blood and tonsillar CD4+ T cells. The demonstration of selective markers for human Th17 cells may help us to understand their pathogenic role. Moreover, the identification of a subset of cells sharing features of both Th1 and Th17, which can arise from the modulation of Th17 cells by IL-12, may raise new issues concerning developmental and/or functional relationships between Th17 and Th1."

"Crohn’s disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn’s disease" in Gut (2009)
"Traditionally, Crohn’s disease has been associated with a Th1 cytokine profile, while Th2 cytokines are modulators of ulcerative colitis. This concept has been challenged by the description of tolerising regulatory T cells (Treg) and by proinflammatory Th17 cells, a novel T cell population characterised by the master transcription factor RORγt, the surface markers IL23R and CCR6, and by production of the proinflammatory cytokines IL17A, IL17F, IL21, IL22 and IL26, and the chemokine CCL20. Th17 cells differentiate under the influence of IL1β, IL6, IL21 and IL23. Recent studies indicate that TGFβ is essential not only for the development of murine Th17 cells but also for differentiation of human Th17 cells. TGFβ reciprocally regulates the differentiation of inflammatory Th17 cells and suppressive Treg subsets, with the concomitant presence of proinflammatory cytokines favouring Th17 cell differentiation. Several studies demonstrated an important role of Th17 cells in intestinal inflammation, particularly in Crohn’s disease. Genome-wide association studies indicate that are associated with susceptibility to Crohn’s disease and partly also to ulcerative colitis. Taken together, both Th1 and Th17 cells are important mediators of inflammation in Crohn’s disease, although activities previously ascribed to IL12 may be mediated by IL23. Anti-IL12/IL23p40 antibody therapy, which targets both Th1 and Th17 cells, is effective in Crohn’s disease. However, the complex relationship between Th1 and Th17 cells has not been completely analysed. This will be of great importance to delineate the specific contributions of these cells to Crohn’s disease and other autoimmune diseases."

"Th1/Th17 Immune Response Is Induced by Mesenteric Lymph Node Dendritic Cells in Crohn's Disease" in Gastroenterology (2008)
"Conclusions: Our findings revealed that mesenteric lymph node is the key pathogenic location of CD elicited by the unique cytokine milieu produced by DCs leading to a dysregulated Th1/Th17 immune response."

"Intestinal homeostasis and its breakdown in inflammatory bowel disease" in Nature (2011)
"The relative enrichment of TH17 cells at mucosal sites, together with the increased levels of TH17 cytokines in the inflamed gut, has fuelled interest in their potential role in IBD pathogenesis36, 39. TH17 cells produce several cytokines, including IL-17A, IL-17F, IL-21 and IL-22 (ref. 36)."

"The Role of Th17 in Neuroimmune Disorders: A Target for CAM Therapy. Part III" in Evidence-Based Complementary and Alternative Medicine (2011)
"Thus, based on the best available evidence, the modification of TH-lineage requires a full understanding of the neuroimmune inflammatory pathway, which is necessary to combat inflammation, autoimmunity and neurodegeneration. In this regard it is vital to understand the significant roles played in neuroinflammation by Th17 and its effector cytokine, IL-17, in conjunction with IL-23, IL-27 and Th1 autoreactive cells."