Vitamin A: The Key to A Tolerant Immune System?
Vitamin D and Vitamin A are essential co-partners in immunological and bone health., I’m particularly excited about vitamin A because of its profound effects on the gut mucosal immune system—a specialty of mine. Just as vitamin D has attracted attention for its ability to increase antimicrobial peptides and help us defeat pathogens, it’s fascinating to me that vitamin A is also essential for the very tissues that protect us from the same pathogens.
The availability of vitamin A in our food is a key factor in a tolerant, highly functional immune system. To quote from the title of a brilliant commentary in the March 2008 issue of Nature’s Mucosal Immunology, “Vitamin A rewrites the ABCs of oral tolerance.”
Vitamin A is crucial to a very sophisticated bi-directional mechanism that takes place in the digestive system and leads to immune tolerance across the entire gut lining. Immune tolerance is the essence of good health. An intolerant immune system will lead to a wide range of illnesses, and the gut is where many people first lose immune tolerance. Vitamin A (retinoic acid) is key to our ability to consume a wide range of antigens (food) and yet not react adversely, and it’s quite fascinating.
When we speak of vitamin A, we are usually speaking of three essential fat-soluble molecules, retinol, retinal and retinoic acid. Retinol is the form in which vitamin A is stored. Retinal is crucial for vision. And retinoic acid actually functions like a hormone, binding to two receptors (RAR and RXR) and impacting over 500 different genes. Vitamin A is required for innate and adaptive immunity and is an immune enhancer that potentiates the antibody response, maintains and restores the integrity and function of all mucosal surfaces.
Vitamin A is also of fundamental importance for energy homeostasis. New research finds that retinol is essential for the metabolic fitness of mitochondria. When cells are deprived of retinol, respiration and ATP synthesis fall. They recover energy output as soon as retinol is restored to physiological concentration. This may answer the nearly 100-yr-old question of why vitamin A deficiency causes so many pathologies that are independent of retinoic acid action. Most important of all, the forgotten genius of vitamin A is its amazing ability to direct immune tolerance in the body through the cooperative interactions of gut-associated lymphoid tissues, Secretory IgA, bacterial communities and dendritic cells.
Immunity Starts in the Mucosa—with Vitamin A
Vitamin A cannot be synthesised by the human body; it must be absorbed by the intestine from the diet. In the presence of innate danger signals Vitamin A effects can diminish or synergise with innate responses to promote or enhance protective immunity, ensuring suitable plasticity.
The cells along the vast mucosal surfaces of your body are constantly in contact with foods, microbes and toxins. They make innumerable immunological decisions every day—so many that a single day’s encounters exceed that of the rest of your immune system over a lifetime. As the gut makes its decisions, it then relays information from the innate to the adaptive, systemic immune system. Mucosal tolerance is a necessity for us to survive; without it we would not survive a single day.
The gut is where health begins, and is also home to a huge microbiome made of innumerable species of bacteria. Vitamin A is the key to the gut making the right decisions. When you are deficient in vitamin A, you veer towards a type of effector T cell called TH17 and its production of IL-17—inflammation pro-inflammatory cytokine, with propensity to causing autoimmune disease. In contrast, when your stores of vitamin A are sufficient, you’ll have enough peripheral naïve T cells converted to T regulatory cells (Tregs) to help maintain tolerance across the immune system, and quench ‘inappropriate inflammation’ derived from the effector T Cells: TH17, TH1 and TH2. 
The discovery of T cells that secrete IL-17 and other inflammatory cytokines-is profoundly important. The TH17 subset is centrally involved in autoimmune disease and is important in host defense at mucosal surfaces. 
Tregs can help control excess IL-17, and retinoic acid is essential to promote Tregs. New research also implicates IL-17 in rheumatoid arthritis; IL-17 may drive the production of harmful auto-antibodies (antibodies to our own tissue) and may trigger and support an inflammatory cascade. We now have a fascinating and emerging area of clinical investigation: finding out if is possible to use vitamin A to actually convert T cells already polarised to an inflammatory subset, back to tolerance. This would allow a restorative use of this nutrient as opposed to preventative only.
In addition to self-tolerance, a functional immune system also needs to be able to tolerate non-self-antigens that do not pose a threat. Such harmless non-self-antigens are abundant in the intestine where trillions of commensal bacteria colonise the colon and where digested food is continuously absorbed via the small intestine epithelium.
Effective immune-regulation is a condition sine qua non for the healthy gut physiology.  The importance of Treg cells to control and prevent aberrant immune responses directed towards self- or non-self-antigens and to establish tolerance has already been demonstrated at length.
An important molecule in this context is TGF-β, abundantly produced in the gut through the gut microbes. TGF-β is a multifunctional peptide that controls proliferation, differentiation, and other functions in many cell types, promoted by commensal organisms in the gut. This is one of the roles where suitable probiotics can really add health benefits, as certain strains are known to increase human originating TGF-β.
Given that effector T cells responsible for the adaptive immune responses can have a long life – sometimes years, and that inappropriate development could produce inadequate immune defenses or autoimmunity, regulatory cell formation is a powerful element of human health. And, since TH17 cells reside mainly in the mucosa of the gut, it is an elegant serendipity that our food (nutrient) choice should have such a potentially powerful effect on our local and systemic immune plasticity.
In brief, then: the achievement of oral tolerance requires the availability of vitamin A (retinoic acid) by enhancing a gut-specific mechanism of retinoic acid-enhanced, TGF-ß–dependent conversion of T cells into Treg cells.
In addition to their crucial roles in development, TGF-β and retinoic acid are involved at almost every level of immune differentiation and function, affecting passive immunity as well as innate and adaptive immunity. Both TGF-β and retinoic acid are actively produced by the intestinal epithelium and play important roles in maintaining the integrity of its barrier function, vital for systemic health. The use of probiotics and suitable Vitamin A supplementation provides a combination of TGF-β and retinoic acid that will support immune tolerance in the immune compromised patient.
Vitamin A and Secretory IgA
Vitamin A has been well known for its protective roles against infections. An important part of the protective roles might be through its ability to enhance antibody responses, especially IgA antibody responses in mucosal tissues.
IgA is secreted into the gut lining and provides protection against harmful pathogens. It thus helps maintain a healthy flora. Retinoic acid, derived from vitamin A in the diet, exerts a positive impact on the precursors for IgA-producing plasma cells.
In the intestine, induction and regulation of mucosal immunity takes place primarily in Peyer’s patches, together with other parts of gut-associated lymphoid tissue (GALT) and the gut-draining mesenteric lymph nodes. Every hour of every day your Peyer’s patches, clusters of cells in the lining of the small intestine, are a hotbed of signaling and conversation about the food you’re eating. Their job is to help us share our gut with trillions of bacteria in a reasonably diplomatic manner, so we have friendly handshakes at the dinner table, not food fights and drunken brawls. With adequate vitamin A our gut won’t be chronically inflamed by inappropriate T-cell conversion leading to a myriad of inflammatory diseases.
Our diets have changed dramatically over time, and to try to compensate for what we’ve lost in fresh, farm grown produce and pastured dairy and meat, we’ve fortified our foods. But if people don’t tolerate fortified milk, wheat and cereals—which are common allergens—and if they don’t eat organ meats and are poor converters of carotene, they may well be deficient in vitamin A. The more deficient in retinoic acid they are, the greater their risk of loss of immunological tolerance.
I give these patients a preformed vitamin A supplement of 12,500 units a day. I often find that will calm a patient’s mucosal immune system down so the foods they’re ingesting don’t act as provocateurs. Adequate vitamin A with suitable probiotics and SIgA promotion with Sacharomyces boulardii is the first step in restoring immunological health.
Carotenoids: Beautiful But Not Sufficient, and Possibly Harmful in Excess
Carotenoids have been called the colors of nature. Over 600 have been identified, and they give vegetables their gorgeous rainbow of hues, from green to orange to red to purple. About fifty can be converted into vitamin A. The major carotenoids in humans are beta-carotene, alpha-carotene, lycopene, lutein, and beta-cryptoxanthin.
However, the conversion of carotenoids to vitamin A is not as efficient or perfect as we’ve been led to believe. They can be difficult to convert, and a recent study from Newcastle University in England found that as many as 50% of women studied were unable to efficiently convert carotenoids into vitamin A—and thus may be retinoic acid deficient.
The lead researcher, Dr. George Lietz, told Science News, “What our research shows is that many women are simply not getting enough of this vital nutrient because their bodies are not able to convert the beta-carotene.”14
Other studies echo Lietz’s. Research reported in the American Journal of Clinical Nutrition in 2000 found no evidence of benefit on vitamin A status from the increased consumption of dark-green or yellow vegetables. Beta-carotene from vegetables provided an estimated vitamin A equivalence of 25 to 1—not the reported 6 to 1 for beta carotene and 12 to 1 for other carotenes. In addition, up to 50% of beta-carotene is highly dependent on fat consumption at the same time, and cooked carotenoids are better absorbed than raw. Poor protein status or zinc deficiency also affects beta-carotene uptake, and its conversion to retinol (vitamin A).
In addition, carotenoids may not always be beneficial. It appears that high doses of beta-carotene under highly oxidative conditions lead to breakdown products that have toxic biological activity. Beta-carotene molecules in vitro can split into carotenoic acids that can lead to toxic cleavage products.
“What happens when these eccentric cleavage products accumulate in large amounts?” asks Robert Russell in an article in the American Journal of Clinical Nutrition, adapted from an award-winning lecture. “Do they have biological activity of their own? Could [they] interfere with the action of retinoic acid?
This may, in fact, partially explain the results from 2 carotene intervention trials…These studies showed a higher incidence of lung cancer in smokers who consumed high doses of beta-carotene.” Animal studies exposing ferrets to smoke and beta-carotene supplements showed “severe proliferation of alveolar cells and squamous metaplasia…in the beta-carotene-supplemented, smoke-exposed ferrets.”
In sum, although carotenoids offer a rainbow of important nutrition, they are not necessarily a reliable source of vitamin A.
What About Toxicity?
I believe vitamin A may, in some cases, decrease bone mineral density and increase the risk of fracture—when vitamin D stores are not adequate. The Council for Responsible Nutrition reviewed all the evidence on vitamin A and fracture risk in a 2004 report, and concluded that:
“the overall database remains…conflicted and unresolved…if anything, the preponderance of evidence may have moved away from the suggestion that vitamin A might increase the risk of hip fracture.”
The council considers supplements of 10,000 IU daily of preformed vitamin A (retinol) to be generally safe. They note a long history of safe use of supplements containing up to 10,000 IU daily. Those who regularly consume liver or organ meats may be getting enough from their diet and may exercise more caution about vitamin A supplements.
Our friend, our helper, is vitamin A, a beautiful nutrient, like vitamin D. Both are sophisticated and capable of wonderful things, but having too much or too little of either one interferes with the other’s capacity to be lovely.
Read Other articles in Focus by downloading the journal here
 Dong P, Tao Y, Yang Y, & Wang W (2010). Expression of retinoic acid receptors in intestinal mucosa and the effect of vitamin A on mucosal immunity. Nutrition (Burbank, Los Angeles County, Calif.), 26 (7-8), 740-5 PMID: 19932006
 Iwata, M., Hirakiyama, A., Eshima, Y., Kagechika, H., Kato, C., & Song, S. (2004). Retinoic Acid Imprints Gut-Homing Specificity on T Cells Immunity, 21 (4), 527-538 DOI: 10.1016/j.immuni.2004.08.011
 Acin-Perez R, Hoyos B, Zhao F, Vinogradov V, Fischman DA, Harris RA, Leitges M, Wongsiriroj N, Blaner WS, Manfredi G, Hammerling U. Control of oxidative phosphorylation by vitamin A illuminates a fundamental role in mitochondrial energy homoeostasis. FASEB J. 2010 Feb;24 (2):627-36. Epub 2009 Oct 7. View Abstract
 Nolting J, Daniel C, Reuter S, Stuelten C, Li P, Sucov H, Kim BG, Letterio JJ, Kretschmer K, Kim HJ, von Boehmer H. Retinoic acid can enhance conversion of naive into regulatory T cells independently of secreted cytokines. J Exp Med. 2009 Sep 28;206(10):2131-9. Epub 2009 Sep 8. View Abstract
 Mucida D, Park Y, Cheroutre H. From the diet to the nucleus: vitamin A and TGF-beta join efforts at the mucosal interface of the intestine. Semin Immunol. 2009 Feb;21(1):14-21. Epub 2008 Sep 21. Review. View Abstract
 Leung WC, Hessel S, Méplan C, Flint J, Oberhauser V, Tourniaire F, Hesketh JE, von Lintig J, Lietz G.Two common single nucleotide polymorphisms in the gene encoding beta-carotene 15,15′-monoxygenase alter beta-carotene metabolism in female volunteers. FASEB J. 2009 Apr;23(4):1041-53. Epub 2008 Dec 22. View Abstract
 Roodenburg AJ, Leenen R, van het Hof KH, Weststrate JA, Tijburg LB. Amount of fat in the diet affects bioavailability of lutein esters but not of alpha-carotene, beta-carotene, and vitamin E in humans. Am J Clin Nutr. 2000 May;71(5):1187-93. View Abstract
 Caire-Juvera G, Ritenbaugh C, Wactawski-Wende J, Snetselaar LG, Chen Z. Vitamin A and retinol intakes and the risk of fractures among participants of the Women’s Health Initiative Observational Study. Am J Clin Nutr. 2009 Jan;89(1):323-30. Epub 2008 Dec 3. View Abstract
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