Celiac & Food Allergies Connected to Retinol Pathways

The only allergy I suffer from is one to cat dander, and considering what my children do to the house and furniture already, I'm probably better off without a cat. But I know many people with food allergies and/or celiac disease. They are all conscientious people who try to eat healthily. Many people are wondering what is causing the rise in celiac disease, an autoimmune disease where the body damages itself after ingestion of gluten and which is related to certain genes and can be triggered by various events, including childbirth, pregnancy, viral infections, and stress. I also wonder, hence this hypothesis.

On p. 236 of a 2013 review of celiac disease (CD) epidemiology, there is a map that shows graphically the reported prevalence of CD by country. Two countries jumped out at me: Finland, with a high prevalence (more than 1 in 100), and Estonia, with a significantly lower prevalence (and apparently not increasing, per this study). Genetically, the Finns and Estonians are reported to be very similar. Their traditional cuisines and geographical situations are also very similar. Why would they have dramatically different rates of developing celiac disease?

The first difference I found between Finland and Estonia concerned Vitamin D fortification. Estonia does not fortify dairy products with Vitamin D at all; Finland puts Vitamin D not just in milk, but also other food products. Also, Estonians, unlike Scandinavia in general, appear to not go in for cod-liver oil or other Vitamin D supplements.

Why would differences in Vitamin D supplementation have an effect on who develops CD? Our bodies make molecules called Vitamin D receptors (VDRs) that are also important in maintaining the health and barrier function of the intestines (see this, this, this, this, this, and this). Perhaps by adding Vitamin D to our milk we are overexposing our intestines to Vitamin D—most Vitamin D is supposed to come from our skin’s production of it, not from our food—and causing our bodies, in line with homeostasis principles, to decrease expression of VDRs in our intestines over time. Something similar does appear to happen with excess folic acid ingestion and folate receptors in the intestines, but there is only one study out there hinting that this might happen with Vitamin D and VDRs.

This Vitamin D receptor hypothesis might be helpful in explaining intestinal permeability problems, but it doesn’t explain the increase in CD seen in many other countries that don’t fortify with Vitamin D or take cod liver oil. As I looked further into CD incidence, I started to see a pattern of correlation between dairy intake and CD. Milkfat is a rich source of Vitamin A, which is also high (rather dangerously so) in cod liver oil. In the US, lowfat and skim milk are now fortified with Vitamin A to supply a higher amount than naturally occurs in whole milk.

Why would high Vitamin A intake cause a hyperimmune reaction to ingested gluten? Well, first off, it’s necessary to point out that CD apparently involves hyperimmune reactions to more than just gluten; one study found that half of CD patients had the same reaction to cow’s milk protein as they did to gluten, indicating that the immune system’s dysfunction is the culprit, not an unavoidable genetic incompatibility with gluten. After all, people typically eat wheat fairly happily before CD is triggered. That hyperimmune reaction, it turns out, is connected to Vitamin A-related processes, for signaling related to retinoic acid—a metabolite of retinol, the storage form of Vitamin A—is a “keystone in the development of oral tolerance” (oral tolerance means “the capacity of the immune system to recognize substances taken in through the digestive system and to weaken or suppress the immune response to them”).

At this point, I feel I must widen the discussion a bit to include all hyperimmune reactions to dietary gluten and other highly allergenic foods, although I will still occasionally address CD specifically.

Several enzymes are involved in transforming retinol into retinoic acid. Retinol is first transformed into retinal, catalyzed by retinol dehydrogenases and alcohol dehydrogenases. Retinal is then transformed into retinoic acid, catalyzed by retinal dehydrogenases (RALDHs) and retinal oxidases. RALDH2, one of the RALDHs, apparently needs to be optimally expressed in order for intestinal dendritic cells to properly carry out their oral tolerance function. (This is a very complex field of study that I won’t pretend to fully comprehend or adequately summarize, so I’ll direct you here, here, here, here, here, here, here, here, here, and here for more information on the subject.) But retinoic acid, the product of RALDH2, can make inflammation worse, not better. This study, in particular, is interesting in that it finds that retinoic acid promotes an inflammatory immune response to dietary antigens in connection with a cytokine that is greatly upregulated in the gut of CD patients; to me, this indicates that 1) retinoic acid might be interfering with RALDH2 expression in a way that negatively affects oral tolerance (it is not unusual for the product of an enzyme to inhibit an enzyme through a process called feedback inhibition), and 2) RALDH2 might have an important immunity-related function besides catalyzing the transformation of retinal into retinoic acid.

My key point in the paragraph above is that we want to optimize expression of RALDH2 in order to avoid hyperimmune reactions to our food. I have come across four ways to do that:

1)      Promote RALDH2 activity with magnesium chloride, which has been found to activate RALDH2.

2)      Don’t inhibit RALDH2 activity with too much citral, which has been found to inhibit RALDH2.

3)      Be cautious about consuming common dietary allergens in conjunction with elevated endogenous or exogenous prostaglandin E2, for prostaglandin E2 inhibits RALDH expression.

4)      Avoid excess retinoic acid by not ingesting too much Vitamin A. We have multiple metabolic pathways that make retinoic acid out of forms of Vitamin A, and there is evidence indicating that retinoic acid and other retinoids suppress expression of RALDH2. Retinoic acid also suppresses IL-12, which is apparently absent during allergic responses, per this study.

#1 Magnesium Chloride –

Magnesium Chloride (MgCl2) is a salt that naturally occurs in the ocean and briny lakes, most notably the Dead Sea, the salt content of which is fully half MgCl2. Until recent times, the salt people ingested typically contained some magnesium chloride, but we now commonly consume nearly pure sodium chloride as our regular table salt. Perhaps, in light of MgCl2’s ability to activate RALDH2, this shift to pure sodium chloride has been detrimental to our ability to orally tolerate some common allergens. It is interesting to note that Japanese people still consume magnesium chloride widely, both in sea salt and as a tofu coagulant, and that celiac disease is nearly unknown in Japan even though Japanese cuisine today includes regular consumption of wheat noodles. There is at least one study finding an apparently protective role for magnesium in acute allergic reactions. Also, a little magnesium chloride looks like it might help bring down abnormally high triglycerides, so it seems a good idea to sometimes use sea salt or drink mineral water containing magnesium chloride. The push to lower salt intake is just to lower sodium intake, not all forms of culinary salt.

#2 Citral –

Citral is present in many lemony oils—per wikipedia, in lemon myrtle (90-98%), Litsea citrata (90%), Litsea cubeba (70-85%), lemongrass (65-85%), lemon tea-tree (70-80%), Ocimum gratissimum (66.5%), Lindera citriodora (about 65%), Calypranthes parriculata (about 62%), petitgrain (36%), lemon verbena (30-35%), lemon ironbark (26%), lemon balm (11%), lime rind (6-9%), lemon rind (2-5%), and orange rind—and used as an additive in flavorings (including as a “natural flavor” in soda pop) and perfumes. Citral is recognized to be a highly sensitizing substance.

#3 Prostaglandin E2 –

In light of prostaglandin E2’s connection to childbirth and fever initiation, it is intriguing that it inhibits RALDH2. Birth and viral infections are both associated with onset of CD. Perhaps we really should “starve a fever” a bit, at least at the beginning. And it probably wouldn’t hurt to give women who are genetically-susceptible to CD a hypoallergenic diet around childbirth, especially if prostaglandin E2 (Cervidil) is being used to soften the cervix.

#4 Excess Vitamin A –

And we end back on Vitamin A, which is easy to overdose on over the long-term because it is a fat-soluble vitamin that our bodies store. A mere teaspoon of cod liver oil contains the daily RDA of Vitamin A. Beef liver is even higher in Vitamin A, and it does appear to be a significant part of the cuisine in many places that are notable for CD prevalence.

There are 8 major food allergens—shellfish, eggs, cow milk, fish, peanuts, tree nuts, wheat, and soy—the first four of which are amongst the highest food sources of retinol (pre-formed Vitamin A, found in animal products). Retinol is what the body breaks down in the enzymatic pathway that includes the RALDH enyzmes.

The other four major allergens—at least if one means wheat to include whole wheat, which still has the germ—are all sources of Vitamin E (tocopherols), which appear to increase the synthesis of retinal and retinoic acid from beta-carotene, especially if there is also Vitamin C present. If someone is eating lots of beta-carotene (orange and yellow fruits and vegetables) and Vitamin C along with whole wheat, soy, peanuts, or tree nuts, that appears to have a similar effect on retinol metabolism as eating animal products that are high in retinol. Unfairly, it would thus appear that many people trying to eat healthily and get all their vitamins regularly are more likely to develop food allergies from RALDH disturbances than someone who consumes a diet that is sometimes deficient in Vitamin A, C, or E.

In support of a retinol-celiac link, I note that China has long eaten wheat in noodles, dumplings, and buns. Yet as China grows wealthier and increases its intake of dairy and other animal products, it is seeing an increase in CD.

Even if Vitamin A doesn’t turn out to be associated with CD, it’s always a good idea to keep pre-formed Vitamin A (i.e., retinol, not beta-carotene) intake within reasonable bounds. Oh, and definitely always consume it with fat, for consuming too much Vitamin A without dietary fatty acids leads to excessive production of retinol, retinoic acid, and other retinoids (the linked article describes this finding). US-sold skim milk with 12% of the RDA of Vitamin A in one cup doesn’t seem like such a great idea.