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.

When did that happen to my blog?

I promise, this is a blog about education/geography/books/basic life of a homeschooling mom who has had the chance to live in several parts of the world. When did it turn into a nutrition/biomedical studies blog? (I take one little online course....) I have a couple more theories I've been working on (food allergies and seizure disorders), but I think I'm mostly done. After all, school starts up again in less than a month!

In the meantime, I need to order math books for my children, I'm learning Arabic (one line a night, but I'm already starting to recognize some words), my favorite fun reads for the summer have been books by Traci Hunter Abramson, and life has been great this summer, as we've learned about Bangladesh, Japan, Austria, Chile, and Senegal. The best part of our country studies is having a reason to invite people to our home to tell about their countries or countries they lived in; they love revisiting their memories and sharing them with us, and we all feel happier as we learn together and make friendships warmer.

Botox and depression

That last post was pretty technical. Time to lighten it up a bit with a fun theory I just came up with yesterday after a friend asked me to send her any recent studies connecting depression/anxiety with nutrition.

A few weeks after receiving botox treatment for wrinkles, around half of patients find relief from depression. (See https://www.ncbi.nlm.nih.gov/pubmed/24910934.) The obvious conclusion is they're simply happier with how they look. But what if it's more than that?

#1 - Botox suppresses the release of acetylcholine.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1192367/

#2 – Nicotinic acetylcholine receptors (nAChRs) respond to acetylcholine. https://en.wikipedia.org/wiki/Nicotinic_acetylcholine_receptor

#3 -  nAChRs in the brain can become desensitized after repeated exposure to stimulants. http://web.as.uky.edu/Biology/faculty/cooper/Bio401G/nicotineDesen.pdf

#4 - Recent drug research on new antidepressants has been targeting nAChRs: http://www.hindawi.com/journals/tswj/2012/104105/

So here's the basic theory:

We in the west eat a large amount of choline-rich food, so we can easily synthesize lots of acetylcholine. The constant exposure to plentiful acetylcholine in conjunction with other internal and external stimulators of nAChRs can result in desensitization of the nicotinic acetylcholine receptors in our brains, dysfunction of which receptors is associated with depression. Botox allows a "reboot" of the system by cutting the acetylcholine supply for a while, and the nAChRs become more sensitive again.

And here's how to test it (beside getting botox treatments): Go on a low-choline diet (unless you're pregnant) for a 3-4 days, during which it would probably be good to also avoid anything that would mess with nAChRs (esp. nicotine, alcohol, and recreational drugs). Here’s a link to the choline content of foods. See if you feel different a couple weeks later. Don't do the low-choline diet for an extended period, though. We need choline, just maybe not quite as constantly as we get it.

Perhaps the non-constant supply of choline-rich animal products (which are relatively expensive) in the diet of people in poor countries is part of the reason why it is sometimes found that rates of depression are higher in richer countries. Also intriguing is the connection between gardening (soil is full of the bacteria that makes botox) and less severe depression.

Carbon monoxide and restless legs syndrome (RLS)

As part of the research I've been doing in nutrition, I have come across studies and information giving rise to a theory in a very different area. Here's the theory:

Restless legs syndrome (RLS) appears to possibly be caused by carbon monoxide buildup in leg muscles. Here's why I think that could be the case:

1) Everyone's body makes endogenous carbon monoxide in small amounts. The endogenous carbon monoxide is a product of the breakdown of heme, a cofactor containing iron that is found primarily in animal products.
2) There appears to be a weak association between a heme oxygenase (which produces carbon monoxide) gene and RLS.
3) When we rest in a horizontal position, we are lowering arterial O2 (oxygen) pressure in the legs, which can cause more carbon monoxide to move from blood to the muscles. This effect should be even more pronounced during pregnancy due to the temporarily increased weight on the legs when standing; pregnancy is associated with increased risk of RLS. Compression stockings would help keep arterial pressure high; many RLS sufferers find that using compression stockings lessens their symptoms.
4) Carbon monoxide binds to myoglobin--"The oxygen carrying and storage protein of muscle, resembling hemoglobin but containing only one subunit and one heme as part of the molecule (rather than the four of hemoglobin), and with a molecular weight approximately one quarter that of hemoglobin," per an online medical dictionary--in the muscles. Thus, those who are already deficient in iron would tend to suffer more from higher levels of carbon monoxide interfering with myoglobin in the muscles. RLS has long been found associated with low stores of iron in the body.
5) The primary (and almost only) treatment for carbon monoxide poisoning is oxygen therapy. Peripheral hypoxia in the legs is associated and correlated in degree with RLS.
6) The most well-known symptom related to RLS is involuntary movement of the leg muscles. This movement could be the body trying to get more oxygen to the leg muscles in order to alleviate carbon monoxide buildup in the legs. Moving muscles take in more oxygen than resting ones.
7) Severe RLS and ischemic stroke are correlated. Carbon monoxide poisoning also correlates with an increased risk of ischemic stroke. This is a point in support of the hypothesis that endogenous carbon monoxide poisoning is behind RLS.
8) Dopamine agonists lessen RLS symptoms. Dopamine is also used to increase arterial pressure in patients with hypotension (low blood pressure). This is another point in support of the hypothesis, for increasing arterial pressure can be expected to help prevent the movement of carbon monoxide from blood into muscles.

Does my theory point to ways to treat RLS? I see a few, many of which have already been studied and shown positive effects:

• Increase oxygen inhalation at night. RLS is associated with reduced oxygen saturation and sleep-related breathing disorders.
• Look into ways to increase arterial pressure at night. Obviously, compression stockings can help do that. Also, progressive exercise programs that increase overall strength help with RLS, perhaps because having stronger cardiac and rib-cage-connected muscles increases arterial pressure and/or oxygen inhalation.
• Massage leg muscles. It can contribute to an increase in muscle blood volume. 
• Dopamine agonists, as mentioned above in #8.
• Don't be deficient in iron.
• Don't over-consume heme, a form of iron from animal products that is the primary source of endogenous carbon monoxide.
• Don't be deficient in vitamin E, which in the form of d, alpha-tocopheryl acetate, appears to relieve RLS leg cramps. I suspect this is partially due to alpha-tocopherol's inhibition of lipid peroxidation, which results in production of endogenous carbon monoxide.
• Perhaps acizol, a new zinc-containing medication for acute carbon monoxide poisoning, would be helpful for RLS. No research has been done on this, though.
• Hydroxocobalamin combined with Vitamin C shows promise as a treatment for carbon monoxide poisoning, per a rat study published last year. If carbon monoxide is connected to RLS, then hydroxocobalamin and Vitamin C supplements together might help with RLS.

Cyanocobalamin - a very poor choice, part 3

Some researchers feel that cyanocobalamin is probably just as good a B12 supplement as other forms of cobalamin. Others prefer methylcobalamin and hydroxocobalamin to cyanocobalamin for purposes of preventing dementia and stroke.

Dr. Dale Bredesen, a doctor and researcher in California, made the news recently for reversing cognitive decline in some Alzheimer's patients. He reported similar results in 2014 in the journal Aging. The full text of the 2014 article lists the details of his treatment protocol in Table 1:

Table 1 - Therapeutic System 1.0

Goal	Rationale and References
Optimize diet: minimize simple CHO, minimize inflammation. Enhance autophagy, ketogenesis Reduce stress Optimize sleep Exercise Brain stimulation Homocysteine under 7 Serum B12 over 500 Etc.*	Patients given choice of several low glycemic, low inflammatory, low grain diets. Fast 12 hr each night, including 3 hr prior to bedtime. Personalized—yoga or meditation or music, etc. 8 hr sleep per night; melatonin 0.5mg po qhs; Trp 500mg po 3x/wk if awakening. Exclude sleep apnea. 30-60′ per day, 4-6 days/wk Posit or related Me-B12, MTHF, P5P; TMG if necessary Me-B12 Etc.*

*Full table found online at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4221920/table/T1/.

Notice the use of methylcobalamin ("Me-B12") both to lower homocysteine and to increase the serum B12 level. Dr. Bredesen is getting results in preventing and reversing dementia, and he's using methylcobalamin as part of his treatment strategy. Why would I use a form of B12 that is tightly bound together, i.e., cyanocobalamin, when methylcobalamin appears to help prevent dementia?

Diet and obsessive thoughts

I have an Aspberger's nephew who exhibits the same tendency to fixate as his father. His father's fixations have been terrible for family relationships for the past few years, and the son really, really doesn't want to fixate, too. So I've been delving into the PubMed database for findings related to obsessive thoughts.

The research repeatedly shows apparent connections between lower levels of GABA & GABA receptors and OCD. See this, this, this, this, this, and this. The GABA(A) receptor is decreased when homocysteine is elevated (which fits with MTHFR defects being associated with autism, for MTHFR defects negatively impact conversion of homocysteine to methionine). Myo-inositol has been shown to help protect subunits of GABA(A) receptors in the hippocampus, and some people on Amazon are reporting that it helps them with OCD thoughts. 

The research thus supports a two-pronged dietary approach to lessening fixations that consists of 

• supporting homocysteine conversion by making sure to consume enough betaine, zinc, B12 (but not the cyanocobalamin form), and folate (definitely avoid folic acid, though; too much of it apparently causes pseudo-MTHFR deficiencies)
• protecting GABA(A) receptors from internal or external antagonists by consuming enough myo-inositol (it seems prudent to limit caffeine consumption, as caffeine appears to interfere with at least one inositol-related function)

What we eat can't change our genetics, but it definitely affects our phenotypes. Fresh fruits and vegetables, whole grains, and moderate intake of animal products (at least after childhood--babies need milk!), combined with avoidance of excess intake of anything, keep popping up as keys to long-term health.

Skin care and manganese

I've become a fan of barley water recently. It is made by boiling a little barley in water for a while until the barley splits and all its soluble fiber and nutrients start dissolving into the water. And barley has a lot of soluble fiber and helpful nutrients! (And for the LDS people out there, I would add that barley is the only beverage grain approvingly mentioned by name in D&C 89.)

In looking for news articles mentioning barley water, I came across one saying that the Queen of England reportedly drank it everyday for her complexion. She really does have a remarkably good complexion for her age. Why would barley water help with skin? It was a traditional acne remedy in the British Isles; what component(s) of it might have been helping acne sufferers?

Acne is correlated with the presence of androgens. See this, this, and this. Apparently, androgens stimulate production of sebum, an oily secretion made in our skin pores. But there are substances that can partially inhibit production of androgens, such as the ones mentioned in this study abstract:

The effects of various calcium-channel blockers on androgen production by collagenase-dispersed mouse testicular interstitial cells were investigated. Cobalt caused a dose-dependent inhibition of the maximum rate of luteinizing hormone (LH)-stimulated androgen production without altering the concentration of LH required for half maximum stimulation (EC50). Nickel and manganese also inhibited LH-stimulated steroidogenesis but were less potent than cobalt. The major site at which cobalt treatment inhibited steroidogenesis was beyond cAMP formation and before 3 beta-hydroxysteroid dehydrogenase. This conclusion was based on the observation that cobalt inhibited dibutyryl cAMP-stimulated androgen production but did not affect protein synthesis and pregnenolone-supported androgen production. Androgen production was unaffected by the organic calcium-channel blockers verapamil and the (+) and (-) enantiomers of D600 at concentrations less than 0.1 mM. At a concentration of 0.1 mM the organic calcium-channel blockers inhibited LH- and dibutyryl cAMP-stimulated androgen production. Unlike cobalt, the organic calcium-channel blockers also inhibited pregnenolone-supported androgen production and reduced the rate of protein synthesis. Similarities between the effects of cobalt in the present study and previous reports of the effects of reduced extracellular calcium concentrations on androgen production suggest that cobalt inhibits androgen production as a result of its ability to block calcium influx. The calcium channels involved in the steroidogenic process appear, however, to be relatively insensitive to the organic calcium-channel blockers.

Two things jump out at me from these findings and conclusions:

1) Blocking influx of calcium might inhibit androgen production in some cells. Perhaps this would in part explain the recurring observations of high dairy intake and acne correlation. See this, this, this, this, this, this, and this. Dairy products are rich natural sources of calcium.

2) Cobalt, nickel, and manganese can inhibit androgen production. I have a nickel allergy, which is quite common, and a little research on cobalt quickly convinced me that I don't want to mess around with it as a supplement.

But manganese...now there's a lead. In small amounts (and small amounts only), manganese is necessary for our bodies. And it is highest in two foods: clove (the spice) and oats. Barley is also a very good source of manganese. Queen Elizabeth II, I salute you for your regular consumption of barley water, which I'm sure provides you with a steady supply of manganese.

Do you know how long oats have been used in skin care? One personal care website claims oats have been used for skin care for 4000 years. The skin and hair care company Aveeno takes its name from the Latin name for oats, avena sativa, and centers its products on oats.

Cloves don't have quite as wide usage as oats in skin care, but anecdotal accounts of clove oil use support its efficacy for some people in clearing up acne. But clove oil often causes a numbing or burning sensation that makes it problematic for widespread use in therapeutic quantities. If the acne-fighting ingredient in clove is manganese, though, perhaps we can just put a little manganese in our acne creams and face lotion. Why fill the body with manganese when we just want a little extra affecting our facial pores? (But don't inhale manganese. That's known to lead to neurological damage.)

Manganese seems a beneficial component of cosmetic creams for other reasons. For instance, it helps protect skin from UVA and hydrogen peroxide damage. A manganese enzyme appears to be involved in helping protect connective tissue from age associated abnormalities. And a manganese peptide complex showed promising results in improving the appearance (especially hyperpigmentation) of photodamaged skin, per a 2007 article.

Chronic exposure to excessive manganese leads to manganism, which resembles Parkinson's disease. One of the ways manganism is treated is with chelation using a salt of EDTA to lower blood manganese levels. Check every chemical product you own that touches your face, and it probably has EDTA in it as a stabilizer unless you purposely avoid EDTA. If we want some manganese in our skin, I wonder whether we are unwise to use a known chelator in so many hair and skin care products.

[Update on June 16, 2018: I saw a few people had been reading this old post, so I thought I'd let anyone reading this know that topical manganese didn't help my teenager in 2018 when she was getting some acne. Oh, well, maybe manganese is good for other things.]

Happy Fourth of July!

A family tradition is to watch National Treasure on Independence Day. The film combines a fun treasure hunt, adventure, and respect for family, freedom, and history. My favorite line from it is the protagonist's speech about the risks that the Founding Fathers* took to establish this nation:

Ben Gates: A toast? Yeah. To high treason. That's what these men were committing when they signed the Declaration. Had we lost the war, they would have been hanged, beheaded, drawn and quartered, and-Oh! Oh, my personal favorite-and had their entrails cut out and *burned*! So... Here's to the men who did what was considered wrong, in order to do what they knew was right...what they knew was right.

* They were men, so I'll call them "Founding Fathers." The word "Founders" calls up images of ships going down at sea and introduces ambivalence towards the brave patriots of 1776.