Wednesday, February 24, 2016

Vitamin D oversupplementation-to-Colitis connection

Since posting my last bit about vitamin oversupplementation in general, I came across this 2009 study from India:

 2009 Jul;29(4):470-8. doi: 10.1007/s10875-009-9277-9. Epub 2009 Feb 14.

Plasma 1,25 dihydroxy vitamin D3 level and expression of vitamin d receptor and cathelicidin in pulmonary tuberculosis.



Vitamin D(3), which exerts its effect through vitamin D receptor (VDR), is known for its potent immunomodulatory activities. Associations between low serum vitamin D(3) levels and increased risk of tuberculosis have been reported.


Plasma 1,25 dihydroxy vitamin D(3) levels (1,25(OH)(2) D(3)) and ex vivo levels of VDR protein from peripheral blood mononuclear cells were studied in 65 pulmonary tuberculosis (PTB) patients and 60 normal healthy subjects (NHS) using enzyme-linked immunosorbent assay-based methods. Using real-time polymerase chain reaction (PCR), induction of VDR, cathelicidin, and CYP27B1 mRNA were studied in live Mycobacterium tuberculosis-stimulated macrophage cultures treated with or without 1,25 dihydroxy vitamin D(3). VDR and CYP27B1 (-1077 A/T) gene polymorphisms were studied using PCR-based methods.


1,25(OH)(2) D(3) were significantly increased (p = 0.0004), while ex vivo levels of VDR protein were significantly decreased in PTB patients (p = 0.017) as compared to NHS. 1,25(OH)(2) D(3) levels were not different between variant genotypes of CYP27B1. A trend towards decreased levels of VDR protein was observed among NHS with BsmI BB and TaqI tt genotypes compared to NHS with other genotypes. Relative quantification of mRNA using real-time PCR revealed increased VDR mRNA expression in live M. tuberculosis-stimulated culture in PTB patients (p < 0.01) than normal healthy subjects. Cathelicidin mRNA expression was significantly increased in vitamin D(3)-treated cultures compared to unstimulated and M. tuberculosis-stimulated culture in both patients (p < 0.001) and NHS (p < 0.05).


The present study suggests that PTB patients may have increased 1,25(OH)(2) D(3) levels, and this might lead to downregulation of VDR expression. Decreased VDR levels could result in defective VDR signaling. Moreover, addition of 1,25(OH)(2) D(3) might lead to increased expression of cathelicidin which could enhance the immunity against tuberculosis.

In combination with the information I posted about below--Vitamin D receptors are essential to avoiding colitis (inflammation and soreness in the intestines)--I think there's a very solid basis to suspect a connection between Vitamin D supplementation and the uptick in people suffering with intestinal problems in the USA.

It takes only 4 cups of milk to get all the Vitamin D you need. For adults. A tablespoon of cod liver oil has more than three times the RDA of Vitamin D. Again, that's for adults. Unless you have reason to think you need supplemental vitamin D, I recommend you don't take it. And be even more cautious when dosing a child.

Vitamin Oversupplementation - Don't do it!

I once had a dentist tell me that I could flush my multivitamins down the toilet for all the good they were doing me. I smiled and thought he was a bit extreme. I now join him in that advice.

Guess what happens if we oversupplement with folic acid for a long time? Our bodies downregulate (make less of) folic acid receptors in our intestines and other folate-related activity gets altered.
Long-term oversupplementation with folate leads to a specific and significant down-regulation in intestinal and renal folate uptake, which is associated with a decrease in message levels of hRFC, PCFT/HCP1, and FR. This regulation appears to be mediated via a transcriptional mechanism, at least for the hRFC system.

And what happens if we oversupplement with Vitamin D for a long time? Do the vitamin D receptors in our intestines also get messed up? If so, that would be a very bad thing. The presence of Vitamin D receptors is essential to not getting colitis, per this study:
Abstract The inhibitory effects of vitamin D on colitis have been previously documented. Global vitamin D receptor (VDR) deletion exaggerates colitis, but the relative anticolitic contribution of epithelial and nonepithelial VDR signaling is unknown. Here, we showed that colonic epithelial VDR expression was substantially reduced in patients with Crohn’s disease or ulcerative colitis. Moreover, targeted expression of human VDR (hVDR) in intestinal epithelial cells (IECs) protected mice from developing colitis. In experimental colitis models induced by 2,4,6-trinitrobenzenesulfonic acid, dextran sulfate sodium, or CD4+CD45RBhi T cell transfer, transgenic mice expressing hVDR in IECs were highly resistant to colitis, as manifested by marked reductions in clinical colitis scores, colonic histological damage, and colonic inflammation compared with WT mice. Reconstitution of Vdr-deficient IECs with the hVDR transgene completely rescued Vdr-null mice from severe colitis and death, even though the mice still maintained a hyperresponsive Vdr-deficient immune system. Mechanistically, VDR signaling attenuated PUMA induction in IECs by blocking NF-κB activation, leading to a reduction in IEC apoptosis. Together, these results demonstrate that gut epithelial VDR signaling inhibits colitis by protecting the mucosal epithelial barrier, and this anticolitic activity is independent of nonepithelial immune VDR actions.
What if all that Vitamin D in our milk, in our multivitamins, and Vitamin D drops is decreasing our intestinal Vitamin D receptor activity and depriving us of protection to our intestinal lining? Would that help explain the mysterious rise of leaky guts and gluten intolerances?
Is it too much for me to ask that the government keeps its meddling hands off of my food? I'll eat tuna and eggs and go get some sunlight on my fair skin. I don't need supplements!

Sunday, February 14, 2016

More on MTHFR mutation (see last post)

A year ago, a study was published finding that high doses of folic acid can apparently make rats develop pseudo-MTHFR deficiency. Lovely.

Here's the abstract:
 2015 Mar;101(3):646-58. doi: 10.3945/ajcn.114.086603. Epub 2015 Jan 7.
High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice.
Christensen KE1Mikael LG1Leung KY1Lévesque N1Deng L1Wu Q1Malysheva OV1Best A1Caudill MA1Greene ND1Rozen R1
Our goal was to investigate the impact of high folic acid intake on liver disease and methyl metabolism. 
Folic acid-supplemented diet (FASD, 10-fold higher than recommended) and control diet were fed to male Mthfr(+/+) and Mthfr(+/-) mice for 6 mo to assess gene-nutrient interactions. Liver pathology, folate and choline metabolites, and gene expression in folate and lipid pathways were examined. 
Liver and spleen weights were higher and hematologic profiles were altered in FASD-fed mice. Liver histology revealed unusually large, degenerating cells in FASD Mthfr(+/-) mice, consistent with nonalcoholic fatty liver disease. High folic acid inhibited MTHFR activity in vitro, and MTHFR protein was reduced in FASD-fed mice. 5-Methyltetrahydrofolate, SAM, and SAM/S-adenosylhomocysteine ratios were lower in FASD and Mthfr(+/-) livers. Choline metabolites, including phosphatidylcholine, were reduced due to genotype and/or diet in an attempt to restore methylation capacity through choline/betaine-dependent SAM synthesis. Expression changes in genes of one-carbon and lipid metabolism were particularly significant in FASD Mthfr(+/-) mice. The latter changes, which included higher nuclear sterol regulatory element-binding protein 1, higher Srepb2 messenger RNA (mRNA), lower farnesoid X receptor (Nr1h4) mRNA, and lower Cyp7a1 mRNA, would lead to greater lipogenesis and reduced cholesterol catabolism into bile.
We suggest that high folic acid consumption reduces MTHFR protein and activity levels, creating a pseudo-MTHFR deficiency. This deficiency results in hepatocyte degeneration, suggesting a 2-hit mechanism whereby mutant hepatocytes cannot accommodate the lipid disturbances and altered membrane integrity arising from changes in phospholipid/lipid metabolism. These preliminary findings may have clinical implications for individuals consuming high-dose folic acid supplements, particularly those who are MTHFR deficient.

It seems long past time that we stop having everyone take folic acid, a molecule that our bodies hardly dealt with until around 60 years ago. There are better options out there.

Sunday, February 7, 2016

More on folic acid

Around half the US population has a mutation in the gene that encodes MTHFR, which mutation limits their ability to turn folic acid into L-methylfolate, which is what the human body uses in nearly every cell for all sorts of purposes, including important functions of the immune and nervous systems. Intriguingly, one study of autistic kids found that all but 2% of them had at least one MTHFR mutation.

Folic acid supplementation has decreased neural tube defects in the USA and Canada by only about 35-45%, raising a suspicion in me that around half the population isn't able to fully utilize the folic acid that is now so plentiful in our food supply. To me, this, combined with our knowledge that half the population has difficulty turning folic acid into L-methylfolate, indicates that instead of folic acid, we should be consuming supplements of L-methylfolate. 

Fortunately, it is now possible to purchase L-methylfolate and take that instead of folic acid. Merck sells it as Metafolin, and no prescription is required. A search of PubMed shows that scientists are starting to promote L-methylfolate's use instead of folic acid for women who could get pregnant. I buy L-methylfolate from Solgar on, and it is also available from various marketers of natural supplements, for people are starting to realize how frequently the MTHFR mutations appear to be correlated with a wide variety of health problems.