Magnesium

This post is being jump started by a PowerPoint presentation by Dr Lynne August, MD of Health Equations. [1] 1000 apologies if there was misunderstanding in what was said in this video. In fact checking this presentation some truly incredible things were learned about how our bodies handle this very essential element.

Dr August states three requirements for mineral absorption:

1. small in size (one-tenth of a nanometer)
2. unbound
3. charged.

Dr August is a fan of absorbing these minerals to negatively charged clays: Ca, Cr, Cu, Mg, Mo, Mn, and Zn. Dr August claims that Mg²⁺ ions from all other magnesium supplements may not be as good. She attributes this to the water of hydration making them 400x larger and thus too large to be absorbed. She also claims that the free divalent cation can bind to nutrients and impede absorption of said nutrient. The complex may also disrupt gut ecology. Dr August recommends the company mineral supplement that contains calcium and magnesium carbonates and hydroxides. Montmorillonite, magnesium silicate, and vegetable cellulose are also found in this product. This post will allow the reader to make those decisions. This post will a more scientific overview of how our bodies acquire this vital mineral.

Magnesium transporters..

A recent review [2] is being used as a source of human magnesium transporters

• Mitochondrial RNA Splicing Protein 2 (MRS2), is particularly abundant in myocyte mitochondria.
• Transient Receptor Potential Cation Channel Subfamily M, Member TRPM6 is a protein kinase domain containing cation channel that is expressed in mainly the brush border membranes of the colon and is also found in the oligodendrocytes and microglia of the brain. Relative mRNA expression in the brain is not being shown because it is non specific.
• TRPM7 is also a magnesium/calcium channel and serine/threonine protein kinase.
• Magnesium Transporter 1 (MAGT1), In addition to being a membrane bound magnesium channel, MAGT1 catalyzes the transfer of sugar groups to asparagine, serine, and threonine. In the duodenum the expression is high in the glandular cells. Endothelial and glandular cell expression is seen in the colon. It is noted that Atlas Antibodies sells antibodies for MAGt1

Yes, we have more than just three types of magnesium channels in our bodies!

• Solute Carrier Family 41 Member 1 (SCL41A1), according to GeneCards.org is a basolateral membrane Na+/Mg²⁺ exchanger.
• Cyclin and CBS Domain Divalent Metal Cation Transport Mediator (CNNM)is found in early spermatids, nhibitory neurons, Excitatory neurons, Horizontal cells, cone photoreceptor cells

Gut lumen to blood: magnesium channels cooperate

The next two cartoons say pretty much the same thing.

The summary of this section is that it makes perfect sense to have delayed release of Mg from whatever form it is released from the oral supplement. After this modified kidney image was created, this image was found in a Chamniansawat 2023 review [8] to which a ProteinAtlas image was added. Note taht CNNM4 is also a primarily colon and rectum expressed transporter.

The cystathionine β-synthase domain in CNNM4 is claimed to participate in magnesium transport. [8] Mutation of cystathionine β-synthase domain divalent metal cation transport mediator 4 does not affect the plasma magnesium concentration in humans according to review authors. [8]

PTH and FGF23 regulation of small intestine expression

The Chamniansawat 2023 review [8] did not go into details as to whether the “expression” meant PKC dependent new mRNA transcripts, translation of those transcripts into proteins, or the transport of those proteins in membrane bound vesicles to the membrane. The cartoon is priceless!

Small intestine and colon PTH and FGF23 questions

The Chamniansawat review [8] discusses the role of serum Ca²⁺ regulating small intestine absorption of Mg²⁺. This entire narrative somewhat validates the ProteinAtlas mRNA data showing more transcripts in the colon and rectum. Are the colonic and rectal transcripts also under PTH and/or FGF23 control?

These transport pathways are supposedly duodenum based and regulated by acid going from the stomach. [8] The cystic fibrosis Cl^– channel CFTR can also transport bicarbonate. The argument is that bicarbonate can somehow form MgO.

This post is not going to get into whether or not CFTR is a major HCO₃ transporter as opposed to the dominate paradigm that it’s a chloride channel.

free Mg²⁺ absorption requires hydration

Some of this came from the August PowerPoint presentation. The argument was that we should not take free magnesium supplements because they are hydrated. What does “hydration” mean?

have a partial negative charge because the massive nucleus of oxygen can suck away the electron from the puny one proton nuclei of the two hydrogens. The two hydrogens have a partial negative charge. Hydration makes ions larger. It should also be noted that electrons can shield the positive charges in the nuclei. The electron structure of a magnesium (from shutterstock) is also included.

Note that Mg²⁺ hydration tends to be more tightly held than Ca²⁺ because there are less electrons to screen the partial negative charge of the water molecule oxygen.

In their introduction Dudev and Lim state the rather large free energy of Mg²⁺ hydration. For readers who’d like a sensory demonstration at the home schooling level, they can mix magnesium sulfate (Epson salt) with water. The solution gets colder rather than warmer. The home school site stops short of getting into Gibbs free energy but glances over thought provoking cocepts of entropy and enthalpy. The intuitive flip side is that stripping the water of hydration off Mg²⁺ will cost a lot of energy.

How does a Mg²⁺ channel filter out more abundant Ca²⁺ ions when Mg²⁺ is hexa hydrated? Not only is the selectivity filter of the pore sufficiently large to accommodate hexahydrated Mg²⁺ ions because the amino acids of the pore interact directly with the waters of hydration! Dudev and Lim experiments were based on previous X-ray crystal structures of TRPM6 and mutagenesis of the same protein channel. They new which amino acids were important in the Mg over Ca selectivity filter. Much of their work was performed in silico. Dudek and Lim used the crystal structure of CorA, a Mg2+ selective channel and used this structure pentameric structure to predict how a tetramer TRPM6. Is it reasonable o think that the six waters of hydration make energetically favorable conacts with the predicted channel cavity? The answer is yes!

Note that the Dudev and Lim study showing extreme in silico plausibility of Mg²⁺ going through in the hexahydrated state is not the same as showing those waters bridging magnesium and amino acids in the mouth of the channel in a crystal structure. We have every reason to think that non chelated magnesium is the best supplement.

Hypothetical use of charge to lure in Mg²⁺ chelates

To summarize previous discussions, hydrated, non-chelated form of magnesium that will go through TRMP6 in our colons. The trick is to get it there before binding to something else in the several meters of small intestine, not to mention our stomachs. Based on the information presented thus far, rectal delivery might be an option. Why then can we get our daily allowance of magnesium in foods that we eat that is almost certainly chelated to something? This thought experiment was performed on the rcsb.og website. This website allows us to color 3D structures based on physical properties such as charge.

The lip of CorA, and probably TRPM6, is charged and probably able to be a docking site for whatever magnesium chelate floats by.

MgO vs Mg citrate, clinical trial [4]

This study compared magnesium oxide and magnesium citrate with respect to in vitro solubility and in vivo gastrointestinal absorption. The solubility of 25 mmol magnesium citrate and magnesium oxide was examined in solutions containing varying amounts of hydrochloric acid (0-24.2 mEq) in 300 ml distilled water. This was intended to mimic no acid to peak acid secretory states in our stomachs. Magnesium oxide was virtually insoluble in water and only 43% soluble in simulated peak acid secretion (24.2 mEq hydrochloric acid/300 ml). Magnesium citrate had high solubility even in water (55%) and was substantially more soluble than magnesium oxide at all concentrations of HCl tested. Reprecipitation of magnesium citrate and magnesium oxide did not occur when the filtrates were adjusted to pH 6 and 7 with bicarbonate to stimulate pancreatic secretion into the duodenum of the small intestine. Approximately 65% of magnesium citrate was complexed as soluble magnesium citrate. MgO did not form complexes. Magnesium absorption in normal volunteers was determined by spikes in Mg in the urine following consumption of 25 mmol of magnesium. MgCitrate vs MgO were adjusted to creatine.

• 4 hours: 0.22 vs 0.006 mg/mg creatinine, p < 0.05
• 2 hours: 0.035 vs 0.008 mg/mg creatinine, <0.05.

Magnesium citrate was concluded to more soluble and bioavailable than magnesium oxide.

Three different Mg supplements [5]

164 study participants were randized : magnesium citrate supplement,magnesium oxide,magnesium sulfate supplement, or placebo, The total daily dose of magnesium was 450 mg. How did these three compare in terms of bioavailability?

It would appear that the magnesium sulfate is less bioavailable than the other two… and that excess magnesium is being peed out.

Unfortunately it is impossible to tell which magnesium supplement is causing the most adverse events in the graph.

AST-120 charcoal and MgO [6]

Andrew McVagh of magnesiumdeficiency.info had some interesting things to say to patients who take magnesium supplements no problem, take something else in addition to the magnesium, then get explosive diarrhea.

This section is mining a clinical trial of coronary artery calcification patients for adverse events of a gastrointestinal nature.

• 330 mg (8.3 mmol) per day of magnesium oxide (elemental magnesium: 198 mg). The doses were adjusted every 1–3 months to achieve serum magnesium levels of 2.5−3.0 mg/dl.
• AST-120 group received 6 g/d of AST-120
• control group received standard therapy for CKD alone.

Only six patients in the MgO group had severe diarrhea vs none in the control group. See Table 4 of the Matsumoto publication. Matsumoto and coauthors did not have much to say about the severe diarrhea except many patients dropped out of the study for this reason.

Osmotic and motility Mg²⁺ diarrhea …. PGE2 !!![7]

Mg²⁺ has most of its transporters in the colon and rectum. What does not get absorb until then can act as an osmolyte sucking out water through osmotic action. We have to remember that Mg²⁺ is very hygroscopic. Verywellhealth claims that magnesium can cause motility diarrhea. Andrew McVagh hinted at this too on his magnesiumdeficiency.info website. How? A 1990 study suggests that the answer is PGE2. Six volunteers more than 55 years old, in a hospital setting, and normal bowel habits, were enrolled in a dose-response study.

Each subject was studied for four inpatient periods of 5 days each on a metabolic ward with 9 days off of all medication between studies. For reasons not disclosed in the abstract, all patients in this metabolic ward were on a controlled diet on the same amount of carbohydrates, electrolytse and calories . …

At 8 p.m. on each study day, each subject took a 45 ml slurry containing either placebo or 1,200, 2,400, or 3,600 mg of Mg(OH)₂ followed by 240 ml of water. It was not not totally clear if this slurry was like Milk of Magnesia followed by a glass of water or the two mixed together. On the fourth and fifth hospital days of each period, 24-h stool output was quantified and analyses performed..

• a) increased number of bowel movements
• (b) increased percentage of stool water
• (c) increased stool volume
• (d) increased stool Mg²⁺
• (e) increased total stool 24-h prostaglandin E2 (PGE2), with mean 24-h excretions as follow: placebo, 95 +/- 18 pg/24 h; 1,200 mg Mg(OH)2, 260 +/- 100; 2,400 mg Mg(OH)2, 357 +/- 117; and 3,600 mg Mg(OH)2, 525 +/- 196.

There was a significant correlation between stool PGE2 excretion and stool water consistent with a causative relationship.

This wonderful publication just does not seem to have received much followup according to the PubMed citation index. The Wikipedia page on magnesium hydroxide suggests that CCK is the intestinal motility increasing culprit. The large variability in the PGE2 suggests that magnesium may not all individuals the same even under very careful dietary restrictions.

Conclusions

Perhaps we do not need to worry about the waters of hydration of Mg²⁺, free vs in complexes, and so on. The number of different Mg²⁺ channels and how they work together speaks to how well evolved this system really is. Unfortunately we do not know more why magnesium supplementation sometimes goes wrong.

References

1. https://www.healthequations.com/magnesium-plus-article and also
2. Auwercx J, Rybarczyk P, Kischel P, Dhennin-Duthille I, Chatelain D, Sevestre H, Van Seuningen I, Ouadid-Ahidouch H, Jonckheere N, Gautier M. Mg²⁺ Transporters in Digestive Cancers. Nutrients. 2021 Jan 13;13(1):210. PMC free article
3. Dudev T, Lim C. Importance of metal hydration on the selectivity of Mg2+ versus Ca2+ in magnesium ion channels. J Am Chem Soc. 2013 Nov 13;135(45):17200-8. PubMed free article
4. Lindberg JS, Zobitz MM, Poindexter JR, Pak CY. Magnesium bioavailability from magnesium citrate and magnesium oxide. J Am Coll Nutr. 1990 Feb;9(1):48-55. doi: 10.1080/07315724.1 PubMed
5. Schutten JC, Joris PJ, Groendijk I, Eelderink C, Groothof D, van der Veen Y, Westerhuis R, Goorman F, Danel RM, de Borst MH, Bakker SJL. Effects of Magnesium Citrate, Magnesium Oxide, and Magnesium Sulfate Supplementation on Arterial Stiffness: A Randomized, Double-Blind, Placebo-Controlled Intervention Trial. J Am Heart Assoc. 2022 Mar 15;11(6):e021783. PMC free paper
6. Sakaguchi Y, Hamano T, Obi Y, Monden C, Oka T, Yamaguchi S, Matsui I, Hashimoto N, Matsumoto A, Shimada K, Takabatake Y, Takahashi A, Kaimori JY, Moriyama T, Yamamoto R, Horio M, Yamamoto K, Sugimoto K, Rakugi H, Isaka Y. A Randomized Trial of Magnesium Oxide and Oral Carbon Adsorbent for Coronary Artery Calcification in Predialysis CKD. J Am Soc Nephrol. 2019 Jun;30(6):1073-1085. PMC free article
7. Donowitz M, Rood RP. Magnesium hydroxide: new insights into the mechanism of its laxative effect and the potential involvement of prostaglandin E2. J Clin Gastroenterol. 1992 Jan;14(1):20-6. PubMed
8. Chamniansawat S, Suksridechacin N, Thongon N. Current opinion on the regulation of small intestinal magnesium absorption. World J Gastroenterol. 2023 Jan 14;29(2):332-342. PMC free article