General Aspects of Magnesium in the Human Body: Comparison
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Magnesium is one of the most prominent cations in the human body, with distribution of its concentrations in both extracellular and intracellular areas. Magnesium, in both complex and ionized form, has critical relevance in metabolic functions and homeostasis, serving as a moderator in enzymatic processes. A first important aspect is the role of magnesium in the activation of Adenosine Triphosphate (ATP), which is the primary energy source for cells. Magnesium improves muscle function by competitively binding to calcium sites and ensuring muscle relaxation.

Recently, there is an increasing amount of studies that suggest an important role of magnesium within the gut-brain axis, by modulating the bidirectional balance, alongside the microbiome. this opens a new research direction in both functional gastrointestinal diseases and psychiatric symptoms management.

  • magnesium
  • orotic acid
  • gut-brain axis
  • functional gastrointestinal disease
  • psychiatry
  • microbiome

1. General Aspects of Magnesium

Magnesium is one of the most prominent cations in the human body, with distribution of its concentrations in both extracellular and intracellular areas. Although general knowledge has been gathered about the importance of magnesium in osteo-articular and cardiovascular function, digestive functions and its role within the nervous system may be more important than current data state. Difficulties in studying magnesium are related to limited possibilities of detecting intracellular levels and how its concentration affects cell metabolism and beyond [1].
Magnesium, in both complex and ionized form, has critical relevance in metabolic functions and homeostasis, serving as a moderator in enzymatic processes. A first important aspect is the role of magnesium in the activation of Adenosine Triphosphate (ATP), which is the primary energy source for cells. Magnesium improves muscle function by competitively binding to calcium sites and ensuring muscle relaxation.
Metabolic functions of the cation are multilateral. Its involvement in carbohydrate metabolism and its function as a regulator for glycolysis and insulin signaling were broadly described. Additionally, it seems that there is an inverted proportionality between levels of magnesium and insulin resistance, especially observed in type 2 diabetes patients [2]. Another metabolic activity, although still debatable, refers to the correlations between extracellular magnesium and the lipid profile, with a further impact on susceptibility to atherosclerosis [3]. Magnesium has important roles in protein metabolism and a concentration-dependent role in DNA structure and stabilization. In high concentrations, it actively induces DNA changes, including Z-DNA formation, and in low concentrations, it can lead to destabilization of the DNA structure, which plays an important role in carcinogenesis [4].
Clinical studies have reveled further roles of magnesium through pathophysiological observations. For example, in acute myocardial infarction, magnesium seems to limit free-radical formation and limit injury to cardiac muscle, increasing reperfusion and oxygenation to the tissue. This benefit may be partially a consequence of the calcium channel-blocking activity of the element, as for free radicals the exact mechanism is somewhat unclear, but it is clear that magnesium exerts antioxidative effects on cells and tissues, as shown in animal studies [5]. The antioxidative effects add-up to the carcinogenesis-protective role of the element. Other roles of magnesium have been revealed in respiratory or renal pathologies, via clinical observations, but information is still limited.

2. Magnesium and Gastrointestinal (GI) Tract Health

On the side of gastroenterology, magnesium is known to have linkage to gastric disorders during developmental stages and also in adulthood, but involvements in intestinal function and the microbiome are scarcely studied. Magnesium absorption takes place in the small intestine, mainly in the distal area, in two pathways, an active transcellular pathway and a passive paracellular pathway. Magnesium needs to be absorbed from diet intake. The absorption level on a normal basis is at 25%, and in a deficient state it can increase up to 80% [6]. As the place of absorption is the intestinal area, connections between gut health and magnesium are taken into consideration. Malabsorptive disorders are known to decrease nutrient intake, but there are also questions to be answered regarding the inverted mechanism and how magnesium could alter gut physiology. Magnesium combinations are known for some of their benefits, such as magnesium oxide which is used for its laxative effects. Still, in its free form, magnesium has been scarcely studied in the literature. A study which followed magnesium effects on the bowel functions via rich magnesium mineral water observed improvements in gut motility, GI symptoms and stool consistency over a six-week follow-up in patients with functional constipation [7]. Additionally, magnesium oxide is used for anti-acid properties and has been proven effective in the short-term relief of functional dyspepsia symptoms, in combination with other therapies [8].
Although magnesium benefits are limited in gut motility and gastric acidity, when speaking of the microbiome, the perspectives become more extensive. Some new studies have demonstrated that gut microbiota is directly affected by fluctuance in the dietary magnesium intake. As such, a model animal study revealed that short-chain fatty acids’ concentration and microbiota diversity were enhanced by administration of magnesium oxide and dietary inulin fiber together, rather than administering inulin alone [9]. Additionally, it seems that a magnesium-rich marine blend supplementation has a positive effect on the microbiome’s diversity. An animal study based on 16S RNA sequencing revealed that adding marine magnesium in an adult male rats’ diet resulted in an increased number of gut bacterial species [10]. Additionally, butyrate and propionate levels were increased, which reinstates the involvement of magnesium in short-chain fatty acid metabolism in the gut or the possible enhancement of butyrate-producing microbial strains [11].
The physiologic interplay between magnesium and gut function and microbiome diversity is still scarcely known. An animal study had some contrasting results regarding microbiota and magnesium. In magnesium non-deficient mice, a high-magnesium diet resulted in dysbiosis, but a low-magnesium diet in a normal magnesium baseline resulted in a higher capacity of energy harvest. These results could mean that magnesium has a very sensitive adjustment activity in the gut microbiota [12]. Another animal study administered a low-magnesium diet to a group of mice versus a normal magnesium diet in another group. At four days, the low-magnesium diet mice presented decreased gut Bifidobacterium levels, lower mRNA content at the gut barrier level in the ileum and higher levels of tumor necrosis factor α (TNF-α), Interleukin 6 (IL-6) and activating transcription factor 4, which indicates cellular and oxidative stress. Interestingly, the mice fed with the low-magnesium diet for 21 days presented higher cecal Bifidobacterium levels. Again, dietary magnesium intake may have a time-dependent influence and a sensitive regulating dose-dependent effect on the gut microbiome but, still, more clinical studies are required to fully understand its physiology [13].
Several animal model studies currently state that magnesium deficiency not only alters the microbial profile but also causes psychiatric symptoms. One study proved that a magnesium-deficient diet over the course of six weeks resulted in anxiety behavior in mice [14]. Another animal model study, also observing behavioral changes in magnesium-deficient mice, revealed depressive-like behavior, an altered microbial profile and found increased neuroinflammatory markers [15].
Recent studies promote the use of a combination of magnesium and orotic acid, in the form of magnesium orotate, as an adjuvant treatment in congestive heart failure, hypertension, post-operative cardiac status or in type 2 diabetes. The superior benefits of magnesium orotate reside in the better absorption, intra-cellular accumulation of magnesium, improving muscular endurance and even the antioxidative effect with some anti-tumoral protective effect [16][17][18]. Moreover, magnesium orotate has minimized the damage of nerve cells and enhanced the restoration of nervous tissue morphology [19]. Therefore, hypotheses about using magnesium orotate in neuropsychiatric disorders have appeared in the scientific community. As such, possible associations of magnesium orotate, the gut microbiome and brain biochemical balance should be further studied.

3. The Brain–Gut Axis

Associations of neuropsychiatric pathology with the gut and microbiome have become more evident, initially in terms of functional gastrointestinal disorders in both children and adults. Now, the bidirectional influence of the enteric system and the nervous system is revealed in even more important pathologies, such as major depression, psychosis, neurodegenerative disorders, Attention-Deficit/Hyperactivity Disorder (ADHD), autism spectrum disorders or gastrointestinal autoimmune diseases [20].

4. The Gut–Brain Axis and the Microbiome Physiology

The bidirectional connection between the gut and the brain represents a complex balance and coordination through the central nervous system and the enteral nervous system through sympathetic and parasympathetic axes, the hypothalamic–pituitary–adrenal axis, neurohormones and the autonomous nervous system (Figure 1). This communication has key roles in maintaining the homeostasis of the gastrointestinal system, but also in maintaining the integrity of emotions, motivation and superior cognitive functions. From stress, medication, diet, environmental impact, social and emotional interactions to genetics and epigenetics that shape the physiology of each person with its strengths and weaknesses, the sensitive equilibrium is always challenged [21].
Figure 1. Generic aspect of the bidirectional mechanism of the gut–brain axis (rebuild after Physio-Pedia: https://www.physio-pedia.com/File:Gut_Brain_Microbiome_Axis.png accessed on 26 March 2022).

5. Brain to Gut Connection

The central nervous system, specifically cognition, affects pain areas, modulates the enteral nervous system through the hypothalamic–pituitary–adrenal axis and releases catecholamines, which will activate and sustain inflammation and will alter gut flora, motility and immune function. Proof of this direction has been revealed by clinical studies, where antidepressant, psychodynamic and cognitive behavioral therapies have significantly improved the symptoms of irritable bowel syndrome [22][23].

6. Gut to Brain Connection

The communication path from the intestinal environment to the brain is characterized by local enteral factors such as production and expression of neurotransmitters, and brain-derived neurotrophic factor, integrity of intestinal wall and tight junctions, modulating the bacterial metabolites and local immune system regulation. The brain controls the composition and functions of the microbiome by altering intestinal permeability and allowing bacterial antigens to penetrate the intestinal epithelium, generating immune responses and inflammatory activity. At a larger scale, dysbiosis and inflammation are yet again the causes of disruptions in the gut–brain axis, but this time, at the enteral end of the pathway. The main disruptive factor is supposed to be TNF-α, a pro-inflammatory cytokine that acts both locally and systemically. The rise of TNF-α and other cytokines has been demonstrated to have proportional connections to the severity of anxiety and depression symptoms, and enteral pro-inflammatory signaling is a big part of the hypothesis. Additionally, dysbiosis can cause dysfunctional secretion of neuroactive chemicals such as GABA, 5-HT precursors and fatty acids, or damage the production of brain-derived neurotrophic factor. Dysbiosis can refer to overgrowth or diminished microbiome populations, especially Bacteroides and Firmicutes phyla being involved in these mechanisms (Table 1) [24]. Magnesium’s role in this bidirectional complex mechanism is yet to be fully uncovered by new research, and finding the most bioavailable and efficient form of magnesium is another theme for future studies.
Table 1. Main bacterial genera involved in modulation of the gut–brain axis and possible candidates as combinative therapy alongside magnesium orotate.
Genera Neurochemical Involvement Deficiency Probiotic Therapeutical

Result		 Reference/

Study
Lactobacillus GABA 1, BDNF 2, Vagal stimulation FGID 3, behavior disorders, affective symptoms Decrease intestinal distension, excitability and inflammation; decrease visceral pain by expression of opioid/cannabinoid receptors; mood and affective symptoms’ improvement [24]
Bifidobacterium GABA, 5-HT 4 Depression, anxiety, cognitive impairment, autism, ADHD 5, FGID Behavioral symptom resolution, digestive symptoms clearing, neurodegenerative protection, visceral pain modulation [25]
Bacillus 5-HT Increased intestinal wall permeability, inflammation, oxidative stress, cognitive impairment, behavior and affective disorders Decrease gastrointestinal inflammation, mood regulation [26]
Saccharomyces Myeloperoxidase, acetylcholine esterase Increases gut inflammation, oxidative stress, neuronal damage Reduces inflammatory cytokine, neurodegenerative protection [27][28]
Enterococcus, Lactococcus Dopamine, Histamine Pathogenic bacteria overgrowth, gut inflammation, eating and affective disorders Inhibits pathogenic bacteria overgrowth, reduces inflammation, histologic changes’ improvement, visceral pain reduction, mood and eating behavior improvement [29]
Streptococcus 5-HT Inflammatory response, depressive/anxiety symptoms, cognitive impairment, Autistic Spectrum Disorder (ASD 6) Digestive symptoms relief, cognitive and affective improvement [30]
Bacteroides Currently under study Apparent role in neurodevelopment disorders (ADHD 5/ASD 6), functional digestive imbalances Suggested cognitive/behavioral improvement, gastrointestinal function improvement in children with ASD/ADHD. [31]
1 Gamma-aminobutyric acid; 2 Brain Derived Neurotrophyc Factor; 3 Functional gastrointestinal disorders; 4 5-hydroxytryptamine; 5 Attention-Deficit/Hyperactivity Disorder; 6 Autistic Spectrum Disorder.

References

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