Can Vitamin D Cause Gas in a Baby
Introduction
Vitamin D is a secosteroid and prohormone which can be obtained from food (every bit either vitamin Dii or Dthree), merely whose main source is endogenous production in the skin. This requires ultraviolet-B radiations (290-315 nm) of at least 18 mJ/cm2 intensity (one), inducing the formation of previtamin D3 from 7-dehydrocholesterol which later on converts to vitamin Diii (cholecalciferol) past body heat (2). Upon reaching the blood, vitamin D3 mainly binds to vitamin-D binding protein (DBP) and gets transported to the liver where it is transformed into its storage course calcidiol (25-hydroxyvitamin D3 or 25(OH)D3) through hydroxylation via the vitamin Diii 25-hydroxylases CYP2R1, CYP27A1 or CYP27B1, all members of the cytochrome P450 enzyme family (3, 4). 25(OH)D3 is the chief laboratory parameter to judge an individual's vitamin D status; concentrations <20 ng/ml (1ng/ml = ii,5 nmol/l) are considered every bit vitamin D deficiency, and 40-60 ng/ml equally ideal (2, 5). 25(OH)Dthree is metabolized in diverse tissues (predominantly the kidneys) to the biologically about active vitamin D hormone calcitriol (i,25-dihydroxyvitamin D or 1,25(OH)2D3) with another hydroxylation at the 1α position by CYP27A1 or CYP27B1 (3, 4). Too regulating calcium metabolism, ane,25(OH)2Diii has multiple pleiotropic furnishings, particularly within the allowed system, and is increasingly utilized not merely within prophylaxis, just also inside therapy of various diseases (ii, six, 7). In particular, binding of one,25(OH)2D3 to the vitamin D receptor (VDR) has been shown to inhibit the differentiation and proliferation of B and T helper (Th) lymphocytes, promoting the shift of an inflammatory to a more tolerant immune status which may explain the protective furnishings of vitamin D against autoimmune diseases [reviewed in (8)].
More recently, Slominski and colleagues have revealed alternative pathways of vitamin D metabolism mediated past the mitochondrial enzyme CYP11A1 which is able to hydroxylate the side chain of vitamin D2/Dthree (9–11). The main production of these reactions is 20-hydroxyvitamin D3 (20(OH)D3), which has a 20-30-fold lower concentration than 25(OH)D3 in human being serum (9, 11) and is the initial substrate for the formation of further hydroxy-derivatives such as 20,23(OH)twoDthree, 17,xx,23(OH)iiiD3 or 20,22(OH)iiDiii [reviewed in (12)]. These nonclassical vitamin D metabolites also act as hormones: besides being partial agonists of the VDR, they take loftier analogousness as agonists of the aryl hydrocarbon receptor (AhR) (13) and as inverse agonists of the retinoid-related orphan receptors (ROR) α and γ (14, fifteen). Notably, CYP11A1 is expressed in immune cells (16) and RORα and RORγ are expressed by inflammatory Th17 cells in which they synergistically regulate differentiation and inflammatory cytokine production (17). Th17-derived cytokines, notably interleukin (IL)17, have been implicated in the etiology of autoimmune disorders such every bit psoriasis (18) and multiple sclerosis (MS) (19). In addition, single nucleotide polymorphisms (SNPs) of the RORA cistron accept been associated with MS (twenty). The binding of ane,25(OH)iiD3, twenty(OH)D and other vitamin D hydroxy-metabolites to both RORα and RORγ, result in IL17 inhibition (14), thus providing another machinery distinct from VDR signaling how vitamin D may protect from, or convalesce symptoms of, autoimmune diseases.
For approximately 15 years, patients with autoimmune diseases, particularly MS, take been successfully treated using a loftier-dose vitamin D protocol. Considering this method has been developed by Prof. Dr. Cicero Coimbra in Sao Paolo, Brazil, it is ofttimes referred to as the "Coimbra protocol"; in Deutschland it is utilized since 2016. Underlying the Coimbra protocol is the hypothesis of a non-hereditary, just acquired grade of vitamin D resistance which this newspaper is going to examine.
A hallmark of acquired vitamin D resistance, if it exists, would be an elevated parathyroid hormone (PTH) concentration despite 25(OH)Diii levels being in the ideal range and thus indicating sufficient production of 1,25(OH)2D3. One cardinal role of i,25(OH)2D3 is to enhance intestinal calcium absorption. If ionized calcium concentrations in blood are low, the parathyroid glands release PTH which stimulates calcium release from bones. Furthermore, PTH increases the conversion of 25(OH)D3 into i,25(OH)iiDiii in the kidneys with subsequent release into circulation. PTH besides inhibits the tubular reabsorption of phosphate which in plough lowers the corporeality of water-insoluble calcium-phosphate salts and thus increases ionized calcium concentrations. In this way, PTH constitutes a direct feedback mechanism inside the vitamin D system. A physiological 25(OH)Diii level should thereby exist able to suppress PTH into the lower third of the reference range. In other words: If 25(OH)Diii levels are high, PTH should be low and vice versa. In patients with autoimmune diseases this negative feedback loop is disturbed. Based on these observations, Prof. Coimbra proposed the hypothesis of a vitamin D resistance.
The Hypothesis of Acquired Vitamin D Resistance
In two intervention studies, Carlberg and colleagues institute evidence that different individuals brandish a unlike molecular and biochemical response to the same dose of either long-term or single-bolus vitamin Dthree supplementation (21). Initially, in the VitDmet written report, 71 elderly prediabetic individuals were supplemented with either 0, 1600 or 3200 I.U. vitamin D3 daily over 5 months of Finnish winter (22). The focus of this work was on the furnishings of vitamin D3 supplementation on mRNA expression of twelve of the vitamin D-regulated genes and several vitamin D-affected laboratory parameters. With the aid of these biomarkers, the grouping was able to show in 2022 that even supposedly adequate high vitamin Dthree doses (3200 I.U.) were not able to exert the expected vitamin D-regulatory effects in all subjects. Focusing on the PTH feedback system lonely, a total of 25% of the patients showed no adequate response of this laboratory parameter. Regarding all 36 tested parameters, Carlberg et al. could cluster their patients in 24% depression responders, 51% mid responders and 25% loftier responders. In 2017, the group was able to reproduce these findings in the VitDbol study, in which a accomplice of healthy Finnish students received a eighty,000 I.U. bolus dose of vitamin D3 with similar low responder rates (23).
These data provided an in vivo confirmation that there exists a spectrum of different vitamin D responsiveness, with approximately 25% of a population not responding adequately to conventional vitamin D3 doses. They may require individually varying, only larger doses. Vitamin D resistance, as proposed by Prof. Coimbra and this commodity, could exist conceived as the extreme depression-response end of the vitamin D responsiveness spectrum. Accordingly, individuals existence vitamin D resistant would require very high doses of vitamin D3 supplementation to reach an adequate physiological response, such as a reduction of PTH concentrations or the down-regulation of an activated adaptive immune organization – the latter issue is important for the treatment of autoimmune diseases as discussed further below.
Indeed, the idea of vitamin D resistance has beginning been proposed in 1937 by Albright, Butler and Bloomberg based on the observation that in rare cases of rickets in children, very high doses of vitamin D were required to relieve symptoms (24). Information technology has later been shown that resistance to 1,25(OH)2D3 in such children is frequently caused past hereditary VDR defects, resulting in hypocalcemia, secondary hyperparathyroidism, rickets and in most one half of the patients baldness (25–27). In contrast to these cases of hereditary vitamin D resistance, which is very rare and already diagnosed in childhood, the hypothesis investigated in this paper concerns a non-hereditary, acquired form of vitamin D resistance which promotes the development of autoimmune diseases. Equally discussed in more particular below, such a course of vitamin D resistance could develop during crumbling based on an interaction between genetic susceptibility polymorphisms of the vitamin D arrangement and an aggregating of environmental factors additionally impairing the hormonal signaling of the vitamin D-derived hydroxy-metabolites. Acquired vitamin D resistance is therefore more common than hereditary vitamin D resistance according to the frequency of susceptibility polymorphisms and the rising incidence of autoimmune diseases.
Diagnosis of Vitamin D Resistance
In their article "The concept of the personal vitamin D response index", Carlberg and Haq (21) proposed the following: "A screening using a single vitamin D bolus treatment and measurements at days 0 and two paired with a simplified protocol of the molecular analysis used in the VitDbol study [… ] may exist the easiest style to identify persons with a low vitamin D response index" (21). Theoretically, people with acquired vitamin D resistance should also be found with this protocol as outliers with extremely low response indices. Yet, the majority of the biomarkers measured in the VitDbol written report tin only be determined in research laboratories. However, PTH provides a valuable and easy-to-measure out biomarker for the clinical therapist. As mentioned to a higher place i,25(OH)2D3 and PTH stand in a directly human relationship with each other. A high PTH concentration in turn is associated with a higher all-cause-mortality in epidemiological studies (28). Hence, the recommended optimal 25(OH)D3 level of >40ng/ml should correlate physiologically with an optimal PTH concentration. Because reference ranges and measurement units for PTH vary amidst different laboratories, it could be stated that a 25(OH)Dthree measurement >40 ng/ml should be associated with a PTH value in the middle of the lower third of its laboratory-specific reference range. In such a case, loftier PTH values are indicative for vitamin D resistance, assuming that dietary calcium and phosphate intake are acceptable and a differential diagnosis of hyperparathyroidism has been ruled out. For example, if a laboratory'southward reference range for PTH is 15-65 ng/ml, the centre of the lower third of that range would exist 23.3 ng/ml.
Furthermore, the constellation of high serum 1,25(OH)twoD3 concentrations with a concurrently physiological 25(OH)Diii concentration is known to occur in hereditary forms of vitamin D resistance or VDR knockout mice (29); it could therefore also exist indicative of acquired vitamin D resistance. The 1,25(OH)2D3 concentration is determined on the one hand by the action of the enzymes CYP2R1, CYP27A1 and CYP27B1 that catalyze production of one,25(OH)iiD3 and on the other mitt CYP24A1 which catalyzes one,25(OH)2D3 degradation. The inactivation of i,25(OH)2D3 occurs either systemically or locally within the cells of target tissues. Because PTH negatively regulates CYP24A1 and positively regulates the hydroxylases converting 25(OH)D3 to 1,25(OH)iiD3, the presence of vitamin D resistance, which results in low intestinal calcium absorption and thus PTH stimulation, would lead to a abiding acme of 1,25(OH)iiD3.
In case of a disturbed VDR response, e.grand., caused by SNPs, an increased 1,25(OH)2D3 concentration is urgently needed to maintain the integrity of VDR signaling. Therefore, an elevated PTH concentration tin result from vitamin D resistance mediated by dysfunctional VDR signaling. It follows that a decreased 25(OH)D3/1,25(OH)2D3 ratio could be perceived every bit a biomarker for vitamin D resistance. However, because PTH tiptop is causally responsible for an increased ane,25(OH)2D3 level, PTH is a clinically sufficient sensitive surrogate biomarker for vitamin D resistance (Figure 1). Especially since, according to our feel, a disturbed 25(OH)D3/1,25(OH)2Diii ratio is perceived as not sufficiently reliable. A reason could be that some cases of vitamin D resistance are based on SNPs in enzymes catalyzing product of 1,25(OH)2D3 such as CYP27B1, as originally proposed by Coimbra and his co-workers (xxx). In this case, PTH would exist elevated, but its activity on expression of this dysfunctional enzyme is not sufficient to heighten 1,25(OH)twoD3 levels.
Effigy 1 Vitamin D metabolism and the sites of vitamin D resistance acquirement. Vitamin D3 is mainly produced in the skin through solar ultraviolet-B (UVB) radiation and gets transported through claret by binding to vitamin D bounden poly peptide (DBP). The liver is the systemic production site of 25(OH)Diii via the enzymes CYP2R1, CYP27A1 or CYP27B1. 25(OH)D3 then gets converted to the agile hormone i,25(OH)2D3 by a second hydroxylation which occurs mainly in the kidneys or in other tissues through paracrine production. 1,25(OH)2Diii binds to the vitamin D receptor (VDR) to promote intestinal calcium (Ca) assimilation and other Ca-mobilization pathways (e.g. in os), so that ionized Ca levels in serum ascension. The paraythroid glands sense Ca2+ levels, and secrete parathyroid hormone (PTH). PTH in turn promotes the production of 1,25(OH)2Diii, due east.g. by inhibiting CYP24A1 which catalyzes the showtime degradation step of 1,25(OH)2D3. Likewise 1,25(OH)iiD3, in that location are other vitamin D3-derived hydroxy-metabolites that exert hormone-like actions. For case, peel besides expresses CYP11A1, which promotes the conversion of vitamin Diii into 20(OH)D3, which has non-calcemic biological effects, for instance on immune cells. The blue flashes show where polymorphisms can interfere with normal vitamin D metabolism, building the basis for the development of caused vitamin D resistance. Boosted factors that impair vitamin D signaling are highlighted in bluish boxes.
Evolution of Vitamin D Resistance
Equally we have just illustrated, susceptibility for vitamin D resistance could arise from multiple polymorphisms of genes expressing for different proteins within the vitamin D system: the cytochrome-P450 enzymes (hydroxylases) needed for the conversion of vitamin D2/Diii into the activated hormone form (CYP2R1, CYP27A1 and CYP27B1), the DBP needed for vitamin D transport, the jail cell-surface receptor megalin-cubilin, which is the membrane receptor for the i,25(OH)2D3/DBP complex, the VDR itself or the recently discovered other receptors for vitamin D hydroxy derivatives such as RORα and RORγ. Indeed, inactivating polymorphisms of the CYP2R1 (31) or CYP27B1 (32) genes, promoter polymorphisms of CYP24A1 (33) or RORA (twenty), and SNPs of the VDR cistron (34–38) have all been associated with autoimmune diseases. All the same, equally suggested by research on hereditary vitamin D resistance, the VDR is probably the almost vulnerable office of the vitamin D metabolic system and constitutes the nigh likely or at least most potent manifestation of acquired vitamin D resistance.
The Vitamin D Receptor
The VDR is a steroid receptor expressed in almost all cell types of the human trunk, in item well-nigh allowed cells (38). The intracellular distribution of the VDR is ordinarily 75-80% in the nucleus, 15-xx% in the cytosol and three-5% in the plasma membrane (39). Bounden of 1,25(OH)2D3 induces translocation of cytosolic VDR into the nucleus in a dose-, fourth dimension- and temperature-dependent manner (40). In the nucleus, the liganded VDR forms a heterodimer with the unliganded retinoid-X receptor which so binds to DNA and recruits either coactivator or corepressor proteins and other transcription factors to exert gene regulatory functions (39). Due to this holding, the VDR is classified as a member of the nuclear receptor family. Other members of this "superfamily" of nuclear receptors are, among others, the thyroid receptor, the estrogen, progesterone and testosterone receptors, the retinoid-Ten receptor every bit well as the cortisol receptor (41). The high importance of the VDR is underscored past the slap-up number of genes that it regulates, both as a classical transcription cistron and through epigenetic furnishings (42). For instance, Seuter et al. take shown that one,25(OH)2Dthree binding to the VDR modulated the transcription of 1204 genes in the human monocytic cell line THP-1 over 24 hours, mostly by modulating the accessibility to their respective chromatin regions (43). The 46 chromatin strands, which mensurate up to 5 cm in length and have a diameter of approximately 0.01 mm, are thereby modified in a way that opens upward the target genes for reading (44). This epigenetic function of the VDR is exerted in almost all tissue types, which underlines its important role equally a regulatory protein well beyond its known function in calcium metabolism (42, 43).
Critically, several VDR SNPs have been revealed that are increasingly associated with multiple autoimmune diseases, either individually or equally haplotypes (34–38). For MS, e.g., a recent meta-analysis revealed a significant clan with rs731236 (TaqI) polymorphisms when comparing heterozygous (Tt) with homozygous (TT) genotypes (45). The rs731236 GG genotype was also a significant predictor of low vitamin D responsiveness in a supplementation written report of 100 Arab women, together with the rs7116978 (CYP2R1 factor) CC genotype (46). This study as well provided an overview showing that the rs7116978 G allele and rs7116978 C allele reached loftier population prevalence of upward to 40% or seventy%, respectively, depending on ethnicity (46). Information technology is known that certain haplotypes of VDR polymorphisms can influence its mRNA expression levels, stability and protein translation efficiency (47). Furthermore, work of Berth et al. who studied polymorphisms within the context of VDR binding to genes in human monocytes and dendritic cells, suggests that certain polymorphisms predispose to autoimmune diseases by perturbing VDR binding at autoimmune affliction take a chance gene variants (38). In other words, SNPs of the VDR may predispose to caused vitamin D resistance, which may become manifest during aging and lead to the development of an autoimmune disease, if additional factors accumulate that contribute to an impairment of VDR signaling. These factors will be reviewed in the next subsection.
The Vitamin D Receptor Is Regulated by Multiple Factors
With first evidence for a VDR in 550 1000000-year erstwhile boneless vertebrates, the VDR is a long-established regulatory poly peptide (48). From an evolutionary perspective it appears plausible that such a conserved and seminal protein is bailiwick to multiple influencing factors. We elaborate on this using the instance of the glucocorticoids in relation to the VDR.
Glucocorticoids (cortisol, cortisone) are excreted as part of a stress reaction (fight or flight, psychological stress) and ensure the supply of energy needed to solve the problem at hand. Within this context, the inhibition of the VDR appears logical, since it would ensure the shift of energy from the allowed to motor systems. Still, if the VDR is chronically inhibited, due east.g., upon long-term cortisone handling or chronic stress, this would explain the occurrence of pathological consequences such as osteoporosis. The clinically important immune-suppressive effect of glucocorticoids could be explained in part by the VDR blockade. Also the positive allowed modulatory issue of low-dose cortisol treatment could be due to an influence on the VDR.
The literature contains an increasing number of data confirming this hypothesis. For example, chronically elevated glucocorticoid levels have been shown to compromise the effects of 1,25(OH)iiDthree and promote the development of osteoporosis (49). Assistants of 10 mg prednisolone, an bogus glucocorticoid, for seven days to salubrious males resulted in enhanced renal calcium excretion, an elevation of biomarkers of bone degeneration and an increase in PTH levels. These effects could be compensated by the assistants of 1,25(OH)iiD3 (l). Another study showed that dexamethasone, another synthetic glucocorticoid, is able to potentiate the VDR-mediated transcription of CYP24A1 by a mechanism involving the recruitment of the glucocorticoid receptor to the CYP24A1 promoter region and its cooperation with C/EBPβ; since CYP24A1 catalizes the first step of i,25(OH)iiDiii deposition, dexamethasone effectively reduced i,25(OH)iiD3 concentrations (51). Finally, multiple putative glucocorticoid responsive elements could be identified inside the VDR gene, which suggest a regulation of VDR expression through endogenous glucocorticoids (52). This is consistent with type II diabetics having both college cortisol secretion (53) and lower VDR mRNA and protein levels (54) compared to healthy controls. In general, both inhibitory and activating tissue-specific furnishings on the VDR could be observed upon dexamethasone administration (52, 55).
Estrogens appear to positively stimulate vitamin D metabolism through a direct effect on the VDR (56, 57). An activation of the thyroid receptor, on the other hand, tin can have an inhibitory effect on vitamin D regulation via the VDR (58). These examples demonstrate that the response of the VDR tin can be modulated past a diverseness of physiological influences.
In addition, farther pathophysiological mechanisms take emerged during the evolution of life. Due to the profound influence of vitamin D on the immune system it appears reasonable from an evolutionary standpoint to view the VDR every bit a strategically of import target for pathological insults that aim to evade the immune arrangement. For multiple tumor cell lines an anti-proliferative issue of one,25(OH)2Dthree has been described (34). An attenuation of these anti-proliferative furnishings would confer a growth advantage for tumor cells. Along these lines, colorectal cancer cells have been shown to regulate the expression or responsiveness of the VDR (59). A blockade of the VDR was likewise revealed equally the pathophysiological mechanism exploited by osteosarcoma cells (sixty).
An increasing number of studies likewise depict the VDR as a strategic target of various pathogens. Lipopolysaccharides for example, which are sepsis inducing bacterial toxins, inhibit the expression of the VDR within THP-1 human monocytes (61).
In mammals, one of the central functions of the protein caspase-3 is the induction of programmed cell death (apoptosis). Thereby, information technology is maybe necessary to inhibit cellular vitamin D metabolism. Indeed, information technology was shown that caspase-3 is able to inhibit vitamin D metabolism by binding to and inactivating the VDR (62). Pathogens such as A. salmonicida, Legionella pneumophila, E. coli or Yersinia spp. in turn are able to interact with, or activate caspase-3 within cells, in this manner inhibiting the VDR and attenuating the immune response of their host (62, 63).
Blockade of the VDR has besides been described for other pathogens. A carefully conducted study has investigated the impact of Borrelia burgdorferi on the transcriptome of monocytes using whole genome microarrays [Supplementary Table S2 in (64)]. This technique revealed a sixty-fold downregulation of the VDR past live Borrelia. In man B lymphocytes, information technology was shown that their infection with Epstein-Barr-virus (EBV) inhibits VDR mRNA and protein expression (65). Yenamandra et al. confirmed this VDR blockade through EBV in B lymphocytes (66) and after showed that the EBNA-3 poly peptide is responsible for this blockade by its affinity to demark to the VDR (67). Finally, human being cytomegalovirus induced a 88% inhibition of VDR expression in infected cells, leading to a gradual increment of the CYP27B1 gene to 970%; notably, no downregulation of the VDR was observed for influenza or adenovirus infection (68). The mechanisms how pathogens disrupt vitamin D signaling may provide a missing link betwixt the clan of infections and autoimmune pathogenesis. Indeed, pathogen infections have been discussed as triggers of autoimmune diseases for a longer time (69). For example, infections with campylobacter, EBV or influenza viruses have been causally connected to the development of Guillain-Barré syndrome (70). Attention has also been paid to the link between EBV infection and MS development (71). As described above, blockade of the VDR by EBV could thereby provide a plausible underlying mechanism behind this link.
In summary, all these examples demonstrate a more or less potent influence on the vitamin D system via the VDR by physiological and pathophysiological influences. In particular, the pathogen-mediated temporary or chronic blockade of the VDR can be explained from an evolutionary view in which pathogens have developed ways to assault this primal target in order to downregulate their host'due south immune response. We thus propose the hypothesis that an interplay between acquired blockades of the VDR and polymorphisms affecting autoimmune disease susceptibility in either the VDR or other genes of the vitamin D organization are able to cause a progressively severe form of low vitamin D responsiveness, which nosotros refer to as acquired vitamin D resistance and which ultimately mediates the development of an autoimmune illness (Figure 2). Ii other autoimmune disease-related factors fit nicely into this picture, namely a lack of sun exposure and the aging process, as abdominal vitamin D3 absorption (72), endogenous pare production (73) and hydroxylation (74) all have been shown to decrease with aging. Finally, environmental toxins could besides exist integrated into this hypothesis if they interfere with vitamin D metabolism. For case aluminum, which has been found in loftier concentrations in brain tissue from MS patients (75), was able to decrease renal CYP27B1 activity in the chick (76). Hither, future inquiry on the effects of ecology toxins such as aluminum and cadmium on the vitamin D organization is urgently needed.
Figure 2 The etiology of acquired vitamin D resistance. Polymorphisms of genes inside the vitamin D organisation constitute the basis for a susceptibitly towards developing vitamin D resistance, and hence autoimmune diseases. Partial blockades of the vitamin D receptor through pathogens, glucocorticoids (chronic stress) and – putatively – environmental toxins such as heavy metals may collaborate with such a susceptibility then that vitamin D resistance emerges. Finally, depression sun exposure and aging, which correlate with autoimmune diseases likewise, volition exacerbate this state of affairs further.
Discussion
Consequences of Vitamin D Resistance
The expression of the VDR every bit a factor regulatory poly peptide in nearly all tissues of the man body suggests functional roles well beyond those classically associated with calcium metabolism. Along these lines, vitamin D is more and more than viewed equally essential for maintaining physiological homeostasis. Vitamin D deficiency is associated with a plethora of cardiovascular and metabolic diseases including cancer, hypertension, infectious and autoimmune diseases (ii, 7, 34). The proof of VDR expression in multiple prison cell types of the immune system such as CD4+/CD8+ lymphocytes, neutrophils and activated T-cell lymphocytes or antigen presenting cells (monocytes, macrophages or dendritic cells) underlines the importance of this receptor within this system (38). Mechanistically, multiple unlike furnishings of i,25(OH)twoDiii on the immune system accept been described, including, just not express to, chemotaxis, phagocytosis, proliferation, differentiation, cytokine production, antigen presentation, antibiotic, cathelicidin and hydrogen peroxide production and memory cell buildup (34). Only recently, Carlberg et al. identified a number of key genes of the allowed system which are expressed by the VDR upon 1,25(OH)2D3 activation (48). Likewise genes whose proteins play an essential role within the innate immune organization by producing antimicrobial peptides, another group of proteins was identified which are closely connected to autoimmune processes. An example is the transmembrane poly peptide Ninjurin1 (NINJ1) which is regulated by one,25(OH)2Dthree. NINJ1 is involved in transmigration of antigen-presenting cells across the blood-brain barrier and in the pathogenesis of MS (77).
In that location also is an epigenetic influence of the VDR on genes of the immune system. An in vivo proof-of-principle study investigated chromatin accessibility in monocytes obtained from a human subject field before and after a vitamin D bolus dose of 2000 µg (80,000 I.U.) (78). The bolus dose, which raised 25(OH)D3 levels by 7.6 ng/ml later on ii days, resulted in a significant opening or endmost of hundreds of gene loci, the most prominent of which belonged to the man leucocyte antigen (HLA) organisation coded on chromosome six. With the help of antigen-presenting proteins of the HLA system, the immune system is able to differentiate betwixt endogenous and exogenous proteins. Therefore, a dysfunction within the HLA arrangement predisposes for the development of autoimmune diseases. Polymorphisms of the HLA system for example found the most meaning genetic influence on MS (79). Interestingly, a vitamin D responsive element could be identified at a factor within the HLA-DRB1 region, which is closely associated with the evolution of MS (80). Likewise the epigenetic influence, this finding also underlines the transcriptional effect of vitamin D on the pathogenesis of this disease.
Looking across the box of autoimmune diseases to the mounting show of Vitamin D as a player in tumor development (81, 82), meaning associations between SNPs of vitamin D system genes and mutual types of cancer (prostate, breast, colorectal and skin cancer) take been reported (83, 84), suggesting a similar predisposing role of SNPs for cancer as for autoimmune diseases. In these cases, a partial blockade of the VDR by pathogens could be some other pathway within the established infectious etiology of cancer (85, 86).
In summary, there is much plausibility for caused vitamin D resistance playing a pathological role in the development of autoimmune diseases, in this manner providing an important component for our understanding and explanation of these diseases.
Therapy of Vitamin D Resistance
Currently no causal and therefore reliable therapies exist for correcting a blockade of the VDR. The just constructive therapy to engagement is the high-dose vitamin D protocol, known subsequently its inventor as the Coimbra protocol (30). With upwards to approximately k I.U. vitamin Dthree per kg body weight, the highest therapeutic vitamin D starting doses are thereby administered for the treatment of MS. For other autoimmune diseases much lower doses appear sufficient (Table ane). Hypercalcemia may be a major concern raised against this protocol. However, as discussed in more detail below, the vitamin D resistance appears to confer an intrinsic protection confronting hypercalcemia. In addition, the therapy requires the patient to take some precautionary measures. Too the avoidance of milk products and a minimum fluid intake of 2.5 50/solar day, patients will need to consistently monitor multiple blood parameters and undergo regular sonographic checks of their kidneys. Practically, this requires close and regular contact with a certified Coimbra practitioner.
Tabular array 1 Initial vitamin Diii doses used within the Coimbra protocol for the treatment of autoimmune diseases.
The Coimbra protocol follows a long medical tradition in which receptor resistances are compensated by applying higher doses. This is exemplified using a simplified analogy of insulin resistance therapy:
The current practice in type 2 diabetes direction consists of calculating the required external insulin dose according to blood glucose levels. Thereby it is nearly irrelevant how high the injected insulin dose actually is. It is the correction of the target parameter, i.due east. claret glucose, which is pivotal. To achieve this goal, total daily insulin doses exceeding 100 I.U. can exist utilized (87). These are doses that would normally be toxic in the absence of an underlying insulin resistance. The diabetic patient is to some extent protected against astringent side effects of what would commonly exist considered an overdose, because this dose simply acts physiologically – provided the practical doses are calculated correctly and there is close supervision by a doctor.
Although we acknowledge that the causes of insulin resistance are very different from those of vitamin D resistance, and loftier-dose insulin injections crusade insufficiently more side effects than high-dose vitamin D3 injections, the above illustration illustrates the principles of the Coimbra protocol: The calculation of the required vitamin D dose depends on the grade of vitamin D resistance and the stage of the particular disease and incorporates the PTH concentration in illustration to the insulin/claret glucose example. Provided shut supervision by an experienced physician, the applied high doses of vitamin D3 are causing neither hypercalcemia nor kidney damage. They will only exert physiological effects – in this fashion, the underlying vitamin D resistance acts protective against what would normally be considered a potentially toxic dose. In Supplementary Table 1 nosotros provide data collected in the corresponding author's practise (DL) revealing no case of calcium circuit in a cohort of 41 patients observed over at least 6 months. The development of their PTH concentrations is plotted in Figure iii and shows a significant decline at three months follow-up.
Figure 3 Longitudinal PTH measurements in a cohort of 41 relapsing-remitting multiple sclerosis patients treated by the corresponding author (DL) with the Coimbra protocol. Black lines indicate the median, blue crosses the hateful. At three months follow-up, PTH levels had dropped significantly compared to the baseline measurement (Wilcoxon rank sum test, p<0.001), while there were no significant differences between any of the follow-up measurements. The reduction of PTH concentrations into the middle of the lower tertiary of its laboratory-specific reference range is judged every bit an indicator for overcoming vitamin D resistance.
However, one case of a 39-year quondam symptomatic MS patient with hypercalcemia and renal insufficiency has been reported by a Swiss team of physicians (88). After 7 months on the Coimbra protocol with 100,000 I.U. of vitamin D3 daily, his calcium concentration at infirmary admission was three.0 mmol/L, his 25(OH)D3 level 697 ng/ml (1742 nmol/50), and his PTH was 96 ng/50. The PTH level was thus much higher than typically observed on the Coimbra protocol (Figure 3). A possible caption is that the patient was a carrier of the Multiple Endocrine Neoplasia, type 1 (MEN1) gene and had a history of elevated PTH levels already prior to starting the Coimbra protocol. Although this case highlights the possibility of high-dose vitamin D toxicity within the Coimbra protocol, it appears to be very rare. Even so, it too highlights the need for a diagnostic assessment of hyperparathyroidism prior to initiating the protocol equally well as a regular endocrinological monitoring during therapy. It is noteworthy that the patient described in the instance report wanted the authors to provide a brief account of his own standpoint according to which he and other patients he knew had improved their MS symptoms significantly on the protocol (88).
Such subjective improvements of autoimmune affliction patients likewise as condom data have also been collected within the network of Coimbra protocol physicians in Germany; these will be subject to future publications.
Finally, nosotros would briefly like to mention the opinion held past some therapists that vitamin D administration is counterindicated in patients with vitamin D resistance. This hypothesis is inconsistent with the medical experience and understanding according to which resistances tin be compensated with normal-to-high doses as described above. In particular, it is inconsistent with the experience gained past many Coimbra protocol physicians specialized in high dose vitamin D therapy that accept nerveless many treatment successes thus far.
In summary, we have reviewed bear witness for the hypothesis of an acquired form of vitamin D resistance, developing on the basis of a genetic susceptibility from sure SNPs within the vitamin D system and its interplay with chronic stress and/or pathogen infections that are able to partially cake the VDR. Other factors that have been associated with autoimmune diseases such as depression sun exposure, aging or environmental toxins could easily be integrated into this hypothesis since they would further exacerbate developing vitamin D resistance arising from the described mechanisms (Figure 2).
The hypothesis of acquired vitamin D resistance thus provides a plausible pathomechanism for the development of autoimmune diseases. We consider its therapeutic exploitation by loftier-dose vitamin D assistants as a promising arroyo. Our key messages reflecting the knowledge about vitamin D resistance and its treatment are summarized in Table two.
Table 2 Cardinal points discussed in this paper.
Information Availability Statement
The original contributions presented in the study are included in the article/Supplementary Material, farther inquiries can be directed to the corresponding authors.
Author Contributions
DL and RJK drafted the initial manuscript. DL and BS collected the information. FS and JS edited the manuscript. All authors contributed to the commodity and approved the submitted version.
Disharmonize of Involvement
DL and BS are certified Coimbra practitioners. BS owns the practise that apply the here described Coimbra protocol to patients with autoimmune diseases.
The remaining authors declare that the research was conducted in the absense of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can exist found online at: https://www.frontiersin.org/manufactures/10.3389/fimmu.2021.655739/full#supplementary-material
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