Open access peer-reviewed chapter - ONLINE FIRST
Abstract
In the latest years, researchers demonstrated a two-way interaction between a balanced diet with sufficient essential micronutrients and the immune response. Unbalanced nutrition can cause a micronutrient deficiency, affecting the susceptibility and severity of infections. It is well known that micronutrients such as vitamins (A, C, D, E, B6, and B12), folic acid, iron, copper, zinc, and minerals play a vital role in the immune system, having a direct influence on antibody formation. From all the micronutrients analyzed, vitamin D has the most important influence on the immune system by regulating innate and adaptive immune responses in bacterial, viral, or fungal infections. All the studies published highlight a strong connection between vitamin D deficiency and the pathogenesis of several infectious diseases.
Keywords
- vitamin deficiency
- vitamin D
- infectious diseases
- bacterial infections
1. Introduction
The study of the main cause of rickets, a condition characterized by skeletal deformities and known as “the English disease,” brought to the discovery of vitamin D and the connection of its deficiency with the development of this condition [1, 2].
In recent years, a growing number of studies have been published highlighting the importance of a well-balanced diet for maintaining a healthy body due to the involvement of micronutrients such as vitamins and minerals in all the biochemical and immunological processes [3, 4, 5]. Of all these micronutrients, vitamin D plays a critical role and is an essential micronutrient for human health. Due to the high prevalence of vitamin D deficiency and the potential role of this deficiency in the etiopathogenesis of many diseases, a multitude of research studies have been conducted worldwide. All their results demonstrated and explained the role of this vitamin in different illnesses such as osteoporosis, autoimmune diseases, different cancers, cardiovascular pathologies, and infectious diseases [6, 7].
The SARS-COV-2 pandemic has been one of the most important worldwide challenges affecting everyday life. All the studies conducted since the begging of this pandemic showed that the complications of the lower respiratory tract had a higher prevalence for patients with vitamin D deficiency, a deficiency caused by food and changing habits during the pandemic. Also, some meta-analyses showed that vitamin D supplementation had a beneficial role by reducing severe complications and enhancing anti-inflammatory, antioxidant, and immunomodulatory responses in SARS-COV2 infections [8, 9].
2. Vitamin D metabolism
Vitamin D, a fat-soluble steroid hormone, is mainly responsible for controlling the absorption and homeostasis of calcium, magnesium, and phosphate. Also, it has an important role in regulating immune and inflammatory responses and maintaining human health [9]. Vitamin D exists in two forms: cholecalciferol (or vitamin D3), found in animal sources, and ergocalciferol (or vitamin D2), found in plant sources [2].
In humans, two sources of vitamin D production have been described. The first and main source also represents a unique property of this vitamin. The metabolic process of vitamin D starts in the skin from exposure to ultraviolet (UV) rays [6, 10, 11]. The second source of vitamin D is represented by a list of a few foods naturally enriched in vitamin D, but dermal synthesis remains the main source (90% of vitamin D replenishment) [2].
During exposure to UV irradiation (spectrum 280–320 UVB), 7-dehydrocholesterol (7-DHC) found in the skin is converted to pre-vitamin D3 (pre-D3), which isomerizes to vitamin D3 in a thermos-sensitive process. The rate of D3-formation depends on UVB intensity, which varies to season or latitude and level of skin pigmentation (UVB can be blocked by the quantity of melanin in the skin). Also, sunscreen and clothing can limit D3 production [2, 6].
Vitamin D3 synthesized in the skin is biologically inactive and needs further enzymatic conversion in order to activate. After binding to vitamin D binding protein (VDBP), D3 enters the lymphatic system and venous blood. Through the circulatory system, D3 undergoes in the liver 25-hydroxylation to 25-hydroxyvitamin D (25(OH)D), which represents the most important circulating form of vitamin D. Its plasma level is used as a biomarker for VB status. Further, a second hydroxylation of 25(OH)D turns into calcitriol (1,25(OH)2D—most active form) through 1-alpha-hydroxylation at the kidney level. Parathyroid hormone (PTH) plays an important role in regulating this process. Also, growth hormone or hypophosphatemia may be involved in this process. Enzyme 1-alpha-hydroxylase is primarily found in kidneys, but its presence has also been described in other places with the possible autocrine-paracrine role of 1,25(OH)2D such as alveolar macrophages, osteoblasts, lymph nodes, placenta, colon, or breasts [2, 12].
When it comes to dietary intake, VD is produced in much smaller proportions because few foods naturally contain forms of VD. D2 is produced from ergosterol found in plants and fungi (e.g., mushrooms) under UVB irradiation, while D3 is found in oily fish. Because of molecular structure differences between D3 and D2, D2 has a lower affinity to DBP with a faster clearance from the circulation and a limited conversion to 25 (OH)D [2, 11].
3. Vitamin D deficiency
Even though vitamin D positively impacts human health, deficiency of this vitamin is still common, according to epidemiological studies. It is estimated that almost 50% of the population across the world has vitamin D deficiency. Institute of Medicine (IOM) has recommended values of 25(OH)D between 21 and 29 ng/mL or less than 0.8 IU in order to define a VDD [6, 7, 10].
The most important VD source for children and adults is represented by exposure to natural sunlight. Studies have shown that sunscreen with an SPF of 30 can reduce by more than 95% the VD synthesis. Also, people with naturally dark skin tones require longer exposure than white people, and body mass index (BMI) is associated with a deficiency of VD. Low levels of VD determine abnormalities in calcium, phosphorus, and bone metabolism by decreasing the absorption of dietary calcium and phosphorus associated with increased PTH levels. These metabolic deficiencies increase osteoclastic activity, resulting in osteopenia and osteoporosis. In younger children, this process causes a little mineralization of their skeleton, resulting in a variety of skeletal deformities known as rickets. Also, the latest research has suggested a correlation of VD serum levels with the occurrence or aggravation of many pediatric diseases. Childhood autism, obesity, asthma, or rickets represent a part of pediatric diseases, which are associated with VD deficiency [1, 2].
There are some groups at risk of VD deficiency because of difficulty obtaining sufficient VD from natural food sources, and dietary supplements may be required to maintain a healthy VD status. Breastfed infants, older adults, people with limited sun exposure or with dark skin, people with fat malabsorption, obese people or those who have undergone gastric bypass surgery, patients with nephritic syndrome, with chronic granuloma-forming disorders, lymphomas, primary hyperparathyroidism, patients treated with a variety of medications including anticonvulsants, or for AIDS/HIV treatment, represent risk groups to develop VD deficiency [7, 11].
Some prevention and treatment strategies should be implemented. Serial monitoring of 25(OH)D and serum calcium levels should be recommended. Also, additional VD through supplementation is the best way to get additional VD. There are studies suggesting supplementation with about 800 IU/per day of VD may reduce hip and nonspinal fractures [6].
4. Vitamin D and the immune system
The immune system is formed of two distinct types of immunity: innate and adaptive. When it comes to the stimulation of innate immunity, it is the activation of toll-like receptors (TLRs) in macrophages, monocytes, polymorphonuclear cells (PMNs), and several epithelial cells. TLRs are a transmembrane pathogen-recognition receptor that interacts with specific membrane structures presented on the surface of infectious agents that trigger the innate immune response in the host. TLRs activation induces the production of antimicrobial peptides (cathelicidin and reactive oxygen species). When TLRs are stimulated by an infectious organism in macrophages, an increase of CYP27B1 and VDR expression occurs. If there is an adequate substrate (25OHD) for activated VDRs, it will determine a cathelicidin induction. Therefore, it can be assumed that adequate levels of VD promote an innate immune response [11].
T and B lymphocytes, cells specialized in antigen presentation, and dendritic cells (DC) are among the cells, which initiate an adaptive immune response. When it comes to this type of immune response, VD exerts, in general, an inhibitory action by decreasing the maturation of DC and decreasing their ability to present antigen and, therefore, to activate T cell lymphocytes. Also, it may suppress IL-12, IL-23, and IL-6 production necessary for T helper cell (Th) development and function by modulating their cytokine production. Also, there are
Other recent studies highlighted the importance of VD in enhancing pathogen elimination mechanisms by increasing the activity of macrophages and their monocyte precursors and by directly affecting the proliferation of B lymphocytes and the production of immunoglobulin [11, 13].
Understanding VD’s immune modulation mechanisms may explain its important role in infectious diseases. Many studies demonstrate the association of low levels of 25(OH)D in upper respiratory tract infections, tuberculosis, chronic obstructive pulmonary disease, cystic fibrosis, or human immunodeficiency virus. The effects of VD on the immune system suggest the importance of this vitamin in immune-mediated disorders in autoimmunity [11, 12, 13].
In multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system, epidemiologic studies revealed a lower prevalence of this disease in equatorial regions, which become higher with increasing latitude. Lack of sunshine in high-latitude regions and, therefore, low levels of cutaneous VD synthesis suggest a potential risk factor deficiency of VD. The same epidemiological studies have been made in other autoimmune diseases such as type 1 diabetes mellitus or systemic lupus erythematosus. Because of those findings, VD supplementation has been considered as a potential treatment, but further well-organized studies and larger randomized trials are necessary in order to confirm the potential of VD to prevent and ameliorate symptomatology in autoimmune diseases [11, 13].
5. Vitamin D deficiency and infectious diseases
Cathelicidin (in the form of LL-37), human beta-defensin 2, and perhaps the generation of reactive oxygen species could account for the antiviral properties of vitamin D. A recent study revealed that vitamin D-induced oxidative stress might be a mediator of the reduction in hepatitis C replication in human hepatoma cells. Given the pleiotropic effects of vitamin D, additional pathways may be present [14].
Because of its capacity to damage bacterial membranes
5.1 Viral infectious
5.1.1 Viral respiratory infections
Recent research emphasizes the potential benefit of vitamin D in the treatment of viral respiratory infections. High baseline levels of CYP27B1 are expressed, while minimal levels of CYP24A are also expressed by lung epithelial cells, favoring the conversion of vitamin D into its active form [18]. These cells raise the expression of the TLR co-receptor CD-14 and cathelicidin when given vitamin D [19]. Treatment with vitamin D causes the NF-kB inhibitor IkB, which reduces the viral activation of inflammatory genes in airway epithelial cells [20].
By analyzing VDR polymorphisms, studies have discovered potential connections between vitamin D and respiratory diseases. Due to the relationship of the
5.1.2 HIV infections
Vitamin D levels in HIV populations have been found to be lower in observational studies. In a German investigation, 25(OH)D concentrations less than 20 ng/ml (50 nmol/l) were discovered in 47.6% of the people with HIV [23].
Only 17% of participants in a study of HIV-positive adults from the United States had serum levels of 25(OH)D below normal levels, and only 11% had low levels of 1,25(OH)2D. However, the differences were statistically insignificant [24]. Additionally, 53 patients in Norwegian research had serum 1,25(OH)2D levels that were considerably lower than the controls [25].
5.1.3 Epstein: Barr virus infections
Multiple sclerosis (MS) and the Epstein–Barr virus (EBV) may be related, according to studies; as a result, vitamin D levels may be important in the emergence of MS [26, 27]. In Medical Hypotheses, Trygve Holmoy examined this subject. According to Holmoy, low vitamin D levels and EBV infection increase the incidence of MS. He suggests that vitamin D modifies the immunological response to EBV and inhibits the activation of auto-reactive T cells, which may be a contributing factor in the pathogenesis of MS [28].
5.1.4 HCV infections
Hepatocytes infected with the hepatotropic, single-stranded RNA virus known as HCV are the hallmark of the inflammatory liver condition known as hepatitis C. Worldwide it is estimated that 170 million people have HCV [29].
One of the most prevalent symptoms of HCV in clinical settings was VD deficit (plasma 25(OH)D3 20 ng/mL), and it was commonly noted that there was a negative association between VD levels and viral loads in HCV patients [30, 31]. Therefore, VD insufficiency has been identified as a risk factor for HCV infection and subsequent chronic progression [32]. In agreement with this finding, HCV patients’ plasma VD levels and the expression of the VDR were found to be negatively correlated [33].
5.1.5 HBV infections
Epidemiological studies consistently show considerably reduced VD levels in chronic HBV individuals [34]. The clinical development of liver cirrhosis and unfavorable clinical outcomes was linked to lower VD levels [35]. This clinical evidence was supported by the finding that HBV transcription and translation were increased in HBV-transfected cells when VDR expression was downregulated [36]. Contrarily, in HBV patients receiving effective antiviral medication, VD levels returned to normal [37].
5.2 Bacterial infections
5.2.1 Streptococcal infections
For many years, vitamin D has been known to have chemotherapeutic potential in the treatment of bacterial infections [38]. Vitamin D has been demonstrated to have immunomodulatory effects within the host, possibly preventing bacterial growth and biofilm formation. But studies have also demonstrated that vitamin D has direct antibacterial and antibiofilm activity against a few organisms, including streptococci.
Recent studies have shown that vitamin D analogs cause the planktonic cultures of
Increased risk of infection is linked to vitamin D deficiency, and supplementing changes how hosts and pathogens interact. Deficiencies in micronutrients, such as inadequate vitamin D levels, have been linked to a higher risk of illness, particularly infections brought on by
A retrospective analysis of 54 individuals with tonsillopharyngitis brought on by GAS revealed that the condition was linked to a serum concentration of vitamin D (25(OH)D) less than 20 ng/mL [43]. These findings support a previous study that discovered men with 25(OH)D blood levels below 40 nmol/L had more severe infections of the respiratory tract [43, 44].
Vitamin D administration has also been demonstrated to increase neutrophil killing of infectious streptococcal bacteria while concurrently reducing severe inflammatory responses and apoptosis, suggesting vitamin D may have anti-streptococcal effects [45].
5.2.2 Mycobacterium tuberculosis infections
Numerous studies have questioned the relationship between vitamin D levels and the likelihood of developing active TB in patients exposed to MT, given the characteristics and mechanisms of action of vitamin D now understood. In patients with active TB, there is a lower level of 25(OH)D than in healthy individuals, according to research [49, 50, 51]. Uncertainty exists regarding the relationship between the vitamin D shortage and infection, as well as whether the vitamin D deficiency favors the infection’s progression. The capacity of vitamin D to prevent the replication of MT
5.3 Fungal infections
Beyond its well-established functions, recent research suggests that vitamin D also has a connection with susceptibility to and management of fungal infections. Fungal infections can be caused by various fungi present in our environment. While most fungi are harmless, a few types can cause diseases, particularly in individuals with compromised immune systems. The body’s ability to resist these infections is heavily dependent on a well-functioning immune system, and this is where the potential link with vitamin D emerges. Vitamin D is known to modulate the immune system, affecting both innate and adaptive immune responses. Its active form, calcitriol, has been shown to stimulate the production of antimicrobial peptides, which are critical in the defense against fungal pathogens [53].
The relationship between vitamin D and fungal infections has been particularly explored in the context of Candida infections. Candida is a type of yeast that lives on the skin and inside the body. While generally harmless, it can cause infections if the body’s natural balance is disrupted, or the immune system is weakened. Several studies have found that individuals with recurrent or severe Candida infections often have low levels of vitamin D, suggesting that this vitamin might play a protective role.
Furthermore,
The correlation between vitamin D and Aspergillus infections is another area of interest. Aspergillus is a common fungus that can cause serious lung infections in people with weakened immune systems. In animal models, vitamin D deficiency has been linked to a higher susceptibility to Aspergillus infections. Moreover, supplementation with vitamin D has been found to enhance the ability of immune cells to kill Aspergillus, providing further evidence of its potential therapeutic role.
However, while these findings are promising, it is important to note that much of the research on vitamin D and fungal infections is still in the preliminary stages. Many of the studies have been conducted
The rising prevalence of candidiasis infections presents a significant threat to public health, given its high morbidity and mortality rates. This critical situation is further exacerbated by the current limitations of antifungal drugs available in the market. Consequently, there has been an increasing interest in the development of novel, more effective antifungal agents to manage and reduce the burden of candida. This study focuses on the potential of vitamin D3 (VD3) as a viable candidate in this regard, especially given its potent antifungal activity against various Candida species.
One study employed both the broth microdilution method and solid plate assay to investigate the antifungal properties of VD3 [54]. The results confirmed that VD3 inhibited the growth of Candida species in a broad-spectrum, dose-dependent manner. This implies that increasing concentrations of VD3 have a stronger inhibitory effect on Candida species, thereby enhancing its potential as an effective antifungal agent [45, 53].
Furthermore, studies reveal that VD3 had a significant impact on the initiation, development, and maturation phases of biofilm formation in
The underlying mechanism through which VD3 exerts its antifungal effects was further explored using transcriptomics and reverse transcription quantitative PCR (RT-qPCR) analysis. Findings from these analyses revealed that VD3 influences several key biological processes, including ribosome biogenesis, coenzyme metabolism, and carbon metabolism. This suggests that VD3’s antifungal activity against
In a murine IAC model, VD3 demonstrated significant efficacy in reducing the fungal burden in various organs, including the liver, kidneys, and small intestine. This points to the potential systemic benefits of VD3 in controlling and reducing the spread of fungal infections within the body, thereby further consolidating its promise as an antifungal agent.
In addition to its direct antifungal effects, the study also revealed that VD3 significantly reduced the infiltration of inflammatory cells, a common occurrence in IAC. This suggests that VD3 may also have potent anti-inflammatory properties that could aid in managing the symptoms and severity of IAC.
The impact of VD3 on plasma cytokine levels was also investigated. Results confirmed that VD3 treatment significantly decreased the levels of plasma interferon (IFN)-γ and tumor necrosis factor (TNF)-α, both of which are typically elevated in response to fungal infections. This suggests that VD3 may modulate the body’s immune response to fungal infections, further enhancing its potential as an antifungal agent [52].
The latest findings provide compelling evidence that VD3 may offer a novel antifungal mechanism with broad-spectrum activity against various Candida species. These results not only enhance our understanding of the antifungal properties of VD3 but also suggest its potential as a therapeutic agent in the treatment of IAC. Future studies should focus on assessing the safety and efficacy of VD3 in clinical settings, as well as exploring possible synergies with existing antifungal agents [45, 54].
5.4 Parasitic infection
In a recent study investigating the correlation between vitamin D levels and parasitic infections, findings indicated that individuals who tested positive for the
Previous research on the association between vitamin D levels and
An inverse relationship between low vitamin D levels and high seroprevalence of parasitic antibodies could be explained by vitamin D deficiency impairing both the innate and adaptive immune responses. There is evidence to suggest that 1,25-dihydroxy vitamin D3, the active form of vitamin D, may inhibit intracellular
It is also possible that factors confounding the estimation of the relationship between vitamin D levels and parasitic infections might explain the study’s results. For example, patients with metabolic syndromes often have lower vitamin D levels. For example,
Despite the study’s thorough efforts to minimize the influence of confounders, several limitations were inevitable. Due to the cross-sectional nature of the study, it was not possible to establish a definitive causal relationship between low vitamin D levels and parasitic infections. However, to validate these hypotheses, further prospective studies would be necessary [55, 56].
6. Conclusions
In the latest years have been extended the knowledge about vitamin D and its implications regarding health. Because of the increasing number of people, both children and adults affected by vitamin D deficiency have recommended supplementation by dietary intake [57, 58].
Because VD has an important influence on the immune system and low levels of 25(OH)D are associated with high incidence and severity of different infectious diseases, VD supplementation should be considered, but further studies are necessary in order to confirm this hypothesis [59].
Conflicts of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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