Vitamin D and the microbiota connection: understanding its potential to improve COPD outcomes

The mucosa of the respiratory system is an essential site for local vitamin D synthesis, degradation, and signaling. It modulates the inflammatory and immune response by saving the integrity of the mucosal barrier and killing the invading pathogen through the induction of antimicrobial peptides. The proper functioning of the immune system within the respiratory system is influenced by the complex interactions of numerous immune pathways, including the gut-lung axis. Recent research has indicated that the gut microbiota is vital in developing and progressing chronic inflammatory chest conditions, such as asthma and chronic obstructive pulmonary disease (COPD). Furthermore, the immune-modulating function of vitamin D operates through the gut mucosa; hence, the vitamin D receptor is expressed to regulate the antimicrobial peptide. The potential protective role of vitamin D and its correlation with COPD has garnered significant interest. It is currently under exploration as a possible adjuvant therapy to aid in managing frequent exacerbation of COPD. In this review, we explored the connection between vitamin D and the immune system, as well as its relationship with microbiota. We also summarized some novel mechanisms of action of vitamin D supplementation that can impact disease exacerbation.


Introduction
Vitamin D (Cholecalciferol) is a nutritional component for good health [1]; it acts as a pleiotropic hormone, which regulates mainly the level of serum calcium, and modulates the homeostasis of phosphate, in addition to its role in bone mineralization [2].Nearly all cell types express receptors for an active form of vitamin D (1,25 (OH) 2D), which is regulated by numerous genes [2,3].Consequently, vitamin D influences different body processes, including DNA repair, cell proliferation, and repair, and it is also involved in cell adhesion and apoptosis, and conversely in oxidative stress response [2,4].
Vitamin D deficiency reflects the shortage of serum VD level and can be defined when the circulating form of VD "25 (OH)" decreases below (50 nmol/L) [5].The bone-related diseases such as rickets and osteoporosis are reported in more than 30% of children and adults with VD deficiency [6].Additionally, several studies report the association between vitamin D deficiency and other diseases such as cardiovascular disease and chronic inflammatory pulmonary diseases such as cystic fibrosis, bronchiectasis, asthma, and COPD.Moreover, some immune-related diseases such as Alzheimer's disease, diabetes mellitus, and inflammatory bowel disease were linked to VD deficiency [6][7][8][9].Despite different studies recording a significant correlation between COPD and VD deficiency, plus their inverse relationship with disease severity and exacerbation frequency, the causality link between them is still undiscovered [8][9][10][11][12][13].Moreover, some observational studies suggested that some polymorphisms of VD receptors are associated with the development of COPD [8,10,11,14].Zosky et al. highlighted the correlation between the maternal level of vitamin D in mice and impaired lung function and structural development of offspring [15], which was an appropriate explanation; hence, the recent data showed an association between impaired lung function in early childhood and evolution of COPD later on [16].Moreover, maternal vitamin D levels notably impact the gut microbiota, indirectly influencing the immune response in the lung through the gut-lung axis [17].This observation highlights the crucial role that vitamin D plays in the complex and interconnected systems of the human body and emphasizes the importance of maintaining healthy levels of this essential nutrient.Additional studies in animal models investigated the effect of sub-acute and chronic exposure to cigarette smoke on mice suffering from vitamin D deficiency; the results showed a significant decrease in lung function, besides the early signs of emphysema and airway inflammation [18].
In the same way, topical application of vitamin D in the lung of elastase-induced COPD mice showed improvement in lung function through the protection of lung damage [19].So far, in human investigations, the impact of vitamin D levels on the evolution and progression of COPD is yet unclear.However, the abovementioned observational study suggests that it is essential to be concerned about the maternal vitamin D level and connect it with the possibility of COPD development later in life.Another pathogenesis explanation was provided by Holick et al.; hence, they focus on the local level of vitamin D in airway mucosa, which is affected by exposure to the pathogen, inflammatory mediators, and inhaled toxins [6].In the same way, in patients with COPD, the respiratory mucosa is continuously exposed to similar hazards, which lead to dysregulation of autocrine (1,25 (OH) 2D) level and VDR signaling in mucosal tissue of the respiratory tract [8,20,21].Therefore, the host defense showed different forms of immune dysregulation, including abnormal secretion of protective molecules, alteration of the epithelial barrier and its protective function, and significant changes in the microbiota composition [20,21].A sufficient level of vitamin D may protect these dysregulated processes in several ways as maintaining the integrity of the mucosal barrier, promoting the killing of pathogens through induction of the antimicrobial peptide (AMP), and modulation both innate and adaptive immune responses [7,22,23].
In this narrative review, we discussed the relationship between COPD pathogenesis and vitamin D deficiency, focusing on the influence of gut microbiota and the potential of vitamin D supplementation to mitigate the frequency of COPD exacerbations.

In healthy condition
The primary source of vitamin D is animal or plantbased food; however, it can be synthesized in the skin by UVR radiation [24].The inactive form of vitamin D enters the circulation after binding with a specific protein (VDBP).It reaches mainly the liver, where it is converted to another inactive form of vitamin D (25 (OH) D) by a specific enzyme, which is expressed in liver cells (CYP2RI and CYP27A1) [25].However, several studies reported that mucosal epithelial cells of the respiratory tract and intestine, as well as monocyte and macrophage cells, expressed the vitamin D converting enzyme, too [24][25][26][27].25 (OH) D needs to be activated by CYP27B1 enzyme, which is expressed in the kidney as well as in other cells such as epithelia and immune cells, to finally active form (1, 25 (OH)2 D) [27][28][29][30] (Fig. 1).In addition, the hormone 1,25 (OH) 2D can regulate the expression of multiple genes by binding with the vitamin D receptor (VDR).This receptor is expressed predominantly in the gastrointestinal system, especially the intestinal enterocytes and pancreatic islets, and it is moderately found on the distal renal tubules and osteoblasts.However, it is also present at lower levels in numerous other tissues and various epithelial and immune cells [31][32][33].1,25(OH)2D regulates the expression of VDR; the later also is regulated by other factors such as FGF-23 and PTH [34].The primary function of 1,25-(OH) 2 D is to ensure an adequate amount of calcium and phosphorus in the bloodstream.This hormone plays a crucial role in regulating the absorption of these essential minerals in the body, which is crucial for maintaining strong bones and teeth, proper muscle function, and overall health.Without sufficient levels of 1,25-(OH) 2 D, the body may struggle to maintain the necessary levels of calcium and phosphorus, which can lead to a range of health problems and complications.If blood calcium levels decrease, 1,25-(OH) 2 D will engage with VDR in osteoclasts to trigger bone resorption and elevate calcium and phosphorus levels [35].However, the effects of vitamin D extend beyond its role in regulating  [2,32,33].Moreover, the immunological functions of vitamin D extend to modulating the cellular immune response in the respiratory system.Vitamin D is a diverter of the inflammation pathway; it can inhibit type I inflammation and switch the direction toward type II inflammation.Hence vitamin D arouses Th2 cells and speculates the production of its cytokines cocktail as IL-1 and TNF-α while suppressing the other inflammatory cytokines as IL-10 and IL-4, in addition to modulating the regulatory function of IL-17 by self-tolerance mechanisms [25,31].

In inflammatory airway disease
Airways in patients with chronic lung disease showed chronic inflammation and impaired defense, increasing susceptibility to repeated infection.In addition to exposure to air pollutants and cigarette smoke, that is involved in disease pathogenesis [36][37][38].Studies showed that airway epithelial cells are associated with impaired 1,25(OH)2D synthesis after viral and bacterial infections.Hence, the expression of catabolic enzymes CYP24A1 and CYP27B1 increased after infection in airway epithelium, and thereby conversion of 25(OH) D into  [29,39,40].On the other hand, some studies explain the impaired local vitamin D level by exposure to proinflammatory mediators, which affect the expression of both VDR and CYP27B1 enzymes in epithelial cells [30,41].However, the opposite condition happened in immune cells (neutrophil, monocyte, and macrophage) [42][43][44].Therefore, it has been observed that administering 25(OH)D to immune cells results in an escalation of antimicrobial responses.This observation could serve as an additional defense mechanism to compensate for the augmented degradation of 25(OH)D and 1,25(OH)2D in the epithelial layer during inflammation.Such a response is crucial in mitigating the effects of inflammation and enhancing the body's immunity against microbial pathogens.Furthermore, two recently conducted studies have delved into the consequences of inhaling toxins on the levels of 1,25(OH)2D and the responsiveness of immune cells.The initial study discovered that the expression of VDR increased but did not significantly affect the response of VD [45].While in the second one, the expression of the CYP2A1 enzyme was induced [46].
The data were limited when considering the consequence of chronic inflammatory status in lung tissue of patients with chronic lung disease in correlation with vitamin D metabolism and responsiveness; hence, only one animal bleomycin fibrosis model showed that TGF-b1 diminished the VDR expression, which might support the hypothesis [47].However, this data is still inadequate to clarify that the disease-associated factors could be implicated in the lack of VD level in some way or another, plus what is the role of other immune cells and epithelial and mesenchymal cells in modifying the action of VD in the experimental situation?

Vitamin D deficiency and COPD
Chronic obstructive lung disease is a non-curable disease and is considered the most common chronic and systemic inflammatory disorder.It is characterized by progressive irreversible limitation of airflow in respiratory airways.The main etiological factors were smoking and different environmental pollution, in addition to associated genetic predisposition.In chronic lung disease, vitamin D insufficiency and deficiency are markedly recorded; however, the underlying mechanism of this link was not fully understood.The experimental animal models showed some promising results, in which VD supplementation enhanced surfactant synthesis and type II alveolar cell synthesis.Moreover, VD positively affected the proliferation of fibroblasts and the process of alveolarization [48].
A recent review emphasizes the importance of measuring vitamin D levels in patients with COPD, as studies have found a correlation between low levels and impaired lung function.Adequate intake of vitamin D may have benefits beyond preventing bone fractures.Factors such as inadequate food intake, aging, lack of sun exposure, medication use, and health issues can contribute to vitamin D deficiency [49,50].
From a genetic and immunologic perspective, a recent study delves into the potential causal link between vitamin D and chronic obstructive pulmonary disease (COPD) development.Research indicates that the Th1 immune response and Th17 cells are implicated in COPD and may contribute to a connection between vitamin D deficiency and the disease.Furthermore, lacking this vitamin may exacerbate inflammation and promote parenchymal degradation by producing chemokines (via NF-ƘB) and Matrix Metalloproteinase (MMP)-9.In addition to affecting the production of IL-18 and TNF-a, it directly influences corticosteroid resistance and histone acetylation [49].Additionally, Pfeffer et al. and Banerjee et al. discovered that vitamin D is critical in regulating smooth muscle remodeling [51,52].
Considering the calcemic effect of VD and the pathogenesis of COPD, research findings indicate a noteworthy connection between airflow limitation and heightened odds ratios (OR) for osteoporosis (OR 1.9).This association becomes even more pronounced in cases of severe airflow obstruction, where the OR escalates to 2.4.Importantly, this pattern holds across both genders.The implications drawn from the study underscore the importance of actively addressing osteoporosis in individuals with moderate to severe COPD [53].
In another study, almost half of the patients, regardless of gender, had osteoporosis or osteopenia [54].The prevalence of osteoporosis varies between 8.7 and 69% with higher rates observed in patients with chronic illnesses or exacerbations.COPD patients are particularly prone to vertebral fractures, with reported incidence rates of 24 to 79% [55].Osteoporosis can be linked to various aspects of lung function.Moreover, a comparative investigation encompassing COPD patients with and without osteoporosis revealed notable disparities.Those who have osteoporosis exhibited marked reduced BMI and elevated residual volume (RV) expressed as a percentage of total lung capacity (RV%TLC) [56].Furthermore, in COPD, osteoporosis can arise due to a convergence of factors leading to vitamin D deficiency and subsequent bone resorption.Individuals with COPD often skew older, exhibit reduced physical activity, are more confined to their homes, and possess diminished muscle mass, all of which contribute to lower vitamin D synthesis.Given that vitamin D deficiency is a crucial driver of osteoporosis, proactive assessment of its levels is imperative in COPD cases.For patients found to be deficient, including replacement therapy warrants consideration [49].
Concerning the non-calcemic effects of vitamin D, substantial studies have highlighted its antibacterial and mycobacterium-related impacts, in addition to its antiviral properties, mediated through diverse mechanisms.Antimicrobial polypeptides, like cathelicidin, are under the genetic control of vitamin D response elements (VDREs) within their promoters.Cathelicidin, with its efficacy against mycobacteria and various antibioticresistant strains such as Pseudomonas aeruginosa and Staphylococcus aureus, as well as different viruses and chlamydia, assumes a pivotal role.These actions bear significant importance due to their influence on the progression of COPD, where infectious exacerbations play a crucial role [49,51,52].Furthermore, many human studies have underscored the clinical link between vitamin D deficiency and respiratory infections.For instance, in an investigation involving 800 healthy males, individuals with serum 25(OH) D concentrations below 40 nmol/L exhibited a notably higher number of days of absence from duty attributed to respiratory infections [57].Similarly, a more comprehensive study encompassing 2135 patients, who assessed VD levels before hospitalization, revealed that those with vitamin D levels lower than (10 ng/mL) had a 2.33-fold increase in hospital-acquired bloodstream infections [58].Data also exists concerning the correlation between viral infection and vitamin D deficiency.Both circumstances exhibit a higher prevalence during winter, and addressing vitamin D deficiency could enhance the prognosis of respiratory infections [59].In a separate randomized controlled trial involving 5292 patients, participants were administered either a placebo or 800 IU of vitamin D. Although there was a trend towards reduced reported infections and antibiotic usage, this trend did not reach statistical significance [60].Accumulated data propose that vitamin D might be linked to recurrent exacerbations, colonization, and bacterial eradication [49,51,52].In a study initially designed to explore the impact of daily azithromycin on COPD exacerbations, Kunisaki et al. observed no significant correlation between VD levels and either the occurrence of the first exacerbation or the frequency of exacerbations.It is worth noting, however, that vitamin D insufficiency was identified in just 33% of the patient cohort [61].The researchers conducted an extensive study involving 97 patients suffering from COPD.The study's primary objective was to explore and establish potential correlations between factors, including vitamin D levels, VDR polymorphism, exacerbations, human rhinovirus (HRV) susceptibility, and outdoor activity.
In doing so, the researchers aimed to understand better the complex interplay between these factors and their impact on COPD patients.According to the study's findings, low levels of 25-hydroxyvitamin D do not correlate with the frequency of exacerbations or susceptibility to HRV-related exacerbations in patients suffering from COPD.Nevertheless, it is worth noting that patients who usually spend less time outdoors are likely to have lower concentrations of 25-hydroxyvitamin D, regardless of the duration of the day [62].In another comprehensive study centered on chronic obstructive pulmonary disease (COPD) exacerbation, it was discovered that the initial vitamin D level significantly correlated with pulmonary function tests, the severity of dyspnea, and the duration of hospital stay.This observation suggests that maintaining adequate vitamin D levels may help COPD patients mitigate exacerbations' effects.However, the study found no significant relationship between the initial vitamin D level and the number of exacerbations experienced in the previous year, indicating that other factors may play a more decisive role in determining the frequency of COPD exacerbations [63].Furthermore, a study conducted over an extended period found that a significant proportion of Chronic Obstructive Pulmonary Disease (COPD) patients who received primary care exhibited a deficiency in vitamin D, specifically; the study found that 77% of these patients lacked sufficient amounts of this vital nutrient.Nevertheless, no discernible differences were observed in terms of exacerbation rates and mortality after factoring in the impact of vitamin D supplementation and categorizing patients based on their vitamin D levels.These findings suggest that vitamin D deficiency is common among COPD patients but may not necessarily contribute to their symptoms or overall health outcomes [64].Nevertheless, a more recent study tracking 426 COPD patients for 3 years did not unveil a noteworthy correlation between VD levels and the incidence of COPD exacerbations or mortality rates [14].An Italian study involving 97 COPD patients revealed a connection between vitamin D deficiency and a higher occurrence of frequent exacerbations along with repeated hospitalizations [65].A recent meta-analysis of patients suffering from exacerbations has shown that their vitamin D levels were lower than stable individuals.However, it must be noted that there is no conclusive evidence that directly links vitamin D deficiency to an increased risk of COPD exacerbation.While the current data does suggest a correlation between vitamin D levels and exacerbations, it does not provide definitive proof of a direct link between the two [8].Therefore, further research is required to establish a clear connection between vitamin D deficiency and COPD exacerbation.

Vitamin D and microbiota
Vitamin D classically regulates gene transcription through vitamin D receptors (VDR).It plays multiple immunological roles by inhibiting Th17 and Th1 responses, impairing the development and function of B cells, promoting Tregs function, and stimulating antimicrobial peptides from immune cells [66].
Recent studies reported that VD level is directly connected with changes in microbiota composition [67,68].Furthermore, animal studies found that dietary restriction of VD in mice promotes the increase of Bacteriodetes and Proteobacteria phyla in gut composition [68,69].Additionally, in a large human study, a significant link has been found between two VDR polymorphisms and microbiota variation in some inflammatory diseases [70]; hence, the genus Parabacterioides (phylum: Bacterioidetes) became more abundant.Another supportive study recorded that repeated ingestion of VD supplementation to healthy subjects enhances the enrichment of Prevotella and Bacteroides, which belong to the Bacteroidetes phylum [71].
In a contrary study, excess VD intake promotes Prevotella abundance and decreases Haemophilus and Veillonella (Proteobacteria and Firmicutes, phylum, respectively) [67].Unexpectedly, data about the direct effect of VD on bacteria still needs to be improved; future in vitro studies are recommended to uncover a possible anti-bacterial action of VD.

Role of vitamin D in the treatment of COPD
Vitamin D has been shown to play a crucial role in host defense mechanisms, particularly in chronic inflammatory lung conditions.However, it is not uncommon for individuals with such conditions to exhibit a deficiency in this essential nutrient.Consequently, there is a growing interest in exploring strategies aimed at boosting local 1,25 (OH) 2D levels or utilizing vitamin D as a potential treatment option.To this end, clinical and animal studies have been conducted to investigate the impact of vitamin D supplementation on chronic airway diseases.These studies provide valuable insights into the potential benefits of using vitamin D as a therapeutic agent for such conditions.

Impact on the response of inhaled steroid therapy
Inhaled corticosteroids (ICS) are the primary treatment for patients with COPD and asthma, sometimes combined with long-acting bronchodilators.However, the effectiveness of corticosteroid therapy varies among patients, particularly those with steroid-resistant (SR) asthma.The reasons behind this resistance are multifaceted and encompass factors such as genetic predisposition, impaired glucocorticoid receptor binding, inflammation driven by T helper type 17 cells (Th17), oxidative stress, and reduced numbers of interleukin-10-secreting regulatory T cells (Tregs) that typically mitigate the Th17-driven inflammation cascade [72].
A study has demonstrated that 1,25(OH)2D can reverse steroid resistance by fostering the ex vivo production of IL-10-secreting Tregs.When applied, vitamin D reinstates corticosteroid sensitivity in CD4+ T cells sourced from individuals with SR-asthma [73].Furthermore, research indicates that administering vitamin D to asthmatic patients with low serum vitamin D levels could enhance their responsiveness to steroids.This therapeutic approach holds promise for countering oxidative stress and alleviating Th17-mediated inflammatory reactions [74][75][76][77][78][79].
Nevertheless, the corticosteroid dexamethasone has been demonstrated to elevate the expression of the 25(OH)D and 1,25(OH)2D-degrading enzyme CYP24A1 in renal cells and osteoblasts.This observation points to a two-way interaction between corticosteroids and 1,25(OH)2D, which may curtail 1,25(OH)2D levels for patients [80].Further investigations are imperative to ascertain whether vitamin D can enhance corticosteroid responsiveness in COPD.

COPD exacerbation and role of vitamin D
COPD patients face a significant burden from exacerbations which can lead to a faster decline in lung function and more frequent hospital admissions [81].Pollutants, bacterial, viral infections, or a combination of all three can trigger these exacerbations [82,83].According to research findings, individuals with Chronic Obstructive Pulmonary Disease (COPD) tend to have lower levels of serum 25-hydroxyvitamin D, commonly referred to as 25(OH) D, compared to control groups matched in age and smoking.This deficiency in vitamin D has been closely associated with the likelihood of experiencing more severe exacerbations of the disease.Studies have shown this is a significant risk factor for COPD patients, with a higher prevalence of exacerbations and increased hospital admissions [8][9][10].Therefore, maintaining adequate levels of vitamin D is crucial in managing the progression of the disease.Bacterial infections significantly cause COPD exacerbations, accounting for 50% of all cases.Advances in study design and sampling techniques have allowed for a better understanding of bacteria's role in causing these exacerbations.New techniques using 16S rRNA sequencing have shown that certain bacterial strains become more abundant during exacerbations, with the Proteobacteria phylum being particularly prevalent [83,84].
A recent study revealed that 1,25(OH)2D can enhance the defensive capability of airway epithelial cells against bacterial threats.Upon treatment with 25(OH)D and 1,25(OH)2D, airway epithelial cells exhibit heightened expression of hCAP18/LL-37, thus fortifying their ability to counter NTHi, a specific Gram-negative bacterium often linked to COPD exacerbations [85,86].Moreover, the administration of 1,25(OH)2D not only amplifies the expression of the antimicrobial peptide (AMP) hCAP18/LL-37 but also demonstrates efficacy in eliminating both Pseudomonas aeruginosa and Bordetella bronchiseptica, both of which are Gram-negative bacteria [86].These observed antibacterial effects of 1,25(OH)2D on airway epithelial cells in vitro have recently received corroboration in vivo through the work of Vargas Buonfiglio et al.Their research showcased that vitamin D supplementation heightens antimicrobial activity against the Gram-positive bacterium Staphylococcus aureus within healthy non-smokers' airway surface liquid (ASL).Notably, this effect is contingent upon the presence of hCAP18/LL-37 [87].
However, according to a separate animal study conducted on the airway, the results obtained were quite different.Specifically, the study found no significant influence of 1,25 (OH) 2D on Defb4 or mCramp (practically the murine equivalent of CAMP) expression [88].This particular outcome could be attributed to the lack of vitamin D response elements (VDREs) in the promotors of mCramp and Defb4.As a result, this suggests that mice may not be the most optimal models for investigating the impact of 1,25(OH)2D on AMP-mediated host defense during infections [89].Therefore, it is necessary to consider other animal models that may be more appropriate for investigating this particular aspect of host defense.
Recent scientific research conducted on mice has revealed that the application of topical vitamin D3 treatment can lead to an increase in CAMP expression [90].This finding, in turn, has demonstrated antibacterial effects on skin mucosa.However, it is essential to note that there is currently no conclusive correlation between vitamin D levels and the occurrence of pulmonary infections caused by Streptococcus pneumoniae or Pseudomonas aeruginosa in murine studies.Nevertheless, findings from other studies conducted on mice have shown that vitamin D can offer protection against gut bacterial infections.This result suggests that vitamin D's antibacterial effects are likely modulated through various mechanisms, including enhancing epithelial barrier integrity [91,92].
Collectively, these observations highlight the capacity of 1,25(OH)2D to bolster defense mechanisms and enhance the clearance of bacterial infections, while simultaneously tempering exaggerated immune responses.These attributes potentially provide insights into the link between vitamin D deficiency and the exacerbation of COPD.
Exceeding the abovementioned observations about the mechanisms by which VD could play a role in minimizing COPD exacerbation, either through its immune modulation effects or with its newly discovered antibacterial action, Table 1 summarizes human observational studies and randomized control trials on the link between VD deficiency and COPD exacerbation, as well as the potential impact of VD intake in reducing the rate of exacerbation.Although there have been conflicting results regarding the effectiveness of using VD supplementation as an add-on therapy to reduce COPD exacerbation rates, all studies agree that measuring the level of VD in the serum of all COPD patients is crucial [93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108][109][110].Additionally, many studies suggest conducting further research to determine the effects of subgroup classification or varying VD supplementation doses [93,106,108,109].

Vitamin D supplementation effect on microbiota
Various studies have contributed to understanding antimicrobial peptides' (AMPs) role in governing the configuration of the gut microbiota.Notably, investigations have highlighted the potential influence of Paneth cellderived defensins in shaping the microbiome's structure [111].This concept gains further validation through the observation that numerous commensal gut bacteria benefit from AMP protection, including examples like the 1,25(OH)2D-inducible hCAP18/LL-37 and hBD-2, whereas pathogens tend to exhibit heightened sensitivity [85].Certain gastrointestinal conditions, like inflammatory bowel disease (IBD), have been associated with shifts in gut microbiota composition.Likewise, conditions that impact the respiratory system, such as COPD and asthma, are also implicated in this dynamic relationship, emphasizing the crucial role played by the so-called gut-lung axis [112,113].
The complex interplay between gut microbiota and lung health involves various mechanisms.One such mechanism is the production of short-chain fatty acids (SCFAs) that have a broad range of effects on immune and structural cells.SCFAs produced in the intestinal environment can directly impact lung immunity.This impact is partly attributed to their ability to influence myeloid cells within the bone marrow, which migrate to the airways and modulate local immune responses.Therefore, SCFAs serve as crucial mediators in the communication between the gut microbiota and the lung, highlighting the importance of maintaining a healthy gut microbiome for optimal lung function [114].
The microbiota landscape is a complex ecosystem that boasts diverse microbial species, each contributing to The study suggests that vitamin D supplementation may be beneficial in reducing the rate of moderate/severe COPD exacerbations in patients with baseline 25-hydroxyvitamin D levels.Further research is needed to confirm these findings and to determine the optimal dose and duration of vitamin D supplementation for COPD patients.its richness and vibrancy.Within this landscape, certain species are exceptionally skilled at producing short-chain fatty acids (SCFAs), which have been shown to impact overall health positively.This concept is just one aspect of the intricate web of interactions that make up the microbiota, and understanding these dynamics is crucial in unlocking the full potential of this fascinating world [115].Notably, strong evidence underscores the significant influence of vitamin D deficiency and supplementation on the makeup of the adult and infant gut microbiota, particularly in various diseases [115][116][117].Nevertheless, due to the current limitations encompassing the number of randomized controlled trials (RCTs) and the relatively small sample sizes, the exact ramifications on the microbiota and the precise mechanisms involved remain to be fully elucidated [115].
However, in a recent review, Bellerba et al. explored the relationship between vitamin D and changes in human gastrointestinal microbiota.This connection is vital because gut microbiota has been linked to various diseases.The review analyzed 25 studies involving human participants investigating the association between gut microbiota and vitamin D. These included examining the effects of vitamin D supplementation, dietary intake of vitamin D, and levels of 25(OH)D.While the studies were diverse and had some limitations, the authors suggest that more research should be conducted using welldesigned animal-based studies or extensive randomized controlled trials (RCTs) to understand better the role of vitamin D in modulating the gastrointestinal microbiota [118].The same author conducted an RCT, which included 60 patients with colorectal cancer to evaluate the effects of VitD supplementation on gut microbiota.It was found that supplementation may impact the microbiota, and this effect may be partially mediated by 25(OH) D. The study also revealed the importance of including sex/gender as a variable in microbiome studies, as differences were observed between male and female participants [119].
Furthermore, another RCT examined the effect of VD3 supplementation in patients with metastatic colorectal cancer; results suggest that vitamin D may fight colorectal cancer.Hence, encouraging results have been seen in a phase 2 trial.However, more research is needed as the evidence examined is preclinical and epidemiological and only reports on current clinical trials [120].
Ongoing research on the effects of vitamin D (VD) on the immune system concerning different diseases has led to promising findings that suggest supplementing with VD could be crucial in supporting a healthy diversity of gut microbiota and strengthening the immune response of beneficial microbiota strains in patients with systemic inflammatory conditions like COPD.This result is because VD has been found to play an important role in regulating immune function, including the proliferation and differentiation of immune cells and the production of inflammatory cytokines.Supplementing with VD may help to restore immune balance and reduce inflammation in patients with COPD, which could have far-reaching benefits for their overall health and well-being.Recent studies have identified notable alterations in the lung microbiome composition of individuals diagnosed with chronic obstructive pulmonary disease (COPD) and asthma.Specifically, these changes have been attributed to the crucial immunological role of vitamin D (VD) in maintaining lung commensal.These findings suggest that the modulation of the lung microbiome through regulating VD levels may hold promise as a therapeutic strategy for managing these respiratory conditions [121].Various factors such as environmental exposures, infections, airway remodeling, and antibiotic treatments can cause changes in the airway epithelial barrier.These changes can trigger immune responses and lead to further microbiome changes, worsening with disease progression [121,122].
Two studies suggest that vitamin D may affect the airway microbiome.Toivonen et al. found a correlation between low vitamin D levels and decreased nasopharyngeal microbiota, with more severe bronchiolitis symptoms [123].The second study examined the impact of vitamin D supplementation on the presence of Staphylococcus aureus, Staphylococcus epidermidis, and Corynebacterium species in the sputum of cystic fibrosis (CF) patients.It found differences in abundance between vitamin D-deficient and sufficient CF patients [124].
A recent review has summarized the current knowledge regarding the interaction between vitamin D, the lung microbiome, and chronic lung diseases like tuberculosis.The study proposes how these factors could affect the outcome of tuberculous granuloma and explains the underlying drivers of MTB infection outcomes within these structures.The authors suggest that potential therapeutic strategies could aim to redirect the outcome of tuberculosis by balancing vitamin D, the lung microbiome, and the tuberculous granuloma.However, the study does not provide specific recommendations for treating or preventing tuberculosis [125].
At that point, research indicates that alterations in microbiota could contribute to the development of chronic respiratory illnesses, and vitamin D deficiency and supplementation may also be factors.Nonetheless, additional research is necessary since the existing evidence is founded on several randomized controlled trials with limited sample sizes.

Conclusion and future prospect
The causes of COPD include chronic exposure to cigarette smoke and air pollution, as well as harmful substances like proteolytic enzymes, cytokines, and chemokines released by inflammatory cells.These substances can damage the epithelial barrier and cause changes in the airway epithelium, impacting the body's ability to defend against infection.This damage can make people more susceptible to bacterial and viral infections, triggering COPD exacerbations and contributing to disease progression.Recent research has linked vitamin D deficiency to COPD exacerbations [8].However, studies indicate that only individuals with 25(OH) D levels below 25 nmol/L can benefit from vitamin D supplements in reducing exacerbations [105,108,109,126,127].Undoubtedly, a thorough investigation is necessary to fully understand the mechanism through which vitamin D supplementation provides its protective effect.
In another aspect, adequate local levels of 1,25(OH)2D can offer partial defense against the consequences of exposure to inhaled oxidants or those generated by recruited inflammatory cells; 1,25(OH)2D can reduce oxidative stress and helps maintain the integrity of the epithelial barrier and regulate immune responses.Moreover, vitamin D helps protect against the adverse effects of both bacterial and viral infections by promoting antiviral responses, increasing the expression of antimicrobial peptides (AMPs), and regulating inflammatory responses.Additionally, proper vitamin D intake can significantly enhance the body's ability to fight off diseases and minimize the risk of adverse outcomes.Furthermore, pairing vitamin D with anti-inflammatory or anti-fibrotic drugs has proven to be an effective treatment method.This technique explicitly targets cytokines and proteins that can decrease levels of 1,25(OH)2D and stimulate the expression of activating enzymes.
Future research should prioritize enhancing local 1,25(OH)2D levels in chronic inflammatory diseases associated with vitamin D deficiency, such as COPD.This approach can help prevent the adverse effects of increased calcium levels and immune system inhibition.Ultimately, this can lead to the creation of more efficient treatment methods.
On the other hand, it is worth considering how taking VD supplements can impact the diversity of gut bacteria and the production of short-chain fatty acids (SCFAs).SCFAs have been shown to have a protective effect on the immune system of patients with COPD, which can slow down the progression of the disease and reduce the number of flare-ups.In the future, more research is needed to determine if VD supplements can protect against chronic inflammatory conditions by changing gut or lung bacteria.
calcium and phosphorus levels and promoting healthy bone development since other extra-renal cells, such as some immune cells and airway epithelial cells, contain the vitamin D receptor (VDR) and have the ability to convert 25-hydroxyvitamin D (25(OH)D)-the inactive form of vitamin D-into its active metabolite, 1,25-dihydroxy vitamin D (1,25(OH)2D).Therefore, vitamin D can affect various physiological processes beyond bone health.The immune function of vitamin D was recorded in different research, and it is considered a neurohormone or even a cytokines-like component with multiple immunological functions.Vitamin D induces its function by enhancing the innate immune response and promoting the production of different immunological cells as neutrophils and monocytes, in addition to facilitating its proliferation and function

Table 1
Association between VD deficiency and COPD exacerbation