Chronic Atrophic Autoimmune Gastritis: The Evolving Role of Vitamin D

Vitamin D possesses a crucial role in preserving bone health, modulating the immune system responses, and supporting various physiological functions throughout the body. Chronic atrophic autoimmune gastritis (CAAG) constitutes an autoimmune condition marked by inflammation and damage to the stomach cells, often resulting in a decreased ability to absorb certain nutrients, including vitamin B12 and iron. Although, vitamin D is not directly affected by this condition, the sufficiency of this micronutrient seems to have important implications for overall health and management of the disease. The aim of the current review was to assess the incidence and related features of vitamin D deficiency in patients with CAAG and to elucidate the complex regulatory role of this nutrient, in an effort to improve patient outcomes. Vitamin D greatly contributes to the regulation of the immune system. In patients with CAAG, the immune system attacks the stomach lining; thus, the maintenance of a healthy and balanced immune response is important. In autoimmune conditions such as CAAG, where inflammation plays a decisive role in disease progression, vitamin D could potentially exert a role in managing and controlling the associated symptoms. Adequate vitamin D levels may help in regulating the immune response and reducing inflammation. In addition, patients with CAAG are at risk of nutrient deficiencies, including vitamin B12 and iron, which can lead to anemia and bone health issues. As vitamin D is critical for calcium absorption and bone health, assurance of sufficient levels of this micronutrient can be beneficial in preventing or mitigating bone-related complications. In conclusion, regular monitoring of vitamin D levels, among other nutrients, and appropriate supplementation, when necessary, can help improve overall health and well-being in these patients.


Introduction
Chronic atrophic autoimmune gastritis (CAAG), also known as type A gastritis or autoimmune metaplastic atrophic gastritis, is a chronic immune-mediated, inflammatory condition that affects the stomach lining and especially the gastric oxyntic mucosa [1,2].The disease is characterized by the auto-immune-induced depletion of gastric parietal cells, resulting in their substitution by atrophic and metaplastic tissues [1,2].Specifically, CAAG undergoes histopathological changes across three distinct phases [3,4].Initially, there is evidence of sporadic damage to oxyntic glands, caused by the infiltration of plasma cells and lymphocytes.This infiltration is frequently observed in a gradient from top to bottom, accompanied by a pseudoenlargement of the parietal cells that remain akin to those under proton-pump inhibitor therapy [4,5].Subsequently, during the florid phase, the dense infiltration of lymphocytes and plasma cells occurs in the lamina propria, accompanied by evident atrophic glandular alterations and replacement of native parietal cells by muco-secreting epithelia resembling antral glands (termed oxyntic antralization) [6].The advanced stages of CAAG feature "oxyntic mucosa desertification", marked by fibrosis of the lamina propria replacing oxyntic glandular units.This stage is also distinguished by foveolar hyperplasia accompanied by microcystic changes underneath, as well as the emergence of inflammatory and hyperplastic polyps.Furthermore, there is a widespread occurrence of intestinal, pancreatic, and pseudopyloric metaplasia, typically accompanied by minimal inflammation [4].
The parietal cells are responsible for producing stomach hydrochloric acid and intrinsic factor, a protein necessary for vitamin B12 absorption [7].CAAG often leads to micronutrient deficiencies due to the autoimmune-mediated destruction of gastric parietal cells, impairing the absorption of essential nutrients such as vitamin B12 and iron [8].This can result in symptoms such as fatigue and bone health issues, necessitating careful monitoring and supplementation to address specific deficiencies and prevent complications [9].
Beyond autoimmune inflammation, Helicobacter pylori infection is also acknowledged as the primary etiological contributor for the progression of chronic atrophic gastritis [10].However, in the autoimmune etiology of gastritis, the inflammation is confined to the glands of the corpus and fundus in the stomach, while the antrum remains unaffected [8].Inflammation of the oxyntic mucosa and its subsequent atrophic development are distinctive features of CAAG, which are essential for a definitive diagnosis [8].The incidence of CAAG is approximately estimated to be around 1-2% and is more common in females than in males, with a ratio of 3:1 between women and men, and increasing occurrence with advancing age [11,12].
Apart from vitamin B12 and iron deficiency, patients with CAAG exhibit deficiencies in various vitamins and micronutrients including vitamin C, vitamin D, and calcium [13][14][15].The underlying pathogenetic mechanism driving these alterations seems to entail either heightened degradation or diminished nutrient absorption in the gastric mucosa, potentially stemming from elevated pH levels and bacterial overgrowth [14].Vitamin D greatly contributes in regulating the absorption of calcium and upholding bone health by facilitating the deposition of calcium in bones.Additionally, it has important immunomodulatory effects, helping to regulate the immune system and reduce inflammation [16][17][18][19].In autoimmune diseases, including CAAG, dysregulation of the immune system responses leads to tissue damage.The function of vitamin D to modulate the immune system balance is essential for maintaining immune equilibrium.Insufficient vitamin D levels might worsen immune regulation, potentially contributing to the onset or advancement of CAAG.Additionally, vitamin D deficiency can impair calcium absorption, which may further exacerbate gastric mucosal damage and contribute to CAAG pathology.
The aim of the current review was to assess the occurrence of vitamin D deficiency among CAAG patients and to elucidate the intricate regulatory function of this nutrient.In parallel, we attempted to elucidate the role of vitamin D role in modulating immune dysregulation and improving overall patient outcomes in this setting.

CAAG Pathophysiology
The pathophysiological processes of autoimmune gastritis entail a multifaceted interplay of genetic, environmental, and immunological parameters [20].The stimulation of autoreactive T cells that identify and attack parietal cells and intrinsic factor is a key player in CAAG pathogenesis.Stimulation of T cells initiates the destruction of parietal cells, which occurs as a consequence of the activity of anti-parietal cell antibodies (PCAs); PCAs identify subunits of the proton pump, H+/K+ ATPase, a distinctive feature found exclusively in parietal cells [8].In vitro studies have shown that PCAs bind to the proton pump, leading to direct cellular damage of parietal cells through complement-dependent cytotoxic activity [21].The destruction of parietal cells leads to a decrease in the secretion of hydrochloric acid, higher pH of the stomach, and reduction in intrinsic factor, which in turn, results into vitamin B12 and iron malabsorption, causing pernicious anemia and iron deficiency anemia, respectively [8].These conditions constitute prevalent clinical manifestations of CAAG; specifically, iron deficiency anemia is observed in approximately 25-50% of CAAG patients [22,23], whereas pernicious anemia may be identified in up to 15-25% of patients [22,24].
Vitamin B12, an indispensable nutrient crucial for various physiological processes such as development of red blood cells, synthesis of DNA, and function of the nervous system faces reduced absorption in this scenario [1].Autoantibodies against intrinsic factor (IFAs) targets intrinsic factor, a protein secreted by parietal cells necessary for vitamin B12 absorption [25].The reduced absorption of vitamin B12 presents with various symptoms, such as anemia and neurological issues, which could escalate if left untreated.
However, PCAs in the circulation are not likely to present a direct pathogenic role in CAAG [8].CAAG patients have been found to be PCA-negative, and a considerable number of individuals diagnosed with common variable immunodeficiency also experience CAAG, with the majority testing negative for PCA antibodies [26,27].In such cases, cell-mediated immunity appears to greatly contribute to CAAG development, and the diagnosis is confirmed through histological examination.IgG4-secreting plasma cells have been noted in the mucosal tissue of patients with CAAG, specifically in individuals with pernicious anemia, yet their presence does not confirm a potential pathogenic effect [28].Thus, although PCAs and IFAs are typically viewed as indicators of autoimmunity in CAAG, they do not directly influence the apoptosis of parietal cells and are not consistently detected in CAAG [8].
Genetic predisposition is a major contributor to the onset of CAAG.Specific alleles of the human leukocyte antigen (HLA), notably HLA-DR isotype (HLA-DR) and HLA-DQ isotype (HLA-DQ) have been linked to an elevated risk of developing this condition [29].Additionally, genetic factors associated with impaired immune regulation and autoimmunity, including specific gene polymorphisms, may further contribute to the susceptibility of this disease [30].In individuals with a genetic predisposition, exposure to specific dietary components or H. pylori infection can trigger the autoimmune response.The involvement of infectious agents as triggers for the disease occurrence has been debated.There are data indicating that H. pylori infection serves as a catalyst for the disease in individuals with genetic susceptibility, based on the theory of molecular mimicry between H. pylori and the H+/K+ ATPase of parietal cells [31].Specifically, microbial antigens resembling self-antigens are able to stimulate autoreactive immune cells that target the gastric mucosa [31][32][33][34][35].
The primary pathogenic role in CAAG is attributed to autoreactive CD4 + T helper 1 (Th1) cells and CD8 + cytotoxic T cells, both identified in the mucosal tissue of patients with CAAG [36].Nevertheless, the specific stimuli prompting the proliferation of these cell clones remain unidentified.D'Elios et al. [36] have shown that the ex vivo proliferation of gastric mucosa CD4 + T cell clones is induced by H+/K+ ATPase, predominantly Th1 cells.Fur-thermore, these cells produced interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α), indicating a characteristic Th1 cytokine pattern.Troilo et al. [37] delved into the immune reaction triggered by intrinsic factor in a cohort of 7 individuals with pernicious anemia.In the gastric mucosa of these patients, stimulated autoreactive Th1 cells targeting intrinsic factor were identified, with a majority displaying either a Th17 or a Th1 phenotype and producing TNF and interleukin 21 (IL-21) [37].Moreover, intrinsic factor was capable of activating CD8 + cells against parietal cells.Importantly, these autoreactive T cell clones were absent in H. pylori patients [37].
Patients with CAAG may progress to intestinal metaplasia.Moreover, the clinical manifestations of CAAG are intricate due to its common correlation with various autoimmune conditions, particularly Hashimoto's thyroiditis [38].Additionally, there exists an increased likelihood of developing gastric adenocarcinoma and type 1 gastric neuroendocrine tumors associated with CAAG [27,29,39].Autoimmune gastritis involves diverse molecular and cellular mechanisms, encompassing genetic susceptibility, autoantibodies, and the development of a pro-inflammatory microenvironment [8]; however, the comprehensive pathophysiological mechanism remains unclear.
The widely discussed potential influence of vitamin D in hindering the progression of inflammatory diseases, stems from the emerging recognition of its antiproliferative and anti-inflammatory properties.The role of vitamin D in autoimmune gastritis is a subject of ongoing research, and while the precise mechanisms are not fully elucidated, there is evidence suggesting a potential association (Fig. 1).

Vitamin D Physiology and Metabolism
Vitamin D, a fat-soluble vitamin, plays a major role in various functions in the human body.Its main role is in regulating calcium and phosphorus metabolism, vital for bone health [40].Additionally, vitamin D is pivotal in modulating the immune system, as well as influencing cell growth and differentiation [40].These physiological effects of this nutrient are orchestrated through a series of metabolic transformations, primarily occurring in the skin, hepatic tissue, and kidneys [40] (Fig. 2A).
Two primary forms of vitamin D exist, each with distinct chemical structures: either as vitamin D2, also known as ergocalciferol, or as vitamin D3, also referred to as cholecalciferol [41,42].The synthesis of vitamin D initiates in the skin when exposure to ultraviolet B sunlight triggers the conversion of 7-dehydrocholesterol into previtamin D3 [41,42].Following this, pre-vitamin D3 undergoes thermal isomerization, leading to its conversion into vitamin D3.Alternatively, vitamin D can be obtained from dietary sources; in this case, the small intestine absorbs this form in conjunction with chylomicrons.After this, vitamin D is conveyed to the liver, bound to vitamin D-binding protein.Upon synthesis or ingestion, the enzyme 25-hydroxylase (CYP2R1) in the liver, transforms vitamin D into 25-hydroxyvitamin D [25(OH)D], which is the primary circulating form of the vitamin [42].Following that, 25(OH)D undergoes further hydroxylation in the kidneys, facilitated by the enzyme 1α-hydroxylase (CYP27B1) to produce the biologically active form of vitamin D, 1,25dihydroxyvitamin D3 [1,25(OH)2D3] or calcitriol [42].Although calcitriol being the active form, the evaluation of vitamin D levels typically hinges on assessing the serum levels of 25(OH)D.This inclination is attributed to its comparatively extended half-life and the consistently observed levels in the blood circulation.Elements such as parathyroid hormone, calcium, phosphorus, and fibroblast growth factor [43] intricately regulate the metabolism of vitamin D. The production of the active form takes place both in renal tissue and extra-renal tissues [44].

Assessment of Vitamin D Prevalence and Status
Vitamin D insufficiency/deficiency is a significant health concern worldwide and a common feature not only among elderly people and patients with chronic diseases but also in the general population, affecting individuals of all ages and demographic groups.Its prevalence can vary based on factors such as geographical location, lifestyle, age, and skin pigmentation [45].[47].The study described a slight decrease in the vitamin D prevalence deficiency from 2000-2010 to 2011-2022, but the levels were still notably high [47].Season and latitude have emerged as significant risk factors for vitamin D deficiency, with more pronounced rates observed among individuals residing in the Eastern Mediterranean and lower middle-income countries [47].Moreover, females exhibit greater susceptibility to vitamin D deficiency [47].The impact of vitamin D deficiency extends beyond bone health, with links to chronic conditions such as cardiovascular disease, cancer, autoimmune disorders, compromised immune function, and mood disorders [48].Addressing this issue through monitoring and supplementation, particularly in high-risk groups, is vital for public health and well-being.The parietal cells, which constitute the primary targets in CAAG, are exclusively situated in the oxyntic mucosa and are responsible for the production of hydrochloric acid and intrinsic factor.Alongside parietal cells, oxyntic mucosa involves many other cells including mucous neck cells, chief cells, enterochromaffin-like cells, ghrelin cells, and D cells.CAAG is mainly characterized by the secretion of autoantibodies, particularly anti-PCAs and anti-IFAs.These antibodies target specific proteins expressed by parietal cells within the gastric mucosa.Parietal cells greatly contribute to gastric acid secretion through the action of the proton pump (H+/K+ ATPase).The autoantibodies produced in CAAG target components of this proton pump, leading to atrophy or destruction of parietal cells.This results in decreased production of hydrochloric acid and intrinsic factor, which are essential for digestion and absorption of nutrients such as B12 and iron, causing pernicious anemia and iron deficiency anemia, respectively.These conditions may lead to impaired absorption of vitamin D and thus vitamin D deficiency.The increased secretion of gastrin by G-cells leads to hypergastrinemia.In parallel, elevated gastrin levels stimulate ECL proliferation, leading to hyperplasia and subsequently to the development of gastric neoplastic lesions.
Increased pH leads to ECL hyperplasia due to increased gastrin levels and to alterations in the gastric microbiota composition and favors adverse outcomes.The composition of the gastric microbiota might also be influenced by the occurrence of vitamin D deficiency, further aggravating these effects.The autoimmune attack on parietal cells triggers an inflammatory response in the gastric mucosa.Activated autoreactive T cells including Th1 and Th17 cells release pro-inflammatory cytokines, which further contribute to tissue damage and inflammation.Chronic inflammation and damage to the gastric mucosa result in tissue remodeling including thinning of the mucosal layer and loss of gastric glandular architecture.Vitamin D deficiency hampers the ability of this micronutrient to repress the Th1 and Th17 immune responses and the cytokine production, further worsening the inflammatory microenvironment.H. pylori may contribute to the autoimmune process via molecular mimicry, leading to an autoimmune response, particularly in patients carrying specific TLRs.Created with BioRender.com.

Vitamin D Receptor
Calcitriol exerts its influence by binding to the vitamin D receptor (VDR), which is found in various tissues in the human body [50].Encoded by the VDR gene and classified within the nuclear receptor superfamily, the VDR function relies on its molecular composition and structure.In the majority of cases, VDR serves as a transcription factor, impacting the expression of genes associated with diverse biological processes in reaction to vitamin D [51].Vitamin D-VDR complex has the potential to promote various biological actions through both genomic and nongenomic mechanisms [52,53] (Fig. 2B).Upon activation, the VDR establishes a complex with the retinoid X receptor (RXR), and this composite binds to vitamin D response elements (VDREs) found in the promoter regions of target genes [52,53].In this manner, the activated VDR assumes a crucial role in the transcriptional activation or suppression of diverse target genes by a vitamin D-mediated signaling or by heterogeneous mechanisms, which involve interplay with transcription factors [54].Target genes encompass calcium channels and transient receptor potential vanilloid member 6 (TRPV6) [55], which are crucial for triggering capsaicin-dependent apoptosis in gastric cancer cells [56].Moreover, various vitamin D target tissues have been revealed in the gastrointestinal tract including colon, stomach, and small intestine, in various animal species [44].Furthermore, VDR is expressed in the gastrointestinal tract of humans, rats, and mice [57][58][59].The functions of vitamin D and VDR in the intestine have been extensively investigated.Vitamin D target genes like intestinal plasma membrane calcium ATPase and TRPV6 play crucial role in maintaining adequate calcium absorption in the intestinal tissue [60].
Beyond the gastrointestinal tract, the expression of VDR is extensive across various tissues, encompassing kid-neys, bones, and immune cells, emphasizing its participation in a range of physiological processes [61,62].Notably, VDR is expressed in various immune cells engaged in gastrointestinal immune response, such as in stimulated T cells, B cells, cytotoxic natural killer (NK) cells, dendritic cells (DCs), monocytes, and macrophages [61,[63][64][65][66][67] (Fig. 2C).Scattered cells located in the pyloric antrum and the isthmus within the corpus have been identified as target tissues for 3H-1,25(OH)2D3 [68].However, the precise role of vitamin D in the normal stomach function remains to be investigated.
VDR is expressed in low levels in gastric cancer [69] and Barrett's esophagus [57].Interestingly, VDR expression has been found higher in premalignant gastric tissues with moderate differentiation compared to those exhibited poor differentiation [57,69].Moreover, vitamin D deficiency has been related to other gastrointestinal diseases such as inflammatory bowel disease [70,71], colorectal cancer [72], and H. pylori infection [73].

Immunoregulatory Effects of Vitamin D-VDR
Vitamin D has been linked to the modulation of bone metabolism; however, growing evidence suggests that it also greatly contributes to numerous biological processes governing immune responses [61,62,74].Interest in the po-tential immunomodulatory effects of vitamin D has been growing since the discovery of VDR in monocytes [74,75], followed by their presence in DCs and activated T cells [76][77][78] (Fig. 2C).VDR agonists selectively hamper exaggerated type 1 Th1-driven inflammatory reactions and limit subsequent Th cell differentiation towards a proinflammatory state [79].Vitamin D suppresses the proinflammatory activity of Th1 cells and the secretion of proinflammatory cytokines such as IL-2, IFN-γ, and TNFα [80-82] (Fig. 2C).The active form of vitamin D also inhibits T cell proliferation and the expression of IL-2 [83] and IFN-γ at both the mRNA and protein levels in T cells [84].This inhibition may be attributed to binding of the VDR-RXR heterodimer to the VDREs, present in the promoter regions of genes that encode IL-2 and IFN-γ [82].Beyond the vitamin D anti-inflammatory role, this nutrient also induces Th2 responses by fostering the secretion of IL-4, IL-5, and IL-10 (Fig. 2C).This shift in the T cell balance from an inflammatory Th1 to an anti-inflammatory Th2 response is facilitated by vitamin D [85].Additionally, certain studies have indicated that vitamin D might dampen Th17 responses [86] and enhance the activity of regulatory T cells (Tregs) [87].The presence of vitamin D in immature DC culture has suggested that it induces their differentiation towards a tolerogenic phenotype; tolerogenic DCs authorize the differentiation of effector T cells into forkhead box protein 3-positive (Foxp3+) Tregs [88].Subsequently, Tregs become activated and undergo proliferation upon exposure to VDR ligands [88].Lastly, vitamin D is essential for the maturation of NK T (NKT) cells and for the secretion of IL-4 and IFN-γ, by these cells [89].Consequently, the wide-ranging influence of vitamin D on various immune cell types strongly indicates its potential significance in immune-related conditions, particularly in autoimmunity [16,90,91].

Role of Vitamin D in CAAG
To date, there are limited data on the relation between CAAG and vitamin D deficiency.Studies evaluating vitamin D levels in patients with CAAG are presented in Table 1 (Ref.[92][93][94][95][96][97]).
The assessment of vitamin D levels in postmenopausal women with pernicious anemia as a potential risk factor for osteoporosis has been first explored in 1992 [92].This study revealed no correlation between vitamin D and the presence of pernicious anemia in a cohort of 21 patients compared to controls.However, the small sample size and the inclusion of postmenopausal women may restrict the reliability of the results [92].In a subsequent study, significantly lower levels of 25-hydroxy vitamin D were observed in CAAG patients compared to those with nonspecific gastritis or healthy controls [93].In CAAG subjects, the mean vitamin D levels were 9.8 ± 5.6 ng/mL (95% confidence interval [CI] 8.4-11.2) versus 21.3 ± 12.2 (95% CI: 19.7-22.9) in healthy individuals.The significantly dimin-ished vitamin D levels in CAAG compared to patients with nonspecific gastritis or the healthy individuals suggested a potential link between hypovitaminosis D and autoimmune disease development [93].In another study, the elevated prevalence of hyperparathyroidism secondary to vitamin D deficiency was observed in individuals with CAAG [94], indicating that the modulation of vitamin D metabolism and/or calcium could be compromised in CAAG patients, possibly due to impaired vitamin D absorption in the intestine [94].The limitation of that study was the inclusion of patients with gastric carcinoid type 1 (24 of 107), which may have compromised the results.Massironi et al. [96] showed significantly lower mean 25(OH)D levels in patients with CAAG compared to healthy controls (18.8 vs. 27.0ng/mL; p < 0.0001).Moreover, a significant association was found between vitamin B12 values at diagnosis and 25(OH)D levels (p = 0.01) [96].Notably, CAAG patients with moderate or severe gastric atrophy showed lower 25(OH)D levels than those with mild atrophy (11.8 vs. 20 ng/mL; p = 0.0047), whereas 25(OH)D levels were significantly decreased in CAAG patients with gastric cancer versus those without (11.8 vs. 19.8ng/mL; p = 0.0041) [96].The relatively small sample size and assessment of 25(OH)D throughout the year, during outpatient examination, is a potential drawback of that study.The prevalence of vitamin D deficiency in patients with CAAG and the potential association of this deficiency with the grade of gastric atrophy or hyperplasia of enterochromaffin-like cells were evaluated in an observational study [97].The results showed that vitamin D deficiency presented in 76 of 122 patients with CAAG [97].25(OH)D levels exhibited a direct correlation with B12 levels and were notably reduced in patients with macronodular hyperplasia compared to those with linear or micronodular hyperplasia [97].This finding suggests the possible pathogenetic effect of vitamin D deficiency in the initiation and progression of CAAG [97].However, the determination of 25(OH)D throughout the year may limit the results of that study.
Both vitamin D and calcium are critical for maintaining bone health, and their deficiency consist of an essential risk factor for osteoporosis development [98].Although there is no evidence on the prevalence of osteoporosis wit-    -hin CAAG patients, there are data reporting a strong correlation between chronic atrophic gastritis and osteoporosis in a study of 401 postmenopausal women [99].Moreover, since vitamin D is critical for absorbing calcium, a lack of vitamin D could also explain a decline in calcium levels in CAAG patients [15].
In a mechanistic study, the role of cluster of differentiation 24 (CD24), an antigen that has been used as a marker to indicate tumor invasiveness in gastric cancer [100], has been explored in patients with chronic atrophic gastritis [101].The study indicated a gradual increase in CD24 expression across samples obtained from normal gastric mucosa, non-atrophic chronic gastritis, chronic atrophic gastritis, chronic atrophic gastritis with intestinal metaplasia, dysplasia, and gastric cancer [101].Moreover, the data demonstrated that CD24 knockdown resulted in significantly increased expression of E-cadherin and VDR in gastric cancer cells, whereas CD24 overexpression led to converse effects [101].VDR has been found to mediate E-cadherin expression, whereas the receptor expression has been eliminated during the progression of colon cancer [102,103].Thus, VDR-mediated reduction in E-cadherin expression indicates a pivotal stage in tumor metastasis and represents a key occurrence in the epithelial-mesenchymal transition (EMT) [104].The EMT may be considered a pathological mechanism that takes part in tumor progression, particularly during the invasion and metastasis of tumor cells [105].Consequently, CD24 might stimulate invasion by controlling the VDR-mediated onset of EMT.
Vitamin D has emerged as a significant factor in various autoimmune diseases, as indicated by numerous epidemiological studies.Its ability to bind to VDR and act as a transcriptional factor allows it to modulate gene expression and influence the immune cells through its immunoregulatory role.Emerging data suggest a close association among VDR polymorphisms, serum vitamin D levels, and the risk of autoimmune diseases such as multiple sclerosis, type 1 diabetes mellitus, and systemic lupus erythematosus [106,107].Thus, disruptions in vitamin D signaling or impaired vitamin D intake, influenced by genetic and environmental factors may be a contributing factor for initiation and progression of autoimmune conditions.Given the high prevalence of vitamin D deficiency observed in patients with autoimmune conditions, vitamin D supplementation has been considered a potential therapeutic approach for this setting.The findings of our study confirm this hypothesis to some extent.First, all of the aforementioned studies presented in the current review report vitamin D deficiency in patients with CAAG, proposing a potential pathogenetic effect of vitamin D deficiency in the initiation and progression of CAAG.Antico et al. [93] supported the notion that hypovitaminosis D could potentially serve as a risk factor for the onset of CAAG, as vitamin D levels in patients with CAAG were notably lower compared to patients with non-specific gastritis or healthy individuals.
The study explored the impact of vitamin D in the gastroentero-pancreatic NENs showed ameliorated clinical outcomes for patients who received vitamin D supplements, enhancing the theory on the antiproliferative role of vitamin D supplementation on NENs [95].The evidence on the role of vitamin D supplements in patients with CAAG remain scarce; however, our findings support the regular assessment of vitamin D and provide supplementation when necessary.However, specific recommendations should be made on a case-by-case basis by healthcare professionals, considering individual patient needs and medical history to conclusively establish the effectiveness of vitamin D supplementation in preventing and alleviating CAAG.

Conclusion
Vitamin D has been greatly associated with various autoimmune diseases in multiple epidemiological studies.Vitamin D-VDR binding enables this complex to act as a transcriptional factor, regulating gene expression and exerting immunomodulatory effects on immune cells.Research has demonstrated the potential of vitamin D to repress Th17 cytokine secretion, promote Treg activity, stimulate NKT cell action, inhibit Th1 responses, and induce Th2 cytokine secretion, thereby influencing T cell polarization towards a Th2 phenotype.Moreover, growing data suggest a close association between serum vitamin D levels, and polymorphisms in the VDR gene with the risk of autoimmune diseases.Consequently, dysregulated vitamin D signaling or impaired vitamin D intake may contribute to the initiation and progression of autoimmunity.
In the setting of CAAG, the current body of literature lacks sufficient evidence to definitively establish a direct correlation between vitamin D status and the pathogenesis or prognosis of disease.It is plausible that vitamin D deficiency could either be a secondary manifestation of the disease or contribute to impaired tissue responsiveness to both physiological and pathological signals.Moreover, to date, the underlying mechanism of vitamin D deficiency in patients with CAAG remains unclear.However, similar to other micronutrients [14], it is plausible to consider a reduced absorption or increased degradation of vitamin D in the gastrointestinal tissue due to hypochlorhydria and overgrowth of bacterial population.The existing evidence suggests a direct link between the extent of atrophy in the mucosal tissue and vitamin D concentrations.A hypothesis could be that in individuals with mild atrophy, the remaining gastric acid secretion may sustain adequate absorption of vitamin D, which becomes insufficient as the disease progresses to more advanced stages.Moreover, vitamin D deficiency in patients with NENs [95,96] enhances the potential role of hypovitaminosis D in the development of such neoplasms.Additionally, there are data on the expression of VDR in neuroendocrine cells.Moreover, vitamin D analogue demonstrated the ability to induce cell cycle arrest in the G0/G1 phase and apoptosis in a murine insulinoma cell line [108].The precise mechanism underlying this correlation remains incompletely understood.Nevertheless, vitamin D has demonstrated involvement in various cellular processes including growth regulation, immune modulation, differentiation, adhesion, angiogenesis, apoptosis, and metastasis in epithelial tissues [109].
In light of the heightened occurrence of vitamin D deficiency among individuals with autoimmune conditions, there is growing interest in exploring vitamin D supplementation as a potential treatment in autoimmune conditions.Based on the data examined in the current review, while the precise mechanisms underlying the role of vitamin D in CAAG remain to be fully elucidated, accumulating evidence suggests that vitamin D may affect immune function and gastric mucosal integrity, making it a promising avenue for further research and potential therapeutic intervention.Thus, the routine evaluation of vitamin D levels in patients with CAAG is essential.Moreover, vitamin D supplementation in CAAG individuals suffering from vitamin D deficiency before the progression of disease may be a crucial preventive factor [110].However, the lack of large, randomized controlled trials necessitates further well-organized studies with robust methodological design to demonstrate the causality of vitamin D in CAAG patients and thus validate the efficacy of vitamin D in preventing CAAG and determine if vitamin D supplementation can restrict the damage of gastric parietal cells.
About 1 billion individuals have insufficient serum levels of 25(OH)D [46].Cui et al. [47], assessed the prevalence of vitamin D deficiency both globally and regionally among individuals aged 1 year or older from 2000 until 2022.The global prevalence was estimated at 15.7% in patients with 25(OH)D <30 nmol/L, 47.9% in those with 25(OH)D <50 nmol/L and lastly 76.6% in patients with 25(OH)D <75 nmol/L, between 2000 and 2022 Fig. 1.CAAG impacts the corpus and fundus, which results in atrophy of the mucosal tissue.The antrum remains unaffected.The parietal cells, which constitute the primary targets in CAAG, are exclusively situated in the oxyntic mucosa and are responsible for