IBDs, which include Crohn’s disease (CD), ulcerative colitis (UC), and IBD unclassified, are chronic inflammatory disorders with periods of activity and clinical remission. Given its function in immune system homeostasis, particularly at the intestinal level, vitamin D has been suggested to be capable of affecting the clinical activity of IBD [19].

The intestinal epithelium is the first line of defense, and its integrity is dependent on vitamin D, among other elements. It has been demonstrated that animals with VDR deletion at the intestinal epithelial level had clinically more severe colitis, with worsened apoptosis and enhanced mucosal response of Th1 and Th17 [13]. In contrast, vitamin D supplementation decreased the severity of colitis in both wild-type and Cyp knock-out mice, who are nonproducers of endogenous 1,25(OH)2D, in a model of acute colitis generated by sodium dextran sulfate. Furthermore, transgenic mice expressing human VDR in intestinal epithelial cells demonstrated better resistance to colitis induction than wild-type mice [20]. Du et al. [21] demonstrated that in inflammatory conditions, intestinal VDR is downregulated, which is related to elevated local CYP27B1 expression, as a protective effect for lowering inflammation and boosting VDR signaling. In fact, animals given antibiotics but unable to upregulate CYP27B1 suffered more severe colitis. Furthermore, elevated vitamin D levels appear to be associated with higher serum cathelicidin concentrations and decreased inflammation in UC patients. In a study conducted by Brandvayman et al. [19], no significant relationship was found between low vitamin D levels and seasonal patterns in disease onset in children; however, in the case of flares, a higher frequency was observed in June and a lower frequency in April (p = 0.016), with significantly lower vitamin D levels as compared to those tested during remission [19]. Low 25(OH)D levels have been linked to a higher incidence of active illness [22]. Notably, low vitamin D levels were seen even in IBD patients in clinical remission [23]. This might be owing to the effect of medicines on micronutrient absorption; for example, glucocorticoids diminish calcium, zinc, and phosphorus absorption and utilization and change vitamin D metabolism. Low or inadequate vitamin D levels are also connected with an increased requirement for admission and surgery in this group of subjects [13].

Vitamin D supplementation in IBD patients may be compromised due to malabsorption; hence, substantial doses of vitamin D are typically necessary to attain optimum serological levels. The optimal dose strategy to treat vitamin D deficiency and maintain adequacy in IBD patients, however, is still being discussed [1]. In pediatric IBD patients, 2000 international unit (IU)/day of vitamin D3 for 6 months was found to be more effective than 400 IU/day or vitamin D2 dosages up to 2000 IU in raising blood 25(OH)D concentrations above 30 ng/mL [24, 25]. Oral dosages of 2000 IU/day vitamin D3 and 50,000 IU/week vitamin D2 for 6 weeks were both well-tolerated and superior to 2000 IU/day vitamin D2 in boosting blood 25(OH)D concentrations in IBD patients with vitamin D insufficiency [26]. Simek et al. [27] discovered that two weekly vitamin D3 administration regimens for 6 weeks (5000 IU/10 kg/week, maximum weekly dose of 25,000 IU, and maximum cumulative dose of 150,000 IU versus 10,000 IU/10 kg/week, maximum weekly dose of 50,000 IU, and maximum cumulative dose of 300,000 IU) were safe and effective in correcting vitamin D status in IBD children with hypovitaminosis D. Current recommendations on vitamin D supplementation and status in pediatric IBD patients are summarized in Table 2 (Ref. [1]).

Supplementing with vitamin D has been shown to improve disease symptoms. It should be noted that if such individuals have genetic variants or VDR malfunction, supplementation may be changed [9].

Vitamin D supplementation and VDR’s anti-inflammatory action are both linked to the gut microbiota. First, there is dysbiosis in IBD patients [28]. CD patients typically have a decrease in the phylum Firmicutes, particularly Faecalibacterium prausnitzii, and a rise in Bacteroidetes and Proteobacteria. The microbiota of UC patients is distinguished by a low number of butyrate-producing bacteria and an enhanced Bacteroides fragilis/Faecalibacterium prausnitzii ratio, which is linked with a poor anti-inflammatory response [28]. Low amounts of Faecalibacterium prausnitzii in the stool have been linked to flares; at normal quantities, they boost IL-10 production while decreasing IL-12 and interferon-$\gamma$ [13]. In a study of adult CD patients in clinical remission, vitamin D administration for four weeks resulted in alterations in the bacterial makeup of the microbiome, that were not observed in healthy people. The microbiome was enriched in Megasphaera and Lactobacillus after four weeks [29, 30]. Another study in adult patients with active and inactive UC found a significant increase in the abundance of Enterobacteriaceae following an 8-week vitamin D supplementation [31]. Zhang et al. [32] showed that VDR promotes the expression of the gene producing claudin-2. When VDR regulation at the intestinal epithelium level is missing in an inflamed gut, this tight junction protein hyperfunctions and the intestinal inflammatory response is amplified.

Celiac disease is a chronic autoimmune enteropathy caused by an immune response provoked by gluten in those who are genetically prone to it. It has been proposed that vitamin D insufficiency in childhood may contribute to the etiology of celiac disease by causing incorrect immunological responses, aberrant intestinal mucosal integrity, and reduced local defense against microbial pathogens [33]. A link between sun exposure and celiac disease pathogenesis has been proposed, suggesting that celiac disease is more frequent in northern than in southern latitudes in the United States [34]. Maternal vitamin D supplementation, as well as maternal and neonatal vitamin D status, were not found to be associated with the risk of celiac disease in children [35, 36].

Patients with celiac disease have lower vitamin D levels than healthy people [1, 37]. Furthermore, patients on a gluten-free diet (GFD) had greater vitamin D levels, with values more equivalent to those reported in healthy controls as compared to patients on a free diet. There is no difference in VDR genotypes between celiac disease patients and controls [38]. The microbiome, which may be important in the development of celiac disease, plays an important role. The microbiome of healthy adults varied from that of celiac patients who have not removed gluten from their diet, and patients on a GFD had a considerable drop in Lactobacillus and Bifidobacterium in the study by Nistal et al. [39]. Furthermore, another study found that pediatric celiac disease patients have a greater incidence of pro-inflammatory and gram-negative bacteria in the duodenum upon diagnosis than controls [40]. As previously stated, vitamin D regulates the gut flora, and a lack of it can increase the evolution of celiac disease through these changes. In addition, celiac disease is linked to gastrointestinal infections. Rotavirus infections in children and Campylobacter infections in adults, as well as antibiotic exposure and early childhood illnesses, are risk factors [38]. Vitamin D deficiency is known to enhance susceptibility to infections. It has also been demonstrated that chronic vitamin D and VDR deficiency might worsen celiac disease and influence prognosis [41].

Based on the research thus far, it is unclear if vitamin D is a contributing factor or a result of celiac disease. Bittker et al. [42] claimed that the high levels of 1,25(OH)2D (as opposed to 25(OH)D, which is low in patients with celiac disease) found in non-GFD patients may be considered a risk factor for celiac disease onset for a variety of reasons, including the association between prolonged oral vitamin D supplementation and an increased risk of celiac disease. The same cytokines, chemokines, and toll-like receptors are upregulated after high doses of vitamin D as well as throughout the disease [42].

Autoimmune hepatitis is a disorder defined by an autoimmune reaction initiated by autoantibodies generated against the liver parenchyma, resulting in liver inflammation and, if not treated promptly, progression to cirrhosis and liver failure. In addition, Tao et al. [43] evaluated the relationship between low vitamin D levels and indicators of T-cell inflammation/subset in a retrospective study on a cohort of adult patients with autoimmune hepatitis. In this study, patients with low vitamin D levels had an increase in inflammatory response, oxidative stress, and a reduction in T cell subsets. These alterations were significantly different in patients with impaired liver function compared to those with autoimmune hepatitis but normal liver function. The amount of 25(OH)D in individuals with autoimmune hepatitis was found to correlate adversely with inflammatory factors (hs CRP, TNF, IL-6) and oxidative stress factor (malondialdehyde) and positively with CD3+ and CD4+ counts, superoxide dismutase, and total antioxidant capacity [43]. Furthermore, a mutation in the FokI gene at the beginning codon of vitamin D receptor exon 2 alters mRNA transcription and replication of VDR, reducing receptor function and leading to immunosuppression, which is the cause of autoimmune hepatitis.

T1DM is a polygenic autoimmune disease characterized by a total lack of insulin secretion. Several studies [1] have given light on the link between vitamin D and this condition. VDRs have been discovered at the pancreatic islet cell membrane, implying a function in glucose regulation [44]. Thus, vitamin D administration may slow the course of previously diagnosed T1DM by boosting pancreatic beta-cell secretion or by immunomodulatory actions. Maretzke et al. [45] examined meta-analyses, systematic reviews, and randomized controlled trials that found an inverse relationship between vitamin D supplementation in childhood and the likelihood of developing T1DM. According to these findings, supplementing with vitamin D during pregnancy has no influence on the risk of T1DM in children. However, all of the previous studies are of poor quality. There is insufficient evidence to support vitamin D supplementation as primary prophylaxis [45]. Data on supplementing during pregnancy are debatable, and no indication of protection has been demonstrated [46]. Epidemiological studies, on the other hand, have shown that patients geographically farther from the equator or in locations with longer winters had a higher risk of developing T1DM, indicating the protective role of vitamin D in the genesis of T1DM. Gregoriou et al. [47] conducted a high-quality systematic review that included seven randomized clinical trials in which alfacalcidol or vitamin D3 supplementation (0.25–0.5 $\mu$g per day) was shown to have beneficial effects on C-peptide levels by lowering daily insulin requirements; calcitriol supplementation had no effect. Polymorphisms in the VDR gene may be associated with T1DM. Several studies have linked an increased risk of T1DM to single nucleotide polymorphisms in VDR, particularly BsmI and FokI. According to Habibian et al. [48], serum levels of 25(OH)D greater than 30 ng/mL, as well as specific TaqI and BsmI SNPS genotypes in VDR, are significantly associated with higher levels of C-peptide (fasting and under stimulus) in patients with TDM1 onset, resulting in increased protection of residual beta-cell quantity and pancreatic function. Further research is needed to better understand the link between T1DM etiology and the aforementioned polymorphisms.

Vitamin D is crucial in autoimmune thyroid disorders. Experiments in animal models have revealed that vitamin D insufficiency (25(OH)D 20 ng/mL) can control Graves’ hyperthyroidism in BALB/c mice and that vitamin D supplementation, when combined with cyclosporine, prevents the development of autoimmune thyroiditis [49]. Vitamin D supplementation showed a protective effect against Graves’ disease recurrence with a borderline significant recurrence rate reduction in individuals with Graves’ disease and vitamin D deficiency [50]. Serum 25(OH)D levels are considerably lower in individuals with Graves’ disease onset when compared to controls, with a clear link between vitamin D insufficiency and increased thyroid volume [51]. Furthermore, severe vitamin D deficiency has been observed in Hashimoto’s thyroiditis patients, and the duration of the deficiency correlates with the severity of the deficiency. A case-control study on 90 pediatric patients with Hashimoto’s thyroiditis (aged 12.32 $\pm$ 2.87 years) and 79 age-matched healthy controls (aged 11.85 $\pm$ 2.28 years) found a higher prevalence of vitamin D deficiency in cases (71.1%) than that in the control group (51.9%) (p = 0.025) [52]. Kivity et al. [53] investigated vitamin D levels in adult patients with thyropathies, as well as the relationship between vitamin D insufficiency and autoimmune thyroid disease, thyroid function, thyroid autoantibodies, and demographic variables. For the first time, a relationship between low vitamin D levels and anti-thyroid antibodies was reported. The latter were substantially more prevalent in vitamin D-deficient individuals than in those with normal levels. Furthermore, because low vitamin D levels and autoimmune thyropathies are more common in women, it is conceivable to propose a link between the two. Women have more autoantibodies, such as thyroglobulin antibody and thyroid peroxidase antibody, and lower 25(OH)D levels than males [54]. This has been confirmed in the pediatric population. In a study of 56 Egyptian children and adolescents with newly diagnosed autoimmune thyroiditis compared to a control group, a significant reduction in vitamin D was shown in subjects with autoimmune thyroiditis [55]. Vitamin D levels also correlated negatively with thyroglobulin antibody, thyroid peroxidase antibody, and thyroid stimulating hormone concentrations and positively with free T4. A lower value of vitamin D levels was shown in patients with overt hypothyroidism rather than in the subclinical disease group [56].

In summary, it is still unknown if vitamin D insufficiency is a cause or a result of autoimmune illness. The role of vitamin D supplementation and its consequent success in the therapy of autoimmune thyroid disease remains debatable.