# Potential Role of Vitamins A, B, C, D and E in TB Treatment and Prevention: A Narrative Review
## 2 Results
### Vitamin D  
Vitamin D (VD) may play a fundamental role in the innate and adaptive immune response against MTB infection and in the progression of the disease. MTB enters the body through the TLRs present on macrophages. Activation of the signaling pathway of TLR and exposure to inflammatory cytokines induce the expression of CYP27B1 oxidase by macrophages. This oxidase is the one that converts 25(OH)-VD into the active form 1,25(OH)-VD, which, in autocrine mode, stimulates the antimicrobial activity of macrophages through the VDR/RXR signaling pathway, inducing the endogenous production of cathelcidin hCAP-18 and its derivative antimicrobial peptide LL-37. LL37 is able to interact with the molecules of the bacterial wall and perforate the cytoplasmic membrane, resulting in the death of the bacterial cell [66; 67; 68; 69]. It also seems that VD induces autophagy in infected macrophages [70]. Autophagy is a process that induces the maturation of phagolysosomes and the degradation of intracellular pathogens. While MTB tries to block the autophagy process, MTB lipoproteins stimulate it by activating the signaling pathway mediated by TLR2/1, CD14 and VDR [71]. In particular, it has been noted that by silencing the expression of LL-37, autophagy is blocked, allowing us to suppose that this antibacterial mechanism depends precisely on the cathelcidin/LL-37 system [72]. In another study it was shown that oral administration of 5000 IU of VD and 500 mg b.d. phenylbutyrate consistently increases the production of LL-37 in both macrophages and lymphocytes and leads to an increase in intracellular killing of MTB by macrophages [73]. VD is also required for acquired immunity to operate against MTB infection. Th1 cells secrete INF \(\gamma\), which causes macrophages to produce antimicrobial compounds, as well as autophagy, phagosome maturation, and other anti-MTB effects. Th2 lymphocytes induce an antibody-mediated response through the secretion of IL-4 and IL-5. It seems that these antimycobacterial activities do not occur in case of VD deficiency [74; 75]. Several studies highlight the anti-inflammatory role of VD, which determines population expansion of T-reg lymphocytes that inhibit the Th1 immune response and reduces the production of MMPs [76; 77]. Furthermore, it appears that VD and its hydroxylated derivatives also promote the stabilization of the endothelium and of the barrier function in the presence of inflammatory mediators [78]. This is essential to reduce the inflammatory state and tissue damage that characterize the pathophysiology of tuberculous disease [78]. Several studies have shown that TB patients have low levels of 25(OH)-VD compared to healthy controls [79; 80; 81]. However, it is unclear whether VD deficiency is a possible cause or consequence of the disease. Numerous in vitro studies have demonstrated the role and potential benefit of VD in TB, showing that VD suppresses the replication of MTB in vitro [82; 83]; few clinical trials have been performed to evaluate the efficacy of VDsupplementation in preventing the development of the disease, failing to show a reduction in the risk of infection and development of disease [84; 85]. However, in a meta-analysis of prospective studies, [PERSON], [PERSON] et al. found a positive dose-dependent correlation between low serum levels of 25(OH)-VD and the risk of developing tuberculous disease [86]. In another meta-analysis, VD deficiency was positively and significantly associated with an increased risk of TB and an increased risk of developing active TB in LTBI subjects/household contacts of active TB patients [80]. Due to heterogeneity in the definition of VD deficiency, which can affect the results of the meta-analysis, more studies are needed to evaluate the effectiveness of the VD supplement in the prevention of TB. The use of VD alongside TB drugs is controversial: a study has demonstrated the efficacy of its use together with PZA in vitro [87; 88], confirmed by an in vivo study conducted in mice by [PERSON] et al. [89].