Calcitriol Exerts Prophylactic Anti-Mycobacterium Effect In A Dose-Dependent Manner

Abstract

Vitamin D was empirically applied for Tuberculosis (TB) treatment in the past, and is currently used as an adjuvant for TB therapy. Although an increasing pile of evidences suggests that vitamin D has no therapeutic effect against TB infection, the prophylactic effect of vitamin D in preventing TB remains largely undetermined. To experimentally valuate the potential prophylactic effect of calcitriol (the active form of vitamin D) against mycobacterium infection, we performed dose-gradient calcitriol soaking in 30-day-old zebrafish before Mycobacterium marinum (M. marinum) challenge through tail vein injection. 1H-NMR metabolomics analysis was further performed for illustration of potential mechanisms underlying the prophylactic effect of calcitriol against M. marinum. The results suggested that calcitriol exerts dose-dependent prophylactic anti-mycobacterium effects, i.e., the bacterial load and the corresponding inflammatory factors (IL-1β, TNF-α, and IFN-γ) expressions in M. marinum challenged zebrafish were reduced by low-dose (25 µg/L) or high-dose (2500 µg/L) calcitriol soaking, rather than by moderate-dose (250 µg/L) calcitriol soaking. Body weight of the M. marinum challenged zebrafish was recovered by high-dose prophylactic calcitriol soaking rather than by low-dose or moderate-dose calcitriol. The 1H-NMR metabolomic profiling identified 29 metabolites with altered abundance among the dose-gradient calcitriol groups, among which 22 metabolites were co-varied with the dose of calcitriol, the rest 7 metabolites were co-varied with the bacterial load and the inflammatory response in term of cytokine expression. Further pathway analysis indicated that the glycine, serine, and threonine metabolism pathway was the activated in both of the two metabolite groups, indicating that the pathway was altered by dose-gradient of calcitriol and was in response to M. marinum infection in zebrafish. The results of the present study suggested that the activation of glycine, serine and threonine metabolism pathway may play a potential role for the dose-dependent anti-mycobacterium effect induced by prophylactic calcitriol soaking.

Potential Protective Effects of Mesna and Vitamin D Separately or Concomitantly on Cyclophosphamide Induced Hemorrhagic Cystitis in Rats

“…It was proved by a significant decrease in tissue MDA and TNF-α levels and a significant increase in tissue TAC in the CH group as compared to the CL group. These results agree with Kianian et al, (2019) 77 and Li et al, (2021) 78 .…”

Preparation and Evaluation of Low-Dose Calcitriol Dry Powder Inhalation as Host-Directed Adjunct Therapy for Tuberculosis

“…The observation that DPI adjunct to ATT cleared the spleen of bacterial burden indicates that calcitriol administered in the form of soluble inhaled particles was systemically absorbed rapidly. Exposing zebra fish infected with Mycobacterium marinum to a high dose of calcitriol (2500 µg/L/day) for 30 days led to significant reduction in bacterial burden; whereas low and medium doses (25 and 250 µg/L/day) showed minimal and no reduction respectively [34]. Another study by Crowle et al demonstrated that calcitriol at concentration 4 µg/ml (supraphysiological, approximately 5 log greater than normal circulating levels) in vitro was able to increase the doubling time of intracellular Mtb but had no significant bactericidal activity [12].…”