By TAP Integrative

Tuberculosis (TB) is responsible for approximately 1.5 million deaths per year worldwide, with 9 million people diagnosed with active pulmonary TB cases. Multidrug-resistant TB is prevalent and often occurs in areas in which HIV and diabetes are also pandemic, which further complicates treatment. What’s more, most drugs used to treat TB were developed more than four decades ago and come with sometimes severe side effects, so there is a significant need for new and more effective treatments.

In vitro studies have found that vitamin D3 induces the gene expression of antimicrobial peptides (AMP) that can suppress the growth of Mycobacterium tuberculosis (Mtb), the bacterium that causes tuberculosis. One of these peptides is called human cathelicidin LL-37. Vitamin D3 has been shown to improve control of the TB infection through a mechanism that depends on LL-37. In addition, several studies have shown that vitamin D deficiency is associated with an increased risk of active TB. For these reasons, researchers have been interested in vitamin D as an adjunctive therapy to standard TB treatment.

In addition, a drug called sodium 4-phenylbutyrate (PBA) has some of the same immune effects as vitamin D3, and the two together have been shown to have a synergistic effect in inducing LL-37. The researchers who made that discovery further tested the effects in a trial published in 2015 in the journal PLoS ONE. In that clinical trial, they sought to determine whether administering an oral adjunct therapy of PBA and/or vitamin D3 to active pulmonary TB sufferers would have an effect on LL-37 expression in immune cells, eventually increasing elimination of Mtb.

To do that, they enrolled 288 adult TB patients in a randomized, double-blind, placebo-controlled trial. Patients continued to receive standard TB therapy and also were administered (1) placebo PBA and placebo vitamin D3, (2) 500mg twice daily of PBA and placebo vitamin D3, (3) placebo PBA and 5,000 IU of vitamin D3 once daily, or (4) 500mg twice daily PBA and 5,000 IU of vitamin D3 once daily (PBA+vitD3).

After four weeks, 71 percent of the patients in the PBA+vitD3 group and 61 percent in the vitD3 group had negative sputum cultures compared to 42.2% in the placebo group (P=0.032). The odds of sputum culture being negative at week 4 was 3.42 times higher in the PBA+vitD3 group (p = 0.001) and 2.2 times higher in vitD3-group (p = 0.032) compared to placebo. At week 12, the concentration of LL-37 in monocyte-derived macrophages (MDM) was significantly higher in the PBA group compared to placebo (P=0.034). Intracellular Mtb growth in MDM began to decline earlier in the PBA group compared to placebo.

This study suggests that adjunct therapy with PBA, vitamin D3, or a combination of the two benefits recovery from TB and may be a promising host-directed TB therapy


Mily A, Rekha RS, Kamal SM, et al. Significant effects of oral phenylbutyrate and vitamin D3 adjunctive therapy in pulmonary tuberculosis: a randomized controlled trial. PLoS One. 2015 Sep 22;10(9):e0138340.


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