Phenylbutyrate and Vitamin D3 as Adjunct Treatment in Pulmonary Tuberculosis

by | Oct 5, 2018 | 2018, Lung Health, Vitamin D - General

Written by Angeline A. De Leon, Staff Writer. Treatment with a combination of phenylbutyrate and vitD3 as adjunct therapy to standard TB treatment significantly reduced cytokines/chemokines in participating subjects with drug-resistant pulmonary tuberculosis.

lung healthTuberculosis (TB), an infectious disease of the lungs caused by the bacterium Mycobacterium tuberculosis (Mtb, remains among the top 10 leading causes of death world-wide 1. In the last decade, the increase in antibiotic resistance to Mtb has spurred the rise of alternative chemotherapies such as host-directed therapy (HDT), which aims to modulate immune response against pathogens by targeting host biological pathways, rather than acting directly on the pathogen itself, as in traditional antibiotics 2,3. Previous research has shown that the combined use of phenylbutyrate (PBA), a compound used to treat urea cycle disorders 4 and vitamin D3  associated with various immunomodulatory properties as a form of HDT can speed up clinical recovery from pulmonary TB, accelerate sputum culture conversion (a positive prognostic marker indicating recovery from TB), and enhance expression of immune cells 5. PBA is also associated with increased macrophage-mediated destruction of Mtb 6 and reduced inflammatory response through diminished endoplasmic-reticulum (ER) stress (linked to cellular death and the pathogenesis of TB 7,8. In a study published in BMC Infectious Diseases (2018), researchers investigated whether HDT with PBA and vitamin D3 could promote immunomodulation and thereby improve treatment outcomes in patients with drug-sensitive pulmonary TB.

A total of 93 patients (aged 18-55 years) with newly diagnosed sputum smear-positive TB were enrolled in a double-blind, placebo-controlled trial. In addition to a standard of care regimen consisting of antibiotic treatment, patients were randomized to receive oral doses of either 1 placebo PBA and placebo vitamin D3, 2 500 mg twice daily of PBA and placebo vitamin D3, 3 placebo PBA and 5000 IU of vitamin D3, or 4 PBA combined with vitamin D3 daily for 8 weeks. Serum concentrations of cytokines/chemokines (signaling proteins which coordinate immune response throughout body) were measured from blood samples collected from patients. As a marker of ER stress, spliced X-box binding protein-1 (XBP1spl) mRNA was also assessed in monocyte-derived macrophages (type of white blood cell involved in inflammatory response) from TB patients.

A significant decline in cytokine/chemokine concentration was observed from baseline to Week 8 for the PBA-group [TNF-α (β = − 0.34, 95% Confidence Interval = − 0.68 to − 0.003; p = 0.04), CCL11 (β = − 0.19, 95% CI = − 0.36 to − 0.03; p = 0.02) and CCL5 (β = − 0.08, 95% CI = − 0.16 to 0.002; p = 0.05)] and vitamin D3 group [(CCL11 (β = − 0.17, 95% CI = − 0.34 to − 0.001; p = 0.04), CXCL10 (β = − 0.38, 95% CI = − 0.77 to 0.003; p = 0.05) and PDGF-β (β = − 0.16, 95% CI = − 0.31 to 0.002; p = 0.05)], compared to placebo. In addition, both PBA- and vitamin D3– groups demonstrated a reduction in XBP1spl mRNA on Week 8 (p < 0.03).

Based on study findings, the combined use of PBA with vitamin D3, through their modification of the host defense system, appears to be an effective adjunct treatment for drug-resistant pulmonary TB. Results point to improvement of patients’ cytokine/chemokine profiles, early biomarkers of a dampened inflammatory response, along with diminished ER stress (based on reduced gene expression of XBP1spl). Thus, PBA and vitamin D3 HDT demonstrate therapeutic potential against TB, warranting further research on their individual and synergistic immunomodulatory effects on other forms of infectious disease.

Source: Rekha RS, Mily A, Sultana T, et al. Immune responses in the treatment of drug-sensitive pulmonary tuberculosis with phenylbutyrate and vitamin D3 as host directed therapy. BMC Infectious Diseases. 2018; 18: 303. DOI: 10.1186/s12879-018-3203-9.

© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/)(http://creativecommons.org/publicdomain/zero/1.0/)

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Posted October 5, 2018.

Angeline A. De Leon, MA, graduated from the University of Illinois at Urbana-Champaign in 2010, completing a bachelor’s degree in psychology, with a concentration in neuroscience. She received her master’s degree from The Ohio State University in 2013, where she studied clinical neuroscience within an integrative health program. Her specialized area of research involves the complementary use of neuroimaging and neuropsychology-based methodologies to examine how lifestyle factors, such as physical activity and meditation, can influence brain plasticity and enhance overall connectivity.

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