Immune responses in the treatment of drug-sensitive pulmonary tuberculosis with phenylbutyrate and vitamin D3 as host directed therapy

Background We have previously shown that 8 weeks’ treatment with phenylbutyrate (PBA) (500mgx2/day) with or without vitamin D3 (vitD3) (5000 IU/day) as host-directed therapy (HDT) accelerated clinical recovery, sputum culture conversion and increased expression of cathelicidin LL-37 by immune cells in a randomized, placebo-controlled trial in adults with pulmonary tuberculosis (TB). In this study we further aimed to examine whether HDT with PBA and vitD3 promoted clinically beneficial immunomodulation to improve treatment outcomes in TB patients. Methods Cytokine concentration was measured in supernatants of peripheral blood mononuclear cells (PBMC) from patients (n = 31/group). Endoplasmic reticulum stress-related genes (GADD34 and XBP1spl) and human beta-defensin-1 (HBD1) gene expression were studied in monocyte-derived-macrophages (MDM) (n = 18/group) from PBMC of patients. Autophagy in MDM (n = 6/group) was evaluated using LC3 expression by confocal microscopy. Results A significant decline in the concentration of cytokines/chemokines was noted from week 0 to 8 in the PBA-group [TNF-α (β = − 0.34, 95% CI = − 0.68, − 0.003; p = 0.04), CCL11 (β = − 0.19, 95% CI = − 0.36, − 0.03; p = 0.02) and CCL5 (β = − 0.08, 95% CI = − 0.16, 0.002; p = 0.05)] and vitD3-group [(CCL11 (β = − 0.17, 95% CI = − 0.34, − 0.001; p = 0.04), CXCL10 (β = − 0.38, 95% CI = − 0.77, 0.003; p = 0.05) and PDGF-β (β = − 0.16, 95% CI = − 0.31, 0.002; p = 0.05)] compared to placebo. Both PBA- and vitD3-groups showed a decline in XBP1spl mRNA on week 8 (p < 0.03). All treatment groups demonstrated increased LC3 expression in MDM compared to placebo over time (p < 0.037). Conclusion The use of PBA and vitD3 as adjunct therapy to standard TB treatment promoted favorable immunomodulation to improve treatment outcomes.This study was supported by the International Centre for Diarrheal Disease Research, Bangladesh (icddr,b), Sida (Sida-icddrb Agreement support; Grant 384, SWE-2008-065) and Swedish Strategic Foundation (SSF, Grant No. RBd08–0014), the Swedish Heart-Lung Foundation (Grant No. 2013–0366) and Swedish Research Council (Grant No. 2016–01496). No funding bodies had any role in the design of the study, collection, analysis, and interpretation of data and in writing the manuscript.Peer Reviewe

Additional file 1: of Immune responses in the treatment of drug-sensitive pulmonary tuberculosis with phenylbutyrate and vitamin D3 as host directed therapy

Table S1. Descriptive statistics of the current studied patients and the patients who were not studied. Table S2. Longitudinal change (week 0, 4, 8 and 12) in TB score in the intervention groups compared to placebo. Table S3. Concentrations of inflammatory cytokines and chemokines in treatment groups at different time intervals. (DOCX 24 kb