Immune responses in the treatment of drug-sensitive pulmonary tuberculosis with phenylbutyrate and vitamin D 3 as host directed therapy

Background We have previously shown that 8 weeks’ treatment with phenylbutyrate (PBA) (500mgx2/day) with or without vitamin D 3 (vitD 3 ) (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 vitD 3 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 vitD 3 -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 vitD 3 -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 vitD 3 as adjunct therapy to standard TB treatment promoted favorable immunomodulation to improve treatment outcomes. Trials registration This trial was retrospectively registered in clinicaltrials.gov, under identifier NCT01580007 .