Abstract
Non-resolving inflammation is characteristic of tuberculosis (TB). Given their inflammation-resolving properties, n-3 long-chain PUFA (n-3 LCPUFA) may support TB treatment. This research aimed to investigate the effects of n-3 LCPUFA on clinical and inflammatory outcomes of Mycobacterium tuberculosis-infected C3HeB/FeJ mice with either normal or low n-3 PUFA status before infection. Using a two-by-two design, uninfected mice were conditioned on either an n-3 PUFA-sufficient (n-3FAS) or -deficient (n-3FAD) diet for 6 weeks. One week post-infection, mice were randomised to either n-3 LCPUFA supplemented (n-3FAS/n-3+ and n-3FAD/n-3+) or continued on n-3FAS or n-3FAD diets for 3 weeks. Mice were euthanised and fatty acid status, lung bacterial load and pathology, cytokine, lipid mediator and immune cell phenotype analysed. n-3 LCPUFA supplementation in n-3FAS mice lowered lung bacterial loads (P = 0·003), T cells (P = 0·019), CD4+ T cells (P = 0·014) and interferon (IFN)-γ (P < 0·001) and promoted a pro-resolving lung lipid mediator profile. Compared with n-3FAS mice, the n-3FAD group had lower bacterial loads (P = 0·037), significantly higher immune cell recruitment and a more pro-inflammatory lipid mediator profile, however, significantly lower lung IFN-γ, IL-1α, IL-1β and IL-17, and supplementation in the n-3FAD group provided no beneficial effect on lung bacterial load or inflammation. Our study provides the first evidence that n-3 LCPUFA supplementation has antibacterial and inflammation-resolving benefits in TB when provided 1 week after infection in the context of a sufficient n-3 PUFA status, whilst a low n-3 PUFA status may promote better bacterial control and lower lung inflammation not benefiting from n-3 LCPUFA supplementation.
Highlights
The bacterial manipulation of host responses in tuberculosis (TB) favours bacterial growth and excessive inflammation, with the resultant lung tissue damage that persists in some TB patients[1,2]
We further aim to mimic this scenario of possible suboptimal n-3 PUFA intakes among TB patients to determine whether supplementation outcomes depend on n-3 PUFA status before Mycobacterium tuberculosis (Mtb) infection
There was a trend towards a main effect of n-3 n-3 long-chain PUFA (LCPUFA) supplementation for a higher percentage weight gain (n-3FAS, 6·65 (SE 0·57) %; n-3 PUFA-sufficient (n-3FAS)/n-3þ, 8·11 (SE 0·89) %; n-3 PUFA-deficient (n-3FAD), 3·23 (SE 1·67) %; n-3FAD/n-3þ, 6·98 (SE 0·60) %, P = 0·07)
Summary
The bacterial manipulation of host responses in tuberculosis (TB) favours bacterial growth and excessive inflammation, with the resultant lung tissue damage that persists in some TB patients[1,2]. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) serve as precursors for specialised pro-resolving mediators (SPM), including resolvins, protectins and maresins These SPM play a role in significantly reducing pro-inflammatory lipid mediator, chemokine and cytokine production and altering immune cell recruitment, whilst promoting anti-inflammatory cytokine release[12]. The incorporation of dietary EPA and DHA into cell membranes has been found to enhance the phagocytosis of apoptotic cells and bacteria, whilst SPM promote bacterial killing[12,13] These functions have not been proven in TB n-3 LCPUFA have been successfully used as anti-inflammatory and inflammation-resolving agents in other conditions driven by inflammation[9]. The aim of the present study is, to determine the effects of EPA and DHA supplementation, administered 1 week after Mtb infection for 28 d, on inflammatory, immune and clinical outcomes in C3HeB/FeJ mice. We further aim to mimic this scenario of possible suboptimal n-3 PUFA intakes among TB patients to determine whether supplementation outcomes depend on n-3 PUFA status before Mtb infection (interaction effects between n-3 PUFA status and n-3 LCPUFA supplementation)
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