Abstract
Progressive inflammation and anemia are common in tuberculosis (TB) and linked to poor clinical outcomes. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have inflammation-resolving properties, whereas iron supplementation in TB may have limited efficacy and enhance bacterial growth. We investigated effects of iron and EPA/DHA supplementation, alone and in combination, on inflammation, anemia, iron status markers and clinical outcomes in Mycobacterium tuberculosis-infected C3HeB/FeJ mice. One week post-infection, mice received the AIN-93 diet without (control) or with supplemental iron (Fe), EPA/DHA, or Fe+EPA/DHA for 3 weeks. Mice supplemented with Fe or EPA/DHA had lower soluble transferrin receptor, ferritin and hepcidin than controls, but these effects were attenuated in Fe+EPA/DHA mice. EPA/DHA increased inflammation-resolving lipid mediators and lowered lung IL-1α, IFN-γ, plasma IL-1β, and TNF-α. Fe lowered lung IL-1α, IL-1β, plasma IL-1β, TNF-α, and IL-6. However, the cytokine-lowering effects in the lungs were attenuated with Fe+EPA/DHA. Mice supplemented with EPA/DHA had lower lung bacterial loads than controls, but this effect was attenuated in Fe+EPA/DHA mice. Thus, individually, post-infection EPA/DHA and iron supplementation lowered systemic and lung inflammation and mitigated anemia of infection in TB, but not when combined. EPA/DHA also enhanced bactericidal effects and could support inflammation resolution and management of anemia.
Highlights
Anemia is a common complication in tuberculosis (TB), affecting 30–94% of diagnosed TB patients [1,2,3,4,5,6]
The control (6.70 ± 0.63%) and Eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) (8.12 ± 1.19%) groups had a significantly higher percentage weight gain compared with the groups supplemented with iron (Fe, 0.88 ± 1.50% and Fe+EPA/DHA, 0.16 ± 1.50%)
This study provides evidence, for the first time to our knowledge, that both EPA/DHA and iron independently administered to Mycobacterium tuberculosis (Mtb)-infected mice, lowers inflammation and improves indices of anemia of infection
Summary
Anemia is a common complication in tuberculosis (TB), affecting 30–94% of diagnosed TB patients [1,2,3,4,5,6]. Hepcidin is the main regulator of iron homeostasis and mediates the degradation and internalization of the iron exporter ferroportin in macrophages, hepatocytes, and enterocytes [11]. This leads to intracellular sequestration of iron and the inhibition of iron absorption [12,13]. Less common in TB, iron-deficiency anemia resulting from low dietary iron intake, amongst other causes, affects TB patients and may contribute to disease susceptibility and progression [1,2,3,19]. The treatment of anemia with iron is complicated by impaired absorption and the risk of promoting bacterial growth and inflammation, resulting in poor clinical outcomes [6,14]
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