| Summary: | Background: <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) is an intracellular pathogen that infects and persists in macrophages. This study aimed to investigate the effects of long-term fenofibrate treatment in patients with tuberculosis (TB), and the intracellular viability of <i>Mtb</i> in human macrophages. Methods: Epidemiological data from the National Health Insurance Research Database of Taiwan were used to present outcomes of TB patients treated with fenofibrate. In the laboratory, we assessed <i>Mtb</i> infection in macrophages treated with or without fenofibrate. <i>Mtb</i> growth, lipid accumulation in macrophages, and expression of transcriptional genes were examined. Results: During 11 years of follow-up, TB patients treated with fenofibrate presented a higher risk of mortality. Longer duration of fenofibrate use was associated with a significantly higher risk of mortality. Treatment with fenofibrate significantly increased the number of bacilli in human macrophages in vitro. Fenofibrate did not reduce, but induced an increasing trend in the intracellular lipid content of macrophages. In addition, dormant genes of <i>Mtb</i>, <i>icl1</i>, <i>tgs1</i>, and <i>devR</i>, were markedly upregulated in response to fenofibrate treatment. Our results suggest that fenofibrate may facilitate intracellular <i>Mtb</i> persistence. Conclusions: Our data shows that long-term treatment with fenofibrate in TB patients is associated with a higher mortality. The underlying mechanisms may partly be explained by the upregulation of <i>Mtb</i> genes involved in lipid metabolism, enhanced intracellular growth of <i>Mtb</i>, and the ability of <i>Mtb</i> to sustain a nutrient-rich reservoir in human macrophages, observed during treatment with fenofibrate.
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