Background: Mycobacterium tuberculosis (Mtb) 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 Mtb 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 Mtb infection in macrophages treated with or without fenofibrate. Mtb 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 Mtb, icl1, tgs1, and devR, were markedly upregulated in response to fenofibrate treatment. Our results suggest that fenofibrate may facilitate intracellular Mtb 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 Mtb genes involved in lipid metabolism, enhanced intracellular growth of Mtb, and the ability of Mtb to sustain a nutrient-rich reservoir in human macrophages, observed during treatment with fenofibrate. people, it still presents the highest incidence and mortality rate [2]. This disease is transmitted via inhalation of aerosolized bacilli, which then replicate within alveolar macrophages in lung tissue. In the host, immune cells can be recruited to the affected sites, and encase the invading mycobacteria, forming a structure known as the granuloma [3,4]. A granuloma is composed of infected alveolar macrophages, monocytes, multinucleated giant cells, epithelioid cells, and most notably, foamy macrophages [4,5]. The foamy aspect of these cells results from the accumulation of neutral lipids, typically triacylglycerides and esterified and non-esterified sterols. These foamy macrophages are nutrient-rich reservoirs for Mtb persistence [6,7].Published data support that regulating cholesterol in macrophages may affect the intracellular growth of Mtb [8,9]. However, questions remain regarding the use of hypolipidemic therapy for the treatment of Mtb infection [10]. By the activation of peroxisome proliferator activated receptor α (PPARα), mainly expressed in the liver, heart, monocytes, and macrophages, fenofibrate increases lipolysis and elimination of lipids from plasma [11][12][13]. It is commonly prescribed for the treatment of hypertriglyceridemia or mixed hyperlipidemia [13][14][15]. This study aimed to investigate epidemiological data to obtain outcomes of TB...
