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Metformin: Candidate host-directed therapy for tuberculosis in diabetes and non-diabetes patients
Tuberculosis xxx (2016) 1e4
Contents lists available at ScienceDirect
Tuberculosis journal homepage: http://intl.elsevierhealth.com/journals/tube
Review
Metformin: Candidate host-directed therapy for tuberculosis in diabetes and non-diabetes patients Blanca I. Restrepo* UTHealth Houston, Department of Epidemiology, School of Public Health at Brownsville, 80 Fort Brown, SPH Bldg, Brownsville, TX 78520, USA
s u m m a r y Keywords: Tuberculosis Diabetes Metformin Host-directed therapy Immunometabolism Inflammation
Despite major advances in tuberculosis (TB) control, TB continues to be a leading cause of death worldwide. The discovery of new anti-TB treatment drugs and regimens that target drug-sensitive and drug-resistant TB are being complemented with a search for adjunct host-directed therapies that synergize for Mycobacterium tuberculosis (Mtb) elimination. The goal of host-directed therapies is to boost immune mechanisms that diminish excess inflammation to reduce lung tissue damage and limit Mtb growth. Metformin is the most commonly-used medication for type 2 diabetes, and a candidate for hostdirected therapy for TB. Preliminary data suggests metformin may be beneficial for TB control by reducing the deleterious inflammation associated with immune pathology and enhancing the antimycobacterial activity of immune cells. In this review I summarize current findings, knowledge gaps and the potential benefits as well as points of caution for using metformin as adjunct therapy for TB in patients with and without type 2 diabetes. © 2016 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4.
5. 6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Immune modulation by MetF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Why is MetF an attractive candidate for HDT for TB? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . What we do not know about MetF and TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Mechanisms by which MetF kills or contains Mtb growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Role of MetF versus glycemic control in TB-DM patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Role of MetF in TB-non DM patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Impact of MetF in TB-naïve and LTBI-positive individuals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.1. LTBI with and without T2DM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.2. TB-naïve with T2DM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Can MetF have deleterious effects as a HDT for TB? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ethical approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Author contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction * Fax: þ1 956 882 5152. E-mail addresses: [email protected], [email protected].
Tuberculosis (TB) affected 9.6 million and killed 1.5 million individuals in 2014 [1]. These statistics reflects the unmet need for
http://dx.doi.org/10.1016/j.tube.2016.09.008 1472-9792/© 2016 Elsevier Ltd. All rights reserved.
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improved treatments for all forms of Mycobacterium tuberculosis (Mtb) infection, including drug-sensitive and drug-resistant TB or latent TB infection (LTBI) [2]. Adjunctive therapy with immunomodulators that enhance TB immunity (host-directed therapy, HDT) could shorten treatment durations and improve TB and LTBI outcomes. A re-emerging concept for TB HDTs is to target the deleterious inflammation that leads to immune exhaustion and tissue pathology, to save the target organ and redirect the host response to more effective immunity against TB (Figure 1) [3]. That is, active TB is characterized by inflammation that can act as a double-edged sword. For example, a Th1 response contributes to Mtb containment, but strong Th1 responses have been identified in patients in whom the pathogen is not contained and who present with clinically severe forms of TB [4]. IL-17 appears beneficial for Mtb containment in early infection, but also contributes to chronic unproductive inflammation with increased neutrophil recruitment and pulmonary damage [5]. B-cells may have a protective role in TB, but appear to contribute to chronic inflammation in active TB [6]. Thus, adjuvants have been investigated for more than a decade to evaluate medications that limit tissue destruction during TB treatment (eg. corticosteroids, TNF blockers, thalidomide, nonsteroidal anti-inflammatory medications), and optimization of these therapies may require knowledge of the host genotype [7,8]. In addition to reduction in deleterious inflammation to achieve the right balance of anti-mycobacterial responses, HDT should further enhance effective immunity against TB, such maturation of phagosomes and Mtb autophagy [3,9,10]. The current re-emergence of type 2 diabetes mellitus (T2DM) as a risk factor for TB may be timely to help identify candidate HDT targets for TB, given the many metabolic similarities between these two seemingly different diseases. That is, the underlying pathology of both diseases is characterized by hyperglycemia (transient; induced by fever in TB), higher levels of systemic pro-inflammatory cytokines (IL-1b, TNF-a, IL-6), and oxidative stress [11e14]. So it may not be unexpected that the most frequently-prescribed medication for DM2, metformin (MetF), is a candidate HDT for
Figure 1. Relationship between Mtb burden and inflammation, and influence of MetF. Highest Mtb burden in TB patients correlates with either diminished immune responses to Mtb (e.g. in immunocompromised hosts with HIV-AIDS or malnutrition) or dysfunctional immunity with excessive inflammation (e.g. in TB and DM comorbidity). MetF has the potential to reduce the excessive (deleterious) inflammation and improve Mtb containment when given at the right dose and time (gray arrow). However, the anti-inflammatory effects of MetF have the potential to hamper effective immunity against Mtb when dosing and/or timing of administration is not appropriate (black arrow). Dark gray, Mtb burden; light gray, inflammation levels.
TB/LTBI [2,7,15,16]. In this review I discuss the potential benefits and points of caution for using MetF as HDT for TB. 2. Immune modulation by MetF The anti-inflammatory effect of MetF is mediated, at least in part, by activating a major energy-sensing kinase, AMP kinase (AMPK). AMPK detects low intracellular ATP and promotes a switch from glycolysis to oxidative phosphorylation [17]. This reduces the proliferation of inflammatory cells which burn glucose for energy (glycolysis) and promotes non-inflammatory cells which burn fatty acids instead (fatty acid oxidation). Accordingly, MetF reduces inflammation by promoting the formation of anti-inflammatory M2 macrophages (vs pro-inflammatory M1) and T-regulatory and CD8 memory T cells (vs proliferating, Th1, Th2, Th17, T-effector, lymphocytes) [18e20]. 3. Why is MetF an attractive candidate for HDT for TB? First, in studies unrelated to TB, MetF has been shown to promote phagocytosis, phago-lysosome fusion and autophagy in macrophages, and differentiation of memory CD8 T cells, which are important for intracellular Mtb killing [15,21] and long-term containment of Mtb, respectively [18,22]. A recent publication reported beneficial immunomodulatory effects of MetF on TB [15]. Singhal et al. found that macrophages exposed to MetF in-vitro (vs no MetF) had higher mycobactericidal capacity attributed to increased mitochondrial reactive oxidative species (ROS) [15]. These effects were associated with activation of AMPK by MetF. Autophagy was induced by MetF but this process did not appear to contribute to Mtb killing. In mice, MetF treatment reduced mycobacterial growth and tissue inflammation and pathology. In a retrospective analysis of 220 DM patients, Singhal et al. also showed that MetF treatment for DM was associated with a lower prevalence of LTBI (26%) vs alternative DM treatments (42%). However, among the LTBI þ DM patients, those taking MetF (vs other DM meds) were more likely to have T cells reactive to CFP10 and ESAT6. From these studies in DM patients the authors concluded that MetF enhances Mtb-specific T-cell responses that may protect against LTBI [15]. Finally, Singhal et al. reported that DM patients on MetF had less cavitation and better survival rates than DM patients without MetF treatment [15]. Second, MetF is ideally suited for re-purposing as HDT for TB because it has been widely used for the management of DM2, is inexpensive and is well-tolerated (category B, no evidence of risk in humans) [23,24]. MetF therapy has a low risk of lactic acidosis in patients with altered liver or kidney function [25]. In contrast to insulin, MetF does not usually cause hypoglycemia (in DM or nonDM), given that its glucose-lowering effect is achieved by enhancing the activity of existing insulin (improve insulin sensitivity) and reducing hepatic glucose production [26,27]. Third, MetF improves glucose control in DM2 patients (with our without TB) that should help correct the dysfunctional immunity associated with hyperglycemia, such as delays in initiation of innate immunity to Mtb, or excessive expression of type 1 cytokines once TB has developed [28,29]. Epidemiological and immunological studies on TB and DM show the importance of glucose control, rather than DM in itself, to the higher risk of DM patients to TB [30e33] and to worse outcomes during TB treatment [34,35]. 4. What we do not know about MetF and TB 4.1. Mechanisms by which MetF kills or contains Mtb growth The experimental studies by Singhal et al. suggests that MetF
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has the potential for HDT for TB, but confirmation and expansion of these findings are required to strengthen the case for MetF [15]. Elucidating the mechanisms by which MetF enhances Mtb killing are central. For example, 1) autophagy has been reported to contribute to Mtb killing [36], and to enhance antigen presentation and stimulation of Th1 immunity in mice vaccinated with BCG [37]. However, MetF-induced autophagy did not affect bacterial viability in the previous study [15]. 2) In Mtb-infected macrophages, MetF promoted mitochondrial ROS that was required for Mtb killing [15]. This upregulation of mitochondrial ROS by MetF is intriguing because in studies unrelated to TB, MetF had the opposite effect: reduction of hyperglycemia-induced mitochondrial ROS [38]. Thus, further studies on MetF in the context of TB are needed to strengthen the case for its contribution to HDT for TB or LTBI. 4.2. Role of MetF versus glycemic control in TB-DM patients MetF is the first option for T2DM management worldwide but we do not know if there is a difference between glucose control with MetF versus other DM meds. Secondary data analysis of medical records from DM patients suggested the beneficial effects of MetF on TB, but it remains unclear if better TB outcomes in DM patients taking MetF were independently explained by better glycemic control or the MetF therapy itself. Would similar beneficial effects be achieved by other glucose-lowering medications to manage DM? This distinction will be difficult to assess with secondary data analysis given that MetF is the most commonlyprescribed medication for T2DM treatment. If MetF monotherapy is insufficient to achieve optimal glucose control, it is complemented (not replaced) with other diabetes medications, including insulin [39]. Furthermore, analysis of T2DM patients not taking MetF will be likely biased towards those with renal failure or at risk of lactic acidosis (more likely if liver function affected). Therefore, clinical trials to distinguish the anti-Mtb effects of MetF vs other glucose-lowering medications for T2DM are needed. 4.3. Role of MetF in TB-non DM patients At least 60% of the TB patients worldwide do not have T2DM comorbidity and the impact of MetF in TB patients without T2DM is unknown. Such studies are justified given that indirect data from non-DM mice or from purified human cells and cell lines suggest that MetF can reduce the exaggerated inflammatory response that favors Mtb replication and TB pathology, and enhance Mtb killing (Figure 1) [15]. Thus, MetF may enhance anti-Mtb responses in TBinfected individuals without DM through several pathways: 1) by reducing the non-DM, transient hyperglycemia characteristic of some TB patients [11]. 2) By promoting a switch in immune cell metabolism to an anti-inflammatory state to avoid deleterious inflammation. 3) By enhancing phagocytosis, phago-lysosome fusion and autophagy to enhance Mtb killing in macrophages [15,21]. 4) By affecting ROS production, which has an impact on inflammation and TB outcomes [15,40]. 4.4. Impact of MetF in TB-naïve and LTBI-positive individuals 4.4.1. LTBI with and without T2DM The anti-inflammatory effects of MetF can be beneficial in TB patients where overt inflammation is associated with tissue pathology and severe TB. But, could MetF also be beneficial as HDT for LTBI, where systemic inflammation is not as evident? Singhal et al. reported that among LTBI-positive individuals with DM, those taking MetF for their T2DM management had a higher number of IFN-gamma secreting cells against Mtb [15]. This secondary data analysis suggested that MetF boosts immunity against Mtb, and
3
would be consistent with studies unrelated to TB where MetF has been shown to boost the development of memory T-cell responses [18]. However, additional studies are needed with sufficient control for confounders to confirm these findings. What will be the outcome in LTBI individuals without DM? How will the balance tilt between the dual effect of MetF on immunity: the antiinflammatory response versus a boost in T-cell immunity? 4.4.2. TB-naïve with T2DM MetF is the most commonly used medication to manage T2DM worldwide, but in these patients MetF may be a double-edge sword for TB prevention. MetF can be beneficial to prevent Mtb infection or TB progression by improving glucose control among DM, which in turn improves their immune status. Conversely, the antiinflammatory effect of MetF may increase the risk of LTBI conversion in TB-naïve individuals by restricting their initial expansion of T-effector lymphocytes specific for Mtb. For example, in an experimental vaccine model unrelated to TB, MetF was administered only after T-effector cell expansion [18]. This is in contrast to the individuals with LTBI or TB who already have a baseline pool of TBspecific effector T-cells that can be expanded to memory T cells by MetF. Singhal et al. reported that DM patients taking MetF were more likely to be LTBI-negative, which would suggest a net protective effect of MetF [15]. However additional studies with sufficient control for confounders are needed to confirm these findings. Thus, it is essential to examine if the widespread use of MetF among DM contributes to their higher TB risk. 5. Can MetF have deleterious effects as a HDT for TB? Yes. First, MetF dosing may be critical. MetF safety is based on current therapeutic doses that are guided by the glucose control in T2DM patients and have a wide range (850e2550 mg daily). Clinical trials for HDT for TB must assess the ideal dose of MetF for TB patients with two essential aspects in mind: 1) Careful monitoring to prevent an “exaggerated” anti-inflammatory effect that can favor Mtb growth (Figure 1), as would be the case with any other immunomodulatory agents for TB (e.g. corticosteroids, rapamycin) [3,18]. Should the dose be the same for T2DM vs non-DM individuals? Should the dose be reassessed in T2DM patients with TB, and should baseline inflammation in TB guide the tailored dosification of anti-inflammatory medications like MetF? Are there drug interactions between TB medications and MetF? What should be the schedule to monitor renal and liver functions during MetF HDT? What other toxicities or side-effects may be expected in the TB patients? with respect to LTBI or TB status, as discussed above for TB-naïve individuals. At what stage of the TB treatment can MetF have its major impact? 6. Concluding remarks The relationship between TB and DM has been described since Roman times, but the parallels in metabolic alterations between both diseases are only becoming evident now. Accordingly, a recent study has provided the foundation for considering the repurposing MetF as HDT for TB. Additional studies are now required to further elucidate the underlying relationship between MetF and Mtb killing, with careful assessment of the risks involved by adding antiinflammatory medications like MetF to the TB regimen. Alternatively, we cannot rule out that MetF in TB-naïve DM patients may be one of the contributing factors to the higher risk of TB among DM patients. This would appear most likely among T2DM patients whose MetF therapy is insufficient for optimal glucose control. Thus, there is a need for experimental, clinical and epidemiological studies to further understand the complex
Please cite this article in press as: Restrepo BI, Metformin: Candidate host-directed therapy for tuberculosis in diabetes and non-diabetes patients, Tuberculosis (2016), http://dx.doi.org/10.1016/j.tube.2016.09.008
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interplay between the impact of MetF on the metabolism of immune cells, and its impact on different stages of the natural history of TB. Finally, the enhancement of CD8 memory T cells by MetF deserves further evaluation: can MetF be an “adjuvant” for T-cell vaccines in LTBI-positive individuals? Acknowledgments I thank the physicians, researchers, health authorities, field and laboratory workers from the Texas-Mexico border who have contributed throughout the years to the development of basic and epidemiological studies of TB and diabetes. Funding: NIH Centers for Translational Science Award (NIH CTSA) grant UL1 TR000371. NIH had no role in the decision to publish. Competing interests: Ethical approval:
None declared. Not required.
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Contents lists available at ScienceDirect
Tuberculosis journal homepage: http://intl.elsevierhealth.com/journals/tube
Review
Metformin: Candidate host-directed therapy for tuberculosis in diabetes and non-diabetes patients Blanca I. Restrepo* UTHealth Houston, Department of Epidemiology, School of Public Health at Brownsville, 80 Fort Brown, SPH Bldg, Brownsville, TX 78520, USA
s u m m a r y Keywords: Tuberculosis Diabetes Metformin Host-directed therapy Immunometabolism Inflammation
Despite major advances in tuberculosis (TB) control, TB continues to be a leading cause of death worldwide. The discovery of new anti-TB treatment drugs and regimens that target drug-sensitive and drug-resistant TB are being complemented with a search for adjunct host-directed therapies that synergize for Mycobacterium tuberculosis (Mtb) elimination. The goal of host-directed therapies is to boost immune mechanisms that diminish excess inflammation to reduce lung tissue damage and limit Mtb growth. Metformin is the most commonly-used medication for type 2 diabetes, and a candidate for hostdirected therapy for TB. Preliminary data suggests metformin may be beneficial for TB control by reducing the deleterious inflammation associated with immune pathology and enhancing the antimycobacterial activity of immune cells. In this review I summarize current findings, knowledge gaps and the potential benefits as well as points of caution for using metformin as adjunct therapy for TB in patients with and without type 2 diabetes. © 2016 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4.
5. 6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Immune modulation by MetF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Why is MetF an attractive candidate for HDT for TB? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . What we do not know about MetF and TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Mechanisms by which MetF kills or contains Mtb growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Role of MetF versus glycemic control in TB-DM patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Role of MetF in TB-non DM patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Impact of MetF in TB-naïve and LTBI-positive individuals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.1. LTBI with and without T2DM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.2. TB-naïve with T2DM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Can MetF have deleterious effects as a HDT for TB? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ethical approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Author contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction * Fax: þ1 956 882 5152. E-mail addresses: [email protected], [email protected].
Tuberculosis (TB) affected 9.6 million and killed 1.5 million individuals in 2014 [1]. These statistics reflects the unmet need for
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improved treatments for all forms of Mycobacterium tuberculosis (Mtb) infection, including drug-sensitive and drug-resistant TB or latent TB infection (LTBI) [2]. Adjunctive therapy with immunomodulators that enhance TB immunity (host-directed therapy, HDT) could shorten treatment durations and improve TB and LTBI outcomes. A re-emerging concept for TB HDTs is to target the deleterious inflammation that leads to immune exhaustion and tissue pathology, to save the target organ and redirect the host response to more effective immunity against TB (Figure 1) [3]. That is, active TB is characterized by inflammation that can act as a double-edged sword. For example, a Th1 response contributes to Mtb containment, but strong Th1 responses have been identified in patients in whom the pathogen is not contained and who present with clinically severe forms of TB [4]. IL-17 appears beneficial for Mtb containment in early infection, but also contributes to chronic unproductive inflammation with increased neutrophil recruitment and pulmonary damage [5]. B-cells may have a protective role in TB, but appear to contribute to chronic inflammation in active TB [6]. Thus, adjuvants have been investigated for more than a decade to evaluate medications that limit tissue destruction during TB treatment (eg. corticosteroids, TNF blockers, thalidomide, nonsteroidal anti-inflammatory medications), and optimization of these therapies may require knowledge of the host genotype [7,8]. In addition to reduction in deleterious inflammation to achieve the right balance of anti-mycobacterial responses, HDT should further enhance effective immunity against TB, such maturation of phagosomes and Mtb autophagy [3,9,10]. The current re-emergence of type 2 diabetes mellitus (T2DM) as a risk factor for TB may be timely to help identify candidate HDT targets for TB, given the many metabolic similarities between these two seemingly different diseases. That is, the underlying pathology of both diseases is characterized by hyperglycemia (transient; induced by fever in TB), higher levels of systemic pro-inflammatory cytokines (IL-1b, TNF-a, IL-6), and oxidative stress [11e14]. So it may not be unexpected that the most frequently-prescribed medication for DM2, metformin (MetF), is a candidate HDT for
Figure 1. Relationship between Mtb burden and inflammation, and influence of MetF. Highest Mtb burden in TB patients correlates with either diminished immune responses to Mtb (e.g. in immunocompromised hosts with HIV-AIDS or malnutrition) or dysfunctional immunity with excessive inflammation (e.g. in TB and DM comorbidity). MetF has the potential to reduce the excessive (deleterious) inflammation and improve Mtb containment when given at the right dose and time (gray arrow). However, the anti-inflammatory effects of MetF have the potential to hamper effective immunity against Mtb when dosing and/or timing of administration is not appropriate (black arrow). Dark gray, Mtb burden; light gray, inflammation levels.
TB/LTBI [2,7,15,16]. In this review I discuss the potential benefits and points of caution for using MetF as HDT for TB. 2. Immune modulation by MetF The anti-inflammatory effect of MetF is mediated, at least in part, by activating a major energy-sensing kinase, AMP kinase (AMPK). AMPK detects low intracellular ATP and promotes a switch from glycolysis to oxidative phosphorylation [17]. This reduces the proliferation of inflammatory cells which burn glucose for energy (glycolysis) and promotes non-inflammatory cells which burn fatty acids instead (fatty acid oxidation). Accordingly, MetF reduces inflammation by promoting the formation of anti-inflammatory M2 macrophages (vs pro-inflammatory M1) and T-regulatory and CD8 memory T cells (vs proliferating, Th1, Th2, Th17, T-effector, lymphocytes) [18e20]. 3. Why is MetF an attractive candidate for HDT for TB? First, in studies unrelated to TB, MetF has been shown to promote phagocytosis, phago-lysosome fusion and autophagy in macrophages, and differentiation of memory CD8 T cells, which are important for intracellular Mtb killing [15,21] and long-term containment of Mtb, respectively [18,22]. A recent publication reported beneficial immunomodulatory effects of MetF on TB [15]. Singhal et al. found that macrophages exposed to MetF in-vitro (vs no MetF) had higher mycobactericidal capacity attributed to increased mitochondrial reactive oxidative species (ROS) [15]. These effects were associated with activation of AMPK by MetF. Autophagy was induced by MetF but this process did not appear to contribute to Mtb killing. In mice, MetF treatment reduced mycobacterial growth and tissue inflammation and pathology. In a retrospective analysis of 220 DM patients, Singhal et al. also showed that MetF treatment for DM was associated with a lower prevalence of LTBI (26%) vs alternative DM treatments (42%). However, among the LTBI þ DM patients, those taking MetF (vs other DM meds) were more likely to have T cells reactive to CFP10 and ESAT6. From these studies in DM patients the authors concluded that MetF enhances Mtb-specific T-cell responses that may protect against LTBI [15]. Finally, Singhal et al. reported that DM patients on MetF had less cavitation and better survival rates than DM patients without MetF treatment [15]. Second, MetF is ideally suited for re-purposing as HDT for TB because it has been widely used for the management of DM2, is inexpensive and is well-tolerated (category B, no evidence of risk in humans) [23,24]. MetF therapy has a low risk of lactic acidosis in patients with altered liver or kidney function [25]. In contrast to insulin, MetF does not usually cause hypoglycemia (in DM or nonDM), given that its glucose-lowering effect is achieved by enhancing the activity of existing insulin (improve insulin sensitivity) and reducing hepatic glucose production [26,27]. Third, MetF improves glucose control in DM2 patients (with our without TB) that should help correct the dysfunctional immunity associated with hyperglycemia, such as delays in initiation of innate immunity to Mtb, or excessive expression of type 1 cytokines once TB has developed [28,29]. Epidemiological and immunological studies on TB and DM show the importance of glucose control, rather than DM in itself, to the higher risk of DM patients to TB [30e33] and to worse outcomes during TB treatment [34,35]. 4. What we do not know about MetF and TB 4.1. Mechanisms by which MetF kills or contains Mtb growth The experimental studies by Singhal et al. suggests that MetF
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has the potential for HDT for TB, but confirmation and expansion of these findings are required to strengthen the case for MetF [15]. Elucidating the mechanisms by which MetF enhances Mtb killing are central. For example, 1) autophagy has been reported to contribute to Mtb killing [36], and to enhance antigen presentation and stimulation of Th1 immunity in mice vaccinated with BCG [37]. However, MetF-induced autophagy did not affect bacterial viability in the previous study [15]. 2) In Mtb-infected macrophages, MetF promoted mitochondrial ROS that was required for Mtb killing [15]. This upregulation of mitochondrial ROS by MetF is intriguing because in studies unrelated to TB, MetF had the opposite effect: reduction of hyperglycemia-induced mitochondrial ROS [38]. Thus, further studies on MetF in the context of TB are needed to strengthen the case for its contribution to HDT for TB or LTBI. 4.2. Role of MetF versus glycemic control in TB-DM patients MetF is the first option for T2DM management worldwide but we do not know if there is a difference between glucose control with MetF versus other DM meds. Secondary data analysis of medical records from DM patients suggested the beneficial effects of MetF on TB, but it remains unclear if better TB outcomes in DM patients taking MetF were independently explained by better glycemic control or the MetF therapy itself. Would similar beneficial effects be achieved by other glucose-lowering medications to manage DM? This distinction will be difficult to assess with secondary data analysis given that MetF is the most commonlyprescribed medication for T2DM treatment. If MetF monotherapy is insufficient to achieve optimal glucose control, it is complemented (not replaced) with other diabetes medications, including insulin [39]. Furthermore, analysis of T2DM patients not taking MetF will be likely biased towards those with renal failure or at risk of lactic acidosis (more likely if liver function affected). Therefore, clinical trials to distinguish the anti-Mtb effects of MetF vs other glucose-lowering medications for T2DM are needed. 4.3. Role of MetF in TB-non DM patients At least 60% of the TB patients worldwide do not have T2DM comorbidity and the impact of MetF in TB patients without T2DM is unknown. Such studies are justified given that indirect data from non-DM mice or from purified human cells and cell lines suggest that MetF can reduce the exaggerated inflammatory response that favors Mtb replication and TB pathology, and enhance Mtb killing (Figure 1) [15]. Thus, MetF may enhance anti-Mtb responses in TBinfected individuals without DM through several pathways: 1) by reducing the non-DM, transient hyperglycemia characteristic of some TB patients [11]. 2) By promoting a switch in immune cell metabolism to an anti-inflammatory state to avoid deleterious inflammation. 3) By enhancing phagocytosis, phago-lysosome fusion and autophagy to enhance Mtb killing in macrophages [15,21]. 4) By affecting ROS production, which has an impact on inflammation and TB outcomes [15,40]. 4.4. Impact of MetF in TB-naïve and LTBI-positive individuals 4.4.1. LTBI with and without T2DM The anti-inflammatory effects of MetF can be beneficial in TB patients where overt inflammation is associated with tissue pathology and severe TB. But, could MetF also be beneficial as HDT for LTBI, where systemic inflammation is not as evident? Singhal et al. reported that among LTBI-positive individuals with DM, those taking MetF for their T2DM management had a higher number of IFN-gamma secreting cells against Mtb [15]. This secondary data analysis suggested that MetF boosts immunity against Mtb, and
3
would be consistent with studies unrelated to TB where MetF has been shown to boost the development of memory T-cell responses [18]. However, additional studies are needed with sufficient control for confounders to confirm these findings. What will be the outcome in LTBI individuals without DM? How will the balance tilt between the dual effect of MetF on immunity: the antiinflammatory response versus a boost in T-cell immunity? 4.4.2. TB-naïve with T2DM MetF is the most commonly used medication to manage T2DM worldwide, but in these patients MetF may be a double-edge sword for TB prevention. MetF can be beneficial to prevent Mtb infection or TB progression by improving glucose control among DM, which in turn improves their immune status. Conversely, the antiinflammatory effect of MetF may increase the risk of LTBI conversion in TB-naïve individuals by restricting their initial expansion of T-effector lymphocytes specific for Mtb. For example, in an experimental vaccine model unrelated to TB, MetF was administered only after T-effector cell expansion [18]. This is in contrast to the individuals with LTBI or TB who already have a baseline pool of TBspecific effector T-cells that can be expanded to memory T cells by MetF. Singhal et al. reported that DM patients taking MetF were more likely to be LTBI-negative, which would suggest a net protective effect of MetF [15]. However additional studies with sufficient control for confounders are needed to confirm these findings. Thus, it is essential to examine if the widespread use of MetF among DM contributes to their higher TB risk. 5. Can MetF have deleterious effects as a HDT for TB? Yes. First, MetF dosing may be critical. MetF safety is based on current therapeutic doses that are guided by the glucose control in T2DM patients and have a wide range (850e2550 mg daily). Clinical trials for HDT for TB must assess the ideal dose of MetF for TB patients with two essential aspects in mind: 1) Careful monitoring to prevent an “exaggerated” anti-inflammatory effect that can favor Mtb growth (Figure 1), as would be the case with any other immunomodulatory agents for TB (e.g. corticosteroids, rapamycin) [3,18]. Should the dose be the same for T2DM vs non-DM individuals? Should the dose be reassessed in T2DM patients with TB, and should baseline inflammation in TB guide the tailored dosification of anti-inflammatory medications like MetF? Are there drug interactions between TB medications and MetF? What should be the schedule to monitor renal and liver functions during MetF HDT? What other toxicities or side-effects may be expected in the TB patients? with respect to LTBI or TB status, as discussed above for TB-naïve individuals. At what stage of the TB treatment can MetF have its major impact? 6. Concluding remarks The relationship between TB and DM has been described since Roman times, but the parallels in metabolic alterations between both diseases are only becoming evident now. Accordingly, a recent study has provided the foundation for considering the repurposing MetF as HDT for TB. Additional studies are now required to further elucidate the underlying relationship between MetF and Mtb killing, with careful assessment of the risks involved by adding antiinflammatory medications like MetF to the TB regimen. Alternatively, we cannot rule out that MetF in TB-naïve DM patients may be one of the contributing factors to the higher risk of TB among DM patients. This would appear most likely among T2DM patients whose MetF therapy is insufficient for optimal glucose control. Thus, there is a need for experimental, clinical and epidemiological studies to further understand the complex
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interplay between the impact of MetF on the metabolism of immune cells, and its impact on different stages of the natural history of TB. Finally, the enhancement of CD8 memory T cells by MetF deserves further evaluation: can MetF be an “adjuvant” for T-cell vaccines in LTBI-positive individuals? Acknowledgments I thank the physicians, researchers, health authorities, field and laboratory workers from the Texas-Mexico border who have contributed throughout the years to the development of basic and epidemiological studies of TB and diabetes. Funding: NIH Centers for Translational Science Award (NIH CTSA) grant UL1 TR000371. NIH had no role in the decision to publish. Competing interests: Ethical approval:
None declared. Not required.
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Please cite this article in press as: Restrepo BI, Metformin: Candidate host-directed therapy for tuberculosis in diabetes and non-diabetes patients, Tuberculosis (2016), http://dx.doi.org/10.1016/j.tube.2016.09.008