Metformin as Host-Directed Therapy for TB Treatment: Scoping Review

Abstract

Tuberculosis (TB) disease is an international health concern caused by the bacteria Mycobacterium tuberculosis (Mtb). Evolution of multi-drug-resistant strains may cause bacterial persistence, rendering existing antibiotics ineffective. Hence, development of new or repurposing of currently approved drugs to fight Mtb in combination with existing antibiotics is urgently needed to cure TB which is refractory to current therapy. The shortening of TB therapy and reduction in lung injury can be achieved using adjunctive host-directed therapies. There is a wide range of probable candidates which include numerous agents permitted for the treatment of other diseases. One potential candidate is metformin, a Food and Drug Administration (FDA)-approved drug used to treat type 2 diabetes mellitus (DM). However, there is a scarcity of evidence supporting the biological basis for the effect of metformin as a host-directed therapy for TB. This scoping review summarizes the current body of evidence and outlines scientific gaps that need to be addressed in determining the potential role of metformin as a host-directed therapy.

Keywords: Mycobacterium tuberculosis; adjuvant; host-directed therapy; metformin; tuberculosis.

FIGURE 1

Flowchart depicting the process of article selection for scoping study assessing the role of Metformin (MET) in tuberculosis.

FIGURE 2

The effect of metformin on macrophage function and clinical outcomes. Studies labeled A, C, F, G, H, I, and J represent the effect of metformin on respective clinical outcomes. These include reduced mortality, 2-month culture conversion and toxicity, and improved glycemic control. Studies B and L: outcome 1 show the effect of metformin on tumor necrosis factor (TNF)-α and interferon γ. TNF-α acts together with interferon γ, causing the production of reactive nitrogen intermediates and facilitating the tuberculostatic function of macrophages and the migration of immune cells to the infection site, contributing to granuloma formation. Study C shows metformin to increase macrophage reactive oxygen species (ROS) production. Evidence suggests that macrophage-produced ROS is responsible for increasing macrophage microbicidal activity by directly killing bacteria (Tan et al., 2016). This study is not part of the inclusion criteria. Study K observes metformin increases superoxide dismutase (SOD) and microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B). Mycobacterium tuberculosis (Mtb) binds the pattern recognition receptor (PRR) on the macrophage which initiates phagocytosis. Superoxide dismutase (SOD) (produced as a by-product of oxygen metabolism within cells) enables clearance of bacteria and restricts inflammation in response to infection by encouraging bacterial phagocytosis, and MAP1LC3B is representative of autophagy while SOD induces autophagy. Study L: outcome 2 shows metformin to increase lactate production within cells. Lactate is formed in large quantities by innate immune cells during inflammatory activation. Lactate modulates the immune cell metabolism which translates to decreased inflammation and ultimately functions as a negative feedback signal to avoid unwarranted inflammatory responses. Study L: outcome 3 observed a macrophage-targeting mechanism for the anti-inflammatory effects of metformin via polarization.