Metformin enhances protection in guinea pigs chronically infected with Mycobacterium tuberculosis

Abstract

Tuberculosis (TB) is a chronic inflammatory disease that is often associated with alterations in systemic and cellular metabolism that resolves following successful antimicrobial drug treatment. We hypothesized that altered systemic glucose metabolism as a consequence of Mycobacterium tuberculosis (Mtb) infection, contributes to TB pathogenesis, and when normalized with anti-glycemic drugs would improve clinical outcomes. To test this hypothesis, guinea pigs were treated daily with the anti-diabetic drug metformin starting 4 weeks prior or concurrent with aerosol exposure to the H37Rv strain of Mtb. In the chronic stages of infection, Mtb infected metformin-treated animals had restored systemic insulin sensitivity but remained glucose intolerant as determined by oral glucose tolerance testing. Despite persistent glucose intolerance, metformin-treated guinea pigs had a 2.8-fold reduction in lung lesion burden and a 0.7 log decrease in CFUs. An alternative hypothesis that metformin treatment improved clinical disease by having a direct effect on immune cell energy metabolism was tested using extracellular flux analysis and flow cytometry. The proinflammatory immune response to Mtb infection in untreated guinea pigs was associated with a marked increase in energy metabolism (glycolysis and mitochondrial respiration) of peripheral blood mononuclear cells (PBMCs), which was normalized in metformin-treated guinea pigs. Moreover, both CD4+ and CD8+ T lymphocytes from Mtb infected, metformin treated animals maintained a more normal mitochondrial membrane potential while those isolated from untreated animals had persistent mitochondrial hyperpolarization. These data suggest that metformin promotes natural host resistance to Mtb infection by maintaining immune cell metabolic homeostasis and function during the chronic stages of active TB disease.

Understanding the Reciprocal Interplay Between Antibiotics and Host Immune System: How Can We Improve the Anti-Mycobacterial Activity of Current Drugs to Better Control Tuberculosis?

“…Additionally, reduction of lung tissue pathology was confirmed in the MET-treated mice, and the number of lung CD8 + IFN-γ + cells was increased in MET-treated mice in both unstimulated and Mtb-stimulated groups, suggesting an enhanced immune response to TB ( 132 ). Similarly, the protective effect of MET was confirmed in a chronically Mtb-infected guinea pig model in which reduced lung legions and Mtb CFU were observed in the MET-treated group compared to those in the untreated group ( 135 ). Further, the MET-treated animals showed a higher proportion of lymphocytes in the acute and subacute stages and well-encapsulated granulomas ( 135 ).…”

“…Similarly, the protective effect of MET was confirmed in a chronically Mtb-infected guinea pig model in which reduced lung legions and Mtb CFU were observed in the MET-treated group compared to those in the untreated group (135). Further, the MET-treated animals showed a higher proportion of lymphocytes in the acute and subacute stages and wellencapsulated granulomas (135). MET reportedly reduces the immunopathological severity by reprogramming T cell metabolism (162,163).…”

“…Additionally, MET induced a significant reduction in TNF-α, IL-1β, IL-6, IFN-γ, and IL-17 release in response to Mtb lysate ( 134 ). These studies indicate that MET protects against Mtb infection via modulation of inflammation and metabolism ( 133 – 135 ). Indeed, MET reduces the type I IFN response and pathological severity of TB while enhancing anti-TB immunity, such as autophagy, ROS production, and phagocytosis ( 132 , 164 , 165 ) ( Figure 3 ).…”

“…MET reportedly reduces the immunopathological severity by reprogramming T cell metabolism (162,163). MET-induced oxidative phosphorylation and glycolysis enhanced the host resistance to Mtb infection in the guinea pig model (135). Moreover, Degner et al demonstrated that MET treatment reduces mortality during TB therapy in a retrospective cohort study in Taiwan (133).…”

Adding Another Piece to the Puzzle of Why NTM Infections Are Relatively Uncommon despite Their Ubiquitous Nature

“…Thus, another potential explanation for impaired control and severe NTM-LD in the absence of Nrf2 could involve metabolic reprogramming. High levels of oxidative phosphorylation is reported in mycobacterial infection, with the potential to generate excess oxidative stress ( 30 , 31 ). Counterregulatory (negative-feedback) mechanisms in response to the increased levels of ROS include the ability of ROS to (i) induce glycolysis which decreases ROS by less reliance on oxidative phosphorylation ( 32 ) and (ii) activate Nrf2 which induces antioxidant mechanisms, such as pentose phosphate pathway and NADPH production ( Fig.…”