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.