A metabolic weakness in tuberculosis: boosting AKG helps host fight infection

Mycobacterium tuberculosis (Mtb) is skilled at evading the body’s defenses by changing the host’s epigenome and metabolism. In new work led by Kithiganahalli Narayanaswamy Balaji, scientists asked whether an epigenetic regulator called Lysine Specific Demethylase 1 (LSD1) helps Mtb manipulate immune cells. The team used both ex vivo and in vivo infection models to study how altering LSD1 activity affects infected macrophages and whole animals. When LSD1 was inhibited, researchers observed fewer mycobacterial colony forming units (CFU) and clearer lung tissue, suggesting that blocking this epigenetic enzyme made it harder for Mtb to survive and reduced disease-related lung damage. To understand why, the investigators looked at cellular metabolism and found changes tied to the tricarboxylic acid (TCA) cycle and glutamine breakdown. By connecting an epigenetic enzyme to metabolic shifts in macrophages, the study set out to trace how those shifts influence oxidative stress and the way fats in cells are damaged during infection. The work therefore links LSD1 activity to metabolic states that either favor or hinder Mtb persistence, and it frames a biochemical pathway that might be targeted to protect the host.

To pinpoint the metabolic drivers, the researchers performed metabolomic analysis on Mtb infected, LSD1 deficient macrophages. This revealed increased levels of alpha-ketoglutarate (AKG), a central TCA cycle metabolite, with the change tied to regulation of genes implicated in glutamine breakdown. The team tested the effects of AKG directly: exogenous addition of AKG reduced oxidative stress and attenuated lipid peroxidation (LPO) in infected cells, and this was accompanied by a drop in Mtb survival. Conversely, when glutamine breakdown was blocked in LSD1 deficient macrophages, the protective fall in LPO did not occur and Mtb intracellular survival was promoted, highlighting the importance of the LSD1–AKG axis. The findings moved from cells to animals: dietary supplementation of AKG to Mtb infected mice improved lung pathology, limited Mtb dissemination and reduced the levels of oxidative Malondialdehyde adducts. Across cellular and animal models the study preserved exact measures such as CFU counts, tracked metabolic shifts with metabolomic analysis, and measured oxidative damage markers to link enzyme activity with infection outcomes.

The study identifies alpha-ketoglutarate (AKG) as a host-protective metabolite that can curb the oxidative damage Mtb exploits to survive. By showing that LSD1, an epigenetic modifier, controls macrophage levels of AKG through genes involved in glutamine breakdown, the work uncovers an epigenetic–metabolic axis Mtb appears to take advantage of. Suppressing lipid peroxidation (LPO) emerged as a key mechanism: higher AKG kept oxidative stress and Malondialdehyde adduct formation low, and that state made the intracellular environment less hospitable for Mtb. Importantly, dietary AKG supplementation improved outcomes in infected mice, suggesting a relatively simple metabolic intervention might add protection against disease. The authors propose that targeting the LSD1–AKG pathway, either by modulating LSD1 activity or by boosting AKG levels, could be explored as a complementary approach to current tuberculosis strategies. While the results are grounded in the reported ex vivo and in vivo models, they point to new directions for research on how host metabolism and epigenetic regulation shape infectious disease.