Multiomics Characterization of Micobiome and Immunometabolic REmodeling in Tuberculosis Stress Hyperglycemia - PROJECT SUMMARY/ABSTRACT Each year ~1.6 million deaths are attributed to tuberculosis (TB) disease. This annual estimate of TB deaths does not include post-TB mortality. Post-TB disease standardized mortality rates are ~4 times that of the general population. One potential reason for this higher mortality is long-term adverse impacts of TB on metabolic health. While diabetes is a well-established risk factor for adverse outcomes in persons with TB disease, recent evidence suggests the relationship between TB and glycemic control is bidirectional. Over half of patients with TB disease experience stress hyperglycemia, and persons recovered from TB disease remain at greater risk for diabetes, dyslipidemia, and cardiovascular disease. Metabolic sequelae of TB disease may therefore be a major contributor to elevated post-TB mortality. Improved understanding of the mechanisms linking TB disease to increased risk of hyperglycemia and diabetes is needed to develop new therapies and interventions that improve post-TB metabolic health and reduce mortality. To address key knowledge gaps, this research will leverage a unique NIAID-funded clinical cohort (R01AI153152) of patients with TB from the country of Georgia. The parent cohort carefully characterizes stress hyperglycemia and metabolic trajectories for 18 months during and after TB treatment, including longitudinal measures of glucose control (HbA1c), insulin resistance (HOMA-IR) and visceral adiposity. Using previously collected plasma samples, we will integrate data using cutting-edge ‘-omics’ platforms to gain unparalleled insight into the impact of the metabolome, immune response, and immune-microbiota interface on stress hyperglycemia and metabolic health during TB disease and after TB cure. This study will determine (1) whether stress hyperglycemia in TB disease results from metabolic signals that drive immune activation and influence insulin resistance; (2) if immunometabolic pathways remain dysregulated in some patients after TB cure, increasing long-term metabolic risks; and (3) whether shifts in the microbiome-immune crosstalk in persons with TB disease contribute to stress hyperglycemia and longer-term metabolic risks. Because patients with TB often have subclinical or clinical TB for months to years before TB diagnosis, we theorize that this duration leads to long- term shifts in the metabolome, chronic activation of inflammatory signaling cascades, and altered microbiome- immune crosstalk, which, in turn, increase the risk of insulin resistance, lipid dysregulation, systemic glucose intolerance, and eventually incident diabetes. This proposal will help to characterize the extent to which changes in immunometabolism and the immune-microbiota interface in TB disease drive short and long-term metabolic sequelae, which may be major contributors to post-TB mortality. Elucidating mechanistic linkages between TB and hyperglycemia will allow our group to evaluate the utility of existing therapies aimed at improving metabolic health in TB disease and identify new pathways that could be targeted to improve clinical outcomes during and after TB treatment.
