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.
