Relations between Vitamin B6, Tryptophan Metabolites, and Inflammation.
Background: A variety of inflammatory conditions, including cardiovascular disease (CVD)
and diabetes, and are associated with both increased kynurenine pathway (KP) activity
and low plasma concentrations of pyridoxal 5'phosphate (PLP), the bioactive form of
vitamin B6. Inflammatory cytokines induce the first enzyme in the KP; downstream enzymes
require PLP as a cofactor to produce ... read moreimmunomodulatory kynurenine metabolites. We
hypothesize low plasma PLP observed during inflammation is due to increased PLP
utilization by KP enzymes during inflammation. This PLP depletion may lead to health
conditions related to PLP-dependent functions such as hemoglobin and neurotransmitter
synthesis. Four studies were conducted to examine the relation between PLP, kynurenine
metabolites, and inflammation in the context of cardiovascular disease, anemia,
diabetes, and cognitive and psychological function. Methods: Secondary data analyses
were conducted on data from Framingham Heart Study Offspring Cohort and Nutrition Aging
and Memory in Elders (NAME) cohorts, separately. As an ancillary to NAME, kynurenine
metabolites were measured in plasma samples using LC-MS/MS. We similarly measured
kynurenine metabolites in plasma, aortic, and lymph node tissues from a porcine model of
atherosclerosis to assess the effect of diet and statin use on PLP, kynurenine
metabolites, and inflammation. Results: CVD status and plasma PLP were interactive
predictors of anthranilic acid concentration: and 2-fold increase in plasma PLP resulted
in 1.06 fold change in plasma anthranilic acid concentration among CVD-free subjects.
CVD was associated with higher prevalence of plasma PLP insufficiency (PLP<30nmol/L)
but not kynurenine metabolite concentrations. Subjects with PLP insufficiency had
greater plasma hydroxyanthranilic acid compared to normal (23%, p=0.02). Anemia
prevalence was dependent on both plasma PLP and CRP concentrations: it was highest among
those in first PLP tertile category with plasma CRP > 10mg/L. Diabetics had lower
plasma PLP and higher xanthurenic acid concentrations than non-diabetics. Plasma PLP and
xanthurenic acid concentrations were interactive predictors of insulin resistance as
measured by HOMA2-IR. PLP insufficiency and the highest plasma concentrations of
xanthurenic acid were associated with the highest insulin resistance. Plasma PLP was
associated with the attention function of cognition, but kynurenine metabolites were not
associated with any domains of cognition or depression. In a porcine model of
atherosclerosis, data were inconclusive. Since we did not observe the expected change in
inflammation due to diet or statin use, there were no discernable effects of diet or
statin use on kynurenine metabolites in plasma, aortic, or lymph node tissues.
Conclusions: This project demonstrated that anemia is associated with both inflammation
and PLP insufficiency. Our findings suggest inflammation associated PLP insufficiency
may increase risk of negative health outcomes comorbid with inflammatory disease.
Additionally, we found xanthurenic acid and PLP are interactively associated with
HOMA2-IR, indicating KP activation may be involved in inflammatory mechanisms underlying
diabetes development. We were unable to observe relations between kynurenines and
cognition, depression, diet, or statin use. Ultimately, we were unable to observe
increased KP activation at sites of inflammation as an underlying cause of
inflammation-associated PLP depletion in the context of these conditions. Associations
between kynurenine metabolites and inflammatory conditions studied here suggest a more
complex relation may underlie these physiologic changes than previously
Thesis (Ph.D.)--Tufts University, 2017.
Submitted to the Dept. of Nutritional Epidemiology.
Advisor: Jacob Selhub.
Committee: Ligi Paul, Paul Jacques, and Dayong Wu.
Keywords: Nutrition, and Epidemiology.read less