Association of Microbial Tryptophan Metabolites and Indoleamine-2,3-Dioxygenase with Immune Activity in Healthy Adults

Abstract Objectives Tryptophan (Trp) metabolites from intestinal bacteria, including indole, indole acetic acid (IAA) and indole propionic acid (IPA), and from the mammalian indoleamine 2,3-dioxygenase (IDO) pathway, including kynurenine (Kyn), can regulate immune activation. IDO activity in vivo is measured by the plasma Kyn/Trp ratio. In this study we hypothesized that (1) the plasma Kyn/Trp ratio, (2) plasma indole, IPA, and IAA concentrations, and (3) intestinal bacteria associated with indole metabolism, would all be associated with inflammation and immune activation markers in a study population of healthy adults. Methods A group of 88 immune markers was assessed using plasma, flow cytometric analysis of whole blood and of peripheral blood mononuclear cells (PBMC), and ex vivo culture of PBMC, in 362 healthy, fasting adults. Plasma Trp metabolites were also measured. Bacterial taxa from stool were identified by 16S rRNA gene analysis and those associated with plasma Trp metabolites were identified. Multiple linear regression analysis was used to identify statistically significant associations (with p < .05 after adjustment for multiple comparisons) of these metabolites and taxa with immune markers. Results Several robust positive associations were found between Kyn/Trp and markers of inflammation including neopterin, IP-10, TNF-α, C-reactive protein, and the regulatory cytokine IL-10. A significant positive association was found between the sum of indole and IAA and natural killer T-cells. Three taxa associated with bacterial Trp metabolites were associated with elevated markers of immune activation: the family Lachnospiraceae with higher lymphocyte counts, the genus Dorea with higher production of the type 1 cytokine IFN-γ by T-cells in PBMC culture, the genus Ruminococcus with higher production of the inflammatory cytokine IL-6 in PBMC cultures stimulated with bacterial lipopolysaccharide. Conclusions IDO activity, bacterial Trp metabolites and indole-associated commensal bacteria were all associated with markers of systemic immune activation, particularly involving inflammatory cytokines, the acute phase response and type 1 innate and adaptive immunity. These findings suggest sub-clinical levels of systemic and/or intestinal immune activity that might be precursors to adverse health outcomes. Funding Sources USDA/ARS 2032-51,530-026-00D.