Association of microbial tryptophan metabolites and indoleamine-2,3-dioxygenase with immune activity in healthy adults

Authors: RIAZATI, NIKNAZ - University Of California, Davis; Kable, Mary; Newman, John; Stephensen, Charles

Submitted to: Current Developments in Nutrition
Publication Type: Abstract Only
Publication Acceptance Date: 6/1/2022
Publication Date: 6/14/2022
Citation: Riazati, N., Kable, M.E., Newman, J.W., Stephensen, C.B. 2022. Association of microbial tryptophan metabolites and indoleamine-2,3-dioxygenase with immune activity in healthy adults. Current Developments in Nutrition. 6/993. https://doi.org/10.1093/cdn/nzac068.022.
DOI: https://doi.org/10.1093/cdn/nzac068.022

Interpretive Summary: Metabolites of the amino acid tryptophan have biological activity and can regulate immune function. Intestinal bacteria produce several such metabolites, including indole, indole acetic acid (IAA) and indole propionic acid (IPA), which can be found both in the intestinal lumen and in human plasma. In this study we examined the association of plasma levels of these metabolites with a broad spectrum of 88 immune markers, finding only one of these, percentage on NK T-cells, was associated with any of these metabolites. NK T-cell play a significant role in intestinal immune function and the positive association reported may be a systemic reflection of increased NK T-cell levels or activity in the intestinal immune system. Tryptophan can also be metabolized by cells of the immune system to a different set of metabolites, including Kynurenine (Kyn). Plasm Kyn concentrations in this study were associated with a broad set of immune markers representing systemic inflammation and activation of the acute phase response. These associations demonstrate that Kyn itself is a marker of systemic immune activity as it is produced by the same cell types, including macrophages, whose activity is measured by several of the immune markers used in this study. In summary, while host immune activity shows strong associations with the tryptophan metabolite Kyn, bacterial metabolites in plasma are not associates with immune markers beyond NK T-cells. This lack of association may be due host metabolism of indole, IPA and IAA, limiting the activity of these metabolites systemically. Stronger associations might be seen with direct measures of intestinal immune function.

Technical 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 broad 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 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-a, 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-' 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.