Oral tryptophan supplementation enhances indole production by the gut microbiota and promotes survival from peritonitis.

Author(s):
Daniel Kim; Robert Keskey; Sanjiv Hyoju; Olga Zaborina; John Alverdy

Background:

Recent studies have demonstrated that maintaining the functional output of the gut microbiota during infection increases survival. We previously identified that indole metabolites produced by the gut microbiota can enhance bacterial clearance and improve survival following infection via aryl hydrocarbon receptor-mediated macrophage activation. However, oral administration of select indoles did not improve survival in this model.

Hypothesis:

Because various indoles are produced by the gut microbiota depending on the availability of dietary tryptophan, we hypothesized that oral tryptophan supplementation would improve survival in this model. Therefore, the aims of this study were to determine the effect of oral tryptophan on mortality following peritonitis in mice.

Methods:

Oral tryptophan was administered in the drinking water at 1mM for 14 days prior to a monomicrobial infection (i.e., intraperitoneal (IP) LD₅₀ of Serratia marcescens or Klebsiella oxytoca) and a polymicrobial infection (i.e., LD₅₀ of S. marcescens + K. oxytoca + E. faecalis + C. albicans). Fecal samples were collected prior to and after 14 days of supplementation. Mice were sacrificed 8 hours post IP injection, and cecal contents were collected. Stool samples were analyzed for tryptophan and indole metabolites via targeted metabolomics.

Results:

Mice that received oral tryptophan supplementation showed significantly increased survival after IP S. marcescens (p=0.0007), K. oxytoca (p=0.0012), and polymicrobial community (p=0.0012). Stool analysis demonstrated that in non-supplemented mice, a significant depletion of indoles (50%) following infection was observed (p=0.0393). In supplemented mice, oral tryptophan maintained tryptophan and indole levels following infection (p=0.8402), which correlated with improved survival.

Conclusions:

Oral administration of tryptophan prevents mortality from monomicrobial and polymicrobial peritonitis in mice by maintaining the production of various gut microbiota-derived indole metabolites. A more complete understanding of the molecular signaling between the gut microbiota and the immune system and how they interact to clear pathogens may inform novel strategies to improve outcomes of this lethal disorder.