Tryptophan pathway catabolites (serotonin, 5-hydroxyindolacetic acid, kynurenine) and enzymes (monoamine oxidase and indole amine 2,3 dioxygenase) in patients with septic shock

Abstract

Septic shock is associated with a strong inflammatory response that induces vasodilation and vascular hyporeactivity. We investigated the role for tryptophan-pathway catabolites of proinflammatory cytokines in septic shock. We prospectively included 30 patients with very recent-onset septic shock and 30 healthy volunteers. The following were assayed once in the controls and on days 1, 2, 3, 7, and 14 in each patient: plasma free and total tryptophan, platelet and plasma serotonin, total blood serotonin, urinary serotonin, plasma and urinary 5-hydroxyindolacetic acid, plasma kynurenine, monoamine oxidase activity, and total indole amine 2,3-dioxygenase activity. Organ-system failure and mortality were recorded. Compared with the healthy controls, the patients with septic shock had 2-fold to 3-fold lower total tryptophan levels throughout the 14-day study period. Platelet serotonin was substantially lower, while monoamine oxidase activity and 5-hydroxyindolacetic acid were markedly higher in the patients than in the controls, consistent with the known conversion of tryptophan to serotonin, which is then promptly and largely degraded to 5-hydroxyindolacetic acid. Plasma kynurenine was moderately increased and indole amine 2,3-dioxygenase activity markedly increased in the patients versus the volunteers, reflecting conversion of tryptophan to kynurenine. Changes over time in tryptophan metabolites were not associated with survival in the patients but were associated with the Sequential Organ Failure Assessment score and hemodynamic variables including hypotension and norepinephrine requirements. Our results demonstrate major tryptophan pathway alterations in septic shock. Marked alterations were found compared with healthy volunteers, and tryptophan metabolite levels were associated with organ failure and hemodynamic alterations. Tryptophan metabolite levels were not associated with surviving septic shock, although this result might be ascribable to the small sample size. Trial registration: ClinicalTrials.gov; No: NCT00684736; URL: www.clinicaltrials.gov.

Multi-omic Profiling Reveals that Intra-abdominal-Hypertension-Induced Intestinal Damage Can Be Prevented by Microbiome and Metabolic Modulations with 5-Hydroxyindoleacetic Acid as a Diagnostic Marker

“…6 ). These findings were consistent with those in previous reports by Troché et al ( 46 ) and Zeden et al ( 47 ) in that the major tryptophan pathway notably changed in septic shock and the levels of tryptophan metabolites were associated with the progression of sepsis. Considering the heterogeneity of sepsis, plasma and/or fecal 5-HIAA is a promising diagnostic biomarker for sepsis.…”

Patients with hypothermic sepsis have a unique gene expression profile compared to patients with fever and sepsis

“… 37 Also, serotonin receptor antagonists has improved survival in experimental settings, but has not been evaluated in humans. 38 …”

Inflammation‐driven brain and gut barrier dysfunction in stress and mood disorders

“…Elevated IDO‐1 expression promotes TRP catabolism pathway to favor KYN synthesis over 5‐HT in the periphery and brain (Ryan et al., 2020). In humans, IDO‐1 is highly upregulated in the gut epithelium during inflammation, injury, and infection (Alvarado et al., 2019), induced by pro‐inflammatory factors: IFN‐γ, TNF‐α, IL‐1β, and IL‐6 (Fujigaki et al., 2006) or directly by LPS (O’Connor et al., 2009; Troché et al., 2020). Indeed, clinical IFN‐α therapy in hepatitis C patients significantly decreased blood TRP levels, while increasing KYN in the blood and cerebrospinal fluid (CSF) (Raison et al., 2010), showing evidence of altered IDO‐1 activity.…”