Gut microbiome-derived tryptophan metabolites predict relapse in alcohol use disorder

• Two gut-derived bacterial metabolites, indole-3-carboxaldehyde and indole-3-acetic acid, predicted relapse risk in patients with severe AUD. • Indole-3-carboxaldeyde in plasma also positively correlated with serotonin and negatively with white blood cell count. • The indoles outperformed proinflammatory cytokines and clinical assessment scores as predictors of relapse risk. • Indole-3-lactic acid was associated with multiple endogenous kynurenine metabolites, suggesting a potential interaction with host metabolism. Relapse is common in alcohol use disorder (AUD), a condition that affects nearly 11 % of adults in the US. Excessive alcohol consumption causes gut dysbiosis, which may in turn alter the production of bacterial-derived tryptophan metabolites. These metabolites impact the intestinal enteroendocrine environment and modulate neuroinflammation. This can ultimately affect behavior. However, the role of bacterial-derived tryptophan metabolites in AUD is not well-understood. Thus, in this study, we enrolled 40 patients admitted for severe AUD (26 males, 14 females) to investigate whether bacterial-derived indoles could predict AUD relapse. Upon enrollment, alcohol use as well as depression and anxiety symptoms were assessed. Peripheral blood samples were collected and analyzed for cytokines, bacterial-derived as well as endogenous tryptophan metabolites, and hematological factors. At three months after discharge, 25 patients completed follow-up and were re-assessed for clinical symptoms to identify AUD relapse. Ten patients relapsed and 15 patients were in early remission. Two bacterial tryptophan metabolites, indole-3-carboxaldehyde (IAld) and indole-3-acetic acid (IAA), significantly predicted relapse versus remission using logistic regression models ( p = 0.019, SGPV = 0, and p = 0.035, SGPV = 0 respectively). These findings remained significant after adjustment for age, sex, BMI, and when additionally adjusting for nicotine use and depression severity. Moreover, higher IAld levels correlated with increased serotonin levels (Pearson’s R; 0.592, p < 0.001) and fewer white blood cells (Pearson’s R; −0.318, p < 0.05) in all 40 patients. Our data indicate significant interactions between microbiome-derived metabolites and host metabolism, and that IAld specifically may have a protective role in AUD, potentially through serotonin modulation.