{"doi":"10.1016/j.bbi.2025.106161","title":"Gut microbiome-derived tryptophan metabolites predict relapse in alcohol use disorder","abstract":"• 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.","journal":"Brain Behavior and Immunity","year":2025,"id":535271,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9536,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1418852,"name":"J. Hans DeVries","orcid":"0000-0001-9196-9906","position":1,"is_corresponding":false},{"id":1419380,"name":"Miles Lou","orcid":null,"position":2,"is_corresponding":false},{"id":1419381,"name":"Samuel Brundin","orcid":null,"position":3,"is_corresponding":false},{"id":1419382,"name":"Tyce Cave","orcid":null,"position":4,"is_corresponding":false},{"id":1418853,"name":"Ehraz Anis","orcid":"0000-0003-2172-4895","position":5,"is_corresponding":false},{"id":1178148,"name":"Zach Madaj","orcid":null,"position":6,"is_corresponding":false},{"id":1330227,"name":"Christine Isaguirre","orcid":"0000-0002-2003-3374","position":7,"is_corresponding":false},{"id":1204478,"name":"Amy Johnson","orcid":"0009-0009-6882-9599","position":8,"is_corresponding":false},{"id":503196,"name":"Ryan D. Sheldon","orcid":"0000-0002-1573-9719","position":9,"is_corresponding":false},{"id":328839,"name":"LeAnn Smart","orcid":"0000-0003-0153-0153","position":10,"is_corresponding":false},{"id":1065107,"name":"Kipling M. Bohnert","orcid":null,"position":11,"is_corresponding":false},{"id":1418854,"name":"Janelle Kassien","orcid":"0009-0009-0660-3578","position":12,"is_corresponding":false},{"id":1419383,"name":"Olivia Holzgen","orcid":null,"position":13,"is_corresponding":false},{"id":264447,"name":"Nagy A. Youssef","orcid":"0000-0002-1922-9396","position":14,"is_corresponding":false},{"id":673892,"name":"Talal W. Khan","orcid":"0000-0002-3022-721X","position":15,"is_corresponding":false},{"id":268533,"name":"Lena Brundin","orcid":"0000-0002-8327-6242","position":16,"is_corresponding":false},{"id":714137,"name":"Cameron Forton","orcid":"0009-0006-4441-0468","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T02:51:56.297114Z","pmid":"41192697","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}