{"doi":"10.1016/j.clnu.2024.09.030","title":"Metabolic phenotypes and vitamin D response in the critically ill: A metabolomic cohort study","abstract":"Background & aims Although vitamin D deficiency is common in critically ill patients, randomized controlled trials fail to demonstrate benefits of supplementation. We aimed to identify distinct vitamin D 3 responsive metabolic phenotypes prior to trial intervention of high-dose vitamin D 3 by applying machine learning clustering method to metabolomics data from the Correction of Vitamin D Deficiency in Critically Ill Patients (VITdAL-ICU) trial. Methods In the randomized, placebo-controlled VITdAL-ICU trial, critically ill adults received placebo or high-dose vitamin D 3 . To distinguish vitamin D 3 responsive metabolic phenotypes prior to intervention, we implemented consensus clustering with partitioning around medoids algorithm to the plasma metabolome data before randomization. Individual metabolite differences were determined utilizing linear mixed-effects regression models stratified for metabolomic phenotypes with false discovery rate adjustment. The association between vitamin D 3 supplementation and 180-day mortality was evaluated in each metabolic phenotype, applying multivariable logistic regression analysis. Results In 453 critically ill adults, the study identified 4 distinct metabolic phenotypes (clusters A. N = 134; B. N = 123; C. N = 92; D. N = 104). We found differential metabolic pathway patterns in the four clusters. Specifically, branched chain amino acid catabolic metabolites, long-chain acylcarnitines and diacylglycerol species are significantly increased in a specific metabolic phenotype (cluster D) following high-dose vitamin D 3 . Further, in cluster D high-dose vitamin D 3 supplementation had a significantly lower adjusted odds of 180-day mortality after controlling age, sex, Simplified Acute Physiology Score II, admission diagnosis, and baseline 25-hydroxyvitamin D (OR 0.28 (95%CI, 0.09–0.89); P = 0.03). In metabotype A, B, and C, high-dose vitamin D 3 supplementation was not significantly associated with lower 180-day mortality following multivariable adjustment. Conclusion In this post-hoc cohort study of the VITdAL-ICU trial, the clustering analysis of plasma metabolome data identified biologically distinct metabolic phenotypes. Among clusters, we found the different associations between high-dose vitamin D 3 supplementation and specific metabolite pathways as well as 180-day mortality. Our findings facilitate further research to validate metabolic phenotype-targeted strategies for critical illness treatments.","journal":"Clinical Nutrition","year":2024,"id":451765,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9446,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":673934,"name":"Karin Amrein","orcid":"0000-0003-0915-085X","position":1,"is_corresponding":false},{"id":934915,"name":"Sherif Hanafy Mahmoud","orcid":"0000-0002-5517-2622","position":2,"is_corresponding":false},{"id":218538,"name":"Jessica Lasky‐Su","orcid":"0000-0001-6236-4705","position":3,"is_corresponding":false},{"id":934916,"name":"Kenneth B. Christopher","orcid":"0000-0001-6067-972X","position":4,"is_corresponding":false},{"id":673933,"name":"H. Kobayashi","orcid":"0000-0002-9516-6016","position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":null,"created_at":"2026-07-19T02:02:45.951080Z","pmid":"39307095","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":[]}