{"doi":"10.1002/ctm2.511","title":"Chemical set enrichment analysis: Novel insights into sex‐specific alterations in primary metabolites in posttraumatic stress and disturbed sleep","abstract":"We found that women demonstrate more primary metabolite disturbances than men with similar posttraumatic stress disorder (PTSD) severity including a decrease in tryptophan metabolites indoles might be due to gut microbiota dysbiosis. PTSD may develop after exposure to actual or threatened death, serious injury, or sexual violence; women are at a greater risk. The contribution of disordered sleep in PTSD in altering primary metabolites was examined. Primary metabolites regulate several physiological functions, serve as substrates for neurotransmitters, and are altered in psychiatric disorders. Mass spectrometry was used to ascertain metabolites in 90 plasma samples from individuals with chronic PTSD and control subjects. We adjusted for BMI and age in our analyses. Men and women with PTSD did not differ in PTSD severity or history of childhood trauma (Table S1). Sex aggregated data analysis revealed several metabolites that were significantly altered between control and PTSD groups (Figure S1). Next, sex-segregated chemical set enrichment analysis1 on primary metabolites identified seven and two metabolite nodes altered in women and men with PTSD, respectively, compared with sex-matched controls (Figure 1A,B). Each node contained two or more metabolites; men and women with PTSD did not share any primary metabolite alterations (Figure 1A,B). Since PTSD symptom presentation is highly variable between individuals,2 and, in our cohort, women had significantly greater PCLC scores than men (Table S1), we reasoned that individual PCL-C measures may associate differently with metabolites (Figure 1C and Table S2). Serine levels were lower in women with PTSD, whereas glycine levels were negatively associated with cluster D symptoms on the PCL-C, suggesting that with more hyperarousal, glycine levels decreased in women, but not men (Figure 1C). Serine, a neurotransmitter, serves as a precursor for the synthesis of glycine, cysteine, and 2-aminobutyric acid, butyrate, and is synthesized directly from glucose (Figure 2A). In the human myocardium, 2-aminobutyric acid increases glutathione levels via activated protein kinas activation to protect against oxidative stress.3 An individual's physiological and metabolic state alters glucose metabolism and the generation of non-essential amino acids. Serine and glycine shuttle between the glia and neurons where glycine induces the release of serine, a coagonist for NMDA receptors. Together they regulate long-term potentiation4 and are critical for the consolidation of extinction of previously conditioned fear memories.5 Our data suggest that alterations in subsets of metabolites could be protective in PTSD (Table S2). Changes in metabolite levels in combat veterans with PTSD are reported,6, 7 but the contribution of sleep or sex has not been investigated. Sleep disturbances are associated with overall poor health.8 Both men and women with PTSD had lower total sleep time (TST) on actigraphy and worse self-reported sleep quality on the Pittsburgh Sleep Quality Index (PSQI) compared with controls (Figure 2B). Delta power, a measure of deep sleep activity, decreased in PTSD and showed a significant sex difference. Men had lower delta power sleep activity than women (Figure 2B). Greater PTSD symptoms were associated with lower TST in both women and men, and PSQI was associated with greater PTSD symptoms in both women and men. Delta power was lower in men with PTSD compared to controls, but not in women (Figure 2C). Humans lack the ability to synthesize eight essential amino acids, including tryptophan, that must be obtained from the diet. They are mostly absorbed by the gut and metabolized by the resident microbiota. Tryptophan is metabolized to a myriad of biologically active compounds by four different pathways (serotonin, tryptamines, kynurenine, and indoles). TST accounted for alterations in all metabolite nodes in men and two of the six metabolite nodes in women (Figures 2D, 3A, and Table S2). When","journal":"Clinical and Translational Medicine","year":2021,"id":196380,"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":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9558,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":331807,"name":"Sili Fan","orcid":"0000-0002-3497-1695","position":1,"is_corresponding":false},{"id":768931,"name":"Callan Lujan","orcid":"0000-0002-6020-1213","position":2,"is_corresponding":false},{"id":6363,"name":"Oliver Fiehn","orcid":"0000-0002-6261-8928","position":3,"is_corresponding":false},{"id":392841,"name":"Thomas C. Neylan","orcid":"0000-0002-1572-2626","position":4,"is_corresponding":false},{"id":392845,"name":"Sabra S. Inslicht","orcid":"0000-0002-2456-1625","position":5,"is_corresponding":false},{"id":631118,"name":"Aditi Bhargava","orcid":"0000-0003-1334-0517","position":0,"is_corresponding":true}],"reference_count":9,"raw_metadata":null,"created_at":"2026-07-18T23:50:15.704473Z","pmid":"34936734","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":[]}