Abstract
BACKGROUND: Recent studies highlight the critical role of gut microbiota in sepsis pathogenesis and its potential link to neurological disorders, particularly sepsis-associated encephalopathy (SAE). However, the exact relationship between gut microbiota, their metabolites, and SAE’s etiology and progression remains enigmatic. We aimed to elucidate how gut bacteria, fungi, and their metabolites contribute to the development and progression of SAE. METHODS: This study was a prospective cohort study. Patients who met the criteria for sepsis 3.0 were included and were divided into SAE and non-SAE groups according to the presence or absence of SAE. Baseline characteristics were collected and mortality was followed up for 28 days. We conducted 16 S and ITS rRNA sequencing of rectal swabs, fecal and plasma metabolomic analysis in septic patients with and without SAE to identify differential bacteria, fungi and microbiota-related metabolites. And we identified potential biomarkers of bacteria and fungi through LEfSe analysis. Differential metabolites were screened and their sources were identified using MetOrigin, followed by identification of KEGG pathways related to gut microbiota, host, and co-metabolism that might play important roles in SAE. Lastly, correlation analysis was performed among differential bacteria, fungi, gut metabolites, plasma metabolites and clinical indicators and we revealed vital flora and metabolites. RESULTS: The study included 42 SAE patients, 129 non-SAE patients, and 35 age-matched healthy volunteers. The 28-day mortality rate of SAE patients was higher than that of non-SAE patients (28.57% vs. 10.08%, P = 0.003), and most baseline characteristics were not statistically different. We identified several pivotal bacteria (Klebsiella_pneumoniae_KP3-S and Prevotella_corporis_DSM_18810_=_JCM_8529) and key fungi (Candida_tropicalis_SH1644546.08FU and Dipodascus_geotrichum_SH1157741.08FU). Additionally, we have uncovered the significance of key microbiota-derived metabolites, particularly cysteinylglycine and tryptophan metabolic products, in SAE pathogenesis. Through comprehensive multi-omics analysis, we revealed the potentially critical role of gut microbiota-related tryptophan and glutathione metabolic pathways in SAE development. CONCLUSIONS: Gut microbiota’s tryptophan and glutathione metabolism may be important to SAE pathogenesis. Our findings deepen understanding of SAE’s pathological mechanisms, providing insights for future research and therapeutic development. CLINICAL TRIAL NUMBER: Not applicable. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12866-026-04929-5.