Microbiome and Enteric Signatures in Sepsis-associated Hepatorenal Injury

Sepsis is a major cause of morbidity and mortality in intensive care units. Sepsis-associated liver injury (SALI) and sepsis-associated acute kidney injury (S-AKI) are common complications associated with adverse clinical outcomes. Altered gut microbial diversity, microbial metabolites, intestinal barrier dysfunction, and systemic inflammation may contribute to hepato-renal injury during sepsis. However, prospective longitudinal evidence in patients with SALI and S-AKI remains limited. This prospective, multicenter, longitudinal observational cohort study will enroll adult patients with sepsis across eight intensive care units at six medical centers and healthy adult volunteers as a baseline reference cohort. For patients with sepsis, stool and blood samples will be collected on Day 0, Days 3-5, Days 7-10, and Days 14-20 after sepsis diagnosis. Healthy volunteers will provide a single baseline stool and blood sample at enrollment. Fecal microbial alpha diversity and community structure will be assessed by metagenomic sequencing and bioinformatic analysis. Plasma metabolites, including total short-chain fatty acids, indoxyl sulfate, and additional targeted plasma metabolites, will be measured by ultra-high-performance liquid chromatography-tandem mass spectrometry. Intestinal barrier and clinical biomarkers will also be assessed. The primary objectives are to evaluate the associations between longitudinal trajectories of fecal microbial alpha diversity, measured by the Shannon diversity index, and the occurrence of SALI and S-AKI within 7 days after sepsis diagnosis. Secondary objectives include evaluating the associations between longitudinal changes in fecal microbial beta diversity and the occurrence of SALI and S-AKI; assessing the associations between longitudinal trajectories of fecal microbial alpha diversity and organ recovery status at Days 14-20 among patients who develop SALI or S-AKI; describing selected plasma metabolite and intestinal biomarker concentrations at prespecified time points; and assessing 28-day all-cause mortality. Exploratory multi-omics analyses will evaluate microbial taxa, microbial functional genes, metabolites, and host biomarkers to identify candidate biomarkers and biological pathways associated with the development and clinical course of sepsis-associated hepato-renal injury.