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.
Age ≥ 18 years；
Admitted to the Intensive Care Unit (ICU) and meets the Sepsis-3 diagnostic criteria (an acute change in total Sequential Organ Failure Assessment [SOFA] score ≥ 2 points consequent to the infection).
Diagnosed with sepsis within 24 hours prior to enrollment.
Informed consent signed by the patient or a legally authorized representative.
History of chronic liver disease (e.g., cirrhosis, chronic hepatitis B/C, autoimmune hepatitis, hepatic carcinoma).
History of chronic kidney disease (e.g., glomerulonephritis, IgA nephropathy).
History of inflammatory bowel disease (including ulcerative colitis and Crohn's disease) or previous major intestinal resection.
Patients with malignant tumors currently receiving chemotherapy or radiotherapy.
The study population comprises two distinct groups recruited from multiple clinical centers. The primary clinical cohort consists of critically ill adult patients (aged ≥18 years) admitted to the Intensive Care Unit (ICU) who are diagnosed with sepsis according to the Sepsis-3 criteria and enrolled within 24 hours after sepsis diagnosis. This cohort will be longitudinally monitored to evaluate changes in the gut microbiome, the occurrence of sepsis-associated liver injury (SALI) and sepsis-associated acute kidney injury (S-AKI) from Day 0 through Day 7 after sepsis diagnosis, and subsequent organ recovery status at Days 14-20 among patients who develop SALI and/or S-AKI. A baseline reference cohort consists of healthy adult volunteers recruited from the community. These volunteers have no history of chronic underlying diseases or recent antibiotic/probiotic use and serve to establish baseline reference profiles for the gut microbiome and circulating metabolites.
Cohort
Prospective
Not listed
Association of Longitudinal Trajectories in Fecal Microbial Alpha Diversity With the Occurrence of Sepsis-Associated Acute Kidney Injury
Sepsis-associated acute kidney injury (S-AKI) occurring from Day 0 through Day 7 after sepsis diagnosis will be assessed according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria using serum creatinine and urine output obtained from routine clinical laboratory testing and medical records. Fecal microbial alpha diversity will be measured using the Shannon diversity index (unitless), calculated from metagenomic sequencing and bioinformatic analysis of stool samples collected on Day 0, Days 3-5, Days 7-10, and Days 14-20 after sepsis diagnosis. Longitudinal trajectories of the Shannon diversity index will be compared between patients with and without S-AKI using linear mixed-effects models accounting for repeated measurements within participants. The primary longitudinal association will be evaluated using the group-by-time interaction term.
Association of Longitudinal Trajectories in Fecal Microbial Alpha Diversity With the Occurrence of Sepsis-Associated Liver Injury
Sepsis-associated liver injury (SALI) occurring from Day 0 through Day 7 after sepsis diagnosis will be assessed using routine clinical laboratory measurements. SALI is defined by at least one of the following: total bilirubin (TBIL) \>2 mg/dL and international normalized ratio (INR) \>1.5; alanine aminotransferase (ALT) ≥5 times the upper limit of normal (ULN); alkaline phosphatase (ALP) ≥2 times ULN; or ALT ≥3 times ULN with TBIL ≥2 times ULN. Fecal microbial alpha diversity will be measured using the Shannon diversity index (unitless), calculated from metagenomic sequencing and bioinformatic analysis of stool samples collected on Day 0, Days 3-5, Days 7-10, and Days 14-20 after sepsis diagnosis. Longitudinal trajectories of the Shannon diversity index will be compared between patients with and without SALI using linear mixed-effects models accounting for repeated measurements within participants. The group-by-time interaction will represent the longitudinal association.
Association of Longitudinal Changes in Fecal Microbial Beta Diversity With the Occurrence of Sepsis-Associated Acute Kidney Injury
Sepsis-associated acute kidney injury (S-AKI) occurring from Day 0 through Day 7 after sepsis diagnosis will be defined according to KDIGO criteria using serum creatinine and urine output. Fecal microbial beta diversity will be assessed using Bray-Curtis dissimilarity (unitless) from metagenomic sequencing of stool samples collected on Day 0, Days 3-5, Days 7-10, and Days 14-20. Longitudinal differences in microbial community composition between patients with and without S-AKI will be evaluated using PERMANOVA including group, time, and group-by-time interaction, with repeated measurements accounted for by constrained permutations. The longitudinal association will be reported as the PERMANOVA R² for the group-by-time interaction.
Association of Longitudinal Changes in Fecal Microbial Beta Diversity With the Occurrence of Sepsis-Associated Liver Injury
Sepsis-associated liver injury (SALI) occurring from Day 0 through Day 7 after sepsis diagnosis will be assessed according to the prespecified SALI criteria. Fecal microbial beta diversity will be assessed using Bray-Curtis dissimilarity (unitless) from metagenomic sequencing of stool samples collected on Day 0, Days 3-5, Days 7-10, and Days 14-20. Longitudinal differences in microbial community composition between patients with and without SALI will be evaluated using PERMANOVA including group, time, and group-by-time interaction, with repeated measurements accounted for by constrained permutations. The longitudinal association will be reported as the PERMANOVA R² for the group-by-time interaction.
Association of Longitudinal Trajectories in Fecal Microbial Alpha Diversity With Kidney Recovery Status After Sepsis-Associated Acute Kidney Injury
Among patients who develop sepsis-associated acute kidney injury (S-AKI) from Day 0 through Day 7 after sepsis diagnosis, kidney recovery status will be assessed at Days 14-20 relative to baseline serum creatinine. Complete recovery will be defined as serum creatinine \<1.2 times baseline without ongoing kidney replacement therapy (KRT); partial recovery as serum creatinine ≥1.2 but \<1.5 times baseline without ongoing KRT; and non-recovery as serum creatinine ≥1.5 times baseline or ongoing KRT. Fecal microbial alpha diversity will be measured using the Shannon diversity index at the four prespecified time points. Longitudinal trajectories will be compared across kidney recovery categories using linear mixed-effects models accounting for repeated measurements within participants.
Association of Longitudinal Trajectories in Fecal Microbial Alpha Diversity With Liver Injury Recovery Status After Sepsis-Associated Liver Injury
Among patients who develop sepsis-associated liver injury (SALI) from Day 0 through Day 7 after sepsis diagnosis, liver injury recovery status will be assessed at Days 14-20 using the prespecified SALI criteria. Recovery will be defined as no longer meeting any SALI criterion; persistent liver injury will be defined as meeting at least one SALI criterion at Days 14-20. Fecal microbial alpha diversity will be measured using the Shannon diversity index at the four prespecified time points. Longitudinal trajectories will be compared between patients with liver injury recovery and those with persistent liver injury using linear mixed-effects models accounting for repeated measurements within participants.
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First Affiliated Hospital of Zhejiang University
Lead sponsor
Taizhou Enze Medical Center Group
Collaborator
The Second Affiliated Hospital of Jiaxing University
Collaborator
Lin'an Traditional Chinese Medicine Hospital
Collaborator
Ningbo Medical Center Lihuili Hospital
Collaborator
