Microbiome and Enteric Signatures in Sepsis-associated Hepatorenal Injury

Official title

The Impact of Gut Microbiota on Sepsis-Associated Acute Hepatorenal Injury: A Prospective, Multicenter, Observational Study

Overview

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 five 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 baseline fecal microbial alpha diversity, measured by the Shannon diversity index, and SALI and S-AKI occurring within 7 days after sepsis diagnosis. Secondary objectives include evaluating the associations of baseline fecal microbial beta diversity with SALI and with S-AKI occurring within 7 days after sepsis diagnosis, characterizing longitudinal changes in fecal microbial alpha diversity, measuring plasma metabolite and intestinal biomarker concentrations at prespecified time points, and assessing 28-day all-cause mortality. Exploratory multi-omics analyses will evaluate Proteobacteria and additional microbial taxa, microbial functional genes, metabolites, and host biomarkers. This study aims to identify candidate biomarkers and biological pathways relevant to hepato-renal injury in sepsis.

Primary outcome measures

• Association of Baseline Gut Microbial Alpha Diversity With Sepsis-Associated Acute Kidney Injury [Time frame: Baseline stool sample collected on Day 0 or within 24 hours after sepsis diagnosis; S-AKI assessed from Day 0 through Day 7 after sepsis diagnosis.]
• Association of Baseline Gut Microbial Alpha Diversity With Sepsis-Associated Liver Injury [Time frame: Baseline stool sample collected on Day 0 or within 24 hours after sepsis diagnosis; SALI assessed from Day 0 through Day 7 after sepsis diagnosis.]

Secondary outcome measures (7)

• Association of Baseline Fecal Microbial Beta Diversity With Sepsis-Associated Liver Injury [Time frame: Baseline stool sample collected on Day 0 or within 24 hours after sepsis diagnosis; SALI assessed from Day 0 through Day 7 after sepsis diagnosis.]
• Association of Baseline Fecal Microbial Beta Diversity With Sepsis-Associated Acute Kidney Injury [Time frame: Baseline stool sample collected on Day 0 or within 24 hours after sepsis diagnosis; S-AKI assessed from Day 0 through Day 7 after sepsis diagnosis.]
• Total Plasma Short-Chain Fatty Acid Concentration [Time frame: Days 0, 3-5, 7-10, and 14-20 after sepsis diagnosis.]
• Plasma Indoxyl Sulfate Concentration [Time frame: Days 0, 3-5, 7-10, and 14-20 after sepsis diagnosis.]
• Fecal Calprotectin Concentration [Time frame: Days 0, 3-5, 7-10, and 14-20 after sepsis diagnosis.]
• 28-Day All-Cause Mortality [Time frame: Day 28 after sepsis diagnosis.]
• Longitudinal Change in Fecal Microbial Alpha Diversity Among Patients With Sepsis [Time frame: Day 0 through Days 14-20 after sepsis diagnosis, with assessments on Day 0, Days 3-5, Days 7-10, and Days 14-20.]

Eligibility criteria

Inclusion criteria

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For Sepsis Patients:

• 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.

For Healthy Volunteers:

• Age ≥ 18 years.
• No chronic underlying diseases (including liver, kidney, gastrointestinal, or immune-related disorders).
• No use of antibiotics or probiotics, and no history of acute infection within 1 month prior to enrollment (to ensure baseline consistency).
• Informed consent signed by the volunteer.

Exclusion criteria

• 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.
• Expected survival time of less than 72 hours.
• Pregnant or lactating women.
• Concurrent participation in other interventional clinical trials.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model

Cohort

Study locations

China · 1 center

• First Affiliated hospital of zhejiang university school of medicine — Hangzhou

Identifiers

NCT: NCT07735182 · IIT20260155B-R2

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗