Bacillus Subtilis and Enterococcus Faecium Probiotic Plus Lipid-Lowering Therapy for Hypertriglyceridemic Acute Pancreatitis: A Prospective RCT

Phase 4RecruitingNCT07720232

Jianyin Zhou180 enrolled

Overview

Background: Hypertriglyceridemia-associated acute pancreatitis (HTG-AP) has become the second most common cause of acute pancreatitis in China, accounting for up to 42.4% of cases, with high recurrence rates and substantial disease burden. Disease severity and recurrence risk are potentially linked to triglyceride (TG) levels. Current lipid-lowering strategies have limitations in efficacy, onset speed, or safety. Increasing evidence suggests that gut microbiota dysbiosis and impaired intestinal barrier function contribute to lipid metabolism regulation and systemic inflammation in HTG-AP patients. Probiotic supplementation may offer a novel therapeutic approach by modulating gut microbiota, improving lipid metabolism, and alleviating inflammation. Objective: To evaluate whether adjunctive treatment with Bacillus subtilis and Enterococcus faecium enteric-coated capsules (LCBE) reduces serum TG and inflammatory markers and improves clinical outcomes in mild to moderate HTG-AP patients. Methods: This is a prospective, randomized, open-label, blinded endpoint (PROBE design), single-center, parallel-group clinical trial. A total of 180 eligible participants will be randomized 1:1 to the intervention group (standard therapy plus oral LCBE 500 mg three times daily for 28 days) or control group (standard therapy alone). The primary endpoints are serum TG, C-reactive protein (CRP), and interleukin-6 (IL-6) levels on day 5 post-intervention. Secondary endpoints include TG normalization rate (\<1.7 mmol/L), lipid profile, inflammatory markers, glucose metabolism parameters, gut microbiota composition, intestinal barrier integrity, symptom relief, length of hospital stay, healthcare costs, quality of life, and safety. Expected Impact: This study aims to provide high-level evidence for probiotic adjunctive therapy in HTG-AP and to explore underlying mechanisms from the perspective of gut microbiota modulation.

Rationale: Timely reduction of serum TG is critical for improving prognosis in HTG-AP. However, conventional therapies-including fibrates, insulin, heparin, and blood purification-have limitations related to onset speed, invasiveness, cost, and adverse effects. Preclinical and clinical studies suggest that Bacillus subtilisand Enterococcus faecium(LCBE) can improve lipid metabolism, restore gut microbial balance, enhance intestinal barrier function, and reduce systemic inflammation. Nevertheless, robust prospective RCT evidence focusing on TG dynamics in HTG-AP remains lacking. Study Population and Setting: Adult patients (18-65 years) diagnosed with mild HTG-AP (serum TG ≥11.3 mmol/L or 5.65-11.3 mmol/L with lactescent serum) within 72 hours of symptom onset will be enrolled from the Department of Gastroenterology, Zhongshan Hospital, Xiamen University. Patients with severe or moderately severe AP, other etiologies of AP, significant organ dysfunction, pregnancy, immunosuppression, diabetes mellitus, lactose intolerance, or recent use of antibiotics/probiotics will be excluded. Intervention and Follow-up: Participants will receive standard care according to the 2021 Chinese Expert Consensus on Emergency Management of HTG-AP, including fenofibrate, low-molecular-weight heparin, fluid resuscitation, somatostatin, ulinastatin, proton-pump inhibitors, nutritional support, and pain management. In addition, the intervention group will receive LCBE 500 mg (2 capsules) orally three times daily for 28 days. Follow-up visits are scheduled at baseline, day 5, day 14, and day 28, with serial assessments of TG, lipid profile, inflammatory cytokines, glucose metabolism, gut microbiota (16S rRNA sequencing), intestinal barrier biomarkers (D-lactate, endotoxin, DAO, zonulin), clinical symptoms, severity scores, and quality of life (EQ-5D-5L). Statistical Analysis: Analyses will follow the intention-to-treat principle, with per-protocol analysis as sensitivity analysis. Continuous variables will be compared using t-tests or Mann-Whitney U tests; categorical variables will be analyzed using chi-square or Fisher's exact tests. Microbiome diversity will be assessed using Shannon index, PERMANOVA, and LEfSe analysis. An independent Data Safety Monitoring Board will conduct one interim analysis when 50% enrollment is reached. Ethical Considerations: The study will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Written informed consent will be obtained from all participants. The trial is approved by the Institutional Review Board of Zhongshan Hospital, Xiamen University

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Meet at least two of the three characteristic criteria for AP:① Acute onset of persistent upper abdominal pain;② Serum amylase and/or lipase activity at least three times above the upper limit of normal;③ Imaging findings on CT, MRI, or abdominal ultrasonography. 2. Meet the diagnostic criteria for hypertriglyceridemia-associated acute pancreatitis (HTG-AP): fulfill the AP diagnostic criteria and concurrent hypertriglyceridemia (serum triglycerides ≥11.3 mmol/L or 5.65-11.3 mmol/L with lactescent serum), with exclusion of other common causes of AP such as cholelithiasis and alcoholism. 3. Admission within 72 hours of symptom onset. 4. Disease severity assessed as mild acute pancreatitis (MAP) within 48 hours of admission, defined by absence of organ dysfunction and absence of local or systemic complications. 5. Age between 18 and 65 years. 6. No history of allergy to microbiological agents. 7. Signed informed consent obtained. Exclusion Criteria: 1. Concurrent biliary, alcoholic, or other etiologies of acute pancreatitis; 2. Acute exacerbation of chronic pancreatitis or pancreatic tumor; 3. Severe hypertriglyceridemia-associated acute pancreatitis, defined as: ① patients classified as moderately severe or severe AP according to the Expert Consensus on the Diagnosis and Treatment of Hypertriglyceridemic Acute Pancreatitis; ② within 48 hours, meeting any one of the following criteria: modified Marshall score ≥2, MCTSI score ≥4, APACHE II score ≥15, BISAP score ≥3, or Ranson score ≥3; patients meeting any of these criteria are excluded; 4. Severe hepatic or renal dysfunction (serum creatinine \>177 μmol/L or ALT \>150 U/L); 5. Active infection, malignancy, immunodeficiency, or requiring long-term use of immunosuppressants; 6. Diagnosed diabetes mellitus; 7. Pregnancy or breastfeeding; 8. History of lactose intolerance; 9. Use within 4 weeks prior to enrollment of antibiotics, probiotics, prebiotics, synbiotics, or other microbiological agents, as well as gastrointestinal motility drugs (e.g., domperidone, mosapride) or other medications that may significantly affect gut microbiota or gastrointestinal function.

Outcomes

Primary Outcomes

Mean Concentration of Serum Triglycerides (TG) in mmol/L at 5 ± 2 days.

Blood samples will be collected after a minimum 8-hour fast. Serum triglycerides (TG) will be measured quantitatively using an enzymatic colorimetric assay on an automated clinical chemistry analyzer in the central laboratory of Xiamen University Zhongshan Hospital. The primary endpoint is the mean concentration of serum TG (in mmol/L) at the intervention visit occurring 5 ± 2 days after randomization. Values are presented as the mean (standard deviation, SD).

Time frame: Baseline through Day 5 (±2 days)

Serum Concentration of C-Reactive Protein (CRP) at Day 5 (±2 days)

Fasting venous blood samples will be collected at the Day 5 (±2 days) visit. Serum CRP will be quantified using a high-sensitivity immunoturbidimetric assay, and will be presented as Mean (Standard Deviation) in mg/L.

Time frame: Baseline through Day 5 (±2 days)

Serum Concentration of Interleukin-6 (IL-6) at Day 5 (±2 days)

Fasting venous blood samples will be collected at the Day 5 (±2 days) visit. Serum IL-6 will be measured via chemiluminescence immunoassay. Data will be presented as Mean (Standard Deviation) in pg/mL.

Time frame: Baseline through Day 5 (±2 days)

Secondary Outcomes

Mean Concentration of Serum Triglycerides (TG) in mmol/L at 14 ± 2 days

Blood samples will be collected after a minimum 8-hour fast. Serum triglycerides (TG) will be measured quantitatively using an enzymatic colorimetric assay on an automated clinical chemistry analyzer in the central laboratory of Xiamen University Zhongshan Hospital. The primary endpoint is the mean concentration of serum TG (in mmol/L) at the intervention visit occurring 14 ± 2 days after randomization. Values are presented as the mean (standard deviation, SD).

Time frame: Baseline through Day 14 (±2 days)

Mean Concentration of Serum Triglycerides (TG) in mmol/L at 28 ± 2 days

Blood samples will be collected after a minimum 8-hour fast. Serum triglycerides (TG) will be measured quantitatively using an enzymatic colorimetric assay on an automated clinical chemistry analyzer in the central laboratory of Xiamen University Zhongshan Hospital. The primary endpoint is the mean concentration of serum TG (in mmol/L) at the intervention visit occurring 28 ± 2 days after randomization. Values are presented as the mean (standard deviation, SD).

Time frame: Baseline through Day 28 (±2 days)

Serum Concentration of C-Reactive Protein (CRP) at Day 14 (±2 days)

Fasting venous blood samples will be collected at the Day 14 (±2 days) visit. Serum CRP will be quantified using a high-sensitivity immunoturbidimetric assay, and will be presented as Mean (Standard Deviation) in mg/L.

Time frame: Baseline through Day 14 (±2 days)

Serum Concentration of C-Reactive Protein (CRP) at Day 28 (±2 days)

Fasting venous blood samples will be collected at the Day 28 (±2 days) visit. Serum CRP will be quantified using a high-sensitivity immunoturbidimetric assay, and will be presented as Mean (Standard Deviation) in mg/L.

Time frame: Baseline through Day 28 (±2 days)

Percentage of Participants Achieving Serum Triglyceride (TG) Normalization (<1.7 mmol/L) at Day 5 (±2 days)

Serum TG levels will be measured from fasting blood samples collected at the Day 5 (±2 days) visit. Normalization is defined as a TG level \<1.7 mmol/L. The outcome is the percentage of participants meeting this criterion at this specific timepoint.

Time frame: Baseline through Day 5 (±2 days)

Percentage of Participants Achieving Serum Triglyceride (TG) Normalization (<1.7 mmol/L) at Day 14 (±2 days)

Serum TG levels will be measured from fasting blood samples collected at the Day 14 (±2 days) visit. Normalization is defined as a TG level \<1.7 mmol/L. The outcome is the percentage of participants meeting this criterion at this specific timepoint.

Time frame: Baseline through Day 14 (±2 days)

Percentage of Participants Achieving Serum Triglyceride (TG) Normalization (<1.7 mmol/L) at Day 28 (±2 days)

Serum TG levels will be measured from fasting blood samples collected at the Day 28 (±2 days) visit. Normalization is defined as a TG level \<1.7 mmol/L. The outcome is the percentage of participants meeting this criterion at this specific timepoint.

Time frame: Baseline through Day 28 (±2 days)

Percentage Change from Baseline in Serum Triglyceride (TG) Concentration at Day 5 (±2 days)

The percentage change will be calculated using the formula: \[(TG at Day 5) - (TG at Baseline)\] / (TG at Baseline) × 100%. Fasting blood samples will be collected at both timepoints. A negative value indicates a reduction in TG levels. Data will be presented as Mean (Standard Deviation, SD).

Time frame: Baseline through Day 5 (±2 days)

Percentage Change from Baseline in Serum Triglyceride (TG) Concentration at Day 14 (±2 days)

The percentage change will be calculated using the formula: \[(TG at Day 14) - (TG at Baseline)\] / (TG at Baseline) × 100%. A negative value indicates a reduction in TG levels. Data will be presented as Mean (SD).

Time frame: Baseline through Day 14 (±2 days)

Percentage Change from Baseline in Serum Triglyceride (TG) Concentration at Day 28 (±2 days)

The percentage change will be calculated using the formula: \[(TG at Day 28) - (TG at Baseline)\] / (TG at Baseline) × 100%. A negative value indicates a reduction in TG levels. Data will be presented as Mean (SD).

Time frame: Baseline through Day 28 (±2 days)

Percentage Change from Baseline in Serum C-Reactive Protein (CRP) at Day 5 (±2 days)

The percentage change will be calculated as: \[(CRP at Day 5) - (CRP at Baseline)\] / (CRP at Baseline) × 100%. Serum CRP will be measured using a high-sensitivity immunoturbidimetric assay. A negative value indicates a reduction in systemic inflammation. Data will be presented as Median (Interquartile Range, IQR).

Time frame: Baseline through Day 5 (±2 days)

Percentage Change from Baseline in Serum C-Reactive Protein (CRP) at Day 14 (±2 days)

The percentage change will be calculated as: \[(CRP at Day 14) - (CRP at Baseline)\] / (CRP at Baseline) × 100%. A negative value indicates a reduction in systemic inflammation. Data will be presented as Median (IQR).

Time frame: Baseline through Day 14 (±2 days)

Percentage Change from Baseline in Serum C-Reactive Protein (CRP) at Day 28 (±2 days)

The percentage change will be calculated as: \[(CRP at Day 28) - (CRP at Baseline)\] / (CRP at Baseline) × 100%. A negative value indicates a reduction in systemic inflammation. Data will be presented as Median (IQR).

Time frame: Baseline through Day 28 (±2 days)

Percentage Change from Baseline in Serum Interleukin-6 (IL-6) at Day 5 (±2 days)

The percentage change will be calculated as: \[(IL-6 at Day 5) - (IL-6 at Baseline)\] / (IL-6 at Baseline) × 100%. Serum IL-6 will be measured using a chemiluminescence immunoassay or ELISA. Data will be presented as Median (Interquartile Range, IQR).

Time frame: Baseline through Day 5 (±2 days)

Change from Baseline in Gut Microbiota Alpha and Beta Diversity Indices Assessed by 16S rRNA Sequencing

Fecal samples will be collected at Baseline, Day 5, Day 14, and Day 28. Gut microbiota composition will be profiled using 16S rRNA gene sequencing (V3-V4 regions). Alpha diversity (including Shannon, Simpson, Chao1, and Observed OTUs indices) and beta diversity (using Bray-Curtis dissimilarity and Weighted UniFrac distances) will be calculated via the QIIME2 pipeline. Changes from baseline at each timepoint will be evaluated. LEfSe analysis will identify differentially abundant taxa (LDA score \>2.0, P\<0.05).

Time frame: Baseline through Day 28 (±2 days)

Change from Baseline in Serum Intestinal Barrier Biomarkers (D-lactate, Endotoxin, DAO, Zonulin)

Fasting venous blood samples will be collected at Baseline, Day 5 (±2 days), Day 14 (±2 days), and Day 28 (±2 days). Serum will be separated and stored at -80°C until batch analysis. Biomarker concentrations will be measured using commercially available ELISA kits: D-lactate by enzymatic spectrophotometry, endotoxin by the chromogenic limulus amebocyte lysate (LAL) assay, diamine oxidase (DAO) by ELISA, and zonulin by ELISA. Changes from baseline at each timepoint will be calculated. Data will be presented as Mean (Standard Deviation, SD) or Median (Interquartile Range, IQR) as appropriate. These biomarkers will be correlated with gut microbiota profiles and clinical outcomes.

Time frame: Baseline through Day 28 (±2 days)

Bacillus Subtilis and Enterococcus Faecium Probiotic Plus Lipid-Lowering Therapy for Hypertriglyceridemic Acute Pancreatitis: A Prospective RCT

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts