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

Official title

Effect of Bacillus Subtilis and Enterococcus Faecium Combination Therapy Combined With Conventional Lipid-Lowering Treatment on Triglyceride Levels in Patients With Hypertriglyceridemic Acute Pancreatitis: A Prospective Randomized Controlled Trial

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.

Detailed description

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

Interventions

• Drug Live Combined Bacillus subtilis and Enterococcus faecium Enteric-coated Capsules (LCBE)
  LCBE 500 mg (2 capsules) orally three times daily for 28 ± 2 days, initiated within 24 hours after confirmation of eligibility.
• Drug Standard Care (in control arm)
  Patients in the control group received standard care exclusively, in accordance with the 2021 Chinese Expert Consensus on the Emergency Diagnosis and Treatment of Hypertriglyceridemic Acute Pancreatitis. This regimen encompassed fenofibrate and low-molecular-weight heparin, alongside goal-directed fluid resuscitation. Comprehensive symptomatic and supportive therapies included somatostatin and ulinastatin infusions, proton pump inhibitor therapy, nutritional support, and analgesia management.

Primary outcome measures

• Mean Concentration of Serum Triglycerides (TG) in mmol/L at 5 ± 2 days. [Time frame: Baseline through Day 5 (±2 days)]
• Serum Concentration of C-Reactive Protein (CRP) at Day 5 (±2 days) [Time frame: Baseline through Day 5 (±2 days)]
• Serum Concentration of Interleukin-6 (IL-6) at Day 5 (±2 days) [Time frame: Baseline through Day 5 (±2 days)]

Secondary outcome measures (12)

• Mean Concentration of Serum Triglycerides (TG) in mmol/L at 14 ± 2 days [Time frame: Baseline through Day 14 (±2 days)]
• Mean Concentration of Serum Triglycerides (TG) in mmol/L at 28 ± 2 days [Time frame: Baseline through Day 28 (±2 days)]
• Serum Concentration of C-Reactive Protein (CRP) at Day 14 (±2 days) [Time frame: Baseline through Day 14 (±2 days)]
• Serum Concentration of C-Reactive Protein (CRP) at Day 28 (±2 days) [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) [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) [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) [Time frame: Baseline through Day 28 (±2 days)]
• Percentage Change from Baseline in Serum Triglyceride (TG) Concentration at Day 5 (±2 days) [Time frame: Baseline through Day 5 (±2 days)]
• Percentage Change from Baseline in Serum Triglyceride (TG) Concentration at Day 14 (±2 days) [Time frame: Baseline through Day 14 (±2 days)]
• Percentage Change from Baseline in Serum Triglyceride (TG) Concentration at Day 28 (±2 days) [Time frame: Baseline through Day 28 (±2 days)]
• Percentage Change from Baseline in Serum C-Reactive Protein (CRP) at Day 5 (±2 days) [Time frame: Baseline through Day 5 (±2 days)]
• Percentage Change from Baseline in Serum C-Reactive Protein (CRP) at Day 14 (±2 days) [Time frame: Baseline through Day 14 (±2 days)]

Eligibility criteria

Inclusion criteria

• 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.
• 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.
• Admission within 72 hours of symptom onset.
• 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.
• Age between 18 and 65 years.
• No history of allergy to microbiological agents.
• Signed informed consent obtained.

Exclusion criteria

• Concurrent biliary, alcoholic, or other etiologies of acute pancreatitis;
• Acute exacerbation of chronic pancreatitis or pancreatic tumor;
• 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;
• Severe hepatic or renal dysfunction (serum creatinine >177 μmol/L or ALT >150 U/L);
• Active infection, malignancy, immunodeficiency, or requiring long-term use of immunosuppressants;
• Diagnosed diabetes mellitus;
• Pregnancy or breastfeeding;
• History of lactose intolerance;
• 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.

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

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

China · 1 center

• Department of Gastroenterology, Zhongshan Hospital, Xiamen University — Xiamen

Publications

• Ranson JH, Rifkind KM, Roses DF, Fink SD, Eng K, Spencer FC. Prognostic signs and the role of operative management in acute pancreatitis. Surg Gynecol Obstet. 1974 Jul;139(1):69-81. No abstract available. PMID 4834279
• Wu BU, Johannes RS, Sun X, Tabak Y, Conwell DL, Banks PA. The early prediction of mortality in acute pancreatitis: a large population-based study. Gut. 2008 Dec;57(12):1698-703. doi: 10.1136/gut.2008.152702. Epub 2008 Jun 2. PMID 18519429
• Knaus WA, Zimmerman JE, Wagner DP, Draper EA, Lawrence DE. APACHE-acute physiology and chronic health evaluation: a physiologically based classification system. Crit Care Med. 1981 Aug;9(8):591-7. doi: 10.1097/00003246-198108000-00008. PMID 7261642
• Mortele KJ, Wiesner W, Intriere L, Shankar S, Zou KH, Kalantari BN, Perez A, vanSonnenberg E, Ros PR, Banks PA, Silverman SG. A modified CT severity index for evaluating acute pancreatitis: improved correlation with patient outcome. AJR Am J Roentgenol. 2004 Nov;183(5):1261-5. doi: 10.2214/ajr.183.5.1831261. PMID 15505289
• Kee Jang D, Kyu Lee J, Yung Jung C, Ho Kim K, Ra Kang H, Sun Lee Y, Hwa Yoon J, Ro Joo K, Kyu Chae M, Hyeon Baek Y, Seo BK, Hyub Lee S, Lim C. Electroacupuncture for abdominal pain relief in patients with acute pancreatitis: A three-arm randomized controlled trial. J Integr Med. 2023 Nov;21(6):537-542. doi: 10.1016/j.joim.2023.10.004. Epub 2023 Nov 2. PMID 37973472
• Tenner S, Vege SS, Sheth SG, Sauer B, Yang A, Conwell DL, Yadlapati RH, Gardner TB. American College of Gastroenterology Guidelines: Management of Acute Pancreatitis. Am J Gastroenterol. 2024 Mar 1;119(3):419-437. doi: 10.14309/ajg.0000000000002645. Epub 2023 Nov 7. PMID 38857482
• Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, Tsiotos GG, Vege SS; Acute Pancreatitis Classification Working Group. Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013 Jan;62(1):102-11. doi: 10.1136/gutjnl-2012-302779. Epub 2012 Oct 25. PMID 23100216
• Pi X, Teng W, Fei D, Zhao G, Liu W. Effects of Live Combined Bacillus subtilis and Enterococcus faecium on Gut Microbiota Composition in C57BL/6 Mice and in Humans. Front Cell Infect Microbiol. 2022 Feb 10;12:821662. doi: 10.3389/fcimb.2022.821662. eCollection 2022. PMID 35223547

Identifiers

NCT: NCT07720232 · XUZH20260005

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗