Efficacy and Safety of Encapsulated Bifidobacterium Longum BBH016 in Subjects With Lower Gastrointestinal Symptoms

Functional lower gastrointestinal (GI) symptoms such as abdominal pain, diarrhea, loose stools, and bloating are common in adults without evidence of organic disease. Although these symptoms are not life-threatening, they substantially impair quality of life, contribute to repeated healthcare utilization, and impose socioeconomic burdens. Current management strategies rely primarily on dietary modifications and symptomatic medications, but these often provide incomplete relief. Increasing evidence indicates that alterations in the gut microbiota play a critical role in the pathophysiology of functional GI disorders, including irritable bowel syndrome (IBS), through effects on visceral sensitivity, motility, immune regulation, and the brain-gut axis. Thus, microbiome-targeted interventions such as probiotics represent a promising therapeutic strategy.

Bifidobacterium longum BBH016 is a probiotic strain originally isolated from a healthy human donor and classified as "Generally Recognized as Safe" (GRAS). Preclinical studies, including murine colitis models and Wistar rat models of stress-induced gut dysfunction, have demonstrated that oral administration of BBH016 ameliorates abdominal symptoms, reduces mucosal inflammation, restores microbial diversity, and improves functional pathways predicted by KEGG analyses. The strain has been formulated as a freeze-dried encapsulated product (1×10⁹ CFU/day) that is stable at refrigerated temperatures and suitable for clinical use.

This investigator-initiated, Ministry of Trade, Industry and Energy (MOTIE)-funded study aims to evaluate the efficacy and safety of B. longum BBH016 capsules in adults with lower GI symptoms, excluding constipation-predominant presentations. The trial is designed as a prospective, randomized, double-blind, placebo-controlled study conducted at Seoul National University Bundang Hospital. A total of 88 participants aged 19-80 years will be enrolled and randomized in a 1:1 ratio to receive either BBH016 capsules or placebo for 8 weeks (two capsules twice daily).

The primary endpoint is the overall improvement in GI symptoms, assessed at 8 weeks compared with baseline, between the BBH016 and placebo groups. Secondary endpoints include changes in individual symptom scores (abdominal pain, bloating, diarrhea, loose stool), global IBS Symptom Severity Score (IBS-SSS), quality of life (IBS-QoL), stool frequency and form (Bristol Stool Form Scale), and psychological status (Hospital Anxiety and Depression Scale, HADS). In addition, stool samples will be analyzed at baseline and week 8 to evaluate alterations in gut microbiome composition and diversity, and to explore correlations with symptom improvement.

Participants will undergo screening (V0), baseline/randomization (V1), an interim 4-week assessment (V2, telephone or in-person), and final evaluation at 8 weeks (V3). Safety will be assessed by monitoring adverse events, laboratory tests (hematology, chemistry, inflammatory markers), and vital signs. The trial is covered by clinical trial insurance, and all adverse events will be reported to the Institutional Review Board (IRB) according to regulatory requirements.

The study is expected to provide important clinical and mechanistic evidence for the use of BBH016 as a safe and effective probiotic therapy for functional lower GI symptoms. Compared with invasive interventions such as fecal microbiota transplantation (FMT), BBH016 capsules offer a standardized, stable, and convenient oral formulation that may be applicable even in secondary care settings. If efficacy and safety are confirmed, this trial could establish a novel, practical treatment option and a theoretical foundation for future use of BBH016 in patients with IBS and related disorders.

Inclusion criteria

• Male or female participants aged 19 to 80 years.
• Subjects with lower gastrointestinal (GI) symptoms (diarrhea, loose stools, abdominal bloating, or excessive gas) in whom constipation is not the predominant symptom.
• Subjects who have undergone colonoscopy within the past 5 years, or who will undergo colonoscopy after enrollment, with confirmation of no organic abnormalities in the colon.

Records from another hospital within 5 years may be accepted. If colonoscopy included biopsy or polypectomy, subjects may be eligible if the investigator confirms no clinically significant abnormality.

• Surgically sterile women or women of childbearing potential with a negative pregnancy test (urine hCG or serum β-hCG).

Women of childbearing potential must agree to use appropriate contraception (e.g., oral contraceptives, intrauterine device [IUD], double-barrier method, or hormonal implant) throughout the study.

• Subjects without major neurological or psychiatric disorders that impair decision-making capacity.

Those with such conditions may still be eligible if deemed adequately controlled with medication or therapy.

• Subjects who voluntarily provide written informed consent after receiving adequate explanation of the study.

Exclusion criteria

• Subjects with constipation as the predominant lower GI symptom.
• Pregnant or breastfeeding women.
• Participation in another clinical trial and receipt of an investigational product within 3 months prior to screening.
• Any condition judged by the investigator to pose a risk to the subject or interfere with study participation.
• Severe congestive heart failure or severe angina.
• Subjects with lactose intolerance or immunosuppression.
• Use of medications that may affect the study product (e.g., GI medications, probiotics, antibiotics).

Probiotics: may participate if discontinued ≥2 weeks before enrollment. Antibiotics or GI medications (potassium-competitive acid blocker, proton pump inhibitor, H2 receptor antagonist, pinaverium, trimebutine, etc.): may participate if discontinued ≥4 weeks before enrollment.

If ongoing GI medication use is necessary, dose and regimen must remain unchanged during the study.

• Uncontrolled hypertension (systolic BP >160 mmHg or diastolic BP >100 mmHg at screening), regardless of current therapy.
• Uncontrolled endocrine or metabolic disease (e.g., diabetes, secondary hyperlipidemia) or hypothyroidism.

Patients with hypothyroidism may be included if on stable replacement therapy for ≥4 weeks and TSH is within normal range at screening.

• Impaired renal function (serum creatinine >2.0 mg/dL) or nephrotic syndrome at screening.
• History of malignancy within the past 5 years (except those judged cured).
• Major psychiatric instability or psychiatric disorders not adequately controlled by therapy.
• Use of systemic corticosteroids within 1 month prior to screening.
• History of abdominal surgery other than appendectomy, cholecystectomy, cesarean section, hysterectomy, or hernia repair.

Other abdominal surgeries may be allowed if deemed appropriate by the investigator.

• Any other condition judged by the investigator to make the subject unsuitable for participation.