A Novel Formulation of Bifidobacterium Longum BB536 and Lactobacillus Rhamnosus HN001 With Vitamin B6 on IBS Patients

Study Overview
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Brief Summary
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Irritable bowel syndrome (IBS) is one of the most frequent functional gastrointestinal disorder with a prevalence ranging from 10 to 15 percent. IBS results from an interaction among several factors, including genetic predisposition, gastrointestinal motility, visceral hypersensitivity, immune activation with minimal inflammation, alterations in intestinal microbiota, increased intestinal permeability, and food sensitivity. Of note, the management of patients with IBS is critical. Since quantitative and qualitative disturbances of intestinal microbiota can occur in IBS, interesting data support the use of probiotics to modulate intestinal microbiota. The present study aimed to investigate the effects of a novel formulation of B. longum BB536 and L. rhamnosus HN001 with vitamin B6 on the gut microbiota and intestinal permeability in IBS subjects.

Detailed Description
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Irritable bowel syndrome (IBS) is one of the most frequent functional gastrointestinal disorder with a prevalence ranging from 10 to 15 percent. It is characterized by recurrent chronic abdominal pain or discomfort in the absence of detectable organic causes with two or more of the following conditions: onset associated with a change in frequency of stool, onset associated with a change in form (appearance) of stool, or improvement with defecation. IBS results from an interaction among several factors, including genetic predisposition, gastrointestinal motility, visceral hypersensitivity, immune activation with minimal inflammation, alterations in intestinal microbiota, increased intestinal permeability, and food sensitivity. IBS is associated with a high economic burden for the health care costs and work absenteeism. The disease course is represented by unchanged symptoms in 30 to 50 percent or progression of symptoms in 2 to 18 percent. On the other hand, an improvement in symptoms was recorded in 12 to 38 percent of patients. Of note, the management of patients with IBS is critical. Several therapeutic options have been proposed looking to the underlying pathophysiological mechanisms (i.e., dietary modification, osmotic laxatives, lubiprostone, guanylate cyclase agonists, 5-hydroxytryptamine (serotonin) 4 receptor agonists, antidiarrheal agents, bile acid sequestrants, 5-hydroxytryptamine (serotonin) 3 receptor antagonists, antispasmodic agents, antidepressants, antibiotics, probiotics, behavior modification, anxiolytics, mast cell stabilizer, and fecal transplantation). Since quantitative and qualitative disturbances of intestinal microbiota can occur in IBS, interesting data support the use of probiotics to modulate intestinal microbiota. The genus Bifidobacterium is one of the most representative member of the intestinal microbiota with large effects on overall gut physiology. Its metabolic activity results from the degradation of oligo-fructose, production of acetate, and promotion of butyrate production by means of cross-feeding. In particular, B. longum has beneficial effects on the immune system, and can be considered a promising candidate for prevention/treatment of immune-mediated inflammatory diseases. The combination of specific bacterial strains of Lactobacillus with Bifidobacterium species plays an interesting role in reserving the intestinal dysbiosis. The synergic action results in survival on adverse gastrointestinal conditions, adhesion to intestinal mucosa, immunomodulatory activities, and restoration of gut environment. The present study aimed to investigate the effects of a novel formulation of B. longum BB536 and L. rhamnosus HN001 with vitamin B6 on the gut microbiota and intestinal permeability in IBS subjects.

Official Title
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The Beneficial Effects of a Novel Formulation of Bifidobacterium Longum BB536 and Lactobacillus Rhamnosus HN001 With Vitamin B6 on Gut Microbiota and Intestinal Permeability in IBS Patients.

Conditions
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Irritable Bowel Syndrome

Intervention / Treatment
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* Dietary Supplement: Zircombi
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of IBS according to Rome IV Criteria Exclusion Criteria: Diagnosis of structural abnormality of the GI tract Inflammatory bowel disorders Biliary duct obstructions Gallstones Abdominal surgery within the previous six months Infective diseases Drug or alcohol abuse Metabolic disturbances Mental illness Concomitant immunological, haematological or neoplastic disease Severe hepatic insufficiency (i.e., Child-Pugh class C) Severe heart failure (NYHA class III-IV)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Patients entered the following program: A run-in period of one month when symptoms, intestinal permeability, intestinal microbiota, and dietary evaluations were performed; Phase 1: randomization to treatment or placebo lasting 30 days; Wash-out period lasting 15 days, at the end of which symptoms were assessed; Phase 2: switch to next treatment in a crossover fashion. Treatment lasted for 30 days and at the end symptoms, intestinal permeability, and intestinal microbiota were evaluated again.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Probiotic<br>The study design is a crossover randomized double-blind two-block placebo-controlled single center trial with an allocation ratio of 1:1 conducted between February 2017 and May 2018. Subjects are randomized at baseline visit to receive Block 1 (Zircombi 3 g, containing Bifidobacterium longum BB536 four billion CFU, Lactobacillus rhamnosus HN001 one billion CFU with B6 vitamin 1.4 mg) and Block 2 (placebo: maltodextrins, corn starch, silicon dioxide) depending on the randomization sequence. Subjects received one sachet pack daily containing placebo or probiotic. The active treatment was undistinguishable from placebo by physical and organoleptic characteristics. Participants in the study followed a free diet. | Dietary Supplement: Zircombi<br>* Twenty-five IBS patients (Rome IV criteria) (M:F= 8:17; age 48 yrs ± 11 SD) were enrolled and randomized to treatment or placebo in a a crossover randomized double-blind two-block placebo-controlled trial. Abdominal pain and bloating, intestinal habits, severity of disease, intestinal permeability, and intestinal microbiota were performed at the different time points.<br>|
| Placebo Comparator: Placebo<br>Same appearance of probiotic. | Dietary Supplement: Placebo<br>* Given as comparable packets. Same duration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visual Analogue Scale, ranging from 0 to 100 | For assessing abdominal pain and bloating | Baseline | 
| Irritable Bowel Syndrome Symptom Severity Score (IBS-SSS) | Developed by Francis et al. (1997), and categorized as follows: remission (score <75), mild (75-175), moderate (175-300) and severe (>300). | Baseline | 
| Bristol Stool Form Scale (BSFS) | To assess bowel movements, consisting of a self-report instrument for classifying stool form into seven types ranging from separate hard lumps like nuts (type 1) to watery, no solid pieces (type 7) | Baseline | 
| MEDSTYLE questionnaire | A custom-designed questionnaire, tested across different ages, and anthropometric groups in health and disease, to measure anthropometric data, medical history, lifestyle and daily intake of foods. Frequency (day, week or month) and portion sizes (small, medium and large, represented by color pictures) of food consumption were estimated by using 35 food items (156 foods).The adherence to a Mediterranean diet was calculated by analyzing nine food categories with a score ranging from 0 point (lowest adherence) to 18 points (highest adherence). | Baseline | 
| Intestinal permeability | It was assessed by oral administration of four sugar probes, which selectively characterize the permeability from different tracts of the gastrointestinal system. Sucrose (SO) was used as a marker of gastro-duodenal permeability; lactulose (LA) and mannitol (MA) were used as markers of small intestine permeability also as (LA/MA), and sucralose (SU) as marker of 8 colonic permeability. | Baseline | 
| Cultivable intestinal microbiota | It was evaluated by faecal samples (5 g) were mixed with 45 mL sterilized physiological solution and homogenized. | Baseline | 
| Community level catabolic profiles | Biolog Eco microplates (Biolog, Inc., Hayward, CA, USA) were used to estimate the microbial diversity. | Baseline | 
| Fecal metabolome | Three grams of fecal sample were placed into 10 mL glass vials and added with 10 μL of 4-methyl- 2-pentanol (final concentration of 33 mg/L) as the internal standard. | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IBS