Laterza L et al. (2025), Multistrain Probiotics Plus Vitamin D Improve G...

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Nutrients 2025 May 18;1710:. doi: 10.3390/nu17101708.

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Multistrain Probiotics Plus Vitamin D Improve Gut Barrier Function and Gut Microbiota Composition in Irritable Bowel Syndrome Without Constipation: Results from a Double-Blind, Randomized, Placebo-Controlled Trial.

Laterza L , Cremon C , Coppola G , Settanni CR , Maresca R , Strazzeri M , Durini E , Petito V , Scaldaferri F , Gargari G , Mora D , Vojoudi Yazdi E , Marangelo C , Ianiro G , Putignani L , Barbaro MR , Marasco G , Barbara G , Gasbarrini A .

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BACKGROUND: The disruption of the intestinal barrier and the imbalance of the gut microbiota (GM) seem to play a major role in the complex pathogenesis of irritable bowel syndrome (IBS). Specific microbial strains could improve the gut microenvironment, promoting anti-inflammatory pathways; similarly, vitamin D supplementation could play a role in enhancing the barrier integrity and modulating the immune response in the gut. This study aims to evaluate the efficacy of a new multistrain probiotic, combined with vitamin D, in improving gut barrier function in IBS without constipation. METHODS: In this phase IIb double-blind randomized placebo-controlled, parallel-group, multicenter, clinical trial, 35 patients were treated for 12 weeks with OttaBac®, a high concentration multistrain probiotic plus cholecalciferol, or placebo and were followed up until week 16. Symptoms, quality of life, intestinal permeability, fecal biomarkers, and microbiota composition were evaluated at 0, 12, and 16 weeks. RESULTS: Mean zonulin values showed a significant progressive reduction in the active group (-10.2 ng/mL at week 12, p = 0.0375; -19.5 ng/mL at week 16, p = 0.0002), with a significant difference between groups at week 16 in the per-protocol population (-19.01, p = 0.0053). The active group showed a more stable trend toward improvement in stool frequency and consistency at both week 12 and 16, with a significant improvement compared to the baseline and to the placebo group (-23.2, p = 0.0265, and 5.57 vs. -23.2, p = 0.0492, respectively). No differences were found in regards to the lactulose/mannitol ratio, Irritable Bowel Syndrome Severity Scoring System (IBS-SSS) and Short Form Health Survey (SF-36) total scores, plasmalemmal vesicle associated protein-1 (PV-1), and citrulline levels. In the active group, Bifidobacterium animalis subsp. lactis and Streptococcus thermophilus levels were increased (p < 0.05), while those for Lachnospira were decreased (p < 0.05), and significant changes in Actinobacteria and Proteobacteria were observed (p < 0.05). Lactate (p < 0.01) and acetate (p < 0.05) levels increased post-treatment. Correlation analysis pointed out a significant association between the microbial biomarkers and the symptoms (p < 0.05). CONCLUSIONS: Probiotic plus vitamin D could improve IBS-associated symptoms through gut microbiota modulation and gut barrier enhancement, with persistent benefits after treatment discontinuation.

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	Figure 1. Schematic representation of study design. PROs, patient reported outcomes; PV-1, plasmalemma vesicle associated protein-1; SF-36, Short Form Health Survey.
	Figure 2. Participant flow diagram according to CONSORT guidelines. A total of 42 patients were enrolled in the study, 3 withdrew their consent, 4 discontinued the study before the randomization, 1 did not take any medication and was excluded from the SAF population, and 3 did not have any data after baseline and were excluded from the intent-to-treat set. One patient discontinued the study/treatment after day 3, and two finished the study before the end. Twenty-eight patients were included in the per protocol set. SAF, safety population; ITT, intent-to-treat population; PP, per-protocol population.
	Figure 3. Distribution of patients with normal intestinal permeability (lactulose/mannitol ratio < 0.03) and with increased permeability (lactulose/mannitol ratio ≥ 0.03) in the placebo group and in the active group at baseline and at the end of treatment (week 12), expressed as percentages.
	Figure 4. Mean values of zonulin in the intent-to-treat (ITT) (A) and in the per-protocol (PP) (B) population are shown. p-values refer to the differences between the active and the placebo group in the mean difference in variation in zonulin levels compared to those at baseline. (See text for p-values for mean difference of variation within groups before and after treatment.)
	Figure 5. Mean percentages of days of abnormal bowel movements on a weekly basis in the per-protocol (PP) population are shown. p values refer to the mean differences in variation between the placebo and active groups (−31.82, p = 0.0377) at week 16.
	Figure 6. Microbiota comparison between the time points per treatment, according to the LEfSE. The figure displays the LEfSE results, with the mean values in the group with higher levels and the LDA for all comparisons between time points (V2, V4, V5) for each treatment (active or placebo). The taxonomy for all variables is provided in the following format: p, phylum; c, class; o, order; f, family; g, genus; s, species; ASV, amplicon sequence variant. The p__Actinobacteria.c__Actinobacteria.o__Bifidobacteriales.f__Bifidobacteriaceae.g__Bifidobacterium.ASV_1629 and the p__Firmicutes.c__Bacilli.o__Lactobacillales.f__Streptococcaceae.g__Streptococcus.s__.ASV_2914 were manually checked using BLAST v1.7.2, matching Bifidobacterium animalis subsp. lactis and Streptococcus thermophilus, respectively.
	Figure 7. Classification of subjects at V4 from different treatments according to PLSDA analyses. The figure displays the clustering results from partial least squares discriminant analysis (PLSDA) of subjects at time point V4, comparing the two treatments, i.e., active and placebo. The PLSDA was conducted using an equal number of subjects from both treatment groups, with a total of 24 subjects. Subjects who received the active treatment are represented by blue circles, while those who received the placebo treatment are represented by orange triangles. ACT, active group; pla, placebo group.
	Figure 8. Classification of subjects at V4 from different treatments and baseline according to PLSDA analyses. The figure displays the clustering results from partial least squares discriminant analysis (PLSDA) of patients from the two groups at time point V4 and V2, with the least amount of clustering labeled as “baseline”. The PLSDA was conducted using an equal number of subjects from both treatment groups, with a total of 36 subjects. Subjects who received the active treatment are represented by blue points, while those who received the placebo treatment are represented by green squares, and the subjects at baseline are labeled with orange triangles. The figure also shows the ROC curve. ACT, active group; pla, placebo.