Probiotics as a Coadjuvant Factor in Active or Quiescent Inflammatory Bowel Disease of Adults—A Meta-Analytical Study

(1) Background: Inflammatory bowel diseases are pathologies of unknown etiology and auto-immune pathogenia. The use of probiotics is studied in order to increase the arsenal of treatments. The aim was to assess the efficacy of the probiotics in these diseases in the active or quiescent phases; (2) Methods: A systematic review with meta-analysis was performed by an exhaustive bibliographic search in Medline, Cinahl, Embase, Scopus, Web of Science, and Cochrane Library. The inclusion criteria were studies of more than 10 years, English/Spanish, clinical trials, and involving human beings. Relative risk was used to compare efficacy, which was meta-analyzed using a fixed effects model. Heterogeneity was evaluated with the Higgins I2 test; (3) Results: Nineteen studies were included in the systematic review and 17 in the meta-analysis, with a total of 1537 patients (nexperimental group = 762; nplacebo group = 775). There are significant remission differences in ulcerative colitis (relative risk (RR) = 0.81; 95% CI = 0.72–0.91; I2 = 32%; p = 0.16). However, no significant differences were found in the use of probiotics for the prevention of ulcerative colitis, and for the remission of Crohn’s disease; (4) Conclusions: There are data showing an additional beneficial effect of probiotics on active ulcerative colitis. More and better studies are needed which assess its possible therapeutic efficacy for quiescent ulcerative colitis and for Crohn’s disease.


SUPPLEMENTARY MATERIAL
. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomized or nonrandomized studies of healthcare interventions, or both

Did the research questions and inclusion criteria for the review include the components of PICO?
For Yes: X Population X Intervention X Comparator group X Outcome Optional (recommended) Timeframe for follow-up Yes No 2. Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol?
For Partial Yes: The authors state that they had a written protocol or guide that included ALL the following: X review question(s) X a search strategy X inclusion/exclusion criteria X a risk of bias assessment For Yes: As for partial yes, plus the protocol should be registered and should also have specified: X a meta-analysis/synthesis plan, if appropriate, and X a plan for investigating causes of heterogeneity X justification for any deviations from the protocol

Did the review authors explain their selection of the study designs for inclusion in the review?
For Yes, the review should satisfy ONE of the following:

Did the review authors perform study selection in duplicate?
For Yes, either ONE of the following: X at least two reviewers independently agreed on selection of eligible studies and achieved consensus on which studies to include  OR two reviewers selected a sample of eligible studies and achieved good agreement (at least 80 percent), with the remainder selected by one reviewer.

Did the review authors perform data extraction in duplicate?
For Yes, either ONE of the following: X at least two reviewers achieved consensus on which data to extract from included studies  OR two reviewers extracted data from a sample of eligible studies and achieved good agreement (at least 80 percent), with the remainder extracted by one reviewer.

Did the review authors provide a list of excluded studies and justify the exclusions?
For

Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review?
For Yes: X There was no significant heterogeneity in the results  OR if heterogeneity was present the authors performed an investigation of sources of any heterogeneity in the results and discussed the impact of this on the results of the review Yes  No

If they performed quantitative synthesis did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review?
For Yes: performed graphical or statistical tests for publication bias and discussed the likelihood and magnitude of impact of publication bias

Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review?
For Yes: X The authors reported no competing interests OR  The authors described their funding sources and how they managed potential conflicts of interest The probiotic group ingested one daily capsule consisting of Bifidobacterium longum 2 × 10 9 colony-forming units and the prebiotic group ingested daily doses of 8.0 g of psyllium.
For 4 weeks.
The prebiotic group ingested daily doses of 8.0 g of psyllium.
The synbiotic group underwent both treatments.
Identical placebo twice a day for 8 weeks.
In DSF treated patients, the expression of DC TLR-2 decreased (p < 0.05), the production of IL-10 increased, and the production of IL-12p40 decreased (p < 0.005); 10/14 patients on DSF showed a clinical response. Corticosteroids also resulted in increased IL-10 and reduced IL-12p40 production by DC. Conversely, in patients on placebo, the expression of TLR-2 and intensity of staining for IL-12p40 and IL-6 increased (all with p < 0.05); 5/14 patients on placebo showed a clinical response (p = NS The colonoscopic index and the amount of myeloperoxidase in a wash solution will be used as indexes of disease activity. Bifidobacterium breve Yakult strain, a probiotic contained in bifidobacteria-fermented milk, and galactooligosaccharide (GOS) as synbiotic.
1 g of the probiotic powder (10 9 CFUs/g) three times a day, and 5.5 g of GOS once a day for one year.
The subjects in the control group were treated as usual on the basis of medical background (salazosulfapyridine, mesalazine, steroids). Placebo.
For 48 weeks.
Relapse-free survival was not significantly different between the BFM and placebo groups (p = 0.643; Risk Ratio = 1.16; 95% CI = 0.63-2.14, logrank test), nor was the incidence of relapse. Therefore, the study was discontinued for lack of efficacy.
Su H., Kang et al.

China 2018
Randomized clinical trial 123 Clinical efficacy: recovery, symptoms and clinical signs disappeared after treatment, routine stool examination was negative, microscopic ulcer healed, mucosal recovery was observed.
Probiotics: Bifidobacterium Lactobacillus triple tablets, at a dose of 4 x 500 mg per time, 2 times a day. Glucocorticoids: prednisone, at an initial dose of 0.75-1.0 mg/kg/day and gradually stopped in 3-4 months.
The patients in the control group were treated with routine treatment of oral sulfasalazine. At the same time, a total of 40 healthy individuals were selected to serve as the healthy group (received no treatment).

3-4 months.
After treatment, the number of intestinal flora in the treatment group reached that of the healthy individuals. The treatment efficiency of the treatment group was significantly higher than that of the control group, and the infection rate of the control group was significantly higher than that of the treatment group (p < 0.05). There were no significant differences in the IBD-QOL scores between the placebo and the probiotic groups.
However, the differences in FCAL between patients with UC before and after probiotics versus placebo approached statistical significance with p = 0.076.
Kamarlı et al. The placebo product had the same taste and appearance as the original product.
For 8 weeks.
The serum C-Reactive Protein (CRP) and sedimentation values in the synbiotic group were statistically significant (p = 0.003). In both groups, a statistically significant improvement was observed in the clinical and endoscopic activity levels at the end of the treatment (synbiotic: p = 0.001 and p = 0.002, respectively; control: p = 0.005 and p = 0.001, respectively).

Sood 2009
Excluded: Oral glucocorticosteroids within 4 weeks of inclusion. Antibiotics within 2 weeks of inclusion. Topical mesalazine or glucocorticosteroids within 7 days of inclusion.

Matthes 2010
Excluded: Topical glucocorticosteroids or aminosalicylates within 2 weeks of inclusion. Immunosuppressants within 90 days of inclusion. Antibiotics or sulphonamides during the study. Permitted: Oral aminosalicylates or glucocorticosteroids at stable dose for 2 weeks prior to inclusion.

Ng 2010
Excluded: Antibiotics within 2 weeks of inclusion. Alteration in dose of topical 5-ASA or steroids within 7 days of inclusion. Alternative probiotics. Permitted: Mesalazine (stable for 4 weeks prior to inclusion). Thiopurines (stable for12 weeks prior to inclusion).

Tursi 2010
Excluded: Oral glucocorticosteroids within 4 weeks of inclusion. Antibiotics within 2 weeks of inclusion. Topical 5-ASA or steroids within 1 week of inclusion. Alternative probiotics within 2 weeks of inclusion. NSAIDs within 1 week of inclusion. Permitted: 5-ASA (stable dose for 4 weeks prior to inclusion). Azathioprine or 6-mercaptopurine (stable for at least 3 months prior to inclusion).

Steed 2010
Excluded: It does not indicate Permitted: Patients were also requested to continue on stable doses of conventional CD medication

Benjamin 2011
Excluded: anti-tumour necrosis factor agents in the preceding 12 weeks; antibiotics, probiotics or prebiotics in the preceding 4 weeks; rectal preparations during the preceding 2 weeks; and any non-steroidal anti-inflammatory drugs during the preceding week. hange in dose of immunosuppressant within 12 weeks and oral 5-aminosalicylic acid or steroids within 4 weeks. The maximum permissible steroid dose was 20 mg/day Permitted: Standard medical care based on physicians' discretion

Wildt 2011
Excluded: Treatment with all UC medications bar stable dose 5-aminosalicylates. Permitted: 5-ASA at stable dose for at least 4 weeks prior to inclusion.

Bourreille 2013
Excluded: Immunosuppressive treatments or anti TNFα within 3 months of inclusion. Probiotics, antibiotics, or antifungal treatments for more than 2 weeks. Permitted: Glucocorticosteroids or budesonide and/or aminosalicylates according to the preference of each investigator to achieve remission, then weaned off within 12 weeks of inclusion.

Tamaki 2016
Excluded: Antibiotics within 2 weeks of inclusion. Topical 5-ASA or glucocorticosteroids within 7 days of inclusion. NSAIDs and antidiarrhoeal drugs during the study period. Figure S1. Single species versus mixture for the remission of UC. Figure S2. Single species versus mixture for the remission of CD.