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

nutrients Review Probiotics as a Coadjuvant Factor in Active or Quiescent Inflammatory Bowel Disease of Adults—A Meta-Analytical Study Manuel Pabón-Carrasco 1, Lucia Ramirez-Baena 1,* , Samuel Vilar-Palomo 2, Aurora Castro-Méndez 3, Raúl Martos-García1and Isabel Rodríguez-Gallego 1 1Spanish Red Cross Nursing School, Universidad de Sevilla, Avda de la Cruz Roja nº 1 Dpdo, 41009 Seville, Spain; [email protected] (M.P.-C.); [email protected] (R.M.-G.); [email protected] (I.R.-G.) 2Hospital Virgen del Rocío, Unidad de Anestesiología y Reanimación, Servicio Andaluz de Salud, Av. Manuel Siurot, SN., 41013 Seville, Spain; [email protected] 3 Faculty of Nursing, Physiotherapy and Podology, Universidad de Sevilla, C/Avenzoar 6, 41009 Seville, Spain; auroracastr[email protected] *Correspondence: [email protected].es; Tel.: +34-954-350997; Fax: +34-954-350997 Received: 2 July 2020; Accepted: 26 August 2020; Published: 28 August 2020   Abstract: (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 I 2 test; (3) Results: Nineteen studies were included in the systematic review and 17 in the meta-analysis, with a total of 1537 patients (n experimental group =762; n placebo group =775). There are significant remission differences in ulcerative colitis (relative risk (RR) =0.81; 95% CI =0.72–0.91; I 2 =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. Keywords: ulcerative colitis; Crohn’s disease; inflammatory bowel disease; efficacy; probiotics 1. Introduction Inflammatory bowel diseases (IBDs) are a group of auto-immune pathologies, with Crohn’s disease (CD) and ulcerative colitis (UC) among the most well-known. They are both of recurrent clinical course and show a higher incidence in developed countries [1,2]. The etiology of IBDs is unknown—an inappropriate activation is produced of the immune system against the intestinal mucosa in individuals with a genetic predisposition. Environmental factors have been involved, with possible mediators including geo-localization, tobacco, rest disorders, surgical interventions or infections during childhood, and diet—the latter considered a higher risk factor in the development of such pathologies [2,3]. Treatment is focused on the accepted pathogenic mechanisms. The following have been recommended: quitting tobacco use, specific diet and nutrition, anti-inflammatories such as corticoids (temporary use), immuno-suppressors, biological therapy, and surgery [ 4 ]. In Nutrients 2020,12, 2628; doi:10.3390/nu12092628 www.mdpi.com/journal/nutrients Nutrients 2020,12, 2628 2 of 17 similar conditions, different types of diet approaches have been developed for IBDs, such as prebiotics/probiotics/postbiotics, to explore their efficacy as possible change agents of the existent inflammatory processes in these diseases [ 5 ]. The microbiota is reciprocally related to the human being: it provides various positive effects in the immune system, competing with harmful micro-organisms, or complementing nutrients which are necessary for the human body [6]. The different types are the following: prebiotics, probiotics, or more recently, postbiotics [ 7 ]. Prebiotics are food substances that the organism does not digest and which, once they reach the colon, favor the growth of bacterial species of the microbiota considered to produce beneficial effects for the human organism. Among the main benefits are improvement in intestinal motility, both in terms of frequency and of volume; reduction in LDL cholesterol and blood triglycerides; contribution to the synthesis of folic acid; improvement in the immunological function; and, thanks to butyric acid, a reduction in the risk of malignant tumors [8]. The change in the microbiota produced by prebiotics in patients with IBDs, that is, those where low levels of Firmicutes and Bifidobacteria and a high number of bacteria which are pro-inflammatory for the organism (Escherichia, Fusobacterium) have been detected, could favor their remission or maintenance [6,7,9]. Prebiotics are found in foods rich in fiber such as whole grains (wheat, oats, and barley derivatives), vegetables (onion, garlic, leek), fruits (apple, banana), and legumes (soya) [ 8 ]. Probiotics are live micro-organisms which have demonstrated a synbiotic effect with the host. Their beneficial effects include re-establishing deficient digestion (sugar intolerances), restitution of the microbiota (diarrhea caused by antibiotics), and prevention of mastitis [ 8 ]. Postbiotics are products or a fraction of the lysis of bacteria [ 10 , 11 ]. One of the most studied postbiotics is butyrate, the energetic base of the colonocytes that has suppressive effects on pro-inflammatory cytokines of the intestine [7]. There are studies which proposed treating UC with foods from germinated barley, a butyrate precursor. These studies turned out to be very promising and guided research in this direction [ 12 ]. Another study proposed that the Escherichia coli Nissle 1917 probiotic was as valid as the usual UC treatment with Mesalazine (5-ASA) to maintain remission. A few years later, studies conducted with the VSL #3 probiotic (a combination of diverse probiotics) and with Lactobacillus GG claimed identical results [ 13 , 14 ]. Likewise, an Italian study found that adding butyric acid in patients with a deficient response to treatment with Mesalazine showed good results in maintaining remission in patients with moderate UC [ 15 ]. Finally, a compound made of fermented oats, Lactobacillus plantarum (L. Plantarum) 299v, barley malt, lecithin, and water (Proferm í n) was tested, which performed well for remission patients in UC [16]. The latest studies have been focusing fundamentally on the use of probiotics and postbiotics. Recent studies have noted that Crohn’s disease and UC affect 1.4 million people in the United States, 2.5 million people in Europe, and millions more in the rest of the world. Besides, during the second half of the 21st century, the incidence of these diseases has risen in developed countries, reaching numbers of 6–10/100,000 inhabitants/year in Europe [ 8 ]. These figures apply to Spain, both in terms of the increasing number of cases and in the cardinal differences, and are evident in the regions of Córdoba and Seville [1]. Considering the chronicity and development of outbreaks of these diseases, and their predominant onset between childhood and the first half of life, it can be asserted that the treatment of IBDs consumes a large quantity of resources, both economic and personal, as well as for the health system (diagnoses tests, drugs, hospital stays, health personnel, etc.) and the work environment due to the length of possible sick leave [ 17 ]. As an example, the cost of caring for a patient with Crohn’s disease is estimated at approximately EUR 7000 per year [17,18], 57% of which is attributable to hospital admissions, 33% to pharmaceutical expenses, and the remainder to different causes such as consultations, tests, and surgical interventions [18]. As a consequence of this, the following research question arose: In individuals with inflammatory bowel disease (P), is the use of probiotics (with diverse families and strains) (I) efficient for Nutrients 2020,12, 2628 3 of 17 starting/maintaining the remission of these diseases (O) with respect to the use of the placebo or conventional treatment (C)? In order to answer that question, the following objective was set out: to analyze the efficacy of using probiotics in patients with inflammatory bowel disease in the active or quiescent phase as a coadjuvant therapy at the beginning of remission or maintenance. 2. Methods 2.1. Search Strategy and Inclusion Criteria A bibliographic search was performed in scientific databases and sources including Medline, PubMed, EMBASE, Scopus, Web of Science, and The Cochrane Library, according to the recommendations set forth in Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA), and was evaluated with the AMSTAR-2 tool (Table S1) [ 19 , 20 ]. Additionally, a search was performed in the Clinical Trial Gov record page, and the nonexistence of similar papers was checked against the Prospero record. The protocol of this study was registered in the Prospero website in February 2019 (ID: 168533; status: not yet registered; last edited: 9 February 2020; consulted: 23 April 2020). The search terms of (“inflammatory bowel diseases” OR “crohn disease” OR “colitis, ulcerative” OR “ulcerative colitis” OR ileitis OR colitis) and (prebiotics OR probiotics OR Saccharomyces OR Lactobacillus OR Bifidobacterium OR “escherichia coli”) and their equivalent in Spanish were used. The descriptors of the search equation were chosen from the Medical Subject Headings (MeSH) thesaurus. The search was performed from January to December 2019. The inclusion criteria were articles published in the last 10 years, in English/Spanish, with a theme related to the objectives of this study, and randomized clinical trials (RCTs) performed on adult human beings. Children were not included in the difference in diagnostic criteria, a narrower therapeutic margin and limitation in the use of probiotics for the treatment of these diseases. Only RCTs were selected to increase the methodological quality of the review and to reduce the number of biases on a theme which, by its very nature, is complex to approach due to the great number of probiotic families, dosing, and stage of the inflammatory bowel diseases. 2.2. Data Extraction Ethical approval was not necessary because of the type of study (systematic review with meta-analysis) and because no patients were involved. The search and selection of articles were performed independently by two researchers; an expert in inflammatory bowel diseases was consulted for resolution in the case of disagreement. Titles and abstracts were read first, then the selected article in its entirety. A reverse and forward bibliographic search was performed of the cited references in the selected studies. The agreement degree between the two researchers in terms of assessing the eligibility of the study was measured using Kappa’s statistical test. A data coding handbook was used. The following variables were obtained from each study: (1) author; (2) year of publication; (3) country of origin; (4) study design; (5) sampling size; (6) criteria used to define remission; (7) types of probiotics of the experimental group and duration; (8) control used and duration; (9) results. Data were extracted as an intention-to-treat analysis. The primary dichotomous results evaluated were the efficacy of the probiotics, comparing it with the usual treatment (Mesalazine or 5-ASA) or with the placebo in terms of failure to achieve remission in active IBDs and relapse in quiescent IBDs. 2.3. Quality and Bias Risk Assessment The bias risk assessment tool was used according to Cochrane [ 21 ], which classifies each type of risk as low, high, or unclear. The types of risk included the following: generation of random sequences, allocation concealment, blinding of the participants and of the personnel, blinding of the Nutrients 2020,12, 2628 4 of 17 results evaluation, data from incomplete results, selective reports, and other possible bias sources. It was considered that the studies without a high bias risk in any category were of high quality (1++) and that those with one high risk or two unclear risks were of medium quality (1+). The rest were considered of low quality (1−). The statistical analysis and the bias evaluation were performed with the Review Manager software, version 5.3 (Cochrane Library, London, UK). Data were also imported into the Grade Pro application, which allows a valuation to be given to the recommendation degree of the data obtained. 2.4. Data Synthesis and Statistical Analysis Relative risk (RR) was used to compare dichotomous variables with a 95% confidence interval (CI). The continuous variables were evaluated through weighted mean differences (WMDs) with a 95% CI. When the study did not offer data on the standard deviation, the Hozo et al. [ 22 ] method was used. Both the binary and continuous data were calculated using random and fixed effects models. The fixed effects model was initially selected if there was not high heterogeneity among the studies (I2 ≤ 50); otherwise, the random effects model was used [23]. The heterogeneity among the studies was evaluated by means of a chi-square test and I 2 test, with a statistical significance level of p<0.05. I 2 values between 0% and 25% suggested low heterogeneity, over 25% moderate heterogeneity, and over 75% high heterogeneity [24]. A forest plot was used for the graphical representation of the meta-analysis results, and a funnel plot was used to evaluate the publication bias among the studies. The asymmetry of this last graphic was assessed by means of the funnel representation and with a statistical significance level of p<0.05 by the Eggers test, which indicates evidence of publication bias. The subgroup analysis was performed based on the IBD typology (UC or Crohn’s disease), whether in the active or quiescent phase. A sensitivity analysis was performed to assess the soundness of the results by serial omission of each study. A p-value <0.05 was considered statistically significant. Data from dichotomous results were grouped by means of a random effects model [ 23 ] to offer a more conservative estimation of the effects of the probiotics on the IBDs, which allows for heterogeneity among studies. The impact of the probiotics, compared to the usual treatment (Mesalazine, 5-ASA, etc.) or placebo, was expressed as an RR of not achieving remission with 95% confidence intervals (CIs) in the therapy trials for active UC or Crohn’s disease, or as RR of relapse in therapy trials for quiescent UC. 3. Results 3.1. Results Obtained in the Selection of Articles A total of 1814 articles were identified in the initial literature search, and 83 additional documents that were found in clinical trial specific records were excluded (Clinical Trial Gov and Prospero). After deleting 885 duplicate articles by means of the Mendeley ® bibliographic manager and applying the inclusion criteria and assessing the articles’ titles and abstracts, 1878 were excluded for not meeting the inclusion criteria. Finally, 19 studies were selected in the analysis for the systematic review, of which 17 offered data to perform the meta-analysis, spanning a sample of 1537 participants with IBDs (experimental group, n=762; placebo group, n=775), as shown in Figure 1. The agreement among the researchers with regards to the assessment of the eligibility of the trials was excellent (Kappa statistics =0.91). Nutrients 2020,12, 2628 5 of 17 Figure 1. Flow diagram in the selection of articles according to PRISMA. CD =Crohn’s disease; IBDs = inflammatory bowel diseases; UC =ulcerative colitis. Nutrients 2020,12, 2628 6 of 17 3.2. Descriptive Analysis of the Results Found Of the 19 clinical trials included in the systematic review, 36.84% (n=7) were randomized, and 63.15% (n=12) were double-blind randomized; no crossed trials were found. Of these, four were published in 2010; three were published in 2019 and 2011; two were published in 2018, 2015, and 2009; and one was published in 2013, 2014, and 2016. The evidence levels evaluated according to the quality of the selected articles were given a score of 1++ in 26.31% (n=5) of cases, the same percentage was scored 1+(n=5), and the remaining 47.36% (n=9) was scored 1−. The probiotics studied belonged to different families and were administered with different doses. Four studies used a synbiotic which is the combination of a probiotic with a prebiotic. In relation to the families used, of a total of 36 different possible agents, 63.15% (n=12) used Lactobacillus; 57.89% (n= 11) used a strain of the Bifidobacterium family; 21.05% (n=4) used the VSL # 3 compound; 10.52% (n= 2) used Escherichia coli,Enterococcus, and Streptococcus; and 5.26% (n=1) were composed of Clostridium, Bacillus mesentericus, and Saccharomyces boulardii, taking into account that there are articles in which diverse probiotic families were analyzed. The mean duration of the treatments was 4.6 months, the longest being 12 months in 26.31% (n= 5) of the studies, and the shortest 0.5 months in 5.26% (n=1) of cases. The details of each article included are provided in Table S2. 3.3. Bias Risk Assessment of the Selected Studies and Publication Bias The bias risk was assessed using RevMan 5 ® , represented in Figures 2and 3by means of bias assessment graphics of all the studies included (Figure 2) and through a summary one-by-one graphic (Figure 3). Allocation concealment was evidenced in 25%, with approximately an 80% blinding of the participants and of the personnel, 75% blinding of the results assessment, and with a generation of a random sequence below 90%. In relation to the publication bias, in a funnel plot for each objective of the study assessed, an inverted funnel can be observed, the most powerful studies being concentrated in the center (Figure 4). Figure 2. Bias analysis of the articles selected altogether. Nutrients 2020,12, 2628 7 of 17 Figure 3. Bias analysis of the articles selected one by one. Red =high risk; Green =low risk; Yellow/? =unclear risk; +/−=risk percentage. Figure 4. Analysis of publication bias by means of a funnel plot. ( A ): ulcerative colitis publications ( B ): Crohn’s disease publications. CD =Crohn’s disease; RR =relative risk; SE =publication bias; UC = ulcerative colitis. Nutrients 2020,12, 2628 8 of 17 3.4. Results of the Meta-Analysis Of the 17 studies included in the meta-analysis, 52.94% (n=9) of the RCTs assessed the efficacy of the probiotics to induce remission of active UC, 17.64% (n=3) studied their efficacy in preventing relapse in quiescent UC, 29.41% (n=5) analyzed their efficacy in inducing remission in active Crohn’s disease, and no studies were found that assessed the efficacy of probiotics in preventing relapse in quiescent Crohn’s disease. The permitted and excluded medications in each of these studies are described in Table S3. 3.5. Efficacy of the Probiotics to Induce Remission in Active UC One of the nine trials, with a sample of 120 patients, compared probiotics with prebiotics and synbiotics for the induction of the remission of active UC [ 25 ], and the remaining eight trials were placebo-controlled [ 26 – 33 ]. Two trials presented a low bias risk [ 29 , 30 ]. Improvements were achieved in the assessment of the IBDs in the three groups, the probiotic group improving the emotional function (p=0.03), the prebiotic group improving the intestinal function (p=0.04), and the synbiotic group improving the social realm and the systematic function (p=0.008 and p=0.002, respectively). The seven RCTs which were placebo-controlled contained a total of 639 patients with active UC [ 26 – 33 ]. In total, 201 out of 362 (55.52%) patients allocated to probiotics did not achieve remission, versus 271 out of 397 (68.26%) patients in the placebo group (RR to achieve remission =0.81; 95% CI = 0.72–0.91), with heterogeneity among the studies (I2=32%, p=0.16). Three of the trials used VSL # 3 (Ferring Pharmaceuticals Ltd., West Drayton, United Kingdom), a combination of probiotics [ 26 – 29 ]. When only these three studies were considered in the analysis, 88 out of 162 (56.2%) patients randomly allocated to VSL # 3 did not achieve remission, versus 118 out of 157 (75.2%) in the placebo group (RR to achieve remission =0.72; 95% CI =0.61–0.85), with no heterogeneity among the studies (I2=16%, p=0.30). Two RCTs used E. Coli [ 27 , 30 ] in a sample of 164 patients. In those studies, 56 out of 95 (58.9%) patients allocated active therapy did not achieve remission, versus 59 out of 95 (62.1%) allocated to the placebo (RR =0.94; 95% CI =0.72–1.23), with no heterogeneity among the studies (I2=0%, p=0.76). The rest of the studies used different families, especially Lactobacillus and Bifidobacterium, among others [ 25 , 31 , 33 ]. Of the patients, 57 out of 105 (54.2%) allocated to active therapy did not achieve remission, versus 94 out of 145 (64.82%) allocated to the placebo (RR =0.88; 95% CI =0.72–1.07), with no heterogeneity among the studies (I2=39%, p=0.18). If we evaluate by strains, an improvement was observed in those studies that used a combination of microorganism (mixture) versus a single strain in patients with UC (Figure S1) and CD (Figure S2). 3.6. Efficacy of Probiotics to Prevent Relapse in UC There were three placebo-controlled trials [ 34 – 36 ] with a total sample of 284 patients which reported the efficacy of the probiotics versus the placebo in preventing clinical or endoscopical relapse of UC. In total, 60 out of 147 (55.52%) patients allocated to probiotics did not achieve remission, versus 60 out of 137 (68.26%) allocated to the placebo (RR of failure to achieve prevention =0.89; 95% CI = 0.68–1.15), with heterogeneity among the studies (I2=0%, p=0.59). In relation to the families used, two of them employed the Bifidobacterium–Lactobacillus acidophilus [ 35 , 37 ] combination, whereas the other used a compound of 2 mg Streptococcus faecalis T–110, 10 mg Clostridium butyricum TO–A, and 10 mg Bacillus mesentericus TO–A [38]. In relation to the general assessment in UC, with a total of 1043 participants, 261 out of 509 (51.27%) patients allocated to probiotics did not achieve remission, versus 331 out of 534 (61.98%) allocated to the placebo (RR =0.83; 95% CI =0.74–0.92), with heterogeneity among the studies (I 2 =14%, p=0.30), as shown in Figure 5and Table 1. A combination of different strains of probiotics were used. Nutrients 2020,12, 2628 9 of 17 Figure 5. Comparison of probiotics versus placebo groups for the remission and prevention of ulcerative colitis (UC). CD =Crohn’s disease; Chi 2 =test Chi 2 ; CI =confidence interval; Green =low risk; M-H = Mantel-Haenszel method; P =statistical significance; Red =high risk; UC =ulcerative colitis; Yellow/? =unclear risk; Z =test for overall effect; +/−=risk percentage. Table 1. Recommendation degree of probiotic versus placebo groups for the remission and prevention of UC. Probiotic Compared with Placebo for Ulcerative Colitis Outcome No. of Participants (Studies) Follow-Up Certainty of the Evidence (GRADE) Relative Effect (95% CI) Absolute Anticipated Effects Placebo Risk The Risk Difference with Probiotics Efficacy of probiotics in inducing remission in active UC 759 (9 RCTs) LLL # MODERATE RR 0.81 (0.72 to 0.91) 683 ×1000 130 less to 1000 (191 less to 61) Efficacy of probiotics in preventing relapse in quiescent UC 284 (3 RCTs) LLL # MODERATE RR 0.89 (0.68 to 1.15) 438 ×1000 48 less to 1000 (140 less to 66) Patient or Population: Ulcerative Colitis, Outcome: Efficacy, Intervention: Probiotic, Comparison: Placebo. The risk in the intervention group (and its 95% confidence interval) is based on the risk assumed in the comparison group and the relative effect of the intervention (and its 95% confidence interval). CI: Confidence Interval; RR: Risk Ratio. GRADE Working Group grades of evidence. High certainty: We are very confident that the true effect lies close to that of the effect estimate. Moderate certainty: We are moderately confident in the effect estimate—the true effect is likely to be close to the effect estimate, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited—the true effect may be substantially different from the effect estimate. Very low certainty: We have very little confidence in the effect estimate—the true effect is likely to be substantially different from the effect estimate.CI =confidence interval; UC =ulcerative colitis; RCTs =randomized controlled trial; RR =relative risk; LLL # =level of recommendation. Nutrients 2020,12, 2628 16 of 17 34. Wildt, S.; Nordgaard, I.; Hansen, U.; Brockmann, E.; Rumessen, J.J. 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