Definitive curative strategies for inflammatory bowel disease remain challenging for physicians and patients. For decades, probiotic organisms have been used in various gastrointestinal diseases. Only recently has comprehension of the pathophysiology of inflammatory bowel disease developed to the point where the significance of the host gastrointestinal microbial population is seen to have marked influence on the initiation and ongoing inflammatory processes of Crohn disease and ulcerative colitis. Well-designed, large randomized controlled trials using probiotics in patients with inflammatory bowel disease are required for probiotics to become mainstream therapy.
Key Points
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The gastrointestinal microbiota is highly diverse. Alterations in this microbiota have been show to both cause and abrogate systemic inflammatory disorders.
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Probiotics are defined as microbiotia that have a beneficial effect on human health.
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Recently, probiotics and probiotic preparations have been studied as therapeutic agents to modify the gastrointestinal microbiota and thereby treat inflammatory bowel diseases (IBDs).
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Randomized clinical trials have shown that select probiotics are efficacious for the induction and maintenance of remission in ulcerative colitis and for the maintenance of remission in pouchitis.
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Not all probiotics are the same or have similar efficacy. Adequately powered, randomized controlled clinical trials are required for each probiotic to confirm its efficacy in IBD.
Introduction
The traditional classification of IBD into Crohn disease and ulcerative colitis offers health care providers a logical and evidenced-based approach in developing a meaningful therapeutic approach for the prevention and treatment of these diseases. Current therapies may leave many patients and physicians frustrated, because persistent symptomatology and endoscopic or histopathologic evidence of active disease usually persist despite optimum medical and surgical management. As comprehension of these diseases has progressed, advanced pharmacologic biologic therapies have been developed, such as anti–tumor necrosis factor α (anti–TNF-α) agents, which have resulted in improved symptom and disease control in many patients. Currently, however, a definitive curative strategy for these diseases, using medical therapy alone, remains elusive. Furthermore, these medications are not without significant cost nor are they without risk of potential, and often substantial, side effects. For these reasons, there is a prevalent interest in patients with IBD in pursuing nonconventional avenues of therapy for both symptoms and disease control.
Given these considerations, there has been an increasing appreciation of the importance in understanding the complexities of the interactions between the human host immune system and its resident gastrointestinal luminal microbial population. Current models for the pathogenesis of IBD have demonstrated evidence for a disturbance in this equilibrium, resulting from either an aberrant host immune response to usual luminal microbiota, an exaggerated physiologic immune phenomenon to an abnormal population of microbes in the gastrointestinal tract, or a combination of both.
Probiotic organisms, which are defined as “live microorganisms which when administered in adequate amounts confer a health benefit on the host,” have been used in attempts to take advantage of this relationship to treat various gastrointestinal diseases, including acute traveler’s diarrhea, infectious diarrhea, and irritable bowel syndrome ; in the prevention of infantile necrotizing enterocolitis in neonates ; and to alter gut microflora in patients with minimal hepatic encephalopathy to prevent the growth of ammonia-producing bacteria in patients with hepatic cirrhosis.
Although the spectrum of diseases of the intestines is broad, this article focuses on the actual and potential roles of the probiotic organism in patients with Crohn disease and ulcerative colitis. To begin with, the basic aspects of the enteric microorganism are reviewed, as they pertain to the development of IBD, and they are compared and contrasted with the host-specific responses to probiotic administration, in both the IBD and non-IBD host. Then the available clinical literature is reviewed, focusing on the use of probiotics in Crohn disease and ulcerative colitis, examining the roles of the probiotic organism in induction of remission as maintenance therapy and in the surgical patient with IBD. Finally, future roles of probiotic therapy in the realm of IBD are proposed.
Gastrointestinal microbes and IBD
The human gastrointestinal tract provides a suitable environment to a diverse microbial population, with more than 400 to 500 different species of bacteria currently identified. The primary introduction of this array to the host most likely occurs in close relationship to labor and delivery of the neonate, with Lactobacillus and Prevotella spp predominating within the vaginal canal at the time of delivery. Once established, this microbial population maybe susceptible to changes in diet, age of the host, disease states, and lifestyle. Nevertheless, the specific changes that are effected in the microbial population by each of these variables, however, remain to be fully elucidated.
The importance of the microbe in IBD is demonstrated by clinical and histologic improvement in fecal diversion in patients with Crohn disease ; recurrence of symptoms and inflammation with re-exposure of the terminal ileum to luminal contents is the rule. Several studies have magnified the importance of enteral microorganisms in the development and maintenance of IBD. Analysis of mucosal-associated and fecal bacteria reveals diminished commensal microbial diversity (decreased numbers of Faecalibacterium prausnitzii and Lactobacillus ), an increased number of mucosal-associated microorganisms, and an orientation toward phylogenetic groups of proinflammatory microbes, such as Escherichia coli, in patients with active inflammation in Crohn disease and ulcerative colitis. It remains to be seen whether this dysbiotic environment is a prerequisite for developing IBD or is a result of it and which bacteria are specifically involved.
To date, the identification of one or more causative organisms in IBD has not been found. Although early association of Mycobacterium avium subsp paratuberculosis with spontaneous granulomatous enterocolitis provided a potential causative organism for IBD, its specific role in IBD remains to be determined. Similarly, although there is a higher prevalence of Yersinia and Camplyobacter species in patients with Crohn disease compared with controls, their roles too remain to be investigated. Particular attention has been paid to the presence of pathogenic adherent-invasive E coli , which has been identified in 36.4% of patients with Crohn disease versus 6% of controls. The reasons for this difference most likely represent a combination of host characteristics (ie, Paneth cell dysfunction; genetic mutations in NOD2, ATG16L1 , or IRGM; and abnormal ileal expression of carcinoembryonic antigen-related cell adhesion molecule 6) and microbial properties (type 1 pili variants and increased TNF-α and IFN-γ secretion). The specific relationships between the host immune system and microbiota in IBD are beyond the scope of this article and are reviewed elsewhere.
The microbe and IBD recall points
- •
400–500 Species of bacteria reside within human gastrointestinal tract.
- •
The human host is colonized at birth with bacteria from caregivers. The majority of the bacteria are constant whereas a small proportion can change with time and circumstance (age, disease, lifestyle, and so forth).
- •
IBD involves dysbiosis and/or abnormal immune host response to the dysbiosis.
Introduction
The traditional classification of IBD into Crohn disease and ulcerative colitis offers health care providers a logical and evidenced-based approach in developing a meaningful therapeutic approach for the prevention and treatment of these diseases. Current therapies may leave many patients and physicians frustrated, because persistent symptomatology and endoscopic or histopathologic evidence of active disease usually persist despite optimum medical and surgical management. As comprehension of these diseases has progressed, advanced pharmacologic biologic therapies have been developed, such as anti–tumor necrosis factor α (anti–TNF-α) agents, which have resulted in improved symptom and disease control in many patients. Currently, however, a definitive curative strategy for these diseases, using medical therapy alone, remains elusive. Furthermore, these medications are not without significant cost nor are they without risk of potential, and often substantial, side effects. For these reasons, there is a prevalent interest in patients with IBD in pursuing nonconventional avenues of therapy for both symptoms and disease control.
Given these considerations, there has been an increasing appreciation of the importance in understanding the complexities of the interactions between the human host immune system and its resident gastrointestinal luminal microbial population. Current models for the pathogenesis of IBD have demonstrated evidence for a disturbance in this equilibrium, resulting from either an aberrant host immune response to usual luminal microbiota, an exaggerated physiologic immune phenomenon to an abnormal population of microbes in the gastrointestinal tract, or a combination of both.
Probiotic organisms, which are defined as “live microorganisms which when administered in adequate amounts confer a health benefit on the host,” have been used in attempts to take advantage of this relationship to treat various gastrointestinal diseases, including acute traveler’s diarrhea, infectious diarrhea, and irritable bowel syndrome ; in the prevention of infantile necrotizing enterocolitis in neonates ; and to alter gut microflora in patients with minimal hepatic encephalopathy to prevent the growth of ammonia-producing bacteria in patients with hepatic cirrhosis.
Although the spectrum of diseases of the intestines is broad, this article focuses on the actual and potential roles of the probiotic organism in patients with Crohn disease and ulcerative colitis. To begin with, the basic aspects of the enteric microorganism are reviewed, as they pertain to the development of IBD, and they are compared and contrasted with the host-specific responses to probiotic administration, in both the IBD and non-IBD host. Then the available clinical literature is reviewed, focusing on the use of probiotics in Crohn disease and ulcerative colitis, examining the roles of the probiotic organism in induction of remission as maintenance therapy and in the surgical patient with IBD. Finally, future roles of probiotic therapy in the realm of IBD are proposed.
Gastrointestinal microbes and IBD
The human gastrointestinal tract provides a suitable environment to a diverse microbial population, with more than 400 to 500 different species of bacteria currently identified. The primary introduction of this array to the host most likely occurs in close relationship to labor and delivery of the neonate, with Lactobacillus and Prevotella spp predominating within the vaginal canal at the time of delivery. Once established, this microbial population maybe susceptible to changes in diet, age of the host, disease states, and lifestyle. Nevertheless, the specific changes that are effected in the microbial population by each of these variables, however, remain to be fully elucidated.
The importance of the microbe in IBD is demonstrated by clinical and histologic improvement in fecal diversion in patients with Crohn disease ; recurrence of symptoms and inflammation with re-exposure of the terminal ileum to luminal contents is the rule. Several studies have magnified the importance of enteral microorganisms in the development and maintenance of IBD. Analysis of mucosal-associated and fecal bacteria reveals diminished commensal microbial diversity (decreased numbers of Faecalibacterium prausnitzii and Lactobacillus ), an increased number of mucosal-associated microorganisms, and an orientation toward phylogenetic groups of proinflammatory microbes, such as Escherichia coli, in patients with active inflammation in Crohn disease and ulcerative colitis. It remains to be seen whether this dysbiotic environment is a prerequisite for developing IBD or is a result of it and which bacteria are specifically involved.
To date, the identification of one or more causative organisms in IBD has not been found. Although early association of Mycobacterium avium subsp paratuberculosis with spontaneous granulomatous enterocolitis provided a potential causative organism for IBD, its specific role in IBD remains to be determined. Similarly, although there is a higher prevalence of Yersinia and Camplyobacter species in patients with Crohn disease compared with controls, their roles too remain to be investigated. Particular attention has been paid to the presence of pathogenic adherent-invasive E coli , which has been identified in 36.4% of patients with Crohn disease versus 6% of controls. The reasons for this difference most likely represent a combination of host characteristics (ie, Paneth cell dysfunction; genetic mutations in NOD2, ATG16L1 , or IRGM; and abnormal ileal expression of carcinoembryonic antigen-related cell adhesion molecule 6) and microbial properties (type 1 pili variants and increased TNF-α and IFN-γ secretion). The specific relationships between the host immune system and microbiota in IBD are beyond the scope of this article and are reviewed elsewhere.
The microbe and IBD recall points
- •
400–500 Species of bacteria reside within human gastrointestinal tract.
- •
The human host is colonized at birth with bacteria from caregivers. The majority of the bacteria are constant whereas a small proportion can change with time and circumstance (age, disease, lifestyle, and so forth).
- •
IBD involves dysbiosis and/or abnormal immune host response to the dysbiosis.
Probiotics
The alteration of the type or number of bacteria within the gastrointestinal tract in states of disease may have various effects on the host. Thus, the potential to manipulate enteric flora for positive therapeutic purposes is an attractive approach for patients with IBD. Probiotic organisms have had a history of both local and systemic beneficial effects. Box 1 summarizes the multiple beneficial effects, relative to IBD, which probiotic bacteria exert on the gastrointestinal tract. Examples of these were investigated in a pilot study, which examined the effects of various Lactobacilli species on various mediators of inflammation and found that the intestinal Lactobacilli of elderly persons are tightly associated with increased serum white blood cell count ( Lactobacillus reuteri ), reduced blood glucose levels ( L fermentum ), and oxidized low-density lipoprotein content (various Lactobacilli ). In another study, one specific probiotic mixture, VSL3, was found to enhance the anti-inflammatory cytokine pathway via induction of mucosal-associated CD425 + and CD4 + LAP cells and reduce the level of proinflammatory cytokines, including TNF-α, interleukin 1β, and interferon γ.
| Host Immune Response Modulation | Epithelial Barrier Function Modulation | Antimicrobial Effects |
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Not all probiotics have similar mechanisms of action and even those with proved efficacy in IBD may exhibit only a few of the beneficial mechanisms outlined in Box 1 . Nevertheless, the ability of probiotics to modulate the microbial-intestinal–immune cascade, even on a minor scale, provides a rational basis for their use in patients with IBD.
Probiotics recall points
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Probiotics are microorganisms, which provide a benefit to the host.
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Probiotics have been shown to have both local and systemic effects on the host.
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Therapeutically successful probiotics have a predominantly anti-inflammatory effect.
Probiotics in the treatment of inflammatory bowel disease
Ulcerative Colitis
Induction of remission
Currently, the data to support clear and consistent clinical benefits in inducing remission in patients with active ulcerative colitis are encouraging, although conflicting data exist ( Table 1 ). The data for probiotics in the induction and maintenance of ulcerative colitis are summarized in Table 1 .
| First Author, Year | Design Duration | Group (dose/d) | Concomitant Therapy | Results | |
|---|---|---|---|---|---|
| Probiotic | Comparator | ||||
| Ulcerative colitis: induction of remission | |||||
| Rembacken et al, 1999 | DB, R, C 1 y | E coli Nissle 1917 (1 × 10 11 CFU) n = 57 | Mesalamine (2.4 g) n = 59 | Prednisolone or hydrocortisone enemas | As effective as mesalamine at attaining remission |
| Borody et al, 2003 | Case reports 2–13 y | Fecal enema n = 6 | None | None | 100% Remission |
| Guslandi et al, 2003 | O 4 wk | S boulardii (750 mg) n = 25 | None | Mesalamine | Reduction in UCDAI scores |
| Kato et al, 2004 | DB, R, C 12 wk | Bifidobacterium -fermented milk (100 mL) n = 10 | Placebo n = 10 | Sulfasalazine and mesalamine | Reduction in UCDAI ( P <.05) |
| Tursi et al, 2004 | R, O 8 wk | Balsalazide (2.25 g) and VSL3 (1 × 10 11 CFU) n = 30 | Balsalazide (4.5 g) n = 30 Mesalamine (2.4 g) n = 28 | None | Balsalazide and VSL3 outperformed the 2 comparator groups (symptoms assessment, endoscopic appearance, and histologic evaluation) |
| Bibiloni et al, 2005 | O 6 wk | VSL3 (3.6 × 10 9 CFU) n = 32 | None | Mesalamine, steroids, or immunosuppressants | Remission (UCDAI ≤2) achieved in 18, response (UCDAI ≥3) achieved in 8 whereas 3 did not have a response and 3 others worsened |
| Furrie et al, 2005 | DB, R, C 1 mo | B longum and Synergy 1 n = 8 | Placebo n = 8 | Mesalamine, immunosuppressants, steroids | NSD re sigmoidoscopy scores |
| Tsuda et al, 2007 | O 4 wk | BIO-THREE n = 20 | None | Mesalamine or 6-mercaptopurine | Remission achieved in 9/20 patients, no response in 8/20, and worsening in 1/20 |
| Miele et al, 2009 | DR, R, C 8 wk | VSL3 (weight-based dosing) n = 19 | Placebo n = 10 | Corticosteroids, immunsuppresants, mesalamine | Remission achieved in 92% of probiotic-treated patients |
| Huynh et al, 2009 | O | VSL3 (weight-based dosing) n = 18 | None | Patients were failing standard ulcerative colitis induction therapy | Remission achieved in 56% of probiotic treated-patients |
| Sood et al, 2009 | DB, R, C 12 wk | VSL3 (3.6 × 10 9 CFU) n = 77 | Placebo n = 70 | Oral mesalamine and immunosuppressants | 43% Achieved remission in probiotic group ( P <.001) |
| Tursi et al, 2010 | DB, R, C 8 wk | VSL3 (3.6 × 10 9 CFU) n = 71 | Placebo n = 73 | 5-ASA or immunosuppressants | Remission achieved in 48% for the probiotic group |
| Ishikawa et al, 2011 | R, C 1 y | B breve strain Yakult (3 × 10 9 CFU) and galacto-oligosaccharide (5.5 g) n = 21 | Placebo n = 20 | Salazosulfapyridine, mesalamine, steroids | Endoscopic score was significantly reduced in probiotic group compared with baseline ( P <.05) |
| Ulcerative colitis: maintenance of remission | |||||
| Kruis et al, 1997 | DB, DD, R 3 mo | E coli Nissle 1917 (CFU >10 10 ) n = 50 | Mesalazine (1.6 g) n = 53 | None | NSD for relapse rates, CAI scores, global assessment |
| Rembacken et al, 1999 | DB, R, C 1 y | E coli Nissle 1917 (CFU > 10 10 ) n = 39 | Mesalamine (1.6 g) n = 44 | Prednisolone (tapered to nil over 4 mo) | NSD |
| Venturi et al, 1999 | O 1 y | VSL3 (1 × 10 12 CFU) n = 20 | None | None | 75% Maintained clinical and endoscopic remission |
| Ishikawa et al, 2003 | R, C 1 y | BFM n = 11 | Placebo n = 10 | Salazosulfapyridine, mesalazine, and steroids | Reduced exacerbation of symptoms ( P <.01) |
| Cui et al, 2004 | DB, C 8 mo | BIFICO (1.26 g) (1 × 10 7 CFU) n = 15 | Placebo n = 15 | Sulphasalazine and glucocorticoids | P <.01 Where 93% of placebo relapsed vs 20% of active treatment group |
| Kruis et al, 2004 | DB, R, C 1 y | E coli Nissle 1917 (2.5–25 × 10 9 CFU) n = 162 | Mesalamine (1.6 g) n = 165 | None | As effective as mesalamine at maintaining remission (SE, P = .003) |
| Zocco et al, 2006 | O 1 y | L rhamnosus GG (1.8 × 10 10 CFU) n = 65 | Mesalazine (2.4 g) n = 60 Mesalazine and LGG n = 62 | None | NSD in relapse rates at 12 months; but probiotic more effective than mesalazine for prolonging duration of remission ( P <.05) |
| Wildt et al, 2011 | DB, R, C 1 y | L acidophilus La-5 and B animalis and Lactis BB n = 20 | Placebo n = 12 | None | Insignificant number of patients achieved remission ( P = .37) |
Recently, Sood and colleagues from India conducted a randomized, multicenter, double-blind, controlled trial evaluating twice-daily probiotic mixture, VSL3 (3.6 × 10 9 colony-forming units [CFU]), in inducing remission in 77 patients with mild to moderately severe ulcerative colitis versus 70 patients given placebo. The primary endpoint was a 50% decrease in ulcerative colitis disease activity index (UCDAI) score at 6 weeks, with final evaluation at 12 weeks. The percentage of patients achieving the primary endpoint was higher in the VSL3 group than the placebo group, both at week 6 (32.5% vs 10%, P = .001) and at week 12 (42.9% vs 15.7%, P <.001).
In a follow-up study, of similar design, Tursi and colleagues sought to evaluate the utility of VSL3 in the treatment of relapsing-remitting mild to moderate ulcerative colitis in a double-blind, placebo-controlled trial involving 144 patients randomly treated for 8 weeks with VSL3 (3600 billion CFU/d) (71 patients) or with placebo (73 patients). As a secondary endpoint, 31 (47.7%) patients in the VLS3 group and 23 (32.4%) patients in the placebo group had remission induced by the end of 8 weeks, yet this difference did not reach statistical significance.
Given the potential efficacy of VSL3 in patients with ulcerative colitis, the authors examined its effect in 32 patients with active ulcerative colitis in 2005. As an open-label trial, twice-daily dosing of 1800 billion bacteria was administered to patients, who were on concomitant medical therapy (steroids, 5-aminosalicylic acid [5-ASA], 6-mercaptopurine, azathioprine, and antidiarrheal agents) for 6 weeks, evaluating for the presence of probiotic bacteria in tissue samples, as well as UCDAI as an intent-to-treat analysis. This analysis demonstrated that remission was achieved in 53% (n = 18) of patients; response in 24% (n = 8) of patients; no response in 9% (n = 3) of patients; worsening in 9% (n = 3) of patients; and 5% (n = 2) did not have final sigmodmioscopic assessment. This yielded a combined induction of remission/response rate of 77%. Some components of the VSL3 bacteria were identified in 3 patients in remission. No adverse events were identified.
A Japanese study investigated BIO-THREE probiotics (each tablet containing 2 mg of Streptococcus faecalis , 10 mg Clostridium butyricum , and 10 mg Bacillus mesentericus ) in an open-label study of 23 patients with mild to moderate distal ulcerative colitis, which was refractory to medical therapy (oral mesalamine, sulfasalazine, 6-mercaptopurine, and mesalamine enema). For 4 weeks, 9 tablets were administered daily. The UCDAI scores were evaluated and fecal microflora were identified by terminal restriction fragment length polymorphism analysis. Remission was observed in 45% (9/20) of patients; response (decrease in UCDAI ≥3 but final score ≥3) in 10% (2/20); no response in 40% (8/20); and worsening in 5% (1/20). There was an overall increase in fecal bifidobacteria counts.
An early single-center, randomized, double-dummy study investigated induction of remission in 116 patients with ulcerative colitis randomized to either standard mesalazine therapy or E coli Nissle 1917. After a run-in course of tapering prednisolone for moderate to severe disease as well as oral gentamicin for existing microbial floral suppression, no significant differences in induction rates at 4 months were identified (75% and 68% in each group, respectively). Nevertheless, this study was not powered for equivalence.
The use of probiotics in pediatric populations has demonstrated similar encouraging results. For example, an open-label trial using VSL3 twice daily in 18 eligible pediatric patients (ages 3–17) for 8 weeks was completed. Patients were evaluated by the simple clinical colitis activity index and the Mayo ulcerative colitis endoscopic score as well as various serologic and histologic profiling, completed at weeks 0 and 8. This trial demonstrated induction of remission in 56% of subjects (n = 10), response in 6% (n = 1), and no change or worse in 39% of subjects (n = 7). Five patients withdrew due to lack of response to therapy.
Likewise, in a small Italian pediatric trial using VSL3, 29 patients (mean age 9.8 years, range 1.7–16.1 years) with newly diagnosed ulcerative colitis, were randomized to receive VSL3 (weight-based dose, range 450–1800 billion bacteria/d) or placebo. Concomitant steroid induction treatment, consisting of oral methylprednisolone (1 mg/kg/d, maximum 40 mg/d) and oral mesalamine maintenance treatment (50 mg/kg/d), was permitted. The Lichtiger colitis activity index as well as a physician’s global assessment measured disease activity. Follow-up occurred at 0, 6, and 12 months as well as whenever relapse occurred. Remission was achieved in 13 patients (92.8%) in the VSL3 group whereas 4 patients (36.4%) treated with placebo and IBD therapy had successful induction of remission ( P <.001).
A Cochrane review was recently performed to delineate the role of probiotics in the induction of remission in ulcerative colitis. The objectives of this review were to analyze and compare the efficacy of probiotics versus placebo or standard medical treatment (eg, corticosteroids, sulfasalazine, or 5-ASA agents) for the induction of remission in active ulcerative colitis. In addition, secondary outcome evaluation included (1) proportion of patients achieving disease improvement, (2) steroid withdrawal, (3) biochemical markers of inflammation, (4) histology scores, (5) progression to surgery, (6) clinical scores, (7) symptomatic severity (stool frequency orabdominal pain), (8) quality-of-life scores, (9) time to remission/improvement, and (10) withdrawal due to adverse events. From a total of 119 references reviewed, 4 randomized controlled trials met the inclusion criteria whereas 2 were excluded. A formal meta-analysis was not performed due to heterogeneity in probiotic types, methodology, and outcomes. The results of this review showed that none of the studies included demonstrated any meaningful differences in remission induction rates in probiotic-treated cohorts compared with placebo or other comparator groups. The investigators concluded, “Conventional therapy combined with a probiotic does not improve overall remission rates in patients with mild to moderate ulcerative colitis.” With respect to safety concerns, however, one of the studies included showed that there was no statistically significant difference in the incidence of adverse events, between a group treated with probiotics and the placebo group (relative risk [RR] 0.75; 95% CI, 0.3–1.88).
In keeping with the Cochrane review, a meta-analysis performed by Sang and colleagues selected 13 randomized control trials that studied the efficacy of probiotics in the induction and maintenance of remission in ulcerative colitis. Seven of the trials examined induction of remission rates in 219 patients who received probiotics as an auxiliary therapy compared with 180 patients treated with placebo or standard therapy. Again, there was no statistically significant difference in the overall induction of remission rates between the 2 groups, although the investigators concluded that the results were subject to heterogeneous bias. Furthermore, heterogeneity was also identified in a subgroup analysis with respect to probiotic type and disease severity (mild, middle, or active disease) and for treatment of less than 12 months in duration.
Optimizing the effects of probiotic organisms, Furrie and colleagues sought to evaluate the effect of the combination of probiotics and prebiotics (synbiotics) containing Bifidobacterium longum and Synergy 1 (6 g of prebiotic fructo-oligosaccharide/inulin mix) in a double-blind randomized controlled trial using 18 patients (N = 9, study group) with active ulcerative colitis for a period of 1 month. The patients’ standard therapy at the time of entry into the study remained unchanged (steroids and/or immunosuppressants and/or 5-ASA). The results demonstrated a systemic anti-inflammatory response with a decrease in serum TNF-α ( P = .018), interleukin 1 ( P = .023), and mRNA levels of defensins 2 and 4. Nevertheless there were no significant differences in sigmoidoscopy or clinical disease activity indices.
Similarly, Ishikawa and colleagues in a randomized controlled trial evaluated 41 patients with mild to moderate ulcerative colitis administered synbiotics. This trial used a B breve strain; Yakult (9 × 10 9 CFU/g) was administered in divided doses 3 times daily in combination with galacto-oligogosaccharide (5.5 g once daily, for 1 year) in comparison to placebo. Both groups were allowed standard medical therapy. Endoscopic evaluation of disease activity was performed at 1 year as well as evaluation of a colonic lavage solution for myeloperoxidase activity. Mean endoscopic disease activity score of patients receiving synbiotics decreased significantly ( P <.05) relative to placebo. Furthermore, myeloperoxidase activity in the treatment group significantly decreased ( P <.05).
In summary, the existing evidence does not support the broad use of probiotics in the induction of remission in patients with active ulcerative colitis. Not all probiotics are the same and randomized controlled trials of each individual probiotic preparation are required to determine its efficacy. Nevertheless, emerging data from 2 double-blind randomized controlled trials and 3 open-label trials with the probiotic preparation VSL3 are supportive of its efficacy in the induction of remission of ulcerative colitis. In addition, a single trial with E coli Nissle 1917 suggests it may be as effective as mesalamine. These trials, however, were underpowered to be statistically confirmatory.
Probiotics and ulcerative colitis: induction of remission recall points
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Currently, there are insufficient data to support the broad use of probiotics in inducing remission in patients with acute ulcerative colitis.
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Nevertheless, underpowered randomized controlled trials with the probiotic preparation VSL3 have demonstrated its efficacy over placebo in the induction of remission, and E coli Nissle 1917 may be as effective as mesalamine.
Maintenance of remission
Kruis and colleagues first examined remission maintenance in ulcerative colitis in 120 patients who previously achieved a mesalamine-induced remission. These patients were subsequently randomized to 1600 mg of mesalamine or E coli Nissle 1917. Similar efficacy was identified in both groups at 3 months, with 89% and 84% of the respective groups in remission. Subsequently, the same investigators completed a multicenter, randomized noninferiority trial comparing mesalamine (1600 mg daily) versus E coli Nissle 1917 in 327 patients over a 12-month period. E coli Nissle was found statistically noninferior ( P = .013), with relapse rates of 34% in the mesalamine group and 36% in the E coli Nissle 1917 group.
A prospective, noninferiority trial by Rembacken found similar results in a study comparing oral mesalamine (1600 mg daily) to E coli Nissle 1917 in 116 patients. After 12 months, 25% and 26% of the respective groups were found in remission. Furthermore, the rates of remission were found similar to known rates of remission achieved with placebo.
In a randomized, placebo-controlled trial in 21 patients, Ishikawa and colleagues examined the effect of fermented milk, which contained live Bifidobacteria and L acidophilus in patients with quiescent ulcerative colitis. Clinical remission was sustained over 1 year in 73% of patients taking the probiotic versus 10% in the placebo arm ( P = .0184). No endoscopic differences, however, were noted.
Shanahan and von Wright compared L salivarius subsp salivarius UCC118, B infatis 35,624 (1 × 10 9 CFU/d) or placebo for 1 year in patients with ulcerative colitis in clinical remission (n = 157 patients). There was no significant difference in time to relapse when placebo was compared with either treatment arm. Nevertheless, the probiotics demonstrated an anti-inflammatory effect.
Another prospective randomized trial by Zocco and colleagues compared Lactobacillus GG (1.8 × 10 9 viable bacteria/d) to delayed-released mesalamine (2400 mg daily) or both in 187 patients with ulcerative colitis. Based on UCDAI scores, relapse rates were similar at 6 months ( P = .44) and at 12 months ( P = .77) in all 3 groups, Lactobacillus GG did prolong relapse-free time more effectively than mesalamine ( P <.05).
A recent trial out of Denmark sought to investigate the clinical effects of a combination of L acidophilus La-5 and B animalis subsp lactis BB (Probio-Tec AB-25) in maintenance of remission in a randomized double-blind placebo-controlled trial in 32 patients with ulcerative colitis. These patients included those with left-sided ulcerative colitis in remission, including proctitis. All patients had at least one relapse within the year preceding the trial. Twenty patients received Probio-Tec AB-25 whereas 12 received placebo. After 1 year of treatment, 5 patients (25%) in the Priobio-Tec AB-25 group and 1 patient (8%) in the placebo group were in remission ( P = .37). The median times to relapse were 125.5 days (11–391 days) and 104 days (28–369 days), respectively ( P = .683). Although encouraging, the study was of small size and did not reach statistical significance.
A Cochrane database review in 2011 was performed by Naidoo and colleagues to evaluate the role of probiotics in the maintenance of remission in patients with ulcerative colitis. Four studies (n = 587) with study duration from 3 to 12 months were included. There were no statistically significant differences between the probiotic-treated and mesalamine-treated patients (40.1% vs 34.1%, respectively; 3 studies; 555 patients; odds ratio [OR] 1.33; 95% CI, 0.94–1.90) and in adverse events (26% vs 24%, respectively; 2 studies; 430 patients; OR 1.21; 95% CI, 0.80–1.84). The investigators identified risk of bias due to lack of blinding and incomplete outcome data (2 studies), and unclear methods of allocation in all 4 studies.
In summary, there is adequately powered randomized controlled trial evidence to support that E coli Nissle 1917 is as effective as mesalamine in maintaining remission in patients with mild to moderate ulcerative colitis. Not all probiotics are the same and randomized controlled trials of each individual probiotic preparation are required to determine their efficacy.
Probiotics and ulcerative colitis: maintenance of remission recall point
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E coli Nissle 1917 is as effective as mesalamine in maintaining remission in patients with mild to moderate ulcerative colitis.
Pouchitis
In patients with ulcerative colitis in whom medical management fails, total colectomy and construction of an ileal pouch–anal anastomosis (IPAA) is the surgical approach of choice ( Table 2 ). More than half of these patients develop inflammation of the pouch, leading to pouchitis, with symptoms of pain, diarrhea, and often fecal incontinence. A summary of the clinical trials that examined probiotics in the induction and maintenance of remission in pouchitis is in Table 2 .
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The Role of Probiotics in the Prevention and Treatment of Antibiotic-Associated Diarrhea and Clostridium Difficile Colitis
Probiotic Bacteria in the Prevention and the Treatment of Inflammatory Bowel Disease
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