Irritable bowel syndrome (IBS) and chronic constipation (CC) are common problems worldwide and are associated with significant impact on activities of daily living and quality of life. Recent interest, in IBS in particular, has focused on the potential roles of the microbiota and its interaction with the host’s immune system. Recently, high-quality clinical trials have been performed on prebiotics and probiotics in IBS or CC. Although strategies that seek to modify the microbiota, such as the use of probiotics, offer much promise in IBS and CC, more high-quality trials and, studies of longer duration are required.
Key Points
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Recent research findings have revealed a potential role for the microbiota and the host immune response in irritable bowel syndrome.
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The primacy of a disturbed microbiota or an altered immune response in the pathogenesis of irritable bowel syndrome remains to be defined.
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Meta-analyses suggest that probiotics, as a therapeutic category, have a beneficial effect in irritable bowel syndrome.
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Studies of specific strains indicate that although some probiotics may ameliorate individual IBS symptoms, few have a global benefit.
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More appropriately powered studies of longer duration are required on the efficacy of probiotics in irritable bowel syndrome.
Introduction
The term functional bowel disorder refers to a group of conditions that feature a variety of gastrointestinal symptoms, such as abdominal pain or discomfort, diarrhea, constipation, bloating, and distension, for which there is no obvious organic cause. Being thus based on a process of exclusion rather than on a diagnostic biomarker, those entities included within this umbrella term are, by default, less circumscribed than more traditional diagnostic entities. Consequently, patient groups encompassed within this term are heterogeneous, and their symptoms are likely to represent the impact of various, as yet undefined, causes. The combination of population heterogeneity, undefined pathophysiology, and diagnostic imprecision is a recipe for therapeutic failure and, undoubtedly, accounts, in large part, for the challenges that these disorders have presented to those who seek to develop new therapies. If therapy cannot be targeted on a well-characterized population whose problem is based on a disease process that is addressed by the new therapeutic entity, expectations for success must be low.
Some progress has been made, however, and concerted efforts to provide reproducible clinical definitions of subgroups within functional bowel disorders have produced more coherent populations. The most widely accepted and best validated of such approaches, the Rome process (now about to embark on its fourth iteration), has provided the clinical investigator with a classification of functional bowel disorders based on presenting symptoms: irritable bowel syndrome (IBS), functional (often referred to as chronic ) constipation, functional diarrhea, and functional bloating.
Foremost is IBS, a common disorder worldwide usually defined by the coexistence of abdominal pain or discomfort and an alteration in bowel habit. IBS may lead to impaired social and personal function and can diminish quality of life to a degree usually associated with major organic diseases such as hypertension and diabetes. IBS continues to represent a significant therapeutic challenge; currently available therapies provide symptomatic relief, at best, and none have been found to alter the natural history of the disorder. According to Rome III, IBS is subtyped based on predominant bowel habit as diarrhea predominant, constipation predominant (IBS-C) and mixed type (formerly referred to as alternating IBS).
Functional constipation represents the other well-characterized (and studied) functional disorder. Like IBS, its definition requires that symptoms (straining, lumpy or hard stools, sensation of incomplete evacuation, sensation of anorectal obstruction/blockage, use of manual maneuvers to facilitate defecation or infrequent defecation [<3 defecations/wk]) be present at a certain frequency (more than 25% of the time) and for a minimum length of time (3 months) with symptom onset at least 6 months earlier. At times, the separation of functional (or chronic) constipation (CC) from IBS-C may pose a challenge, and debate continues as to whether these are overlapping disorders or part of a continuum. The prominence of pain in IBS traditionally is used as a differentiating factor; assigning the appropriate category to the patient with constipation, abdominal discomfort, and bloating is more challenging.
Drug discovery pathways and clinical trialists tend to treat these entities, IBS-C and CC, separately; accordingly, they will be addressed separately in this article. Because there have been few studies of probiotics in the other functional disorders (eg, functional bloating), these are discussed en passant in the context of IBS.
Introduction
The term functional bowel disorder refers to a group of conditions that feature a variety of gastrointestinal symptoms, such as abdominal pain or discomfort, diarrhea, constipation, bloating, and distension, for which there is no obvious organic cause. Being thus based on a process of exclusion rather than on a diagnostic biomarker, those entities included within this umbrella term are, by default, less circumscribed than more traditional diagnostic entities. Consequently, patient groups encompassed within this term are heterogeneous, and their symptoms are likely to represent the impact of various, as yet undefined, causes. The combination of population heterogeneity, undefined pathophysiology, and diagnostic imprecision is a recipe for therapeutic failure and, undoubtedly, accounts, in large part, for the challenges that these disorders have presented to those who seek to develop new therapies. If therapy cannot be targeted on a well-characterized population whose problem is based on a disease process that is addressed by the new therapeutic entity, expectations for success must be low.
Some progress has been made, however, and concerted efforts to provide reproducible clinical definitions of subgroups within functional bowel disorders have produced more coherent populations. The most widely accepted and best validated of such approaches, the Rome process (now about to embark on its fourth iteration), has provided the clinical investigator with a classification of functional bowel disorders based on presenting symptoms: irritable bowel syndrome (IBS), functional (often referred to as chronic ) constipation, functional diarrhea, and functional bloating.
Foremost is IBS, a common disorder worldwide usually defined by the coexistence of abdominal pain or discomfort and an alteration in bowel habit. IBS may lead to impaired social and personal function and can diminish quality of life to a degree usually associated with major organic diseases such as hypertension and diabetes. IBS continues to represent a significant therapeutic challenge; currently available therapies provide symptomatic relief, at best, and none have been found to alter the natural history of the disorder. According to Rome III, IBS is subtyped based on predominant bowel habit as diarrhea predominant, constipation predominant (IBS-C) and mixed type (formerly referred to as alternating IBS).
Functional constipation represents the other well-characterized (and studied) functional disorder. Like IBS, its definition requires that symptoms (straining, lumpy or hard stools, sensation of incomplete evacuation, sensation of anorectal obstruction/blockage, use of manual maneuvers to facilitate defecation or infrequent defecation [<3 defecations/wk]) be present at a certain frequency (more than 25% of the time) and for a minimum length of time (3 months) with symptom onset at least 6 months earlier. At times, the separation of functional (or chronic) constipation (CC) from IBS-C may pose a challenge, and debate continues as to whether these are overlapping disorders or part of a continuum. The prominence of pain in IBS traditionally is used as a differentiating factor; assigning the appropriate category to the patient with constipation, abdominal discomfort, and bloating is more challenging.
Drug discovery pathways and clinical trialists tend to treat these entities, IBS-C and CC, separately; accordingly, they will be addressed separately in this article. Because there have been few studies of probiotics in the other functional disorders (eg, functional bloating), these are discussed en passant in the context of IBS.
A scientific basis for the use of probiotics in functional bowel disorders
Irritable Bowel Syndrome
The precise pathophysiology of IBS remains to be elucidated. For some time, pathophysiologic and pharmacologic research efforts focused on 2 principal targets: dysmotility and altered visceral sensation. Although there is no doubt that IBS is associated with several disturbances in motor function, not only in the colon, but throughout the gastrointestinal tract, and that visceral hypersensitivity is a common phenomenon in IBS, it seems unlikely that they represent fundamental pathophysiologic mechanisms.
More recently, roles for enteric infection and intestinal inflammation have been proposed. Thus, both retrospective and prospective studies have documented the new onset of IBS after bacteriologically confirmed bacterial gastroenteritis ; postinfectious irritable bowel syndrome (PI-IBS) is not a transient entity but may cause long-lasting symptoms. Furthermore, several risk factors for the development of PI-IBS have been identified. Although results have not always been consistent, others have described low-grade mucosal inflammation and immune activation in IBS in general as well as evidence of microbe-host engagement.
The enteric flora has also been implicated in the pathogenesis of non–PI-IBS. First came the suggestion that some patients with IBS may harbor bacterial overgrowth and that their symptoms may be ameliorated by its eradication. However, this proposal has met with considerable skepticism, and several subsequent studies have failed to confirm the original findings. More recently, the focus has shifted to the colonic microbiota, and several studies using high-throughput sequencing approaches have described differences in the microbiota in IBS. These observations, coupled with our ever-increasing understanding of gut flora-mucosa interactions, including in IBS, and the existence of a significant body of basic research to support a role for inflammatory and immune processes in contributing to enteric neuromuscular dysfunction, have resulted in microbiota-host interactions gaining considerable credibility in explaining the pathophysiology of IBS and the precipitation of its symptoms.
Why use probiotics in IBS?
Probiotics, defined as live or attenuated bacteria or bacterial products that confer a significant health benefit to the host, have the potential to provide a clinical tool to explore interactions between the resident flora, the intestinal epithelium, and the gut- or mucosa-associated lymphoid tissue. There are several reasons why these agents might, in theory, prove therapeutically beneficial in IBS.
Antibacterial and antiviral effects
Many probiotic organisms exert antibacterial and antiviral effects and could, thereby, prevent or modify the course of postinfective IBS. Probiotics have been found to be beneficial in the prevention of human diarrheal conditions, such as toddlers’ diarrhea and antibiotic-associated diarrhea, including that related to Clostridium difficile . These effects could be especially relevant to postinfectious IBS. Although probiotics have not been evaluated in the context of postinfectious IBS, the ability of probiotic preparations to influence the outcome of bacterial infections, such as C difficile colitis, and viral infections, such as rotavirus diarrhea, and the experimental demonstration of bacteriocidal, toxin-neutralizing, and antiviral effects for specific probiotic strains, suggest that probiotics may have a role in the prevention or treatment of postinfectious IBS.
Anti-inflammatory effects
IBS may also be associated with inflammation or immune activation in the absence of an infectious trigger. That inflammation could lead to altered enteric nerve or muscle function had been amply shown in the past in such disorders as Chagas’ disease and postviral gastroparesis. Furthermore, IBS-type symptoms also have been associated with inflammatory bowel disease and celiac disease, even when in apparent remission. Coupled with the aforementioned data to suggest activation of mast cells and lymphocytes in the colonic mucosa and elevated proinflammatory cytokine levels in the systemic circulation, a plausible hypothesis has emerged to suggest a role for immune dysfunction or low-grade inflammation in IBS. Caution must be exercised, however, as results regarding mast cell and lymphocyte numbers have been variable ; immune dysfunction associated with a disrupted intestinal barrier may be more universally relevant to IBS. Alterations in systemic cytokines also have not been documented consistently, and the impact of central factors, such as stress, must also be borne in mind before attributing a causal role to cytokines.
Laboratory experiments have repeatedly found the anti-inflammatory effects of certain probiotics. For example, oral administration of a Bifidobacterium exerted a profound anti-inflammatory effect in the interleukin (IL)-10 knock-out mouse, a potent model of inflammatory bowel disease that was associated with a suppression of the proinflammatory cytokines interferon-γ, tumor necrosis factor-α, and IL-12, while preserving activity of the anti-inflammatory cytokine transforming growth factor-β. Others have found similar effects for the probiotic cocktail VSL#3 in another animal model of colitis; in this instance, the anti-inflammatory effect was evident with bacterial DNA alone. In clinical practice, probiotics have been found to prevent the development of pouchitis and reduce the relapse rate of this condition after successful antibiotic treatment. By reducing mucosal inflammation, probiotics could decrease immune-mediated activation of enteric motor and sensory neurons and modify neural traffic between the gut and the central nervous system. There is some preliminary evidence that specific probiotics can diminish visceral hypersensitivity in animal models, whereas others can reverse changes in intestinal muscle function induced by inflammation consequent on infection of an animal model with Trichinella spiralis . Furthermore, several probiotics have been found to restore intestinal barrier function in various animal models.
Evidence of immunologic effects in vivo in humans is limited; the most complete data coming from studies on Bifidobacterium infantis 35624, which found not only that this probiotic engaged with dendritic cells but that its consumption led to an augmentation of levels of the anti-inflammatory cytokine IL-10 in the systemic circulation in healthy volunteers, indicating that this particular strain is capable of exerting immunoregulatory effects in man. These findings are of particular relevance to IBS because this same probiotic has been found to ameliorate IBS symptoms in 2 randomized, controlled clinical trials.
Altering the composition of the gut flora, effects on luminal contents
Changes in the composition of the microbiota as a consequence of the administration of probiotics could, given the various and important metabolic functions of the microbiota, such as fermentation, bile salt deconjugation, and mucus degradation, alter the volume or composition of colonic gas, influence stool consistency, or increase intestinal mucus secretion; effects that could influence intestinal handling of its contents and thus modulate such symptoms as constipation and diarrhea.
Effects on gut flora and luminal contents are not mutually exclusive and could also interact with other factors, such as diet, which are known to influence symptom onset in IBS. There is great interest in the role of diet and such dietary constituents as FODMAPS (fermentable, oligo-, di-, mono-saccharides and polyols) and gluten in the genesis of IBS symptomatology. Qualitative changes in the gut flora with a shift toward more gas-producing organisms, could interact with unabsorbed carbohydrates (such as in the patient with lactase deficiency or fructose intolerance) to increase colonic fermentation, which could not only increase intestinal gas-related symptoms, but also affect function in the proximal gut by promoting gastroesophageal reflux and modifying proximal gastric relaxation. These latter effects could contribute to the well-recognized overlap between IBS and other functional gastrointestinal disorders, such as nonerosive gastroesophageal reflux disease and functional dyspepsia.
Modulation of the gut-brain axis
The concept of the brain-gut axis has been applied widely to IBS, and a variety of experimental and clinical observations have supported the importance of bidirectional interactions between the gut and the brain in the pathophysiology of IBS and the accentuation of its symptoms ; more novel has been the recent suggestion that this model could be extended to incorporate the microbiota: the microbiota-gut-brain axis. Although considerable experimental evidence has been advanced to support this model, its clinical relevance has yet to be defined.
Functional (Chronic) Constipation
The pathophysiology of CC is equally complex and undoubtedly encompasses at least 2 often overlapping entities: slow transit constipation and difficult defecation (also referred to as anismus ). The former is assumed to be based primarily on colonic hypomotility, the latter, on a disturbance in the coordination of the various entities that normally promote a successful act of defecation: the anatomic arrangement of the ano-rectum, the anal sphincters, the pelvic floor musculature, the abdominal muscles and the diaphragm. Although it is evident that symptoms are far-from-perfect predictors of underlying pathophysiology and that these 2 entities commonly coexist, therapeutic strategies have, traditionally, attempted to address one or the other, for example, prokinetics for slow transit constipation and biofeedback for anismus.
Why use probiotics in CC?
Given the impact of fiber and fiber supplements on the colonic microbiota and that the use of prebiotics and probiotics is presumed to be based on their ability to modify this population of microorganisms, one would assume that the role of microbiota-host interactions in a disorder as common as constipation is well defined; however, little is known of either quantitative or qualitative changes in bacteria or other organisms in this condition.
Zoppi and colleagues reported increased numbers of clostridia and bifidobacteria among children with constipation, whereas Khalif and colleagues noted that populations of lactobacilli and bifidobacteria were reduced among their adult subjects. Zoppi and colleagues, while noting a modest symptomatic improvement with the administration of calcium polycarbophil, failed to detect an impact of this fiber analogue on the colonic microbiota. In a more indirect piece of evidence, Celik and colleagues found that a course of vancomycin to constipated patients increased stool volume, frequency, consistency, and ease of defecation.
Recently, an impact of the small intestinal microbiota on constipation has been suggested by studies reporting that the excretion of abnormal amounts of methane after the administration of lactulose as part of a lactulose breath test to detect small intestinal bacterial overgrowth (SIBO) among subjects with IBS is associated with symptoms dominated by constipation (C-IBS). Although the status of SIBO in IBS remains a controversial issue, the association between methane excretion and constipation in IBS has been reasonably consistent. In the study by Attaluri and colleagues, methane production was more prevalent and higher among slow-transit than normal-transit constipation, again, supporting the idea that methane can slow gut transit. It must be stressed that the origin of methane (or for that matter hydrogen) that is excreted in expired air in excess among these and other study subjects with constipation and C-IBS remains to be defined, and some would contend that this signal originates from colonic and not small intestinal methanogens.
These observations notwithstanding, the database on the microbiota and host-microbiota in chronic constipation, apart from the constipated variety of IBS, remains scanty. That modulation of the microbiota might benefit constipated individuals and those with slow-transit constipation, in particular, is suggested by studies in animal models and humans, which indicate the ability of certain probiotic strains to stimulate motility and peristalsis and accelerate gut transit.
Clinical studies of probiotics in functional bowel disorders
Irritable Bowel Syndrome
Up to the year 2000, a small number of studies evaluated the response of IBS to probiotic preparations and, although results between studies were difficult to compare because of differences in study design, probiotic dose, and strain, there was some evidence of symptom improvement. Most studies up to then were small in size and almost certainly underpowered to demonstrate anything other than a striking benefit. Several did not verify bacterial transit and survival by confirmatory stool studies. Many different organisms and strains were used, and dosages varied from as little as 10 5 to as many as 10 13 colony forming units. Furthermore, some used probiotic cocktails rather than single isolates, rendering it difficult to induce what was/were the active moiety/moieties.
Further studies have assessed the response to several well-characterized organisms and have produced discernible trends. Thus, several organisms, such as Lactobacillus GG, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus casei, the probiotic cocktail VSL#3, and Bifidobacterium animalis/lactis , have been found to alleviate individual IBS symptoms, such as bloating, flatulence. and constipation. Only a few products have been found to affect pain and global symptoms in IBS. Results of other studies have been negative.
Among the various species studied, Bifidobacteria have attracted particular attention. Thus, B infantis 35624 was found to be superior to both a Lactobacillus and placebo for each of the cardinal symptoms of IBS (abdominal pain/discomfort, distension/bloating, and difficult defecation) and for a composite score. A larger, 4-week, dose-ranging study of the same Bifidobacterium in more than 360 community-based subjects with IBS confirmed efficacy for this organism in a dose of 10 8 ; again, all of the primary symptoms of IBS were significantly improved, and a global assessment of IBS symptoms at the end of therapy found a greater than 20% therapeutic gain for the effective dose of the probiotic over placebo. Another strain, B lactis DN-173-010A, has shown particular promise among IBS subjects with predominant constipation and prominent bloating ; the clinical effects of this strain on constipation and bloating have been supported by evidence that this bacterium accelerates colon transit and reduces abdominal distension. Yet another bifidobacterial strain, Bifidobacterium bifidum MIMBb75, also proved effective in both symptom relief and improvement in quality of life.
IBS typically is a chronic, relapsing condition, yet most studies of probiotics in this disorder have lasted no more than 408 weeks. Two longer-term studies (of 5 and 6 months’ duration) involving the same probiotic cocktail did show a sustained, albeit modest, response.
Further large, long-term, randomized, controlled trials of this Bifidobacterium and other strains are warranted in IBS, and detailed explorations of their mechanism(s) of action are indicated.
Chronic Constipation
Very few double-blind, placebo-controlled trials of probiotics in acute or chronic constipation (ie, other that in association with irritable bowel syndrome) are available. Among the few positive randomized, controlled trials are those of Koebnick and colleagues, which documented a positive benefit for a probiotic beverage containing L casei Shirota, and of Yang and colleagues, which reported benefits from B.lactis DN-173010, in patients with chronic constipation. In their study using Lactobacillus GG as an adjunct to lactulose, Banaszkiewicz and Szajewska found no additional benefit from the probiotic. Coccorullo and colleagues fed Lactobacillus reuteri (DSM 17938) or placebo to 44 consecutive infants who had a diagnosis of functional constipation and described a significant increase in stool frequency, although not in other constipation-related symptoms. Other studies, which were uncontrolled, or in which the probiotic was combined with some other form of therapy, reported variable benefits for bifidobacteria, lactobacilli, and Propionibacteria and infusions of fecal suspensions. In a systematic review of probiotics in constipation, Chmielewska and Szajewska identified only 5 randomized, controlled trials involving only 377 subjects. The available data suggested a favorable effect of treatment with B lactis DN-173 010, L casei Shirota, and Escherichia coli Nissle 1917 on defecation frequency and stool consistency in adults. In children, L casei rhamnosus Lcr35, but not Lactobacillus rhamnosus GG, showed a beneficial effect. They concluded, however, that pending the arrival of more data, the use of probiotics for the treatment of constipation should be considered investigational. Other, more recent reports have described benefits for probiotics in a variety of formulations ; comparisons among these studies are hampered by differences in study population, outcome measures, and probiotic strain, dose, and formulation.
Related posts:
Clinical Applications of Probiotics in Gastroenterology: Questions and Answers
Probiotics in the Management of Functional Bowel Disorders
Probiotic Bacteria in the Prevention and the Treatment of Inflammatory Bowel Disease
Treatment of Necrotizing Enterocolitis with Probiotics
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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