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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Microbiota as a therapeutic target
  5. Methods
  6. LAB and abdominal pain/discomfort in IBS
  7. LAB and abdominal bloating/distension
  8. LAB and defecatory function
  9. LAB and miscellaneous outcomes
  10. LAB and global outcomes
  11. Summary of clinical trials to date
  12. Mechanisms of therapeutic action of LAB in IBS
  13. Safety and LAB
  14. What do we not know about LAB in the treatment of IBS?
  15. Discussion, conclusion and future directions
  16. Acknowledgements
  17. References
  18. Supporting Information

Background

Irritable bowel syndrome (IBS) is a poorly understood, yet highly prevalent functional gastrointestinal disorder (FGID). The withdrawal, due to adverse events, of a number of pharmacological agents that were approved for the treatment of IBS has left a therapeutic vacuum for patients suffering from the disorder.

Aim

To review, summarise and critically evaluate current knowledge of lactic acid bacteria (LAB) used to treat IBS.

Methods

We assessed a comprehensive range of relevant literature from Pubmed, Medline and online sources based on our definition of LAB which included both typical and atypical species, covering Lactobacilli, Bifidobacteria, Enterococci, Streptococci and Bacilli.

Results

Of the 42 trials evaluated examining the efficacy of LAB in IBS, 34 reported beneficial effects in at least one of the endpoints or symptoms examined, albeit with tremendous variation in both the magnitude of effect and the choice of outcome under consideration. However, numerous concerns have been expressed over deficits of trial design and execution relating to strain selection, optimum dosage, mode of action, safety and long-term tolerability in a disorder that can persist throughout the lifetime of affected individuals.

Conclusions

Progress in the field will require an improved understanding of how the microbiota impacts on health and disease, adequately powered long-term multicentre trials and the embracing of bench to bedside approaches. Recent incremental advances suggest these areas are being addressed and that the future holds much promise for the use of lactic acid bacteria in the treatment of irritable bowel syndrome.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Microbiota as a therapeutic target
  5. Methods
  6. LAB and abdominal pain/discomfort in IBS
  7. LAB and abdominal bloating/distension
  8. LAB and defecatory function
  9. LAB and miscellaneous outcomes
  10. LAB and global outcomes
  11. Summary of clinical trials to date
  12. Mechanisms of therapeutic action of LAB in IBS
  13. Safety and LAB
  14. What do we not know about LAB in the treatment of IBS?
  15. Discussion, conclusion and future directions
  16. Acknowledgements
  17. References
  18. Supporting Information

Irritable bowel syndrome (IBS) is a very common functional gastrointestinal disorder (FGID) which impacts the individual as well as society. At the individual level, patients experience recurrent abdominal pain or discomfort and an alteration in bowel habit along with a range of other features including bloating, distension, flatulence, borborygmi and disturbances in defecatory function.[1] These symptoms range from mild to severe and although the prognosis for IBS is benign, the overall impact can engender serious disruptions in an individual's well being and quality of life. Moreover, for many it is a life-long affliction, marked by unpredictable flares of activity and periods of remission.[2] At the macroeconomic level, given an estimated prevalence in industrialised countries of 10–15% and its recognised association with work absenteeism and presenteeism, IBS, undoubtedly, exerts a significant drain on a nation's economy.[3]

Within the clinical realm, where it is the disorder most frequently encountered by gastroenterologists, the impact is no less disconcerting. Despite the regularity with which the disorder is encountered and the considerable resources deployed towards its treatment, it is still poorly understood and the diagnosis of IBS is commonly based solely on symptom-based criteria such as the ‘Rome Criteria' following the exclusion of organic diseases of the gastrointestinal tract (GIT),[4] the latter an expensive process in itself. Traditionally, pathophysiological insights into the cardinal symptoms of the disorder have centred on the primacy of visceral hypersensitivity in the development of pain or discomfort, and on the impact of gut dysmotility in the development of the underlying disturbance in bowel habit.[5] The more holistic concept of a dysregulated brain-gut axis has integrated these separate theories into a more complex view of IBS aetiology.[6] This theory drew on the principle that bidirectional signalling between the gastrointestinal tract and the brain (regulated at neural, hormonal and immunological levels) is vital for maintaining homeostasis; perturbation of these systems leads to disease states.[7] Despite these advances, IBS is still largely characterised by the lack of a reliable biological marker and inadequate treatment options.[8, 9]

The dearth of successful pharmacological interventions has shifted the gaze of the research community away from the largely failed strategy of drug development based on visceral hypersensitivity and gut dysmotility towards other facets of the brain-gut axis construct.[8] This is an especially pressing goal given the withdrawal of agents that held promise in the treatment of IBS like alosetron, cilansetron and tegaserod,[10] due to adverse events. Thus, in addition to visceral hypersensitivity and dysmotility, altered central nervous system perception of visceral events and psychopathology as well as infection and inflammation are now routinely considered as important pathophysiological factors.[11] The importance of the microbiota within the brain-gut axis construct has also seen the emergence of the bacterial flora as a therapeutic target with the use of antibiotics[12] and probiotics[13, 14] being the primary means of intervention.

In this review, we focus on the rationale behind this approach and provide an overview of the clinical trials that have used lactic acid bacteria (LAB), the most commonly used bacteria in probiotic preparations,[15] to modulate the gut microbiome and in doing so evaluate their effects on the cardinal symptoms of IBS (abdominal pain/discomfort, bloating/distension, alterations in defecatory function), other benefits (flatulence, borborygmi), as well as more global indices. We also explore the mechanistic insights that have been gained from both clinical and preclinical datasets and examine the gaps in knowledge that still exist surrounding this treatment strategy. Finally, the challenges facing researchers and clinicians in this area are evaluated and the obstacles that need to be cleared to allow further progress in this field outlined. For the purposes of this review, our definition of LAB includes both typical and atypical species, covering Lactobacilli, Bifidobacteria, Enterococci and Streptococci and Bacilli.[15] Although we acknowledge that not all the strains discussed are ‘true’ lactic acid bacteria in the strictest sense, it is important to point out that the term itself owes more to a functional classification than to a taxonomical description.[16, 17]

Microbiota as a therapeutic target

  1. Top of page
  2. Summary
  3. Introduction
  4. Microbiota as a therapeutic target
  5. Methods
  6. LAB and abdominal pain/discomfort in IBS
  7. LAB and abdominal bloating/distension
  8. LAB and defecatory function
  9. LAB and miscellaneous outcomes
  10. LAB and global outcomes
  11. Summary of clinical trials to date
  12. Mechanisms of therapeutic action of LAB in IBS
  13. Safety and LAB
  14. What do we not know about LAB in the treatment of IBS?
  15. Discussion, conclusion and future directions
  16. Acknowledgements
  17. References
  18. Supporting Information

Facilitated by the sterile uterine environment, the gastrointestinal tract of a normal foetus lacks a microbial ecology and it is only during and after the birthing process that the complex microbiota starts to develop.[18, 19] Many studies have taken advantage of this fact by using germ free or gnotobiotic animals to elucidate the role of the gut microbiome in health and disease and assign the collective protective, structural and metabolic effects of the commensal bacteria on the intestinal mucosa.[20] There is a delicate balance between these bacteria, the gut epithelium and the gut-associated lymphoid tissue (GALT) which is critical to intestinal homeostasis, essential to health and, conversely, a risk factor for disease.[21, 22] This confers the enteric microbiota with an important role in the modulation of gastrointestinal functions (including motility, secretion, blood flow, intestinal permeability, mucosal immunity and visceral sensations) at a critical terminus of the brain-gut axis.[23]

Recent studies in germ-free animals have highlighted additional behavioural and neurochemical consequences of an absent microbiota[24-26] and led to the modification of the brain-gut axis concept to the ‘microbiome-gut-brain axis’ to acknowledge the critical importance of the microbiota in this construct.[7] These and other findings have also led to calls for a more detailed assessment of the cognitive neurobiology of IBS.[27] Interestingly, based on faecal sample analysis, LAB are thought to have a moderate to high presence in the commensal bacterial load.[19] This provides a strong theoretical rationale for targeting the microbiome, especially with LAB, as a therapeutic strategy in IBS. This is backed up by strong lines of evidence, from both clinical and preclinical sources, including the potential role of infection in the development of the disorder, the link between dysbiosis of the microbiota and the expression of gastrointestinal symptoms (including alterations in stool volume and consistency as well as gas volume and composition), the increasing evidence of a low-grade inflammation in IBS, as well as evidence of qualitative and quantitative changes in the enteric flora in IBS.[7, 28-31]

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Microbiota as a therapeutic target
  5. Methods
  6. LAB and abdominal pain/discomfort in IBS
  7. LAB and abdominal bloating/distension
  8. LAB and defecatory function
  9. LAB and miscellaneous outcomes
  10. LAB and global outcomes
  11. Summary of clinical trials to date
  12. Mechanisms of therapeutic action of LAB in IBS
  13. Safety and LAB
  14. What do we not know about LAB in the treatment of IBS?
  15. Discussion, conclusion and future directions
  16. Acknowledgements
  17. References
  18. Supporting Information

All relevant trials involving the administration of LAB to clinical IBS populations were considered for this review. In addition, we considered preclinical studies in animal models of IBS or those carried out to provide insight into the mechanism of action of LAB. Tables S1–S5 list only trials in clinical populations. We performed and assessed a comprehensive range of relevant literature from Pubmed, Medline and online sources using the following search terms (MeSH/All fields): ‘lactic acid bacteria’, ‘probiotic’, ‘lactobacillus’, ‘bifidobacterium’, ‘streptococcus’, ‘bacillus’, ‘enterococcus’, ‘irritable bowel syndrome’, ‘gastrointestinal’, ‘spastic colon’, ‘abdominal pain/discomfort’, ‘abdominal bloating/distension’, ‘global symptoms’, ‘health-related quality of life’, ‘constipation’, ‘diarrhoea’, ‘defecatory function’, ‘animal models’, ‘motility’, ‘functional’. The bibliographies of relevant studies and systematic reviews were also considered. Studies were excluded if the abstract and title contained sufficient information to render it irrelevant or if the study was only published in abstract form. Foreign language publications were only considered if sufficient study detail was already available in translated form. All potentially eligible studies were discussed in detail by the authors prior to selection for inclusion. Studies were further excluded if the minimum duration of treatment was less than 7 days or if the species administered did not meet our definition of LAB. Trials using both symptom-based criteria and physician's opinion for the diagnosis of IBS were included. Moreover, trials were included if they assessed at least one of the cardinal symptoms of IBS, included an assessment of global symptoms or if the assessment carried out provided potential insights into the mechanism of action of LAB. Studies in both adults and children with IBS were included.

LAB and abdominal pain/discomfort in IBS

  1. Top of page
  2. Summary
  3. Introduction
  4. Microbiota as a therapeutic target
  5. Methods
  6. LAB and abdominal pain/discomfort in IBS
  7. LAB and abdominal bloating/distension
  8. LAB and defecatory function
  9. LAB and miscellaneous outcomes
  10. LAB and global outcomes
  11. Summary of clinical trials to date
  12. Mechanisms of therapeutic action of LAB in IBS
  13. Safety and LAB
  14. What do we not know about LAB in the treatment of IBS?
  15. Discussion, conclusion and future directions
  16. Acknowledgements
  17. References
  18. Supporting Information

A number of clinical trials involving LAB have included improvements in abdominal pain/discomfort as one of their endpoints (primary or secondary) with 20 of the 34 trials assessed reporting at least some benefits over placebo (see Table S1). Of the LAB used, perhaps the most compelling evidence comes from trials involving Bifidobacterium infantis 35624 where both a single centre[32] and a multi-centre trial[33] have demonstrated efficacy in the reduction of abdominal pain/discomfort compared with placebo (36% and 17% improvement respectively over placebo reduction). From a mechanistic point of view, a recent study demonstrated that this probiotic may promote immunoregulatory responses in a selective manner.[34] Of further interest is that a preclinical study using the same LAB found that CRD-induced visceral pain behaviours were significantly reduced in both viscerally normosensitive Sprague–Dawley and viscerally hypersensitive Wistar-Kyoto rat strains.[35] Furthermore, this LAB has been shown to induce an elevation in plasma tryptophan levels, a precursor to serotonin which is a key neurotransmitter within the brain-gut axis, in Sprague–Dawley rats.[36] Recently, B. bifidum MIMBb75 also showed efficacy in reducing pain/discomfort[37] (0.64 point Likert scale improvement over placebo).

A trial with Lactobacillus acidophilus-SDC 2012,2013 also demonstrated a reduction in abdominal pain/discomfort[38] (24% improvement over placebo) as did trials with L. paracasei B2106[39] (8% improvement over prebiotic alone) and L. plantarum 299V[40] (Resolution in 100% of probiotic-treated patients compared to 55% resolution rate following placebo treatment). Data from preclinical trials demonstrated that L. acidophilus can up-regulate μ-opioid and cannabinoid receptors in both colonic epithelial cell lines and in the colonic epithelium of rodents[41] whereas L. paracasei reduced abdominal pain and mucosal inflammation in a preclinical rodent model of visceral hypersensitivity.[42] Interestingly, in children with IBS, L. rhamnosus GG was shown to variably reduce the frequency of pain[43] [28% improvement over placebo for treatment success (no pain)] and both the frequency and severity of pain[44] [32–34% improvement over placebo for treatment success (no pain)], a finding not replicated in an earlier study.[45] A meta-analysis of these three trials concluded that this LAB moderately increased treatment success in children with IBS.[46] However, a number of other trials have also shown no effect of certain Lactobacillus strains on this cardinal symptom including L. casei GG,[47]L. plantarum DSM 9843[48] and L. salivarius UCC4331.[32] This illustrates a key point in LAB trials: findings from one strain cannot be readily extrapolated to another.

A number of multispecies LAB preparations (see Table S1 for list of LAB in mixtures), including VSL #3, have also demonstrated efficacy in the alleviation of abdominal pain.[49-55] In contrast, many multispecies LAB trials, again including VSL #3, have not been able to demonstrate an effect of the LAB on abdominal pain.[56-62]

LAB and abdominal bloating/distension

  1. Top of page
  2. Summary
  3. Introduction
  4. Microbiota as a therapeutic target
  5. Methods
  6. LAB and abdominal pain/discomfort in IBS
  7. LAB and abdominal bloating/distension
  8. LAB and defecatory function
  9. LAB and miscellaneous outcomes
  10. LAB and global outcomes
  11. Summary of clinical trials to date
  12. Mechanisms of therapeutic action of LAB in IBS
  13. Safety and LAB
  14. What do we not know about LAB in the treatment of IBS?
  15. Discussion, conclusion and future directions
  16. Acknowledgements
  17. References
  18. Supporting Information

Benefits over placebo were reported in 12 of the 24 trials assessed using an index of abdominal bloating/distension (see Table S2) as one of their endpoints (primary or secondary). As was the case with abdominal pain, both single centre (29% improvement over placebo) and multi-centre trials (13% improvement over placebo) with B. infantis 35624 showed efficacy in the reduction of bloating.[32, 33] Similarly, B. bifidum MIMBb75 reduced distension/bloating scores in a multicentre trial[37] (0.71 point Likert scale improvement over placebo). Subjects treated with B. lactis DN-173 010 also showed an improvement in distension as indicated by abdominal girth measurements[63] (39% reduction compared to control). L. rhamnosus GG treated subjects has also demonstrated a lower incidence of deterioration in perceived abdominal distention compared with placebo (0% vs. 24% of subjects)[45] although both L. casei GG[47] and L. salivarius UCC4331[32] had no effects on bloating/distension per se.

Of the multispecies LAB trials, VSL #3 has proved effective at reducing bloating in both adults[56] (12 point improvement over placebo on 100 mm VAS) and children[50] (0.55 point improvement over placebo on 0–4 Likert scale) although the benefit in adults was not demonstrated in a subsequent study.[57] Of the other trials of multispecies bacteria where bloating/distension were assessed, two demonstrated positive effects,[54, 64] whereas another showed no improvement on this particular symptom.[58]

LAB and defecatory function

  1. Top of page
  2. Summary
  3. Introduction
  4. Microbiota as a therapeutic target
  5. Methods
  6. LAB and abdominal pain/discomfort in IBS
  7. LAB and abdominal bloating/distension
  8. LAB and defecatory function
  9. LAB and miscellaneous outcomes
  10. LAB and global outcomes
  11. Summary of clinical trials to date
  12. Mechanisms of therapeutic action of LAB in IBS
  13. Safety and LAB
  14. What do we not know about LAB in the treatment of IBS?
  15. Discussion, conclusion and future directions
  16. Acknowledgements
  17. References
  18. Supporting Information

Benefits over placebo were reported in 13 of the 24 trials assessed using an index of defecatory function (see Table S3) as one of their endpoints (primary or secondary). B. infantis 35624 has been shown to improve bowel habit satisfaction (0.29 point improvement over placebo) as well as reduce passage of gas (0.24 point improvement over placebo), incomplete evacuation (0.3 point reduction over placebo) and straining (0.31 point reduction over placebo) using a 6-point Likert scale.[33] Similarly, B. bifidum MIMBb75 treated IBS subjects showed a significant reduction in urgency[37] (0.62 point reduction compared to placebo on a 7-point Likert scale)whereas B. animalis DN 17310 exhibited an ability to increase stool frequency in a subgroup of patients with less than three bowel movements per week.[65] Of the Lactobacilli strains evaluated, L. plantarum 299V showed a trend towards normalisation of stool frequency in constipated patients[40] and L. paracasei B2106 significantly reduced bowel movements[39] (20% improvement over prebiotic alone). However, trials evaluating L. salivarus UCC4331[32] and L. casei GG[47] showed no beneficial effects on bowel movements or urgency respectively. Bacillus coagulans GBI-30 6086 was found to reduce the average number of bowel movements per day.[66] Although VSL #3 had no effect on urgency,[56] it did retard colonic transit[57] (0.56 points over placebo on scintigraphy score) suggesting a possible role in the treatment of diarrhoea-predominant IBS (D-IBS). Of the other multispecies LAB preparations, benefits were found for stool frequency in a C-IBS subgroup[51] (45% increase in stool frequency over placebo at 3 weeks), as well as defecation duration, urgency, straining and feelings of incomplete evacuation[54] although the latter trial was designed to assess the additive benefits of dietary fibre rather than the benefits of probiotics per se.

LAB and miscellaneous outcomes

  1. Top of page
  2. Summary
  3. Introduction
  4. Microbiota as a therapeutic target
  5. Methods
  6. LAB and abdominal pain/discomfort in IBS
  7. LAB and abdominal bloating/distension
  8. LAB and defecatory function
  9. LAB and miscellaneous outcomes
  10. LAB and global outcomes
  11. Summary of clinical trials to date
  12. Mechanisms of therapeutic action of LAB in IBS
  13. Safety and LAB
  14. What do we not know about LAB in the treatment of IBS?
  15. Discussion, conclusion and future directions
  16. Acknowledgements
  17. References
  18. Supporting Information

Benefits over placebo were reported in 17 of the 20 trials assessed using a variety of miscellaneous outcomes (see Table S4) as one of their endpoints (primary or secondary) L. plantarum DSM 9843 was found to rapidly and significantly reduce flatulence[48] (28% reduction over placebo in number of days with abundant gas production) whereas L. plantarum 299V had no effects on colonic fermentation.[67] Although L. casei strain Shirota did show benefits for the passage of gas on a visual analogue scale (VAS), it should be noted that this was not a placebo controlled trial.[68] This trial also reported altered breath hydrogen results following probiotic treatment which the authors assessed as an index of small intestine bacterial overgrowth (SIBO), a controversial area both in terms of the accuracy of the measurement and its relevance to IBS.[28] VSL #3 has demonstrated a capacity to reduce flatulence[57] (9.3 point improvement over placebo on average daily score) although an alternative mixed preparation had no effects on the frequency of gas expulsion.[52] In a trial with a multispecies LAB preparation, borborygmi were less prominent following treatment.[58]

LAB and global outcomes

  1. Top of page
  2. Summary
  3. Introduction
  4. Microbiota as a therapeutic target
  5. Methods
  6. LAB and abdominal pain/discomfort in IBS
  7. LAB and abdominal bloating/distension
  8. LAB and defecatory function
  9. LAB and miscellaneous outcomes
  10. LAB and global outcomes
  11. Summary of clinical trials to date
  12. Mechanisms of therapeutic action of LAB in IBS
  13. Safety and LAB
  14. What do we not know about LAB in the treatment of IBS?
  15. Discussion, conclusion and future directions
  16. Acknowledgements
  17. References
  18. Supporting Information

Benefits over placebo were reported in 16 of the 24 trials assessed using a global index (see Table S5) as one of their endpoints (primary or secondary). Composite symptom severity scores were improved in two trials using B. infantis 35624[32, 33] (40% and 14% improvement over placebo respectively) whereas an unspecified Bifidobacterium proved more efficacious for general symptom relief when administered with acupuncture compared with acupuncture alone.[69]Bifidobacterium bifidum MIMBb75 significantly reduced global IBS symptoms[37] (0.72 point improvement over placebo on 7-point Likert scale) and L. plantarum 299V improved the overall IBS symptom score in one trial[40] (improvement in 95% of subjects on probiotic vs. 15% of subjects on placebo). According to a physicians overall assessment, Streptococcus faecium improved 81% of treated patients.[70] A trial with L. reutari ATCC 55730A showed no improvement on overall IBS symptom severity scores.[71] Of more concern is the recent report of an increased composite symptom score, albeit to a modest degree, following treatment with L. plantarum MF1298[72] (1.09 point increase in IBS sum score over placebo). A significant improvement in the subjective assessment of symptom relief, as well as an improvement in overall symptoms in 90% of patients was reported in two trials with VSL #3[50, 73] although another trial with the same multispecies LAB reported no global symptom relief.[56] A number of trials with multispecies LAB have demonstrated improvements in global composite scores,[49, 58-60, 74] symptom severity scores[53] or patient assessments of efficacy.[75] Equally, a number of trials with multispecies LAB has reported no improvements in global symptom scores[52, 53, 61, 62, 64] or patient reported adequate symptom relief.[62]

Fewer trials have examined quality of life indices, but overall quality of life scores were not significantly improved following treatment with B. infantis 35624 although the health worry subscale did show significance in the earlier of the two trials.[32, 33] A significant gain in quality of life measures was reported for B. bifidum MIMBb75,[37] but not for L. reuteri ATCC[71] or L. salivarius UCC4331.[32] VSL #3 was reported to have a beneficial effect in children according to a family assessment of life disruption.[50] Of the other multispecies LAB trials assessed, five did not report any benefit in quality of life indices.[51, 55, 59, 61, 64]

Summary of clinical trials to date

  1. Top of page
  2. Summary
  3. Introduction
  4. Microbiota as a therapeutic target
  5. Methods
  6. LAB and abdominal pain/discomfort in IBS
  7. LAB and abdominal bloating/distension
  8. LAB and defecatory function
  9. LAB and miscellaneous outcomes
  10. LAB and global outcomes
  11. Summary of clinical trials to date
  12. Mechanisms of therapeutic action of LAB in IBS
  13. Safety and LAB
  14. What do we not know about LAB in the treatment of IBS?
  15. Discussion, conclusion and future directions
  16. Acknowledgements
  17. References
  18. Supporting Information

A cursory examination of the trials discussed above might lead one to the conclusion that LAB preparations have shown a remarkable ability to alleviate the cardinal symptoms of IBS as well as producing improvements across more global assessments of disease severity. However, a number of caveats exist, suggesting that this assessment should be tempered somewhat. The trial designs show tremendous variation ranging from single centre open label studies with small numbers of subjects to the more acceptable and adequately powered multicentre double blind projects (see Tables S1–S5). This point is well illustrated in a recent systematic review which removed 11 of the 16 trials they originally considered for inclusion in the meta-analysis on the basis of a suboptimal study design, citing issues such as inadequate blinding, inadequate trial length, inadequate sample size and/or lack of intention-to-treat analysis.[76] Of the design issues raised, inadequate sample size is the most prevalent; as evidenced by the recent critical analysis of a trial which showed no improvement following treatment with a multispecies LAB preparation.[61, 77] Furthermore, there is a lack of standardisation across trials in the assessment techniques and endpoints used making these trials difficult to compare directly. These factors are further compounded by questions surrounding the delivery vehicle and evaluation of viability[28] along with the high variability in dosing levels across studies,[78] a parameter whose importance was underlined when one of the few studies to examine the issue demonstrated dose-dependant effects.[33]

Nevertheless, despite these deficiencies, it is difficult to ignore the fact that of the 42 trials assessed (see Tables S1–S5) that examine the impact of LAB in IBS, 34 reported beneficial effects in at least one of the endpoints or symptoms examined. It is also open to debate whether the trials that reported no improvement were adequately powered, of appropriate duration, used the correct dose to explore the beneficial effects of the particular LAB preparation under study, or indeed addressed the correct endpoint for that strain/strains. Moreover, all trials must overcome the high placebo response rate that is present in IBS.[8] What is clear from the entire battery of trials is that, when considering the effects of LAB, not all strains or even all doses of the same strain are equal. Nonetheless, despite the limitations outlined, there appears to be an emerging consensus among experts in the field that some LAB are indeed efficacious in IBS, albeit to varying degrees, with a moderate magnitude of benefit and with effects that are limited to the duration of their administration.[46, 76, 79-81]

Mechanisms of therapeutic action of LAB in IBS

  1. Top of page
  2. Summary
  3. Introduction
  4. Microbiota as a therapeutic target
  5. Methods
  6. LAB and abdominal pain/discomfort in IBS
  7. LAB and abdominal bloating/distension
  8. LAB and defecatory function
  9. LAB and miscellaneous outcomes
  10. LAB and global outcomes
  11. Summary of clinical trials to date
  12. Mechanisms of therapeutic action of LAB in IBS
  13. Safety and LAB
  14. What do we not know about LAB in the treatment of IBS?
  15. Discussion, conclusion and future directions
  16. Acknowledgements
  17. References
  18. Supporting Information

Few of the trials assessed (see Tables S1–S5) have made an attempt to unravel the mystery surrounding the mechanism of action of the particular LAB utilised. Nevertheless, a number of theories exist, backed up by varying degrees of evidence. The possibility that the administered LAB restore a disturbed bacterial flora to one resembling that of healthy individuals is partially supported by a study demonstrating exactly such a phenomenon with a multispecies LAB preparation previously shown to be effective in the treatment of IBS.[58, 82] Similarly, alterations in the faecal metabolome following administration of an alternative LAB preparation were linked to its previously demonstrated efficacy.[55, 83] However experts in the field consider such a mechanism, along with the assumption of competition with and exclusion of pathogens, to be overly simplistic and undermined by an incomplete knowledge of what constitutes a ‘normal’ microbiome.[29]

The notion that efficacious LAB strains might exert their beneficial effects through modulation of host immunity is gaining traction, especially in the light of the expanding repertoire of studies supporting a state of low-grade inflammation in IBS.[8] Of the strains evaluated, B. infantis 35624 has been shown to have immunoregulatory potential in addition to showing efficacy in treatment of the disorder.[32, 34] Interestingly, this strain and L. paracasei NCC2461 have been shown to reduce visceral hypersensitivity in preclinical models of IBS,[35, 42] suggesting a potential mechanism by which LAB might influence abdominal pain. In addition, L. acidophilus has been shown to induce the expression of μ-opioid and cannabinoid receptors in human intestinal epithelial cells.[41]

B. infantis 35624 has also been shown to modulate depression-like behaviour and putative peripheral biomarkers of depression in preclinical studies as well as an ability to reverse some early-life stress induced changes in an animal model of IBS.[7, 36, 84] Of further interest is that vagotomy prevented the anxiolytic and antidepressant effects of L. rhamnosus in mice, indicating an ability of LAB to modulate parasympathetic innervation of the gastrointestinal tract.[85] This is a concept also backed up by a study which demonstrated anxiolytic-like effects in rats and beneficial psychological effects in healthy human volunteers following administration of a combination of L. helveticus R0052 and B. longum R0175.[86] Such findings needs to be considered along with the growing realisation that the disturbances noted in IBS might manifest as an impairment in cognitive functioning across a number of domains.[27]

That certain LAB might work by enhancing barrier function and motility has also been considered and is supported primarily by data from Ussing chamber studies. B. breve C50 and its soluble factors have been shown to reduce chloride secretion in human intestinal epithelial cells.[87] Bioactive peptide factors secreted by LAB have been shown to enhance epithelial cell barrier function both in vitro and in vivo.[88] Pre-treatment with a probiotic mixture containing L. helveticus and L. rhamnosus was shown to prevent bacterial translocation and improve intestinal barrier function in rats following chronic psychological stress.[89] Similarly, L. plantarum 299V was shown to inhibit Escherichia coli-induced intestinal permeability.[90]

In reality, the mechanism of action is likely to be multifactorial with particular strains exerting their influence either though one or more of the modes outlined above or via yet unidentified means.[28] It is also interesting to note that although classification of LAB under the umbrella term ‘Probiotic’ requires the use of live organisms, it has been demonstrated in an early trial that this is not an absolute prerequisite for functionality.[91]

Safety and LAB

  1. Top of page
  2. Summary
  3. Introduction
  4. Microbiota as a therapeutic target
  5. Methods
  6. LAB and abdominal pain/discomfort in IBS
  7. LAB and abdominal bloating/distension
  8. LAB and defecatory function
  9. LAB and miscellaneous outcomes
  10. LAB and global outcomes
  11. Summary of clinical trials to date
  12. Mechanisms of therapeutic action of LAB in IBS
  13. Safety and LAB
  14. What do we not know about LAB in the treatment of IBS?
  15. Discussion, conclusion and future directions
  16. Acknowledgements
  17. References
  18. Supporting Information

As the selection of LAB strains for use in clinical trials has largely been based on those with a historical profile free of harmful side effects, it is perhaps not surprising that they have an excellent safety record.[92] Although they are, in the view of the FDA, ‘Generally Regarded as Safe’,[15] that is not to say that there are no safety issues to address with the use of LAB. This is especially pertinent considering the abundance of newly developed single and multispecies options now available that lack the benefit of historical evidence and the scant attention given to interactions that may occur between LAB strains. Given that efficacy is strain- and dose-dependent with multiple potential mechanisms of action that are also likely to be specific to the particular LAB administered, it would seem prudent to consider safety issues at this level as well. Of the trials listed in Tables S1–S5, only one reported anything unfavourable[72] and even this can be considered modest and certainly nontoxic. However, it should also be pointed out that these trials are characterised by the lack of quantifiable data supplied about either tolerability or adverse events.[76] On a broader level, although instances of horizontal gene transfer have been reported between LAB and their enteric counterparts within the context of virulence acquisition or antimicrobial resistance, this is not considered a major safety issue.[93] The major concern with LAB use is the risk of sepsis, based on fears of bacterial translocation across the gut, but this has rarely been reported outside of immune compromised individuals or preterm infants[94] and should not be an obstacle to their use in IBS.

What do we not know about LAB in the treatment of IBS?

  1. Top of page
  2. Summary
  3. Introduction
  4. Microbiota as a therapeutic target
  5. Methods
  6. LAB and abdominal pain/discomfort in IBS
  7. LAB and abdominal bloating/distension
  8. LAB and defecatory function
  9. LAB and miscellaneous outcomes
  10. LAB and global outcomes
  11. Summary of clinical trials to date
  12. Mechanisms of therapeutic action of LAB in IBS
  13. Safety and LAB
  14. What do we not know about LAB in the treatment of IBS?
  15. Discussion, conclusion and future directions
  16. Acknowledgements
  17. References
  18. Supporting Information

Despite the relative success with the use of LAB in IBS, it is difficult to ignore the fact that, in essence, a disorder of unknown origin is being treated by agents with an unknown mechanism of action. This point is worth framing in the context of the many trials discussed which were performed before the brain-gut axis concept became embedded in the literature. Indeed, the rationale for their use outlined above followed rather than preceded the generally positive trends found in those early trials. Even still there are large gaps in knowledge surrounding the use of LAB as a therapeutic strategy in IBS. As outlined above, the mechanism of action is unclear for particular strains that have shown efficacy and, in many cases, there is a disparity between these strains and the ones used to provide mechanistic insight in preclinical studies. Similarly, a strain specific dose response is likely, but remains unknown for the majority of LAB in use. The main exception to this is B. infantis 35624 where evidence of efficacy, potential modes of action and optimum dose is accumulating from both preclinical and clinical datasets.[32, 33, 35, 36, 84] Although there is debate as to whether single strains or mixtures are best,[95] this has not extended to a clear strain selection process for mixed preparations. Neither is it clear whether multiple efficacious strains will, when mixed, maintain their individual profile of activity or be inhibited by the presence of the other strains.[96] The optimum delivery vehicle, which has included milk based formulations, powdered forms and capsules, also needs to be addressed. Of the trials that have demonstrated some efficacy for particular LAB, the patient populations have generally been of mixed subtypes with varying degrees of symptom severity and in diverse phases of disease activity. This criticism should be qualified by the knowledge that IBS is an inherently heterogeneous disorder characterised by temporal instability across the various proposed subtypes and additional refinements will be necessary before subgroup specific treatment assessments can yield meaningful results. Furthermore, the selection of therapeutic agents on the basis of their efficacy against specific symptoms is not a strategy that has met with success in the past.[8] Finally, as pointed out at the outset, IBS is a lifelong affliction and, to date, most trials have been conducted over a 4–12 week timeframe. There is, consequently, a paucity of data pertaining to the long-term effects of LAB in IBS although it is encouraging to note that trials with a multispecies LAB preparation conducted over 6 and 5 month periods showed major benefits for both distension and abdominal pain in conjunction with a stabilisation of the microbiota and were completed without any adverse effects.[58, 59]

Discussion, conclusion and future directions

  1. Top of page
  2. Summary
  3. Introduction
  4. Microbiota as a therapeutic target
  5. Methods
  6. LAB and abdominal pain/discomfort in IBS
  7. LAB and abdominal bloating/distension
  8. LAB and defecatory function
  9. LAB and miscellaneous outcomes
  10. LAB and global outcomes
  11. Summary of clinical trials to date
  12. Mechanisms of therapeutic action of LAB in IBS
  13. Safety and LAB
  14. What do we not know about LAB in the treatment of IBS?
  15. Discussion, conclusion and future directions
  16. Acknowledgements
  17. References
  18. Supporting Information

The lack of therapeutic options in IBS is a serious issue and LAB have emerged as serious candidates to fill this unmet medical need. Whether they fulfil this role as adjunctive therapies to symptom alleviating agents or as therapies in their own right remains to be seen.[97] There is now a strong rationale behind their use, solid evidence for strain specific efficacy and emerging data identifying potential mechanism of action for agents that have an enviable safety profile compared with pharmacological agents. It should be noted that this has been achieved in a disorder with a notoriously high placebo response rate which all trials must overcome to demonstrate efficacy.[8] However, many challenges remain that hinder further progress in this field, not least of which is a more complete characterisation of the microbiota in health and disease. Herein, too the outlook is positive with modern molecular methods and the diverse portfolio of ‘omic’ techniques being applied to the problem.[20, 28, 98-100] This may enhance our understanding of who responds and why, but needs to be augmented with a better comprehension of interactions at the phenotype and genotype level. Regulatory hurdles also need to be cleared with the current classification of LAB as food supplements limiting sanctioned use to healthy populations and restricting claims relating to the treatment of disease states.[101] Even these functional claims are the subject of controversy with agencies like the European Food Safety Authority (EFSA) in disagreement with advocates of LAB over what constitutes solid scientific evidence for a particular health claim.[102] The resolution of such difficulties will require clarification on the specific assessment criteria of agencies like EFSA, in addition to long-term studies that address other areas of concern like dose, mechanism of action and safety on a strain-by-strain basis in adequately powered multicentre trials. It is likely that this can best be achieved by taking a translational ‘bench to bedside’ approach. Current indications indicate that these lessons are being absorbed by researchers in the field and that the use of LAB in IBS has a bright future.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Microbiota as a therapeutic target
  5. Methods
  6. LAB and abdominal pain/discomfort in IBS
  7. LAB and abdominal bloating/distension
  8. LAB and defecatory function
  9. LAB and miscellaneous outcomes
  10. LAB and global outcomes
  11. Summary of clinical trials to date
  12. Mechanisms of therapeutic action of LAB in IBS
  13. Safety and LAB
  14. What do we not know about LAB in the treatment of IBS?
  15. Discussion, conclusion and future directions
  16. Acknowledgements
  17. References
  18. Supporting Information

Declaration of personal interests: None. Declaration of funding interests: The writing of this paper was funded in part by the Alimentary Pharmabiotic Centre which is a research centre funded by Science Foundation Ireland (SFI), through the Irish Government's National Development Plan. The writing of this paper was specifically supported by SFI (grant nos. 02/CE/B124 and 07/CE/B1368) and by GlaxoSmithKline (Grant no N/A). GC's contribution to the writing of the paper was in part supported by a research grant from the American Neurogastroenterology and Motility Society (ANMS, grant no N/A).

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Microbiota as a therapeutic target
  5. Methods
  6. LAB and abdominal pain/discomfort in IBS
  7. LAB and abdominal bloating/distension
  8. LAB and defecatory function
  9. LAB and miscellaneous outcomes
  10. LAB and global outcomes
  11. Summary of clinical trials to date
  12. Mechanisms of therapeutic action of LAB in IBS
  13. Safety and LAB
  14. What do we not know about LAB in the treatment of IBS?
  15. Discussion, conclusion and future directions
  16. Acknowledgements
  17. References
  18. Supporting Information

Supporting Information

  1. Top of page
  2. Summary
  3. Introduction
  4. Microbiota as a therapeutic target
  5. Methods
  6. LAB and abdominal pain/discomfort in IBS
  7. LAB and abdominal bloating/distension
  8. LAB and defecatory function
  9. LAB and miscellaneous outcomes
  10. LAB and global outcomes
  11. Summary of clinical trials to date
  12. Mechanisms of therapeutic action of LAB in IBS
  13. Safety and LAB
  14. What do we not know about LAB in the treatment of IBS?
  15. Discussion, conclusion and future directions
  16. Acknowledgements
  17. References
  18. Supporting Information
FilenameFormatSizeDescription
apt4965-sup-0001-TableS1.docWord document181KTable S1. Lactic acid bacteria effects in trials which assessed an index of abdominal pain/discomfort.
apt4965-sup-0002-TableS2.docWord document136KTable S2. Lactic acid bacteria effects in trials which assessed an index of abdominal bloating/distension.
apt4965-sup-0003-TableS3.docWord document139KTable S3. Lactic acid bacteria effects in trials which assessed an index of defecatory function.
apt4965-sup-0004-TableS4.docWord document119KTable S4. Lactic acid bacteria effects in trials which assessed miscellaneous outcomes.
apt4965-sup-0005-TableS5.docWord document148KTable S5. Lactic acid bacteria effects in trials which assessed global outcomes.

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