INTRODUCTION
The gastrointestinal (GI) microbiome is a complex and metabolically active ecosystem that plays a key role in health and disease. Microbiome research has transformed in the past decade, with the understanding of what constitutes a ‘core’ microbiome that is associated with health having expanded beyond taxonomy and shared species across individuals to include temporal stability, ecological influence and functional capacity [1▪]. The functional capacity of the GI microbiome describes its metabolic activities, which include fermentation of undigested nutrients and subsequent generation of organic acids, of which short-chain fatty acids (SCFA) are of particular importance to health [2▪]. Moreover, the functional capacity of the GI microbiome appears to be relatively stable across individuals despite compositional diversity [1▪].
With a more advanced understanding of the GI microbiome, it is clear that its microbial ecosystem is strongly influenced by environmental and lifestyle factors, particularly ageing, diet and disease [1▪]. For example, a comprehensive synthesis of taxonomic changes during ageing revealed that putatively beneficial bacteria (e.g. Akkermasia muciniphila, Bifidobacteria, Faecalibacterium prausnitzii) were displaced by putatively pathogenic bacteria (e.g. Bilophila, Enterobacteriaceae, Escherichia coli), with more pronounced shifts observed in those with accelerated age-associated physiological decline [3]. In terms of diet, the impact of food and nutrient intake on the GI microbiome has been thoroughly investigated, with two comprehensive studies demonstrating that microbiome composition and function are modulated by both short-term dietary intervention and habitual long-term dietary intake [4▪▪,5▪▪]. As a result, dietary interventions are one of the simplest and safest approaches for targeting the GI microbiome.
Dysregulation of the microbiome has been consistently demonstrated in some disorders. Compositional alterations include reduced abundance of putatively beneficial taxa (e.g. A. muciniphila and F. prausnitzii) and higher abundance of putative pathogenic taxa (e.g. E. coli and certain Enterobacteriaceae) as reported across multiple conditions [2▪,3]. Meanwhile, functional alterations associated with disease include a general reduction in SCFA-producing bacteria, which appear to be particularly pronounced in conditions with severe intestinal inflammation, such as in certain cancers and diabetes [2▪]. However, in most cases the primacy of the microbiome changes in disease causation described has not been established. Extensive changes in microbiome composition and metabolism have been reported in both irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) and will be reviewed here.
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PROBIOTICS
Probiotics are a commonly employed dietary approach targeting the GI microbiome. The definition of probiotics has undergone a minor update by the International Scientific Association for Probiotics and Prebiotics (ISAPP): “live microorganisms that, when ingested in adequate amounts, confer a health benefit to the host” [6]. Two concepts are crucial in qualifying the term ‘probiotic’. First, evidence of a health effect is now required, second, the probiotics must be defined and characterized to a strain level [6]. In addition, definitions for fermented foods were introduced by ISAPP, such that foods containing live microorganisms lacking a demonstrated strain-specific benefit would instead be termed as a product that “contains live and active cultures” [7]. Together, these revised criteria removed some of the uncertainty from the previous definition where the ‘probiotic’ term was more broadly used for products with little evidence of health benefit, had not undergone efficacy testing in humans or were not microbiologically well characterized.
Strains from the Bifidobacteria, Lactobacillus and Saccharomyces genera are the most commonly used in probiotic products, and are generally considered to be safe to use [8]. Although probiotic mixtures containing multiple strains are often utilized in research and practice, a recent meta-analysis comparing randomized controlled trials (RCTs) of single strains with those of multiple strains (including that specific single strain) found that, in general, for most disease indications, multistrain mixtures were not more effective than single-strain probiotics [9▪▪]. There is growing interest in utilizing bacteria identified from comparative analyses of human microbiome compositions, such as A. muciniphila and F. prausnitzii, as probiotic candidates, collectively described as ‘next-generation’ probiotics. Translating these observations in to a successful therapy has been challenging for a number of reasons not least the fact that these are strict anaerobes [10], and also given their lack of widespread use, are not yet proven safe for commercial use [11].
Major advances in microbiome research have further clarified the possible mechanisms of action for health benefits conferred by probiotics, which appear to be diverse and likely to work in concert. For example, probiotic strains from the Bifidobacteria and Lactobacillus genera possess genes encoding enzymes with the metabolic capacity to generate acetate and lactic acid from the fermentation of carbohydrates [12]. Generation of these metabolites contribute to acidification of the lumen, which can inhibit pathogen growth [13], while the metabolites can serve as substrates for bacterial cross-feeding to produce other metabolites, notably butyrate that has immunomodulatory properties [14]. Certain probiotic strains can also assist with enzymes production, namely β-galactosidase to improve digestion of lactose, and bile salt hydrolase that can facilitate bile salt deconjugation to modulate blood lipids [12]. The capacity for certain probiotic strains to increase expression of tight junction proteins has been demonstrated in vitro, which, together with the other mechanisms described, can contribute to enhance intestinal barrier function [15▪,16▪].
These multiple mechanisms suggest that probiotics may offer therapeutic value in the management of IBS and IBD. Numerous mechanistic studies, RCTs, systematic reviews and meta-analyses relating to this area have been published in the previous 18 months. The aim of this paper is to critically review the emerging evidence for the mechanisms and effectiveness of probiotics in the management of IBS and IBD.
IRRITABLE BOWEL SYNDROME
Irritable bowel syndrome is characterized by abdominal pain and an altered bowel habit in the absence of an organic cause. Abdominal bloating and distension are frequently present. The prevalence of IBS is approximately 4% worldwide [17▪] and is associated with compromised quality of life and substantial economic burden, with direct healthcare costs estimated of up to £2 billion in the UK alone (approximately US$2.4 billion) [18▪].
The pathogenesis of IBS is unclear but is postulated to be multifactorial, including roles for diet, genetics, dysfunction along the gut–brain axis, visceral hypersensitivity and alterations to the GI microbiome [19▪]. Regarding the microbiome, data indicates not only are there differences between patients with IBS and healthy controls, but that there is substantial heterogeneity within the patient population. For example, a 16S rRNA sequencing study found that while the microbiome composition of 95 patients in Sweden were similar to 466 healthy controls, the composition was more heterogeneous within the patient cohort [20]. In terms of microbiome function, a metagenomic sequencing study showed there were two distinct microbiome profiles in a cohort of 56 patients with IBS in the United Kingdom [21▪▪]. One group of patients had microbiome composition similar to healthy controls and another had a more “pathogenic” composition characterized by lower α-diversity, lower abundance of Bacteroidetes and higher abundance of Firmicutes, and functionally, specifically enriched with genes for carbohydrate and amino acid metabolism [21▪▪], thus enabling a greater capacity to ferment undigested substrates. Moreover, symptom severity tended to be greater in those with more “pathogenic-type” microbiome composition than those with a more “healthy type” composition [21▪▪]. However, whether these alterations to the GI microbiome contribute to the onset of IBS or are a manifestation of the condition, remains unclear.
There are two notable mechanisms that suggest probiotic use may offer particular utility in the management of IBS. First, the metabolic activity of these some probiotics may assist with cross-feeding and possible disposal of gaseous metabolites to reduce luminal distension [13]. Secondly, the immunomodulatory and cross-feeding effects conferred may assist with symptom management through attenuation of low-grade mucosal inflammation and reinforcement of barrier function [22].
Guidelines recently published by the British Society of Gastroenterology (BSG) identified 45 RCTs of probiotics in adults with IBS [19▪]. Details of many older trials that are not the focus of the current review can be found in that report. At least six systematic reviews have since been published on probiotics in IBS, examining the effects of probiotics at different levels of specificity [23▪–28▪]; the considerable variation in reported effectiveness between different genera, species and strains is summarized in Table 1.
Table 1 -
Summary of three recent meta-analyses and two network meta-analyses of probiotic in irritable bowel syndrome on symptom relief and global symptoms, from effects across probiotics overall to effects across genera, species and strains
| All probiotics |
Genus; Xie et al.[26▪] |
Species; Zhang et al.[28▪] |
Strain; McFarland et al.[23▪] |
All probiotics
RR 0.7 (0.5, 0.9) [25▪]
SMD −0.6 (−0.8, −0.3) [27▪] |
Bifidobacteria
RR 1.8 (1.0, 3.1)
SMD −0.7 (−1.7, 0.3) |
B. bifidum
OR 2.6 (0.8, 9.0) |
NR |
|
|
B. longum
OR 2.5 (0.3, 19.2)
SMD −0.1 (−0.3, 0.2) |
NR |
|
|
B. lactis
OR 1.5 (0.3, 7.4) |
NR |
|
|
B. infantis
OR 1.2 (0.2, 6.6)
SMD −0.7 (−1.5, 0.0) |
B. infantis 35624
RR 1.1 (0.8, 1.6)
SMD −9.4 (−13.0, −5.8) |
|
Lactobacillus
RR 1.7 (1.2, 2.5)
SMD −0.9 (−1.5, −0.3) |
L. plantarum
OR 15.6 (2.9, 84.2)
SMD 0.3 (−0.3, 0.9) |
L. plantarum 299v
RR 3.1 (1.0, 9.9) |
|
|
L. rhamnosus
OR 1.2 (0.2, 8.5) |
NR |
|
|
L. acidophilus
OR 3.0 (1.0, 8.7)
SMD −0.3 (−0.9, 0.3) |
NR |
|
|
L. casei
OR 0.9 (0.2, 3.6) |
NR |
|
|
L. reuteri
SMD −0.2 (−0.7, 0.3) |
NR |
|
Bacillus
RR 5.7 (1.9, 17.4)
SMD −2.3 (−3.9, −0.7) |
B. coagulans
OR 60.7 (14.8, 248.6)
SMD −2.0 (−2.4, −1.6) |
B. coagulans 5260
SMD −2.5 (−2.8, −2.2) |
|
Saccharomyces
RR 1.0 (0.5, 2.0)
SMD −0.2 (−1.1, 0.8) |
S. cerevisiae
OR 1.4 (0.4, 4.6) |
NR |
|
|
S. boulardii
SMD −0.3 (−1.0, 0.4) |
S. boulardii I-745
RR 1.1 (0.8, 1.6) |
|
Enterococcus
RR 2.0 (0.8, 5.1) |
NR |
NR |
|
Other |
Clostridium butyricum
OR 1.8 (0.3, 10.3)
SMD −0.4 (−1.4, 0.6) |
NR |
|
|
Escherichia coli
RR 1.9 (0.9, 3.8) [26▪]
OR 2.3 (0.6, 8.4) |
NR |
|
|
Ligilactobacillus salivarius
SMD 0.3 (−0.5, 1.0) |
NR |
Data per column from studies as labelled unless otherwise indicated. Dichotomous data are reported as the relative risk (RR) of symptoms persisting between probiotic and placebo
[26▪]; the RR of number of patients showing improvement of global symptoms between probiotic and placebo
[23▪]; or the odds ratio (OR) of symptom relief between probiotic and placebo
[28▪]. Continuous data reported as the standardised mean difference (SMD) in global symptom or abdominal pain scores between probiotic versus placebo. All data are followed by 95% confidence intervals.
These meta-analyses found that, when analysed globally across all probiotics, overall they led to beneficial impacts on global symptoms, abdominal pain and bloating in IBS patients [25▪,27▪]. However, aggregating the effects of different probiotics into a meta-analysis should be undertaken with caution as different probiotics have different characteristics that will inevitably impact on their efficacy. Indeed, network meta-analyses at genus and species levels showed differential effects across specific probiotics in IBS-C and IBS-D [24▪,27▪]. At a strain level, the effects were even more specific, with only four of six probiotics meta-analysed shown to be effective for improving global symptoms (Bacillus coagulans MTCC5260, Bifidobacterium infantis 35624, two multistrain mixtures), and only four of 12 probiotics effective for reducing abdominal pain (B. coagulans MTCC5260, Lactobacillus rhamnosus GG, two multistrain mixtures) [23▪].
These variations in effectiveness of probiotics when analysed at species and strain level call into question the synthesis of data from all probiotics in a single meta-analysis, however, meta-analysis at the species- or strain-level inevitably reduces the data available for synthesis, introducing greater heterogeneity [29]. Moreover, the effect sizes for probiotics in IBS appear to be relatively small. For example, in probiotic trials reporting symptom response using the IBS Severity Scoring System global scores, where the minimally clinically important difference is a 50-point reduction, only three of 21 trials reported mean changes in symptom scores meeting this threshold, despite the statistical significances demonstrated [23▪]. However, due to their safety and availability, these smaller effects may still offer therapeutic value to some patients.
Consequently, the BSG guidelines have eschewed recommendation of specific probiotics in IBS, instead advising ‘probiotics may be an effect treatment for global symptoms in IBS’ with the caveat that a specific recommendation is not possible based on current data [19▪]. On the basis of not being able to identify more specific effects, guidelines from the United States have also advised against their use [30▪] or refrained from making a recommendation [31].
INFLAMMATORY BOWEL DISEASE
Inflammatory bowel disease, principally ulcerative colitis (UC) and Crohn's disease, is characterized by chronic immune-mediated inflammation of the GI tract. The prevalence of IBD is approximately 0.3% worldwide [32] and while the conditions vary in disease extent and severity, they can inflict a tremendous impact on quality of life and have considerable socio-economic consequences for the individual and society. Problems of mental ill health are a considerable burden in IBD with symptoms of anxiety (pooled prevalence 32.1%) and depression (25.2%) having been shown to be common in a recent systematic review of 77 studies [33▪].
The pathogenesis of IBD is incompletely understood but is generally accepted that perturbations to the GI microbiome and/or in microbiome–host interactions are involved [34]. Indeed, a comprehensive longitudinal study conducted in a cohort of patients with IBD as part of the Human Microbiome Project found that the microbiome of patients differed from healthy individuals specifically during active disease: compositional alterations included reductions in F. prausnitzii and other butyrate-producing taxa in concert with enrichment of E. coli; with dysfunctions in microbiome metabolism including depletion of SCFAs and accumulation of primary bile acids [35]. These effects suggest that, broadly, the GI microbiome in IBD lacks temporal stability and has been shifted more to pro-inflammatory effects, particularly during active disease [36]. As with IBS, there are some challenges to establishing causation for the microbiome in IBD. However, numerous germ-free animal studies have shown that the microbiome is a requirement of disease. Indeed, a recent study showed that healthy relatives of people with IBD (who are themselves at increased risk of developing disease), have altered microbiome and impaired gut permeability [37▪▪] suggesting that such change may predate disease.
Based upon these observations of differences in microbiome in IBD, plus the numerous probiotic mechanisms discussed earlier, there is rationale for their therapeutic application in IBD, with extensive literature investigating their impact in experimental models and in patients with IBD [38], highlighted by two recent examples. First, a series of in vitro experiments conducted on HT-29 cells demonstrated that treatment with Bifidobacteria strains led to reduced expression of inflammatory genes and lower cytokine production compared with untreated and pathogen-exposed cells [39▪]. Secondly, a RCT investigating Bacillus clausii UBBC-07 in 108 patients with IBD showed that supplementation with the probiotic led to increased abundances of putatively-beneficial bacteria (Bifidobacteria, Lactobacillus, Faecalibacterium) compared with placebo in conjunction with increased secretion of IL-10 [40▪]. Translating the mechanistic rationale and experimental data to clinical evidence, however, has proven to be limited. Cochrane reviews found minimal evidence supporting the use of probiotics for induction of remission in Crohn's disease (relative risk [RR] = 1.1, P = 0.82) based upon two RCTs in 46 patients [41], and while probiotics overall may induce remission in active UC (RR = 1.7, P = 0.005) based upon nine RCTs in 596 patients, no strain-specific effects were found [42].
Despite these findings, the development of probiotic-inspired interventions may hold great future benefit in IBD. For example, a recent study of a probiotic E. coli Nissle 1917 that had been genetically engineered to reduce reactive oxygen species in the gut by producing superoxide dismutase, was shown, in a mouse model, to propagate anti-inflammatory effects and improve barrier function by modulating cytokine production and up-regulating expression of tight junction proteins, respectively [43▪]. Furthermore, while not strictly probiotics, phage therapy is beginning to emerge as a microbiome-targeted approach in IBD, with a research programme spanning in vitro experiments demonstrating efficacy in attenuating inflammation via specific suppression of pathogenic bacteria, to a proof-of-concept human trial establishing safety [44▪▪]. Such an approach, which may offer therapeutic utility in its own right, may uncover further mechanisms and pathways for probiotics to be used in IBD in the future.
CONCLUSION
It is becoming increasingly clear that the GI microbiome plays a critical role in health and disease. Importantly, diet appears to be a reliable modulator of the microbiome, and as such, opens up avenues for nutrition therapies targeting the microbiome. In gastrointestinal disorders, the use of probiotics appears to be a safe and simple therapeutic approach with plausible mechanisms of action. Though there are many studies supporting their use in IBS, albeit with relatively modest effect sizes, the evidence of effectiveness in IBD remains limited. Moreover, with advancing understanding of the GI microbiome and the specific mechanisms of action for different probiotics, there is a movement away from aggregating the effects of probiotics overall to highlighting the therapeutic value of specific probiotic strains. High-quality trials of well defined and specific probiotics in IBS and IBD, alongside laboratory investigations of their mechanisms of actions, should allow us to understand which strains offer therapeutic value in these conditions, and how.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
D.S. is a shareholder in Atmo Biosciences. K.W. has received research funding from Almond Board of California, Danone, International Nut and Dried Fruit Council and is the co-inventor of volatile organic compounds in the diagnosis and dietary management of IBS. E.M.M.Q. has received research funding, speaker's honoraria or consulting fees from a range of research and charitable bodies, including Alimentary Health, Salix, Danone, Yakult, Ironwood, Almirall, Shire, Sanofi-Synthelabo and Procter and Gamble.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
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