Irritable bowel syndrome (IBS) is a frequent functional gastrointestinal disorder (FGID), calculated to affect around 11.2% of the world’s population [1
]. Symptoms include bloating, flatulence, abdominal pain, or discomfort associated with a change in bowel habits (diarrhea, constipation, or mix). The pathophysiology of IBS is not clearly understood, and it is suggested that the condition is multifactorial, affected by environmental, inherited, and psychosocial factors. Suggested mechanisms include visceral hypersensitivity, dysfunction in the gut–brain axis, disturbances in the epithelial barrier integrity causing abnormal change in intestinal permeability, altered gastrointestinal motility, immune activation, abnormal enteroendocrine signaling, as well as dysbiosis in the gut microbiota [2
]. The diagnosis of IBS is based on exclusion of other severe gastrointestinal disorders and fulfilling of the Rome criteria, a collection of symptom-based diagnostic criteria for IBS and other FGIDs [4
Medical treatment of IBS is most commonly based on targeting the predominant symptom experienced by the patient. In addition, a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) has been shown to improve IBS symptoms and is currently a recommended dietary strategy [5
]. Although IBS is a non-fatal condition, the symptoms are experienced as troublesome for those affected and the condition is associated with increased rates of depression and anxiety, as well as economic challenges, hence often leads to severe reduction in quality of life (QoL) [6
]. Neither pharmacological treatment nor diet changes tend to completely eliminate symptoms, therefore alternative approaches to improve symptoms and better life for those affected are of great need [7
Alteration in the gut microbiome is suggested as a likely contributor to IBS, a concept arisen from clinical observations of symptoms developing after an infection, commonly described as post-infectious IBS [8
]. Small intestinal bacterial overgrowth often causes symptoms similar to those of IBS, in particular bloating in relation to food intake [10
]. Studies comparing the gut microbiota of IBS patients to healthy controls have suggested an altered microbiota profile in IBS [11
], and specific gut microbiota profiles have been associated with particular symptoms and severity of disease [15
Probiotics are defined as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” [17
]. The concept of probiotics was, for the first time, suggested in 1908 by Elie Metchinkoff, a Russian Noble Laureate who observed that consumption of fermented foods containing lactic acid bacteria had a beneficial effect on human health. Based on his own theory that lactic acid could prolong life, he consumed sour milk every day, and was the one to first name it yoghurt [18
]. Since then, the effects of probiotics have been widely investigated in a broad spectrum of diseases and are currently suggested as a possible treatment or prevention in several gastrointestinal disorders [19
The exact mechanisms of probiotics in the human body are currently only partly known. Probiotics have been suggested to act through inhibition of pathogenic bacteria overgrowth and prevention of pathogenic invasion of the host, improvement of gut barrier function and receptor interactions, as well as production or secretion of substances such as short chain fatty acids (SCFAs) and neurotransmitters [21
]. Studies in both animals and humans have suggested that different strains of probiotics may improve abdominal pain and reduce visceral hypersensitivity by modulation of expression of neurotransmitters and receptors involved in the modulation of pain, such as the opioid receptor or the cannabinoid receptor [22
]. In addition, probiotics have been shown to reduce intestinal cytokine secretion and improve epithelial barrier function in a mice model of intestinal inflammation [24
], and reduction of IBS symptoms in response to probiotic supplementation in subjects with IBS have been associated with improved cytokine profile [25
Identification of specific bacterial strains or probiotic supplements with beneficial effects on IBS symptoms may lead to more effective therapy strategies. The theory that probiotic supplements improve IBS symptoms through modulation of the gut microbiota or its metabolic pathways needs further mechanistic evidence [26
]. Hence, the aim of this systematic review was to assess the most recent randomized controlled trials (RCTs) evaluating the effect of probiotic supplementation on symptoms in IBS patients.
Overall, the studies included in the current review report varying results with regard to the effect of a probiotic supplement on IBS symptoms. When comparing studies administering multi-strain probiotic supplements with studies administering mono-strain probiotic supplements, the tendency is a more beneficial effect of multi-strain probiotic treatment compared to placebo and mono-strain probiotic treatment in alleviating IBS symptoms. Of note, the small sample size does not enable a conclusion, but rather suggests a trend.
Our findings are consistent with several recent meta-analyses and systematic reviews highlighting that probiotics in general have significant, however limited, effects on gastrointestinal symptoms [39
]. A review and meta-analysis by Ford et al., including RCTs published between 1946 and 2013 evaluating probiotics as treatment for IBS symptoms, concluded that probiotics had a beneficial effect on IBS symptoms, and emphasized that the effect was more distinct when using multi-strain probiotics [40
]. Results from another more recent review and meta-analysis by Ford et al., evaluating the efficacy of probiotics, prebiotics, and antibiotics in IBS, support their previous publication. They concluded that particular combinations of probiotics, or specific species and strains, appeared to have beneficial effects on general IBS symptoms and abdominal pain; however, based on current evidence, it was not possible to conclude in detail on which particular combination is the most efficient [39
]. Hungin et al. recently performed a systematic review reporting on beneficial effects of specific probiotic supplements on lower gastrointestinal problems in IBS, and highlighted great differences observed between different types and strains of probiotic supplements [41
The type of probiotic supplement administered in the trials included in this review are all different from each other according to form, amount, microbial strains, and combinations of microbial strains (see Table 2
). The separation between studies that administered mono- and multi-strain probiotic supplements presented an important difference in results across these two groups of studies, which is consistent with results from the meta-analysis by Ford et al. [40
]. Furthermore, there is a wide variety between the multi-strain probiotic supplements administered in the included studies. However, the two most common bacterial families administered as probiotics in the included studies were the Lactobacillaceae
), and all of the eight studies that administered a multi-strain probiotic supplement in their study had either one or both of these two bacterial families included in their supplement. In former studies conducted to examine the fecal microbiota of IBS patients, counts of Lactobacillus were reported to be both heightened and lowered in IBS patients compared to healthy controls in different studies [11
], and more studies are still needed to affirm any tendencies in Lactobacillus
counts in IBS patients. Bifidobacterium, on the other hand, has been reported by former studies to be found exclusively in reduced amounts in fecal samples of IBS patients [12
], which supports the findings in the current study, indicating that it is a tendency of significant improvement in symptoms of IBS patients consuming a multi-strain probiotic containing this bacterial family. Still, what strains and what combination of strains that are most effective remains unclear and needs further investigations.
The duration of intervention varied between the eleven studies and spanned from 4 to 16 weeks. Sisson et al. had an intervention period of 12 weeks and reported a significant improvement in the intervention group compared to the placebo group after finished intervention [36
]. However, they did not find a significant difference between groups at the 4-week and 8-week check-ups. This proposes a potential delayed effect of probiotic supplementation in reducing IBS symptoms, which may give a non-significant result in shorter studies (≤8 weeks). Three of the four studies (75%) reporting a non-significant improvement in IBS symptoms had an intervention period of 8 weeks or less [31
], whereas four out of seven of the studies (57.2%) reporting significant improvements in symptoms had an intervention period of 8 weeks or more. These findings suggest that probiotic supplements have a delayed effect in the improvement of IBS symptoms.
Several issues have to be considered when interpreting the present results. Firstly, the current review only includes RCTs published in the last five years, thus does not include relevant findings from earlier publications. Secondly, methodological differences between studies, such as type of probiotic, duration of intervention, sample size, and symptom evaluation, might affect the findings. In addition, the included studies used different symptom evaluation tools. Among the eleven included studies, the validated IBS-SSS [44
] was the most frequently used questionnaire for symptom evaluation, implemented in five of the trials [28
]. Based on the validity of IBS-SSS, we suggest this for standardized use in future studies.
The treatment of IBS should ideally be based on IBS subtype. However, there are limited results to support such a practice, and multiple treatments may be tested before the patient experiences symptom relief. Still, there is some evidence of subtype-specific treatments such as the low-FODMAP diet, which gives the best results in patients with IBS-D [45
], and supplementation with psyllium husk which gives best results in IBS-C [46
]. In the current review, one study included all subtypes of IBS and conducted a separate analysis to evaluate any potential differences in symptom improvement in the different IBS subtypes; however, no significant differences were found between subgroups [30
]. Four studies included participants with only one subtypes of IBS; three studies only included participants with IBS-D [29
]; and one study only included participants with IBS-C [35
]. Two of the studies including participants with IBS-D reported significant improvement in symptoms after probiotic supplementation [29
], whereas one study reported no significant improvement in symptoms and even reported a suggested negative effect of probiotic supplementation compared to placebo [31
]. The one study only including IBS-C patients reported a significant improvement in increased number of symptom-free days and quality of life [35
]. Future studies should aim to evaluate the effect of probiotic supplementation comparing different subtypes of IBS, which requires large sample sizes where all IBS subtypes are sufficiently represented.
IBS has a higher prevalence in women than men [1
], and a trial by Camilleri et al. reported gender differences in IBS patients in response to a pharmaceutical treatment (Alosetron, a 5-HT3receptor antagonist) [47
]. Three of the included studies conducted a separate analysis to evaluate gender differences in their study population [33
]. Wong et al. reported a difference in symptom improvement between gender, emphasizing that the male intervention group had a significant improvement in IBS symptoms compared to males of the placebo group, whereas the female participants in the intervention group did not show the same significant improvement compared to females in the placebo group [38
]. None of the two remaining studies reported any significant difference between gender [33
]. Notably, Hod et al. included only females in the trial [31
]. Based on the reported results in the current review, there seem to be no difference between male and female participants in symptom improvement after consuming a probiotic supplement. However, there is still not enough data on how potential gender differences may interfere with probiotic treatment of IBS, and large studies with separate gender analyses are needed in the future to declare any potential differences between male and female IBS patients.
Overall, the concept of the human microbiome and the dysbiotic gut as a target for novel therapeutic strategies for improving gastrointestinal symptoms in IBS suggests that more individualized and tailored probiotic supplements will be available in the future. In this context, Akkermansia
are the microbes proposed to be relevant for further investigation [48