Probiotics, Prebiotics, and Synbiotics in the Irritable Bowel Syndrome Treatment: A Review

Abstract

Irritable bowel syndrome is not a life-threatening disease, yet it significantly affects the quality of life and contributes to economic loss. It is estimated that even up to 45% of the world’s population can suffer from the disease. The first attempts to diagnose irritable bowel syndrome were made at the end of the 19th century; however, establishing appropriate diagnostic criteria and treatment methods is still ongoing. To date, little is known about the etiology of irritable bowel syndrome; however, growing attention is drawn to the intestinal microbiota as a factor in the disease development. For this reason, researchers have conducted many studies on therapies that modulate the microbiota, among which probiotics, prebiotics, and synbiotics are widely studied. To date, most studies have examined probiotics; however, there are also several studies demonstrating the efficacy of prebiotics and synbiotics. The aim of this review was to summarize findings on the usefulness of probiotics, prebiotics, and synbiotics in the treatment of irritable bowel syndrome.

1. Introduction

Irritable bowel syndrome (IBS) is an intestinal functional disorder that is classified as a non-life-threatening disease. It causes a decline in life quality and abates an ability to function in society, as well as attributes to economic losses [1,2]. The cost of IBS is estimated to be up to EUR 8 billion in Europe, nearly USD 2 billion in China, and up to USD 10 billion in the United States of America [1]. It is predicted that up to 10% of the worldwide population suffers from this disease. Some sources estimate an even higher prevalence reaching 45% [1,3]. Women are 1.5–3 times more likely to develop IBS than men, with a two times higher possibility of constipation-associated symptoms, whereas men exhibit a diarrheal form of the condition [4].

Based on the manifestation of the disease, IBS is divided into four subtypes, namely, forms with predominant diarrhea (IBS-D), with prevailing constipation (IBS-C subtype), or mixed defecation types (IBS-M), as well as IBS that cannot be subdivided [5,6]. Besides altered bowel habits, IBS patients may also suffer from abdominal pain or discomfort, flatulence, nausea, dyspepsia, or reflux [7].

The etiology of IBS is still unknown. However, many factors could be responsible for the development of the disease. Besides psychological disturbances, the altered intestinal motility, food hypersensitivity, genetics, abnormalities of the intestinal microbiota, and impairment of the bidirectional communication pathways between the gut, its microbiota, and the central nervous system, called the gut–brain axis (GBA), could trigger the disease [8,9]. Moreover, bacterial overgrowth or post-infectious (PI) changes in the gastrointestinal tract (GIT) and inflammation are acknowledged as IBS initiators [10]. Physical or sexual abuse in childhood, a short period of breastfeeding, food allergies, obesity, or surgical interventions might also lead to the evolvement of the disease [6]. IBS patients are more prone to exhibit psychological disorders, such as anxiety or depression. This makes them less receptive to IBS treatment when it is introduced alone [11]. Therefore, psychological therapy is recommended for these individuals either as an alternative to medication or to support it [12].

Antispasmodic, antidiarrheal drugs, and laxatives are the most commonly used pharmaceuticals to treat IBS, but long-term use can lead to severe side effects [13]. Additionally, acupuncture and massage, along with traditional Chinese medicine (TCM; e.g., Huoxiang Zhengqi Soft Capsule, Guchang Zhixie Pill, Shugan Decoction, and Sishen Pill), which comprise natural plant-based ingredients, are applied as remedies for IBS [13,14]. Another promising approach to alleviate IBS is targeting the gut microbiota, for which probiotics, prebiotics, and synbiotics can be used [15]. Probiotics are defined as live microorganisms that confer a health benefit on the host, while prebiotics are substrates for the favorable microorganisms inhabiting the host’s GIT [16,17,18]. Synbiotics combine probiotics and prebiotics to improve the health effects on the host compared to using these components separately. There are two types of synbiotics: synergistic, in which prebiotic serves as a substrate for administered probiotic microorganisms, or complementary, which influence the host’s indigenous microbiota [19].

This review aimed to recapitulate the literature in the field of IBS since its early diagnosis and the first treatment attempts, as well as compile the information on the alteration of GIT microbiota among IBS individuals. Above all, the following paper intended to summarize research on the use of probiotics, prebiotics, and synbiotics in the treatment of IBS and to assess the limitations of the studies cited.

2. Method

The literature search was conducted until June 2021 in the PubMed Central database. Terms: “IBS”, “Irritable Bowel Syndrome”, “Irritable Bowel”, “IBS AND Microbiota”, “Irritable Bowel AND Microbiota”, “IBS AND Probiotics”, “Irritable Bowel AND Probiotics”, “IBS AND Prebiotics”, “Irritable Bowel AND Prebiotics”, “IBS AND Synbiotics”, “Irritable Bowel AND Synbiotics” were used in the field of article’s title, abstract, as well as keywords. We included studies of all types and did not restrict the search by publication date or IBS diagnosis criteria.

3. History of the Illness Recognition

The history of the IBS diagnosis began in 1871 when da Costa described a condition called membranous enteritis in which patients suffered from intestinal pain accompanied by excretion of mucus [20,21]. Doctor Hale-White, who studied patients with various conditions of organic origin (e.g., colon cancer, ulcerative colitis, or appendiceal abscess), mentioned the disease at the beginning of the 20th century [22]. On the other hand, when doctor Herbert P. Hawkins (1906) analyzed reasons for the misdiagnosis of appendicitis, he concluded that there are several symptoms associated with intestines functionality, which do not have an origin in any pathological changes. The scientist speculated that constipation, diarrhea, intestinal spasms, and abdominal pain can have a nervous etiology [23]. Doctor John R. Ryle investigated a similar problem, which he termed spastic colon, as he also observed a number of unnecessary abdominal surgeries that failed to provide relief to patients suffering from chronic abdominal pain. He emphasized the vital importance of a detailed diagnosis, focusing on continuous pain, not typical for acute enteritis or bowel obstruction, as well as unusual palpability of patients’ colon caused by muscle spasm [24]. In 1937, doctor Earle P. Scarlett agreed that Ryle’s term “spastic colon” was more appropriate, rather than “colitis”, which should be used only in cases of clearly demonstrated inflammation of the colon. Additionally, the “irritable colon” appellation, first introduced by doctor Sippy, was mentioned as the equally appropriate term for this spectrum of symptoms. Although, doctor Scarlett pointed out that the disturbance of functionality might not only affect the colon but the whole intestines [25]. In the following years, IBS was found to be related to the overstimulated autonomic nervous system and patients’ personality, which, together with X-ray examinations and observations of symptomatology, led to correct diagnostics [26]. Furthermore, Misiewicz, Wallet, and Eissner (1966) observed the impact of elevated levels of 5-hydroxytryptamine (5-HT, serotonin), an amine produced in the alimentary tract, on intestinal motility resulting in diarrhea. It marked the beginning of extensive studies on the role of serotonin in the etiology of IBS [27]. Moreover, the role of the gut microbiota in IBS etiology has been extensively analyzed since the 1980s [28]. It was not until the late 1990s that gastroenteritis was found to be a contributing factor to the development of IBS [29,30]. However, the differences between the fecal microbiota of healthy individuals and IBS patients were not described until the early 2000s [31,32].

In 1962, Chaudhary and Truelove, who studied IBS as a spectrum including both mucus colitis and spastic colon, divided 130 patients into those with painless diarrhea and ones with abdominal pain, among whom Ritchie and Tuckey (1969) observed similarities in colon motor activity, although bowel function ranged from normal to diarrhea or constipation [21,22]. Meanwhile, Connell (1968) described diagnostic criteria based on the combination of symptoms such as abdominal pain and bowel function abnormalities without pathological changes [33]. Ritchie (1970) added the sensitivity of the colon while being pressured, as well as the profuse excretion and transition of the mucus to the list of typical symptoms [21]. Both researchers stressed the significance of excluding other gastroenterological diseases that might present with similar manifestations [21,33]. Moreover, Manousos et al. (1967) analyzed intestinal content transition time in 75 individuals with irritable colon syndrome, 43 patients with diverticulosis, and 88 subjects who had no abnormalities in bowel functions. The results showed that people suffering from both irritable colon and diverticulosis had a shortened transition time of food through the digestive tract. The researchers believed it might be related to a disturbance in colonic muscle function [34]. However, Cann et al. (1983) noted changed food transition time not only in the colon but also in the small intestine. It proved that IBS should be considered a disease affecting the whole intestine. The researchers also described that individuals with constipation had a prolonged transition time of intestinal content, whereas diarrheic ones shortened [35].

Since 1978, researchers and physicians have referred to the criteria described by Manning et al. (1978). They included flatulence, pain relief after intestinal movement, frequent and looser stools, the presence of mucus, or the impression of incomplete defecation as a highly possible differentiation of IBS from organic diseases [36]. A few years later, Kruis drew attention to the duration of symptoms as an essential diagnostic criteria, which was not universally accepted [37]. Subsequently, the Rome criteria for IBS were first presented at the 13th Rome Congress in 1988 and published as a result of Thomson, Drossman, Heaton, Dotteval, and Kruis collaboration [38]. The Rome Committee continued its work on the proper definition and diagnosis of IBS, which was amended in 1992, 1999, and 2006. The latest version was presented in 2016 as the Rome IV criteria. It states that IBS must manifest with abdominal pain relapsing at least one day per week for the past three months, began at least six months before diagnosis, and correlate with no less than two of the following criteria: being linked to defecation, be associated with shifts in stool regularity and/or its form [37]. Besides the typical symptoms of IBS, nausea, vomiting, heartburn, or even anxiety, insomnia, or depression have been observed in some patients suffering from the disease [39].

As more became known about IBS, more attention was paid to the treatment methods. In 1966, doctor MacDougall recommended a psychological and physical approach to managing the disease. This included reducing bowel stimulation through a diet adapted to the observed symptoms, the use of pharmaceuticals (e.g., codeine phosphate, diphenoxylate, propantheline), and reducing stress [40]. Later, in 1977, Diamant published a review on irritable colon syndrome in which he analyzed the latest reports on the treatments of the disease. The researcher drew attention to the importance of psychological factors since almost 50% of patients responded positively to placebo in various trials. However, Dotevall and Groll (1974), in their studies on mepiprazole, a type of tranquilizer, found that the placebo was ineffective after some time compared to the analyzed substance. In addition to tranquilizers, antispasmodic drugs such as anticholinergics or mebeverine, as well as agents to increase stool mass, were also prescribed by physicians for patients with IBS, either individually or as a combination of treatments [41]. Diamant (1977) also suggested that a low-fiber diet may be responsible for the development of the syndrome. The researcher proposed the adjustment of the dosage of dietary fibers to the observed symptoms of patients as an approach to treat the disease [42]. Nowadays, the European Food Safety Authority (EFSA) defines dietary fibers as non-digestible carbohydrates, such as pectins, cellulose, resistant starch, and non-starch polysaccharides, or fructooligosaccharides, as well as lignin [43]. At the end of the 20th century, psychological treatments (e.g., psychotherapy, behavioral or group therapy, and hypnotherapy) and the exclusion of certain foods, were also acknowledged as an additional or alternative approach to the medical treatment of IBS [44]. Simultaneously, preliminary studies of agents modifying 5-HT receptors’ functionality had begun [45]. To date, the greatest interest in the pharmacological management of IBS patients is focused on receptor subtypes 5-HT₃ and 5-HT₄ due to their impact on the functionality of GIT [46]. In the early 2000s, it was hypothesized that 5-HT₃ receptor antagonists such as ondansetron and granisetron might be effective in IBS treatment, while cilansetron was already approved for use [47]. Moreover, studies have been conducted on 5-HT₄ receptor agonists, namely, tegaserod or prucalopride [48]. Currently, new 5-HT₃ receptor antagonists and 5-HT₄ receptor agonists are still being sought [49,50].

Since the late 1970s, researchers have searched for natural ways of symptomatic treatments of IBS because of the side effects associated with prolonged pharmaceutical treatment. One of the alternatives was peppermint oil, whose antispasmodic properties were observed both in vitro and in vivo by Rees et al. (1979) [51]. However, it was not until the turn of the 20th to the 21st century that probiotics began to be investigated as a means of treating IBS [28]. Furthermore, Hunter et al. (1999) initiated studies on prebiotics as management of IBS [52]. Nowadays, synbiotics are also a subject of interest in IBS management analysis. However, even after 2010, there was not much data available on synbiotics’ impact on gastrointestinal disorders [53,54]. To date, research groups have focused on probiotics, prebiotics, and synbiotics as means to help IBS patients.

4. Intestinal Microbiota in Patients with Irritable Bowel Syndrome

Human GIT is colonized by up to 10¹⁴ organisms belonging to about 1000 species, among which prokaryotes (bacteria and unicellular microbes) dominate. However, fungi, archaea, parasites, and viruses are also inhabitants of the gut [55,56]. Bacteria residing in the GIT are mostly classified into four phyla, namely, Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria [57]. Differences in the GIT microbiota of individuals can be attributed to the type of delivery and feeding of the infant, age, sex, diet, sanitary and living conditions, health issues, and administrated pharmaceuticals, as well as geographical regions [58]. Nevertheless, dysbiosis of the GIT microbiota can trigger immune system responses that result in inflammation in the gut and disruption of the GBA [59]. The imbalance of the gut microbiota, which may be associated with overgrowth or lack of certain microorganisms, or genetic abnormalities, can lead to a variety of cardiovascular, neurological, or intestinal diseases, one of which is IBS [19,57].

Pittayanon et al. (2019) conducted a systematic review of 24 studies on the microbiota of IBS patients and observed significant differences in the results. These researchers found that in some studies, the number of potentially harmful bacteria from Enterobacteriaceae family and Bacteroides genus was increased. Simultaneously, a decrease in the prevalence of representatives of the beneficial microbiota, namely, genus Bifidobacterium and Faecalibacterium, was observed in individuals with IBS compared to the healthy ones [60]. Chong et al. (2019) made analog observations in their review. Additionally, the article mentioned the increased number of bacteria belonging to Firmicutes phyla, including Lactobacillus and Ruminococcus genus, as well as a decreased abundance of Erysipelotrichaceae and methanogens in IBS patients [61]. Mei et al. (2021), who analyzed only IBS-D patients in China, also observed elevated abundance of bacteria belonging to Enterobacteriaceae family, as well as Proteobacteria phyla, and decreased prevalence of Firmicutes, Fusobacteria phyla, and Alloprevotella, Fusobacterium genus in contrast to the healthy population [62]. Tap et al. (2017) observed the correlation between the severity of IBS and the number of Methanobacteriales capable of producing methane, which is linked to the occurrence of constipation [63]. In addition, the research group noted the reduced number of bacteria from Prevotella genus in IBS patients compared to healthy subjects. However, Su et al. (2018) and Barandouzi et al. (2021) found increased abundance of this genus in IBS individuals [63,64,65]. What is more, Shukla et al. (2015) found a lower abundance of Bifidobacterium and Lactobacillus genus and increased prevalence of Veillonella genus, Clostridium coccoides, Bacteroides thetaiotamicron, Ruminococcus productus, and P. aeruginosa [66]. Although several studies have described an increased ratio of Firmicutes to Bacteroidetes in patients with IBS compared to healthy individuals, Barandouzi et al. (2021) observed a similar abundance of bacteria belonging to these two phyla, that constitute about 90% of the total microbiota of GIT [65,67]. This research group observed, among IBS patients, a higher prevalence of bacteria belonging to Verrucomicrobia phyla, as well as from Blautia genus, which is acknowledged as a marker of microbiota imbalance [65]. Similarly, Lee et al. (2021) found no significant differences in phyla levels in fecal samples of IBS patients and healthy population. However, these researchers observed an increase in pathogenic bacteria from Desulfovibrionaceae family, and a simultaneous decrease in the beneficial Lachnospiraceae family [68]. On the contrary, Ahluwalia et al. (2021) did not notice any differences between the fecal microbiota of IBS and healthy individuals. They concluded the variations were likely related to microbiota functionality rather than composition [69]. Moreover, Dlugosz et al. (2015) reported no significant differences in the small intestine microbiota of IBS and healthy subjects [70].

Despite the efforts of researchers to find the dysbiosis patterns in the microbiota of people suffering from IBS, there are still many inconsistencies in the obtained results. It could be due to different GIT parts from which samples were gathered, different analytical methods, or even population disparity [71].

5. Probiotics, Prebiotics, and Synbiotics in IBS Treatment

Growing evidence of GIT microbial population disturbances and gastroenteritis being factors of IBS development resulted in the search for therapies based on microbiota manipulations. For this purpose, probiotics, prebiotics, and synbiotics could be used [72,73]. To date, researchers have carried out multiple studies on the impact of various probiotic strains, prebiotics, and their mixtures on people suffering from IBS. A few studies were conducted on animal models which can be applied if the etiology of the induced disease is as similar as possible as it is in humans. These models play an important role in pre-clinical research on the treatment or mechanisms of functional gastrointestinal disorders, including IBS [74]. Since psychological pressure might cause the development of IBS or provoke its symptoms in humans, stress is an inducing factor for most animal models. Nevertheless, IBS might emerge in individuals after infections; therefore, the post-infectious animal models are also used, which are caused by pathogenic bacteria or parasites. Chemical or mechanical stimulation might also trigger IBS symptoms in rodents [75].

5.1. Probiotics

The probiotic effect is attributed to the strain and even two different strains of the same species might impact the patient to various extension [76,77]. Therefore, the influence of one probiotic cannot be extrapolated to another one from the same species or even to a different strain [78]. Moreover, probiotics can act differently in various populations, as well as stages and types of diseases [77,78].

In 2002, Sen et al. published a study on the influence of Lactobacillus plantarum 299V on IBS patients. The strain did not exhibit any beneficial effect on the disease symptoms [79]. On the contrary, Ducrotté et al. (2012) described the potentially beneficial impact of the strain on the IBS symptoms of studied subjects [80]. Nevertheless, the research conducted by Sen et al. (2002) was not the only one leading to the conclusion that tested probiotic might not be effective in IBS treatment [79]. Pedersen et al. (2010), Simrén et al. (2010), Søndergaard et al. (2011), Amirimani et al. (2013), Roberts et al. (2013), Lorenzo-Zúñiga et al. (2014), and Cremon et al. (2018) obtained analog results [81,82,83,84,85,86,87]. Both Simrén et al. (2010), and Søndergaard et al. (2011) analyzed probiotic Cultura, which was milk fermented with Lactobacillus bulgaricus, as well as Streptococcus thermophilus, and containing three probiotic strains, namely, Lactobacillus paracasei F19, Lactobacillus acidophilus La5, and Bifidobacterium animalis subsp. lactis Bb12 [82,83]. Pedersen et al. (2010), who studied the same probiotic fermented milk product, observed that acidified milk itself caused the improvement in IBS symptoms [81]. Robert et al. (2013) also studied dairy product, which was yogurt with starter cultures of S. thermophilus CNCM I-1630, Lb. bulgaricus CNCM I-1632 and Lb. bulgaricus CNCM I-1519, as well as probiotic strain B. lactis DN-173 010 [85]. On the other hand, Amirimani et al. (2013) analyzed the influence of probiotic tablets Biogaia^® containing Lactobacillus reuteri on IBS patients [84]. Lorenzo-Zúñiga et al. (2014) conducted research on encapsulated multi-strain probiotic, including Lb. plantarum CECT7484, Lb. plantarum CECT7485, and Pediococcus acidilactici CECT7483, whereas Cremon et al. (2018) analyzed the influence of capsules containing Lb. paracasei CNCM I-1572 [86,87]. Furthermore, Ligaarden et al. (2010) observed an unfavorable effect of encapsulated Lb. plantarum MF1298 on IBS subjects [88].

However, there are several trials, which proved the beneficial influence of probiotics on IBS symptoms and their severity. Among them, there were probiotic capsules with Bifidobacterium infantis 35,624, or Bifidobacterium bifidum MIMBb75, or Lactobacillus brevis KB290 studied by Whorwell et al. (2006), Guglielmetti et al. (2011), and Murakami et al. (2012), respectively [89,90,91]. Additionally, Martoni et al. (2020) performed the analysis involving two separate probiotics Lb. acidophilus DDS^®-1, and B. lactis UABla-12™, in a form of capsules. Besides improvement in overall IBS symptoms, Martoni et al. (2020) described the positive influence of both probiotic strains on stool consistency and the severity of abdominal pain. Additionally, Lb. acidophilus DDS^®-1 contributed to the reduction of stress levels of IBS individuals [92]. Caviglia et al. (2020) and Zhou et al. (2020) used Bifidobacterium langum as a probiotic in studies conducted on humans and rats, respectively [93,94]. Caviglia et al. (2020), who analyzed strain B. langum ES1, observed improvement in overall IBS symptoms and enhanced intestinal barrier integrity, as well as immune-inflammatory state of IBS-D patients [93]. Similarly, Zhou et al. (2020) noted the improvement of intestinal permeability, along with positive changes in GIT microbiota in the rat WAS (water avoidance stress) model after B. langum treatment [94]. However, contrary to Caviglia et al. (2020), the research team did not establish any impact of B. langum on serum cytokines levels in rats [93,94]. Lewis et al. (2020) conducted a trial involving two separate probiotics. Besides B. longum HA-196 Lb. paracasei R0175 was administrated to IBS individuals. Both probiotics ameliorated the social quality of participants’ lives. Although, only B. langum HA-196 contributed to the increase of Bifidobacterium genus abundance in fecal samples, which was not observed for Lb. paracasei R0175 and corresponding Lactobacillus spp. [95]. What is more, Lb. gasseri BNR17 has been described by Kim et al. (2018) as suitable for use as IBS treatment since it improved its symptom [96]. Shin et al. (2018) analyzed the same strain and noted its impact on intestinal microbiota, as well as bowel habits of trial participants [97]. Lb. casei is yet another species from Lactobacillus genus, which researchers studied as probiotics in IBS treatment [98,99]. Compare et al. (2017), who performed ex vivo analysis on ileal and colonic mucosa culture tissue model harvested from PI-IBS-D patients, established that Lb. casei DG is able to diminish mucosal inflammation [98]. On the other hand, Seong et al. (2021) conducted a study on a rat IBS model induced with chronic restrain stress. Those researchers also observed the capability of Lb. casei DKGF7 to decrease inflammatory cytokines in colonic tissue, as well as serum corticosterone levels, along with amelioration of IBS symptoms and increased expression of tight junction proteins [99]. Furthermore, Dapoigny et al. (2012) described the trial in which participants received Lb. rhamnosus. This probiotic improved symptoms of IBS only among individuals suffering from the IBS-D subtype [100]. Other effective probiotics in improving IBS symptoms are strains of Bacillus coagulans [101,102,103,104]. Majeed et al. (2018) observed that B. coagulans MTCC 5856 could reduce sleeplessness and depression in IBS-D patients [102]. Gupta et al. (2012) noted the beneficial impact of B. coagulans LBSC on GIT microbiota of IBS individuals [104]. Likewise, Sun et al. (2018) used Clostridium butyricum as IBS treatment in the trial, in which probiotic exhibited the ability to ameliorate symptoms of the disease. However, no significant impact on the intestinal microbiota of tested subjects was observed [105]. Zhao et al. (2019) introduced C. butyricum probiotic strain to mice PI-IBS model induced with 2,4,6-trinitrobenzenesulfonic acid (TNBS). They described a decrease in intestinal visceral hypersensitivity, along with reduced low-grade mucosal inflammation [106]. Interestingly, only Kruis et al. (2012) used Escherichia coli Nissle 1917 (MUTAFLOR^®) in their trial on IBS-C and IBS-D patients and concluded that it poses therapeutic potential for PI-IBS, as well as post-antibiotic IBS individuals [107]. Other rarely studied probiotics are Saccharomyces spp. yeast, among which Saccharomyces cerevisiae CNCM I-3856 strain was used as probiotic in de Chambrun et al. (2015) and Spiller et al. (2016) studies. De Chambrun et al. (2015) observed reduced severity of abdominal pain and discomfort, whereas Spiller et al. (2016) noted overall improvement of IBS symptoms but only among IBS-C subjects [108,109]. Moreover, Abbas et al. (2014) described the potential of Saccharomyces boulardii to reduce inflammation in the GIT of IBS-D individuals [110]. Probiotic S. boulardii yeast were also used as a component of multi-strain preparations studied by Hong et al. (2019), as well as Leventogiannis et al. (2019) [111,112]. Hong et al. (2019), who used the PI-IBS mice model, established that studied probiotic preparation composed of S. boulardii, Lb. acidophilus LA-5, and B. lactis BB-12, contributed to the reduction of serum levels of pro-inflammatory cytokines, and visceral hypersensitivity [111]. Leventogiannis et al. (2019) conducted human studies and noted that Lactolevure^® probiotic, including S. boulardii, B. lactis BB-12, Lb. acidophilus LA-5, and Lb. plantarum, can be effective in attenuation of bloating and abdominal pain severity, especially in patients with IBS combined with small intestinal bacterial overgrowth (SIBO) [112]. Reduction of SIBO was also observed by Barret et al. (2008), who studied Yakult^® dairy product containing Lactobacillus casei Shirota. This probiotic also decreased the early rise in breath hydrogen after lactulose (ERBHAL), and, simultaneously, abdominal pain [113]. Lee et al. (2018) described the comparable observation concerning the influence of probiotic on SIBO. Their trial involved only IBS-D patients treated with a multi-strain probiotic (Ther-Biotic^® Complete) containing S. thermophilus, along with strains belonging to Lactobacillus spp. (7) and Bifidobacterium spp. (4) [114].

Multi-strain probiotic preparations are widely studied as the mode of IBS management [81,82,83,85,86,111,112,114,115,116,117,118,119,120,121,122,123,124,125,126]. They can be effective in attenuation of IBS symptoms, such as, ones including Lb. acidophilus SDC 2012, along with Lb. acidophilus SDC 2013 tested by Sinn et al. (2008), as well as a bifid triple viable capsule containing B. longum, and Lb. acidophilus used in Cui and Hu (2012) trial, or Bio-Kult^® composed of five Bifidobacterium spp. and six Lactobacillus spp. strains, along with S. thermophilus PXN 66 analyzed by Ishaque et al. (2018) [115,118,123]. Sisson et al. (2014) described another multi-strain probiotic Symprove, comprising Lb. rhamnosus NCIMB 30174, Lb. plantarum NCIMB 30173, Lb. acidophilus NCIMB 30175, and Enterococcus faecium NCIMB 30176, which exhibited a beneficial impact on IBS symptoms [119]. Oh et al. (2019), also described the amelioration of IBS symptoms among participants of the trial, which excluded individuals suffering from IBS-C, after treatment with Foodies Lactobacillus (Lb. paracasei, Lb. salivarius, Lb. plantarum) [124]. The results of this study indicate the ability of the preparation to reduce the severity of abdominal pain, which was similar to results obtained by Hong et al. (2009), Zhang et al. (2019), and Skrzydło-Radomańska et al. (2021) [116,124,125,126]. Hong et al. (2009) used the preparation including B. bifidum BGN4, B. lactis AD011, Lb. acidophilus AD031, and Lb. casei IBS041 [116]. Bifico^® (B. longum, Lb. acidophilus, E. faecalis) administrated to IBS-D individuals in the trial conducted by Zhang et al. (2019) not only reduced abdominal pain but also exhibited beneficial impact on GIT microbiota and short-chain fatty acids (SCFAs) concentrations, as well as reduced plasma levels of cytokines [125]. Skrzydło-Radomańska et al. (2021) observed additional improvement in quality of life after treatment of IBS-D patients with NordBiotic™ including S. thermophilus ST250, as well as Lactobacillus spp. (5), and Bifidobacterium spp. (3) strains [126]. Michail and Kenche (2011), as well as Hod et al. (2018), focused their research on the influence of multi-strain probiotics on IBS-D patients’ microbiota [117,122]. Michail and Kenche (2011) did not observe any impact of VSL#3 probiotic (S. thermophilus, B. breve, B. longum, B. infantis, Lb acidophilus, Lb plantarum, Lb paracasei, Lb. bulgaricus) on fecal microbiota, and, additionally, no significant changes in participants’ body mass index (BMI) [117]. Additionally, Hod et al. (2018), who analyzed BIO-25, composed of S. thermophilus ST3, Lactococcus lactis SL6, along with Lactobacillus spp. (6), and Bifidobacterium spp. (4) strains, in management of IBS-D, noted that the preparation did not affect microbial diversity in participants’ feces. Nevertheless, they observed increased abundance of Lactobacillus spp. and Lactococcus spp. in stool samples of subjects whose abdominal pain and bloating were reduced, and a simultaneous decrease in Bilophila genus prevalence among individuals with decreased abdominal pain and improved stool consistency [122]. Furthermore, Yoon et al. (2015), established that LacClean Gold-S^® (B. bifidum KCTC 12199BP, B. lactis KCTC11904BP, B. longum KCTC 12200BP, Lb. acidophilus KCTC 11906BP, Lb. rhamnosus KCTC 12202BP, S. thermophilus KCTC 11870BP) improve symptoms only among patients with IBS-D, whereas probiotic strain included in the preparation were present in fecal samples of all trial participants [120]. Comparable results, on two different products containing Lb. acidophilus DSM 24936, and Lb. reuteri DSM 25175, or Lb. rhamnosus DSM 25568, Lb. plantarum DSM 24937, and B. lactis DSM 25566, were obtained by Mezzasalma et al. (2016) among individuals suffering from IBS-C [121].

Most of the cited research was carried out in double-blind mode; however, there are still some trial designs conducted without placebo, or control group [93,112,113,114,125], as well as research conducted in full awareness of investigators, and/or participants of the administrated product (treatment/control) [81,93,112,113,114,125]. Moreover, the number of studies including the dose-related effect of probiotics on IBS subjects is very limited [86,89,96]. Animal or ex vivo culture tissue models are also rarely used for the analysis of active agents’ potential impact on IBS individuals [94,98,99,111]. Most of the above-described studies are focused on all IBS subtypes [80,81,82,87,88,89,95,100,108,109,112,113,115,116,118,119,120]. Although, several studies did not differentiate the form of the disease among participants [79,83,84,85,90,91,92,96,101,103,104,127]. Moreover, Oh et al. (2019) performed the analysis of probiotic impact on IBS patients with the exclusion of subjects suffering from IBS-C [124]. This subtype was chosen as the inclusion criteria only by Kruis et al. (2012) and Mezzasalma et al. (2016) [107,121]. However, Kruis et al. (2012) included also people with IBS-D, which was the subtype on which Michail and Kenche (2011), Abbas et al. (2014), Lorenzo-Zúñiga et al. (2014), Majeed et al. (2016), Compare et al. (2017), Hod et al. (2018), Ishaque et al. (2018), Lee et al. (2018), Shin et al. (2018), Sun et al. (2018), Zhang et al. (2019), Caviglia et al. (2020), and Skrzydło-Radomańska et al. (2021) focused [86,93,97,98,102,105,107,110,114,117,122,123,125,126]. Details of the above-mentioned trials are listed in

Table 1. Studies on the impact of probiotics on IBS patients.

Paper	Research Type	Participants Selection Criteria	Participants 1	IBS Subtype	Preparation (Dosage)	Placebo/Control (Dosage)	Duration	Outcomes
Sen et al. (2002) [79]	The randomized, double-blind, placebo-controlled study	Rome I	12 males/females 18–65 y 2	wd 3	ProViva (oatmeal gruel, 5 × 107 cfu/mL 4 of Lb. plantarum 299V) 125 mL/d 5	Oatmeal gruel 125 mL/d	First 4 weeks of placebo administration, then 4 weeks of treatment	No beneficial effect
Whorwell et al. (2006) [89]	The randomized, double-blind, placebo-controlled, multicenter, dose-ranging stud	Rome II	362 females 18–65 y	All	Excipient (no data on used compounds), B. infantis 35,624 (three different doses: 1.0 × 106, 1.0 × 108, or 1.0 × 1010 cells/capsules) 1 capsule/d 6	Excipient (no data on used compounds) 1 capsule/d	2 weeks of the run-in period, then 4 weeks of treatment, and 2 weeks of follow up	Improvement of IBS symptoms The effective dose was 1.0 × 108 cells/capsule
Barrett et al. (2008) [113]	Uncontrolled pilot study	Rome II	18 males/females 20–70 y	All	Yakult® (sucrose, skim milk powder, dextrose, 6.5 × 109 cells/dose L. casei Shirota) 65 mL/d	na 7	Up to 2-week run-in period, 6 weeks of treatment	Reduction in SIBO 8 Regression of ERBHAL 9, accompanied by improved abdominal symptoms
Sinn et al. (2008) [115]	The randomized, double-blind, placebo-controlled human study	Rome III	40 males/females 18–70 y	All	Excipient (no data on used compounds), freeze-dried Lb. acidophilus SDC 2012, and Lb. acidophilus SDC 2013 (a total of 2.0 × 109 cfu/mL) 2 capsules/d	Excipient (no data on used compounds) 2 capsules/d	4 weeks	Improved IBS symptoms
Hong et al. (2009) [116]	The randomized, double-blinded, placebo-controlled parallel-group clinical study	Rome III	70 males/females 19–75 y	All	B. bifidum BGN4, B. lactis AD011, Lb. acidophilus AD031, Lb. casei IBS041 (a total of 2.0 × 1010 cfu/packet 10 viable, lyophilized probiotics) 2 packets/d 11	Skim milk powder 2 packets/d	8 weeks	Reduced abdominal pain and defecation discomfort
Ligaarden et al. (2010) [88]	The randomized double-blind, placebo-controlled, crossover trial	Rome II	16 males/females 18–75 y	All	1010 cfu/capsule 12 Lb. plantarum MF1298 (live, freeze-dried) 1 capsule/d	No data on used compounds 1 capsule/d	1 week run-in period, followed by 3 weeks of treatment (probiotc/placebo), then 4 weeks of wash-out phase, and another 3 weeks of alternate treatment (placebo/probiotic)	Adverse effects of probiotic
Pedersen et al. (2010) [81]	Placebo-controlled study	Rome II	61 males/females 18–79 y	All	Milk (a total of 107–109 cfu/g 13 acidifiers: Lb. delbruckeii ssps. bulgaricus, S. thermophilus; probiotics: 5 × 107 cfu/mL Lb. paracasei F19, 5 × 107 cfu/mL Lb acidophilus LA-5, 5 × 107 cfu/mL B. lactis BB-12) 400 mL/d	Milk (acidifiers: D-(+)-gluconic acid, δ-lactone) 400 mL/d	2 weeks of wash-out period, then 8 weeks of treatment	Observed effects of treatment were due to acidified milk itself, not the probiotic
Simrén et al. (2010) [82]	The randomized, double-blind, placebo-controlled study	Rome II	74 males/females 18–70 y	All	Cultura (fermented with: Lb. bulgaricus, S. thermophilus; containing probiotics: 5.0 × 107 cfu/mL Lb. paracasei F19, 5.0 × 107 cfu/mL Lb. acidophilus La5, 5.0 × 107 cfu/mL B. lactis Bb12) 400 mL/d	Acidified milk 400 mL/d	2 weeks of the run-in period, then 8 weeks of treatment, and 8 weeks of follow-up	No beneficial effect
Guglielmetti et al. (2011) [90]	The prospective, multicenter, randomized, double-blind, placebo-controlled, two-arm nutritional study	Rome III	122 males/females 18–68 y	wd	Excipient (no data on used compounds), 1 × 109 cfu/capsule B. bifidum MIMBb75 1 capsule/d	Excipient (no data on used compounds), maltodextrin 1 capsule/d	2 weeks of the run-in period, then 4 weeks of treatment, and 2 weeks of wash-out phase	Improvement of IBS symptoms Maintained beneficial impact of probiotic during the wash-out period
Michail and Kenche (2011) [117]	The randomized, double-blind, placebo-controlled trial	Rome III	24 males/females average age of 21.8 ± 17	IBS-D	VSL#3 (cornstarch, S. thermophilus, B. breve, B. longum, B. infantis, Lb acidophilus, Lb plantarum, Lb paracasei, Lb. bulgaricus) 9.0 × 1011 cells/d 14	Cornstarch	8 weeks	No impact on fecal microbiota No influence on BMI
Søndergaard et al. (2011) [83]	The randomized, double-blind, placebo-controlled, parallel-group trial	Rome II	64 males/females 18–70 y	wd	Cultura 1000 mL/d	Acidified milk 1000 mL/d	2-week run-in period, then 8 weeks of treatment	No effect on IBS symptoms
Cui and Hu (2012) [118]	The double-blind, placebo-controlled study	Rome III	60 males/females average age between 44.38 ± 15.08 and 48.45 ± 14.08	All	Bifid triple viable capsule (B. longum, Lb. acidophilus) 6 capsules/d	No data on used compounds 600 mg/d 15	4 weeks	Improvement in overall IBS symptoms Higher abundance of gene copies of Bifidobacterium spp. and Lactobacillus spp. in feces
Dapoigny et al. (2012) [100]	The prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group pilot trial	Rome III	50 males/females 18–70 y	All	2 × 108 cfu/capsule Lb. rhamnosus (total freeze-dried culture) 3 capsules/d	No data on used compounds 3 capsules/d	2 weeks of the run-in period, then 4 weeks of treatment, and 2-week follow-up	Improvement of symptoms only among IBS-D patients
Ducrotté et al. (2012) [80]	The multicenter, parallel-group, double-blind, placebo-controlled study	Rome III	216 males/females 18–70 y	All	Excipients (potato starch, magnesium stearate) and 1 × 1010 cfu/capsule Lb. plantarum 299V DSM 9843	Potato starch and magnesium stearate	4 weeks of treatment, then 3 weeks of follow-up	Potentially beneficial in the management of IBS
Kruis et al. (2012) [107]	The randomized, double-blind, parallel-group, monocenter study	Rome II	120 males/females 18–65	IBS-C, IBS-D	MUTAFLOR® (2.5–25 × 109 cfu/capsule Escherichia coli Nissle 1917) 1 capsule/d (first 4 days) 2 capsules/d (the rest of the trial)	No data on used compounds 1 capsule/d (first 4 days) 2 capsules/d (the rest of the trial)	12 weeks	Therapeutic potential for PI-IBS 16 PA-IBS 17 subjects
Murakami et al. (2012) [91]	The placebo-controlled, double-blind, crossover trial	Rome III	35 males/females ≥ 6 y	wd	Corn starch, maltitol syrup, hydroxypropyl methylcellulose, calcium stearate, ≥1.0 × 1010 cfu/capsule Lb. brevis KB290 1 capsule/d	Corn starch, maltitol syrup, hydroxypropyl methylcellulose, calcium stearate1 capsule/d	4-week run-in period, followed by 4 weeks of treatment (probiotic/placebo), then 4 weeks of wash-out phase, and another 4 weeks of alternate treatment (placebo/probiotic)	Increased abundance of Bifidobacterium spp. and decrease of Clostridium spp. in fecal samples Improvement of IBS symptoms and subjects’ quality of life
Amirimani et al. (2013) [84]	The randomized parallel-group, single-blind, placebo-controlled study	Rome III	72 subjects (no information on sex, and age)	wd	Biogaia® (1 × 108 viable cells of Lb. reuteri) 1 tablet/d 18	1 tablet/d	4 weeks	Increased frequency of defecation No vital differences in IBS symptoms
Roberts et al. (2013) [85]	The randomized, double-blind, placebo-controlled trial	Rome III	179 males/females 18–65 y	wd	Yogurt with 1.2 × 109 cfu/cup 19 of standard strains (S. thermophilus CNCM I-1630, Lb. bulgaricus CNCM I-1632, and I-1519) with the addition of 1.25 × 1010 cfu/cap B. lactis DN-173 010 2 cups/d 20	Milk-based non-fermented dairy product without probiotics and with similar lactose content to the test product2 cups/d	12 weeks	No impact of tested probiotic on IBS symptoms severity
Abbas et al. (2014) [110]	The randomized, double-blind, placebo-controlled trial	Rome III	72 males/females 18–60 y	IBS-D	S. boulardii 750 mg/d	No data on used compounds 750 mg/d	2 weeks run-in period, then 6 weeks of treatment	Decreased blood levels of pro-inflammatory cytokines (IL 21-8, TNF-α 22) Increased tissue levels of anti-inflammatory cytokines (IL-10)
Lorenzo-Zúñiga et al. (2014) [86]	The multicenter, randomized, double-blind, placebo-controlled intervention clinical trial	Rome III	84 males/females 20–70 y	IBS-D	Lb. plantarum CECT7484, Lb. plantarum CECT7485, and P. acidilactici CECT7483 (ratio 1:1:1; a total of 1–3 × 1010 cfu/capsule in high dose or 3–6 × 109 cfu/capsule in low dose) 1 capsule/d	No data on used compounds 1 capsule/d	6 weeks	Improvement of IBS-related life quality No significant relief in the severity of IBS symptoms Lack of significant improvement of IBS symptoms Amelioration of quality of subjects’ life
Sisson et al. (2014) [119]	The single-center, randomized, double-blind, placebo-controlled trial	Rome III	186 males/females 18–65 y	All	Symprove (water-based barley extract, Lb. rhamnosus NCIMB 30174, Lb. plantarum NCIMB 30173, Lb. acidophilus NCIMB 30175, E. faecium NCIMB 30176; total of 1.0 × 1010 bacteria/50 µ) 1 mL/kg a day 23	Water, flavorings 1 mL/kg a day	12 weeks of treatment, and 4 weeks of follow-up	Significantly improved symptoms of IBS, especially pain and bowel habits Ameliorated symptoms severity The effect was not sustained during the follow-up period
Urgesi et al. (2014) [101]	The monocentric, double-blind, placebo-controlled, parallel-group clinical trial	Rome III	52 males/females 18–75 y	wd	Colinox® (excipient—no data on used compounds, simethicone, 1.5 × 109 spores/g 24 B. coagulans) 3 tablets/d	Excipient (no data on used compounds) 3 tablets/d	4 weeks	Significant improvement of IBS symptom
de Chambrun et al. (2015) [108]	The randomized, single-center, double-blind, placebo-controlled, parallel-group clinical study	Rome III	179 males/females 18–75 y	All	8 × 109 cfu/g S. cerevisiae CNCM I-3856 1 capsule/d	Dibasic calcium phosphate 1 capsule/d	2 weeks of the run-in period, then 8 weeks of treatment, and 3 weeks of follow-up	Reduced severity of abdominal pain/discomfort The relief of symptoms was limited to the duration of treatment
Yoon et al. (2015) [120]	The randomized, double-blind, placebo-controlled trial	Rome III	81 males/females 19–75 y	All	LacClean Gold-S® (maltodextrin, corn starch, silicon dioxide, B. bifidum KCTC 12199BP, B. lactis KCTC11904BP, B. longum KCTC 12200BP, Lb. acidophilus KCTC 11906BP, Lb. rhamnosus KCTC 12202BP, S. thermophilus KCTC 11870BP; a total of 5 × 109 viable cells/capsule) 2 capsules/d	Maltodextrin, corn starch, silicon dioxide 2 capsules/d	4 weeks	Increased abundance of administrated probiotic strains in fecal samples Amelioration of diarrhea-predominant symptoms of IBS
Majeed et al. (2016) [102]	The randomized, double-blind, parallel-group, placebo-controlled, multi-centered study	Rome III	36 males/females 18–55 y	IBS-D	Microcrystalline cellulose, starch, sodium starch glycolate, magnesium stearate, and B. coagulans MTCC 5856 2 × 109 spores/tablet 25 1 tablet/d	Maltodextrin 1 tablet/d	90 days	Attenuation of symptoms (bloating, vomiting, stool frequency, abdominal pain, diarrhea) Improved quality of life
Mezzasalma et al. (2016) [121]	The randomized, double-blind, placebo-controlled study	Rome III	157 males/females 18–65 y	IBS-C	Product 1: 5 × 109 cfu Lb. acidophilus DSM 24936, 5 × 109 cfu Lb. reuteri DSM 25175, inulin, silica, talc; product 2: 5 × 109 cfu Lb. rhamnosus DSM 25568, 5 × 109 cfu Lb. plantarum DSM 24937, 5 × 109 cfu B. lactis DSM 25566, inulin, silica, talc	Inulin, silica, talc	60 days of treatment, then 30 days of follow-up	Increasing abundance of tested strains in fecal samples during treatment Probiotic strains remained in the stool samples during follow-up period, except B. lactis Both products diminish severity of IBS-C symptoms
Spiller et al. (2016) [109]	The multi-center, randomized, double-blind, placebo-controlled trial	Rome III	379 males/females 18–75 y	All	S. cerevisiae I-3856 2 capsules/d	No data on used compounds 2 capsules/d	2-week run-in period, then 12 weeks of treatment	Improved GIT symptoms of IBS-C subjects
Compare et al. (2017) [98]	Ex vivo study	Rome III	20 males/females 18–70 y	PI-IBS/IBS-D	Lb. casei DG and its postbiotic	Healthy controls (10 out of 20)	na	Decreased inflammatory mucosal response in ex vivo model of PI-IBS-D subjects
Cremon et al. (2018) [87]	The multicenter, randomized, double-blind, cross-over, placebo-controlled, pilot trial	Rome III criteria	40 males/females 18–65 y	All	Gelatin capsule containing 2.4 × 1010 viable cells of Lb. paracasei CNCM I-1572 2 capsules/d	No data on used compounds 2 capsules/d	2 weeks of the run-in period, next 4 weeks of treatment (probiotic/placebo), followed by 4 weeks of wash-out phase, and another 4 weeks of alternate treatment (placebo/probiotic), then 4-week follow-up	No significant improvement of IBS symptoms compared to placebo Reduced Ruminococcus spp. Diminished levels of pro-inflammatory cytokines IL-6, and IL-15 Increased levels of butyrate
Hod et al. (2018) [122]	The randomized, double-blind, placebo-controlled, parallel-group clinical trial	Rome III	97 females 18–70	IBS-D	BIO-25 (3.0 × 109 cfu/capsule Lb. rhamnosus LR5; 2.0 × 109 cfu/capsule Lb. casei LC5; 1.0 × 109 cfu/capsule Lb paracasei LPC5; 1.0 × 109 cfu/capsule Lb. plantarum LP3; 5.0 × 109 cfu/capsule Lb. acidophilus LA1; 4.0 × 109 cfu/capsule B. bifidum BF3; 1.0 × 109 cfu/capsule B. longum BG7; 2.0 × 109 cfu/capsule B. breve BR3; 1.0 × 109 cfu/capsule B infantis BT1; 2.0 × 109 cfu/capsule S. thermophilus ST3; 3.0 × 109 cfu/capsule Lb. bulgaricus LG1, 3.0 × 109 cfu/capsule L. lactis SL6) 2 capsules/d	Cellulose2 capsules/d	2 weeks of run-in period, then 8 weeks of treatment	No effect on fecal microbiota diversity Increased abundance of Lactobacillus spp. and Lactococcus spp. in stool samples of subjects whose abdominal pain and bloating were reduced Individuals with decreased abdominal pain and improved stool consistency showed a decrease in Bilophila genus prevalence
Ishaque et al. (2018) [123]	The randomized, double-blind, placebo-controlled, equal allocation ratio, parallel-group, clinical trial	Rome III	360 males/females 18–55 y	IBS-D	Bio-Kult® (B. subtilis PXN 21, B. bifidum PXN 23, B. breve PXN 25, B. infantis PXN 27, B. longum PXN 30, Lb. acidophilus PXN 35, Lb. delbrueckii spp. bulgaricus PXN39, Lb. casei PXN 37, Lb. plantarum PXN 47, Lb. rhamnosus PXN 54, Lb.helveticus PXN 45, Lb. salivarius PXN 57, L. lactis PXN 63, S. thermophilus PXN 66; a total of 2.0 × 109 cfu/capsule) 4 capsules/d	Microcrystalline cellulose, hydroxypropyl methylcellulose4 capsules/d	16 weeks	Significantly improved IBS symptoms and their severity
Lee et al. (2018) [114]	The single-arm, open-label, pilot study	Rome III	11 males 19–70 y	IBS-D	Ther-Biotic® Complete (Lb. rhamnosus 6.0 × 109 cfu/capsule, B. bifidum 5.0 × 109 cfu/capsule, Lb. acidophilus 3.0 × 109 cfu/capsule, Lb. casei 2.5 × 109 cfu/capsule, Lb. plantarum 2.0 × 109 cfu/capsule, Lb. salivarius 2.0 × 109 cfu/capsule, B. longum 1.0 × 109 cfu/capsule, S. thermophilus 1.0 × 109 cfu/capsule, Lb. bulgaricus 1.0 × 109 cfu/capsule, Lb. paracasei 5.0 × 108 cfu/capsule, B. lactis 5.0 × 108 cfu/capsule, B. breve 5.0 × 108 cfu/capsule)	No placebo or control group	8 weeks	Ameliorated abdominal discomfort, dyspepsia, flatulence, and stool consistency Decreased SIBO prevalence Beneficial impact on GIT microbiota
Kim et al. (2018) [96]	The double-blind, randomized, placebo-controlled, parallel study	individual protocol	42 males/females 20–54 y	wd	Lb. gasseri BNR17 Low dose: 2 × 108 cfu/d 26 Medium dose: 2 × 109 cfu/d High dose: 2 × 5 × 109 cfu/d	Dextrin	7 days of the run-in period, then 4 weeks	Amelioration of IBS symptoms The abundance of probiotic strain in fecal samples of treated subjects The optimal dosage appeared to be high dose (2 × 5 × 109 cfu/d)
Majeed et al. (2018) [127]	The randomized, double-blind, placebo-controlled, multicenter, parallel-group clinical study	Rome III	40 males/females 20–65 y	wd	Microcrystalline cellulose, starch, sodium starch glycolate, magnesium stearate, 2.0 × 109 spores/tablet B. coagulans MTCC 5856 1 tablet/d	Microcrystalline cellulose, starch, sodium starch glycolate, magnesium stearate1 tablet/d	90 days of treatment, then 15 days of follow-up	Decrease in depression, along with diminished IBS symptoms Reduced sleeplessness Decreased serum levels of myeloperoxidase
Shin et al. (2018) [97]	The single-center, randomized, double-blind, placebo-controlled clinical trial	Rome III	51 males/females 20–55 y	IBS-D	Maltodextrin, microcrystalline cellulose, magnesium stearate, Lb. gasseri BNR17 (total of 1010 cfu/d) 4 capsules/d	Maltodextrin, microcrystalline cellulose, magnesium stearate4 capsules/d	8 weeks	Improved bowel habits (longer colon transit time) Positive impact on intestinal microbiota (decreased Firmicutes, increased Actinobacteria, and Bacteroidetes)
Sun et al. (2018) [105]	The prospective, multicenter, randomized, double-blind, placebo-controlled trial	Rome III criteria	200 males/females 18–65 y	IBS-D	1.5 × 107 cfu/capsule C. butyricum 9 capsules/d	No data on used compounds 9 capsules/d	4 weeks	Improvement in overall IBS symptoms and quality of patients’ life No significant changes in intestinal microbiota diversity Reduction of Clostridium sensu stricto in microbial community Improvement of alanine and tryptophan metabolism
Hong et al. (2019) [111]	Animal study	na	54 males C57L/B6 mice (15.5 ± 1.0 g) aged 4 weeks	na PI-IBS model (Trichinella)	Formulated probiotics (DW; Lb. acidophilus LA5, B. lactis BB12, S. boulardii) 0.2 mL of the solution of 5.0 × 109 cfu/g VSL#3 0.2 mL of the solution of 5.0 × 109 cfu/g	No data on used compounds 0.2 mL of the solution of 5.0 × 109 cfu/g	4 weeks	Decreased levels of serum pro-inflammatory cytokines in uninfected and infected mice treated with probiotics (DW and VSL#3) Diminished visceral hypersensitivity (DW)
Leventogiannis et al. (2019) [112]	Open-label clinical study	Rome III/SIBO-positive or SIBO-negative	Males/Females ≥ 18 y	All	Lactolevure® (1.5 × 109 cfu/capule S. boulardii, 1.75 × 109 cfu/capsule B. lactis BB-12, 1.5 × 109 cfu/capsule Lb. acidophilus LA-5, 5.0 × 108 cfu/capsule Lb. plantarum) 2 capsules/d	No placebo/control group	30 days	Amelioration of bloating More significant improvement of symptoms among IBS patients with SIBO Decreased abdominal pain severity
Madempudi et al. (2019) [103]	The randomized, double-blind, placebo-controlled trial	Rome III	108 males/females 18–60 y	wd	Excipient (maltodextrin), 2.0 × 109 cfu/capsule B. coagulans Unique IS2	Excipient (maltodextrin)	8 weeks	Relief in the severity of symptoms (bloating, incomplete evacuation, urgency, straining, the passage of gas, bowel habit satisfaction, and stool consistency) Reduced abdominal pain Increased number of complete spontaneous bowel movement
Oh et al. (2019) [124]	The randomized, double-blind, placebo-controlled trial	Rome III	50 males/females 19–60 y	With the exclusion of IBS-C	Foodis Lactobacillus—excipients (olive oil, pine oil), and Lb. paracasei, Lb. salivarius, 1 × 109 cfu/mL Lb. plantarum (ratio 5:4:1)	Excipients (olive oil, pine oil)	1 week screening period, then 4 weeks of treatment	Relief in global IBS symptoms Decreased severity of abdominal pain
Zhang et al. (2019) [125]	Pilot study	Rome III	15 males/females 18–65 y	IBS-D	Bifico® (B. longum, Lb. acidophilus, E. faecalis; a total of ≥1.0 × 107 cfu)20 mg 3 times a day	Antidepressant (Duloxetine) 30 mg/d for 4 days, then 60 mg/d	8 weeks	Changes in gut microbiota and SCFAs 27 concentrations (probiotic and antidepressant) Reduced severity of abdominal symptoms (probiotic and antidepressant) Decreased plasma levels of cytokines (probiotic and antidepressant)
Zhao et al. (2019) [106]	Animal studies	na	24 C57BL/6 male mice aged 6–8 weeks	na PI-IBS model (TNBS 28)	1 × 108 cfu/mL C. butyricum 200 µL/d	Saline	4 weeks of model preparation, one week of treatment	Attenuated intestinal visceral hypersensitivity Diminished low-grade mucosal inflammation (suppressed production of cytokines, decreased number of lamina propria dendritic cells)
Caviglia et al. (2020) [93]	The prospective study	Rome IV	16 males/females 16–65 y	IBS-D	B. longum ES1 1 × 109 cfu	Lack of control	8–12 weeks	Improvement in general IBS symptoms Amelioration of the immune-inflammatory condition (reduced cytokines, and zonulin levels) Increased integrity of the intestinal barrier
Lewis et al. (2020) [95]	The randomized, double-blind, placebo-controlled, 3-arm parallel-group study	Rome III	285 males/females ≥ 18 y	All	Excipients (potato starch, and magnesium stearate), and 10 × 109 cfu/capsule of B. longum HA-196, or Lb. paracasei R0175	Potato starch, and magnesium stearate	2-week run-in period, next 8 weeks of treatment	Significantly improved bowel habits, and stool consistency in IBS-D, and IBS-C subjects (Lb. paracasei R0175) The positive impact of social aspects of life (both probiotic strains) Increased number of Bifidobacterium ssp. in fecal samples (B. langum HA-196)No vital changes in A. muciniphila, and F. prausnitzii abundance Distinct placebo effect
Martoni et al. (2020) [92]	The randomized, double-blind, placebo-controlled, multicenter study	Rome IV	336 males/females 18–70 y	wd	Microcrystalline cellulose, and ≥1 × 1010 cfu/capsule of Lb. acidophilus DDS®-1, or B. animalis subsp. lactis UABla-12™ 1 capsule/d	Microcrystalline cellulose 1 capsule/d	2-week run-in period (only placebo), 6 weeks of treatment (probiotic/placebo)	Improvement in stool consistency Reduced abdominal pain severity Vital amelioration of IBS symptoms Diminished stress levels (Lb. acidophilus DDS®-1)
Zhou et al. (2020) [94]	Animal study	na	Male Sprague-Dawley rats (weight: 225~260 g)	na WAS model	B. longum 1 × 109 cfu/mL once a day	0.9% saline	10 days	Influenced Paneth cells function—enhanced lysozyme production, and repair of mucus No difference in serum cytokines levels Beneficial alteration of GIT microbiota Improved intestinal permeability
Gupta et al. (2021) [104]	The prospective, interventional, randomized, double-blind, placebo-controlled clinical study	Rome IV	40 males/females 18–65 y	wd	Excipient with B. coagulans LBSC 2 × 109 spores/sachet 3 sachets/d 29	Excipient with maltodextrin 3 sachets/d	Up to 80 days	Improvement in abdominal symptoms (pain, stomach rumbling) Attenuation of bloating, cramping, nausea, vomiting, diarrhea, anxiety Beneficial modulation of GIT microbiota Amelioration in stool consistency
Seong et al. (2021) [99]	Animal study	na	14 male Wistar rats (weight: 304 ± 1.4 g) aged 8 weeks	na IBS induced by chronic restraint stress	Maltodextrin and heat-killed 1 × 1011 cfu Lb. casei DKGF7	Maltodextrin	4 weeks	Improvement of IBS symptoms in the animal model Decrease in serum corticosterone levels, inflammatory cytokines in colonic tissue Enhanced expression of tight junction proteins
Skrzydło-Radomańska et al. (2021) [126]	The randomized, double-blind, placebo-controlled, parallel-group trial	Rome III	51 males/females 8–75 y	IBS-D	NordBiotic™ (B. breve BB010 B. longum BL020, B. bifidum BF030, B. lactis BL040, Lb. rhamnosus LR110, Lb paracasei LPC100, Lb acidophilus LA120, Lb. casei LC130, Lb plantarum LP140, S. thermophilus ST250; Total 2.5 × 109 cfu/capsule) 2 capsules/d	Maltodextrin 2 capsules/d	8 weeks	Improved quality of patients’ life Diminished severity of abdominal pain

¹ the final (after screening) number of participants who received treatment is given; ² years old; ³ without differentiation; ⁴ colony-forming units per milliliter, ⁵ milliliters per day; ⁶ capsules per day; ⁷ not applicable; ⁸ small intestinal bacterial overgrowth; ⁹ early rise in breath hydrogen after lactulose; ¹⁰ colony-forming units per packet; ¹¹ packets per day; ¹² colony-forming unit per capsule; ¹³ colony-forming units per gram; ¹⁴ cells per day; ¹⁵ milligrams per day; ¹⁶ post-infection IBS; ¹⁷ post-antibiotic IBS; ¹⁸ tablets per day; ¹⁹ colony-forming units per cup; ²⁰ cups per day; ²¹ interleukins; ²² tumor necrosis factor α; ²³ milliliters per kilogram; ²⁴ spores per gram; ²⁵ spores per tablet; ²⁶ colony-forming units per day; ²⁷ short-chain fatty acids; ²⁸ 2,4,6-trinitrobenzenesulfonic acid; ²⁹ sachets per day.

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5.2. Prebiotics

At present, only a few pieces of research on the impact of prebiotics on the health improvement of people suffering from IBS have been conducted. Therefore, this area of study is still in need of investigation.

The first study on the influence of prebiotics on IBS management was published in 1999 by Hunter et al., who analyzed the oligofructose, the effect of which was marginal and only in patients with IBS-C [52]. Similarly, Olesen et al. (2000), who studied fructooligosaccharides (FOS), did not conclude whether use of prebiotic helped to improve the condition of IBS patients or not [128]. Short-chain FOS (scFOS) was also studied by Azpiroz et al. (2016), who described the influence of the prebiotic on the anxiety level of IBS individuals and Bifidobacterium spp. count in their stool [129]. Silk et al. (2009) tested the effectiveness of another prebiotic, namely, the trans-galactooligosaccharide (GOS) mixture produced by Bifidobacterium bifidum NCIMB 41171 from lactose. They observed that it not only relieved symptoms such as flatulence, abdominal pain, and discomfort, as well as stool patterns but also increased the number of Bifidobacterium spp. in fecal samples [130]. Both GOS and FOS, along with inulin and anthocyanins, were included in the preparation used in the trial conducted by Chen et al. (2017) in the IBS mice model. The product exhibited the ability to diminish inflammation and improve the intestinal barrier. Additionally, if used prior to infection, it could help to establish PI microbial homeostasis in the GIT. Nonetheless, the blend of prebiotics needs to be further investigated in humans [131]. Niv et al. (2016) proved the effectiveness of partially hydrolyzed guar gum (PHGG) for IBS patients suffering mostly from gasses and bloating. The use of this compound did not cause any side effects. However, it did not exhibit any influence on the rest of the possible IBS symptoms [132].

All of the cited research was placebo-controlled [52,128,129,130,132], except from animal studies described by Chen et al. (2017) [131]. Among mentioned human trials, only ones conducted by Olesen et al. (2000) [128], and Silk et al. (2009) [130], were not carried out in a double-blind system. However, the study design by Silk et al. (2009) was the only one including the influence of a dose on prebiotic effectiveness in IBS therapy [130]. Research carried out by Hunter et al. (1999) and Olesen et al. (2000) did not differentiate IBS subtypes [52,128], whereas ones conducted by Silk et al. (2009), Azpiroz et al. (2016), and Niv et al. (2016) included patients exhibiting all forms of the disease [129,130,132]. Details of the above-mentioned research are presented in

Table 2. Studies on the effect of prebiotics on IBS individuals.

Paper	Research Type	Participants Selection Criteria	Participants 1	IBS Subtype	Preparation (Dosage)	Placebo/Control (Dosage)	Duration	Outcomes
Hunter et al. (1999) [52]	The randomized, controlled, double-blind, crossover study	Individual protocol	21 males/females 18–65 y 2	wd 3	Oligofructose (Raftilose P95) three times 2 g/d 4	Sucrose three times 1 g/d	First 2 weeks of normal diet, then 2 weeks of controlled standard UK diet (45% carbohydrate, 40% fat, and 15% protein)	No significant results
Olesen et al. (2000) [128]	The prospective, randomized, placebo-controlled, single-blind, and double-blind phases	Manning	98 males/females 18–70 y	wd	FOS 5 10 g/d (2 weeks)/20 g/d (next 10 weeks)	Glucose 10 g (2 weeks)/20 g/d (next 10 weeks)	First 2 weeks of single-blind phase (only placebo), then 12 weeks of double-blind phase (prebiotic/placebo)	FOS may increase the severity of IBS symptoms; however, patients might adapt after prolonged usage
Silk et al. (2009) [130]	The single-center, parallel, patient blinded, randomized, crossover, placebo-controlled trial	Rome II	44 males/females 20–79 y	All	trans-GOS 6 3.5 or 7.0 g/d	Maltodextrins DE 20 3.5 or 7.0 g/d	Baseline period—2 weeks (only placebo); next phase—3 months (prebiotic/placebo)	Increased number of Bifidobacterium spp. to a level comparable with healthy people (both doses of GOS) Increased number of Eubacterium rectale/C.coccoides (GOS dose of 3.5 g/d) Reduced number of C. perfringens (GOS dose of 7.0 g) Changes in the consistency of feces, flatulence, and overall improvement of IBS symptoms (GOS) The reduced anxiety level in the IBS-D group (GOS dose of 7.0 g/d)
Azpiroz et al. (2016) [129]	The parallel, placebo-controlled, randomized, double-blind study	Rome III	79 males/females 18–60 y	All	scFOS two times 2.5 g/d	Maltodextrins two times 2.5 g/d	28 days	Increased number of Bifidobacterium spp. Decreased level of anxiety Attenuated severity of IBS symptoms No effect on rectal hypersensitivity
Niv et al. (2016) [132]	The prospective, randomized, double-blind, placebo-controlled study	Rome III	108 males/females 18–77 y	All	PHGG 3 g/d (first week)/6 g/d (11 weeks)	Maltodextrin 3 g/d (first week)/6 g/d (11 weeks)	First 2 weeks without prebiotic/placebo, next 12 weeks of product administration, then 4 weeks of follow-up	Improvement on bloating and gasses
Chen et al. (2017) [131]	Animal study	na 7	60 four-week-old female specific pathogen-free (SPF) C57BL/6 mice	na PI-IBS 8 model	The PB (FOS, GOS, inulin, and anthocyanins) 1.26 mg/g body weight	Saline/healthy control group	8 weeks of preventive administration of the PB/saline before infection with Trichinella spiralis larvae, then 8 weeks for recovery without prebiotic	Faster recovery from body weight loss Pretreatment with PB could help to improve the well-being of PI-IBS patients PB can diminish inflammation both in the Caco-2 cells and the IBS mice model Protection of intestinal barrier integrity PB could help protect the homeostasis of GIT microbiota

¹ the final (after screening) number of participants who received treatment is given; ² years old; ³ without differentiation; ⁴ gram per day; ⁵ fructooligosaccharides; ⁶ galactooligosaccharides; ⁷ not applicable; ⁸ post-infection IBS.

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5.3. Synbiotics

Despite the concept of synbiotics being introduced in 1995, and the first attempts to recognize IBS were made at the end of the 19th century, the idea of using these preparations to treat the disease appeared in the last decade [133].

In 2013, Cappello et al. performed the first analysis of Probinul^® and its impact on IBS individuals. The synbiotic included inulin, tapioca-resistant starch, and Lactobacillus spp. (6) and Bifidobacterium spp. (2) strains, as well as Streptococcus thermophilus. Probinul^® did not diminish flatulence and bloating to the satisfying level according to participants of the trial [134]. Shavakhi et al. (2014), who studied the impact of Balance^®, which included FOS, and probiotic strains from Lactobacillus (4) and Bifidobacterium (3) genus, as well as S. thermophilus, did not observe any influence of the preparation on IBS patients [135]. Similar results were obtained by Bogovič Matijašic et al. (2016), who studied synbiotic fermented milk product containing Lb. acidophilus La-5, B. lactis BB-12, and 2% dietary fiber (Beneo Orafti Synergy1; 90% inulin, 10% oligofructose) [136]. On the contrary, Bucci et al. (2014) noted the attenuation of flatulence in IBS subjects after 4 weeks of the disease treatment with Probinul^®, which was sustained during a 6 months period of therapy [137]. Another synbiotic, namely, Lactol^®, including B. coagulans and FOS, was tested by Rogha et al. (2014). The research team noted relief of abdominal pain, discomfort, and diarrhea in IBS individuals; however, no improvement in constipation-related symptoms was observed. Nonetheless, the study revealed some side effects of the preparation; therefore, its safety has to be further evaluated [54]. Although, Asgarshirazi et al. (2015), who analyzed the effectiveness of Lactol^® in treating functional abdominal pain in children, did not notice any side effects of the preparation [138]. Moser et al. (2019) conducted a study on the impact of yet another synbiotic preparation named OMNi-BiOTiC^® Stress Repair on IBS-D patients. The preparation comprised prebiotics, namely, corn starch, maltodextrin, inulin, and FOS, along with Lactococcus lactis W19, Lactobacillus spp. (5), and Bifidobacterium spp. (3) strains. Results showed a positive influence of the mixture on mucosal microbiota diversity and concentrations of acetate and butyrate in fecal samples [139]. Lee et al. (2019) studied the impact of another synbiotic preparation, containing inulin, FOS, and probiotic strains from Lactobacillus (6) and Bifidobacterium (2) genus on IBS patients. The research team observed improvement in bloating, fatigue, and abdominal discomfort in trial participants [140]. On the other hand, Min et al. (2012) and Bahrudin et al. (2020) analyzed the influence of synbiotic dairy products, such as yogurt with the addition of Bifidobacterium animalis subsp. lactis Bb-12 and acacia dietary fiber, and drink containing Lb. helveticus and polydextrose as a prebiotic, respectively, on IBS subjects [141,142]. Min et al. (2012) described that the studied product could attenuate symptoms of the disease in both IBS-C and IBS-D patients [141]. Bahrudin et al. (2020) observed the beneficial effect of synbiotic only in studied IBS-C individuals. Nevertheless, the researchers concluded that probiotic strain alone is the active agent [142]. The effective mixture of pro- and prebiotics for IBS-D patients, which reduce the feeling of incomplete intestinal movements, release abdominal pain, and help to regulate stool patterns, have been described by Skrzydło-Radomańska et al. (2021). The synbiotic comprised probiotics, namely, Lb. rhamnosus FloraActive 19070-2, Lb. acidophilus DSMZ 32418, B. lactis DSMZ 32269, B. longum DSMZ 32946, B. bifidum DSMZ 32403 strains, and scFOS as a prebiotic compound [143]. Last but not least, in 2020, Seong et al. described a synbiotic, containing Lb. paracasei DKGF and Opuntia humifusa extract as a prebiotic, effective in IBS murine model. Nevertheless, its functionality must be further assessed in humans [144].

Most of the cited research [54,134,135,136,137,140,142,143] was conducted as double-blind, placebo-controlled, except from Moser et al. (2019) [139], as well as Seong et al. (2020) [144], who performed the animal study. Two studies were conducted on people suffering from the IBS-C subtype [136,142], and the other two on subjects with IBS-D [139,143]. Four studies did not differentiate subtypes of the disease [54,134,135,137], whereas the rest of mentioned research focused on all subtypes [140,141]. Furthermore, only one trial involved dose-related dependencies [140]. Detailed descriptions of the aforementioned studies are listed in

Table 3. Researches on the influence of synbiotics on IBS patients.

Paper	Research Type	Participants Selection Criteria	Participants 1	IBS Subtype	Preparation (Dosage)	Placebo/Control (Dosage)	Duration	Outcomes
Min et al. (2012) [141]	The randomized, double-blind, controlled trial	Rome III	117 males/females 18–70 y 2	All	Yogurt with standard strains S. thermophilus (≥3 × 109 cfu 3/bottle) and Lb. acidophilus (≥109 cfu/bottle) with the addition of Bifidobacterium animalis subsp. lactis Bb-12 (≥1011 cfu/bottle), Bifidobacterium enhancer, and acacia dietary fiber	Yogurt with standard strains S. thermophilus (≥3 × 109 cfu/bottle) and Lb. acidophilus (≥109 cfu/bottle) with the addition of Bifidobacterium animalis subsp. lactis Bb-12 (≥1011 cfu/bottle)	8 weeks	Improvement in bowel habits and IBS symptoms
Cappello et al. (2013) [134]	The parallel-group, double-blinded, placebo-controlled study	Rome III	64 males/females 18–75 y	wd 4	Probinul ® (5 × 109 Lb. plantarum, 2 × 109 Lb. casei subp. rhamnosus, 2 × 109 Lb. gasseri, 1 × 109 B. infantis, 1 × 109 B. longum, 1 × 109 Lb. acidophilus, 1 × 109 Lb. salivarus, 1 × 109 Lb. sporogenes, 5 × 109 S. thermophilus, 2 g inulin, 1.3 g tapioca-resistant starch) twice 5 g/d 5	No data on used compounds product by CaDi Group (Rome, Italy)	2 weeks prior to synbiotic/placebo administration, then 4 weeks of treatment	Decreased flatulenceThe increased transition time of intestinal content Improved in self-scored quality of IBS patients’ life No overall relief of symptoms
Bucci et al. (2014) [137]	The parallel-group, double-blinded, randomized, placebo-controlled study (core study) and the open-label prospective, partially controlled	Rome III	64 males/females 18–75 y	wd	Probinul® twice 5 g/d (during extension period only 2 weeks/month)	Lack of information	4 weeks of core study, then 6 months of the extension period	Decreased flatulence even during cyclic administration
Rogha et al. (2014) [54]	The randomized, double-blinded, placebo-controlled trial	Rome III	56 males/females The average age of 39.8 ± 12.7	wd	Lactol® (1.5 × 108 spores of B. coagulans and FOS) 100 mg	Lactose starch and tartazine 100 mg	12 weeks	Relief from abdominal pain/discomfort and diarrhea
Shavakhi et al. (2014) [135]	The randomized, placebo-controlled, triple-blinded study	Rome II	129 males/females average age of 36.2 ± 9.3	wd	Balance® (FOS, magnesium stearate, hydroxypropyl methyl cellulose, Lb. casei, Lb. rhamnosus, Lb. acidophilus, Lb. bulgaricus, B. breve, B. longum, S. thermophilus; a total of 1 × 108 cfu/capsule) 2 capsules a day	No data on used compounds 2 capsules a day	14 days	No effect of treatment
Bogovič Matijašic et al. (2016) [136]	The double-blind, randomized, placebo-controlled multicenter trial	Rome III	30 subjects 18–65 y	IBS-C	Fermented milk (starter culture: S. thermophilus ABT-21, probiotics: 1.8 × 107 cfu/g Lb acidophilus La-5, 2.5 × 107 cfu/g B. lactis BB-12, 2% dietary fiber Beneo Orafti Synergy1—90% inulin, 10% oligofructose) 360 g/d	Heat-treated fermented milk without probiotic bacteria and dietary fibers 360 g/d	2 weeks run-in period, then 4 weeks of treatment, and 2 weeks of follow-up	Increased abundance of used probiotic strains in subjects’ fecal samples Transient colonization of used probiotics The abundance of the Enterobacteriaceae family was not affected No significant changes in fecal microbiota
Moser et al. (2019) [139]	Pilot study	Individual protocol	10 males/females 37–53 y	IBS-D	OMNi-BiOTiC® Stress Repair (corn starch, maltodextrin, inulin, FOS, potassium chloride, magnesium sulfate, mangan sulfate, enzymes, 7.5 × 109 of each strain: Lb. casei W56, Lb. acidophilus W22, Lb. paracasei W20, Lb. salivarius W24, Lb. plantarum W62, L. lactis W19, B. lactis W51, B. lactis W52, B. bifidum W23)	na 6	4 weeks	Increased phylogenetic diversity of gastric and duodenal microbiota Reduced number of CD4+ T cells in the ascending colon Higher levels of acetate and butyrate in fecal samples
Lee et al. (2019) [140]	The single-center, randomized, double-blind, placebo-controlled clinical trial	Rome III	28 males/females ≥19 y	All	Ultra-Probiotics-500 (1 × 1013 cfu of probiotic strains: Lactobacillus (rhamnosus, acidophilus, casei, bulgaricus, plantarum, and salivarius), Bifidobacterium (bifidum and longum, 175 mg of FOS, 150 mg of Ulmus davidiana, 10 mg of Geum urbanum, and 100 mg of inulin) 1 capsule/d (low-dose group)2 capsules/d (high-dose group)	The same material used for encapsulation. No data on used compounds. 1 capsule/d (low-dose group) 2 capsules/d (placebo group)	8 weeks	No dose-dependent effects Decrease the fatigue in IBS individuals (high-dose) Relief in abdominal pain/discomfort, bloating, stool patterns
Bahrudin et al. (2020) [142]	The prospective, double-blind, randomized, controlled trial	Rome III	163 males/females 22–37 y	IBS-C	Synbiotic drink (water, sugar, skimmed milk powder (cow), stabilizers (polydextrose), fermented milk (water, acidity regulator, skimmed milk powder (cow), and lactobacillus), acidity regulators, soybean fiber, and flavoring) with Lb. helveticus and 1.5 g/100 mL polydextrose 350 mL/d 5	Probiotic drink ((water, sugar, skimmed milk powder (cow), stabilizers (polydextrose), fermented milk (water, acidity regulator, skimmed milk powder (cow), and lactobacillus), acidity regulators, soybean fiber, and flavoring)) with Lb. helveticus 350 mL/d	1 week	Shortened intestinal transition time Reduced fecal pH Relief in constipation-related symptoms No difference between synbiotic and control group—probiotic alone conferred a health benefit
Seong et al. (2020) [144]	Animal study	na	20 male Wistar rats (weight: 350 ± 50 g) aged 8 weeks	na	Treatment group 1—maltodextrin, 1 × 1010 cfu/g Lb. paracasei DKGF; Treatment group 2—maltodextrin, 1 × 1010 cfu/g Lb. paracasei DKGF, 10.0 mg (w/w) Opuntia extract; Treatment group 3—maltodextrin, 1 × 1010 cfu/g Lb. paracasei DKGF, 30.0 mg (w/w) Opuntia extract	Maltodextrin	4 weeks	Improved stool consistency (better in synbiotic groups) Decreased serum corticosterone levels (lower in synbiotic groups) Low levels of TNF-α 7 in the colonic mucosa (both synbiotic and probiotic groups) Increased expression of the tight junction proteins (higher in synbiotic groups) Higher abundance of Lb. paracasei in fecal samples (more significant difference in synbiotic groups)
Skrzydło-Radomańska et al. (2021) [143]	The randomized, double-blind, placebo-controlled, parallel group trial	Rome III	68 males/females 18–60 y	IBS-D	Synbiotic containing a total of 5.0 × 109 probiotic strains (B. lactis DSMZ 32269, B. longum DSMZ 32946, B. bifidum DSMZ 32403, Lb. rhamnosus FloraActive 19070-2, Lb. acidophilus DSMZ 32418) and 947 mg of scFOS 2 sachet/d	978 mg of maltodextrin2 sachet/d	2 weeks screening period, then 8 weeks of treatment	Attenuation of IBS symptoms (pain, flatulence, stool pressure, feeling of incomplete bowel movements) Decreased severity of IBS symptoms

¹ the final (after screening) number of participants who received treatment is given; ² years old; ³ colony-forming units; ⁴ without differentiation; ⁵ not applicable; ⁶ milliliters per day; ⁷ tumor necrosis factor α.

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6. Summary

In conclusion, the use of probiotics, prebiotics, and synbiotics in IBS treatment is still in need of investigation and standardization. Researchers focused mostly on probiotics, especially multi-strain ones, creating a demand for new research on prebiotics, and synbiotics in the management of IBS.

The vast majority of trials are double-blind and placebo-controlled; however, there are still studies conducted in an open-label system, as well as with no control or placebo group, which could bring unreliable results. Additionally, analyzed preparations differ in probiotic strains, their number, and density, as well as amount and type of prebiotic or their combination, in the case of synbiotics. Moreover, the dosage of studied preparations varied among research, and its impact is rarely analyzed. Most of the trial designs would benefit from a longer treatment period and additional follow-up phase since this aspect is mostly described by researchers as a study limitation. Another obstruction of research might be the number of participants that rarely exceeded 100. However, this obstacle is hard to avoid because individuals are entering the trials voluntarily. Lastly, not every probiotic, prebiotic, and their combination would be an appropriate mode of treatment for each IBS subtype, which also needs to be studied in more detail.

Nevertheless, the last two decades of research on probiotics, prebiotics, and synbiotics bring satisfying results and they are acknowledged as effective and safe in IBS therapy. These preparations can be introduced as an alternative to drugs that might carry a risk of side effects, especially in long-term use. Among the field of microbiota-manipulation-based therapies, probiotics, prebiotics, and synbiotics are a promising direction of alleviation of symptoms for people suffering from IBS.