The role of the gut microbiota in the treatment of inflammatory bowel diseases

Microbial Pathogenesis 137 (2019) 103774

Contents lists available at ScienceDirect

Microbial Pathogenesis journal homepage: www.elsevier.com/locate/micpath

The role of the gut microbiota in the treatment of inflammatory bowel diseases

T

Ioanna Aggeletopouloua, Christos Konstantakisa, Stelios F. Assimakopoulosb, Christos Triantosa,∗ a b

Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, 26504, Greece Department of Internal Medicine, University Hospital of Patras, Patras, 26504, Greece

A R T I C LE I N FO

A B S T R A C T

Keywords: Gut microbiota Inflammatory bowel diseases Immune system Treatment Pathogenesis Cross talk

The human intestinal microbiota coevolves with its host through a symbiotic relationship and exerts great influence on substantial functions including aspects of physiology, metabolism, nutrition and regulation of immune responses leading to physiological homeostasis. Over the last years, several studies have been conducted toward the assessment of the host–gut microbiota interaction, aiming to elucidate the mechanisms underlying the pathogenesis of several diseases. A defect on the microbiota–host crosstalk and the concomitant dysregulation of immune responses combined with genetic and environmental factors have been implicated in the pathogenesis of inflammatory bowel diseases (IBD). To this end, novel therapeutic options based on the gut microbiota modulation have been an area of extensive research interest. In this review we present the recent findings on the association of dysbiosis with IBD pathogenesis, we focus on the role of gut microbiota on the treatment of IBD and discuss the novel and currently available therapeutic strategies in manipulating the composition and function of gut microbiota in IBD patients. Applicable and emerging microbiota treatment modalities, such as the use of antibiotics, prebiotics, probiotics, postbiotics, synbiotics and fecal microbiota transplantation (FMT) constitute promising therapeutic options. However, the therapeutic potential of the aforementioned approaches is a topic of investigation and further studies are needed to elucidate their position in the present treatment algorithms of IBD.

1. Introduction Crohn's disease (CD) and ulcerative colitis (UC) are the main types of inflammatory bowel diseases (IBD). UC is usually limited to the colon and consists of diffuse mucosal inflammation with neutrophils predominating in the lamina propria and crypts [1,2]. By contrast, CD can involve inflammation at any part of the gastrointestinal tract but the typical preferential regions of involvement are the small intestine, especially the terminal ileum, and the colon [1]. The exact underlying mechanism of IBD is a topic of research. Interactions among genetic and environmental factors, impaired immune regulation, gut barrier dysfunction and changes in the intestinal flora are related to the pathogenesis and development of IBD [1,3–6] (Fig. 1). Αlterations of the composition and function of the gut microbiota, which is referred as dysbiosis, have gained attention as an important pathogenetic factor for IBD, with the advent of next generation sequencing. Dysbiosis in patients with IBD can modulate all major pathogenetic factors, such as impaired epithelial barrier function,

defective bacterial recognition, antigen presentation and autophagy, dysregulated T cell responses leading to aberrant innate immune responses [1,3–6]. 2. Gut microbiota composition A complex community of microorganisms including fungi, parasites, viruses, archaea and mainly bacteria, called gut microbiota, is located in the human gut [7,8]. Based mainly on culturing techniques it had been estimated that more than 1000 bacterial species inhabit the gastrointestinal tract [9]. The magnitude of bacterial species diversity raised from 15000 to 36000 species based on rRNA sequence analysis, with the advancement of metagenomic technology [10]. The Metagenomics of the Human Intestinal Tract (Meta HIT) project revealed a total of 3.3 million non-redundant microbial genes in human fecal specimens [11]. The composition and volume of gut microbiota varies across the gastrointestinal tract. The colon is colonized by over 160 to 500 different bacterial species, characterized by a considerable range of

∗

Corresponding author. D. Stamatopoulou 4, Rio, 26504, Patras, Greece. E-mail addresses: [email protected] (I. Aggeletopoulou), [email protected] (C. Konstantakis), [email protected] (S.F. Assimakopoulos), [email protected] (C. Triantos). https://doi.org/10.1016/j.micpath.2019.103774 Received 30 May 2019; Received in revised form 30 September 2019; Accepted 2 October 2019 Available online 03 October 2019 0882-4010/ © 2019 Elsevier Ltd. All rights reserved.

Microbial Pathogenesis 137 (2019) 103774

I. Aggeletopoulou, et al.

and synthesizes short chain fatty acids (SCFA) such as butyrate, propionate and acetate, which are rich sources of energy for the intestinal epithelium [20]. In addition, gut microbiota synthesizes vitamins B and K, niacin, biotin and folate and completes the entero-hepatic cycle of biliary acids [21]. Immunologically, the gut microbiota contributes to gut immunomodulation interacting with both the innate and adaptive immune systems, through production of microbial-associated molecular patterns (MAMPS), which are recognized by specific receptors of intestinal immune cells [22]. In addition, intestinal microbiota prevents growth of potentially pathogenic bacteria by antagonizing them for nutrients and receptors, by producing antimicrobial factors and exerting colonization resistance. 4. Gut microbiota – intestinal epithelium cross talk Through all these functions, gut microbiota exerts a pivotal role in preserving the integrity of the intestinal epithelium, affecting intestinal epithelial cell turnover, apoptosis, and tight junctions’ expression and function. A number of studies have demonstrated that gut microbiotaproduced signals control intestinal epithelial cell apoptosis, proliferation and differentiation, thus leading to altered epithelial morphology and architecture in germ-free animals [23,24]. Oral administration of non-pathogenic Escherichia coli and other commensal bacteria in germfree experimental animals induced a compensatory response characterized by increased crypt epithelial proliferation and intestinal villi apoptosis, to regenerate the injured gut epithelium through increase in the overall intestinal epithelial cell turnover, while concurrently brush border enzymes activity were restored [24,25]. These protective actions of commensal flora on intestinal epithelial cell turnover and regenerative capacity have been demonstrated in experimental animal models of intestinal inflammation, such as the dextran sodium sulfate (DSS) model of colitis [26]. The potential mechanism(s) controlling the positive effect of commensal flora on epithelial regeneration involve an oxidative stress induction of a mitogen-activated protein kinases dependent pathway and inactivation of focal adhesion kinase phosphatases, which alter the status of growth regulatory proteins, while apoptosis is induced via a cytochrome c-mediated activation of the caspase family [27,28]. Tight Junctions (TJs) between adjacent intestinal epithelial cells constitute another major factor implicated in epithelial integrity and gut permeability. Several factors associated with an altered bacterial balance of the intestinal ecosystem have been associated with injurious effects on the regulation of TJs expression, localization, assembly and function, such as direct attachment of pathogens on intestinal epithelium, increased levels of proinflammatory mediators and oxidative stress [29]. Commensal bacteria and probiotics have a positive effect on the TJ barrier, thus enhancing the epithelial resistance to pathogens, reducing also the paracellular permeability of antigens that may cause inflammation [30]. In experimental animal models of colitis (DSS-induced colitis), probiotics prevented gut barrier dysfunction and increased permeability through restoration of TJs’ proteins expression [31]. In addition, in vitro studies have demonstrated that SCFAs, a bacterial flora fermentation product, increase intestinal epithelial monolayer resistance, through modulation of TJs assembly via an AMPactivated protein kinase pathway [32]. Gut microbiota exerts a pivotal role in orchestrating the innate and adaptive immune response of the intestinal immune system. MAMPs can be recognized by intestinal epithelial cells as well as by myeloid cells in the lamina propria and induce a variety of effects, including tissue repair, and production of antimicrobial peptides. Pathogen-associated molecular patterns (PAMPs) are recognized by pattern recognition receptor (PRR)-bearing cells [Toll-like receptors (TLRs) and Nod-like receptors (NLRs)] of the innate immune system and many epithelial cells [22]. Diverse substances originating from commensal bacteria, like SCFAs, fragelin, lipopolysaccharide (LPS) and sphingolipids modulate B-cell switch to IgA producing plasma cells, induce T-cell

Fig. 1. The complex interplay of host microbiota dysbiosis, dysregulation of immune response, host genetic background and environmental factors have been implicated in the pathogenesis of the IBD. The perturbation of gut microbiota influences the metabolic and immunological environment of the intestine leading to the development of inflammation. Dysbiosis influences both innate and adaptive immune responses, perpetuating the inflammation and increasing the risk of disease initiation.

microbiological characteristics [8]. Despite this unique biodiversity, gut microbes are mainly distributed in only four bacterial phyla, namely Firmicutes, Bacteroidetes, Actinobacteria and Proteobacteria [12]. The Firmicutes phylum is composed mainly by Gram+, aerobic and anaerobic bacteria. Prominent members are Clostridia strains, but potentially pathogenic Gram+ (streptococci, enterococci, staphylococci) are also members. Bacteroidetes are Gram− bacteria which are extremely well adapted to the intestinal environment. Actinobacteria are Gram + bacteria generally considered beneficial, such as the Bifidobacterium genus and the Proteobacteria phylum contains Gram-bacteria, most notably the family Enterobacteriaceae. The onset of bacterial colonization of the previously sterile fetal gut is considered to take place at birth [13]. Moreover, there is evidence supporting the existence of microbes even in womb tissues, such as the placenta [14,15]. The first bacterial species acquired from the maternal, anal or vaginal flora at birth, consist mainly of species such as Bacteroidetes, Bifidobacterium, Prevotella and Lactobacillus spp [13]. During the first year of life, gut microbiota diversity is expanded, and its composition nearly reflects that of an adult-like microbial profile [16]. During adulthood, gut microbiota composition is relatively stable; however, various alterations which are mainly related to dietary, or overall health changes could occur over time [17,18]. Bacteroidetes and Firmicutes phyla are the representative bacterial species isolated from human feces or mucosal biopsies [19]. The whole genome of the host's gut microbiota consists the gut microbiome, which encodes about 3 million genes that is 100fold more than the human genome. Gut microbiome is unique among hundreds of people and a vast proportion of it (80%) remains stable over time. However, existing differences are adequate to characterize everyone, therefore gut microbiome consists a molecular fingerprint of each one of us. 3. Gut microbiota physiological functions The intestinal epithelium is in contact with the microbial ecosystem of the gut, establishing a dynamic relationship. This relationship is not only commensal, but also mutualistic. Microbiota displays important metabolic, immunologic and gut protective functions. Metabolically, microbiota ferments carbohydrates, and indigestible oligosaccharides 2

Microbial Pathogenesis 137 (2019) 103774

I. Aggeletopoulou, et al.

Fig. 2. Schematic representation of the host-bacteria interactions in the intestinal mucosa of a A. healthy individual and B. an IBD patient. A. In healthy gut both commensal and pathogenic bacteria are distributed throughout the mucous layer, whereas the intestinal epithelium is intact and therefore resistant to bacterial invasion. Commensal microbiota and associated produced substances (SCFA, sphingolipids, fragellin, PAMPs) positively affect enterocytes' turnover, TJ's structural and functional integrity and mucosal immune responses. The pathogenic bacteria and the pathobionts are suppressed by the commensal microbiota, maintaining the intestinal homeostasis. B. In patients with IBD, gut microbiota disruption caused by various factors leads to imbalance in the intestinal microbiota composition, in favor of pathogenic bacteria and pathobionts (dysbiosis). Pathogenic bacteria gain increased attachment to the intestinal epithelium through a disrupted and thinner mucus layer, which is the first step in the bacterial translocation process. In addition, dysbiotic microbiota through altered production of SCFA, sphingolipids and fragelin deprive enterocytes from necessary energy supply thus promoting a defective regenerative response and increased apoptosis, disrupt the integrity of TJs and dysregulate mucosal immune responses. Pathogenic bacteria translocate through this defective intestinal epithelium and cannot be effectively cleared by the dysregulated gut immune system. Increased production of cytokines and reactive oxygen species, produced by activated mucosal macrophages, further damage the intestinal epithelium promoting the bacterial translocation process, thus preserving this vicious cycle of intestinal inflammation.

the role of the gut microbiota has been found to play a major role, as it can be modified through its interactions with environmental factors or by the genetic predisposition of the host [35].

differentiation to T-helper 17 (Th17) cells and promote T regulatory cells (Tregs) proliferation and differentiation [22]. Antigen-presenting cells (APCs) also rely on the microbiota to organize the immune response [33]. The above analyzed beneficial and complex interplay of gut microbiota with the underlying intestinal epithelium may be disrupted by an alteration in the microbiota composition which leads to a microbial imbalance, known as dysbiosis (Fig. 2). Dysbiosis is characterized by a significant decrease in beneficial microbial populations and their functional diversity and stability; it is considered to be a key element in inflammatory processes of the gut, as the reduction in beneficial anaerobes results in the release of inflammatory agents further inducing gut inflammation [34].

5.1. Dysbiosis and reduced diversity in IBD Dysregulated gut microbiota with decreased bacterial diversity and higher bacterial instability have been reported in IBD patients compared to healthy controls [36]. Microbes that normally exist in the healthy gut, such as members of the phyla Bacteroidetes and Firmicutes, are severely diminished in IBD with a concomitant increase of harmful populations, such as the phyla Actinobacteria and Proteobacteria [4,37–39]. A pyrosequencing study has demonstrated a rise in Enterobacteriaceae, with a concomitant decrease in Faecalibacterium, suggesting that bacterial populations differ among patients with different CD phenotypes [40]. Beyond the changes in the microbiota composition, reduced microbial diversity has been observed in IBD patients [38,39,41]. Studies have shown that the adherent-invasive E. coli pathotype, Yersinia and Clostridioides difficile are in abundance in patients with CD compared to the healthy population [42–44]. Alterations in the levels of bacterial species encountered in patients with IBD have been associated with changes in key functions of the gut microbiota. Namely, such changes are the reduced metabolism of SCFAs, mainly acetate, propionate and butyrate, the decreased biosynthesis of amino acids and the increased auxotrophy, oxidative stress

5. Role of gut microbiota in IBD pathogenesis The gut microbiota plays a crucial role in the development and function of the physiological immune responses, and in parallel, immune responses regulate the composition and function of the gut microbiota. The pathogenesis of IBD, as described in Fig. 1, is based on the interplay among genetic susceptibility, dysregulation of immune responses, dysbiosis and environmental factors [1,3–6]. The function of bacteria in the pathogenesis of colitis was first reported in the 1900s. However, over the last years, substantial evidence on the role of gut microbiota in the immunopathogenesis of IBD has emerged. Especially, 3

Microbial Pathogenesis 137 (2019) 103774

I. Aggeletopoulou, et al.

severe inflammatory response [65,66]. Bacterial recognition through TJs and the underlying gut-associated lymphoid tissues (GALT) are among the key strategies to reach an ideal balance between tolerance and immune response. IBD pathogenesis has also been associated with the aberrant activation of the GALT against components of the gut microbiota leading to the development of intestinal inflammation [67]. This process is fostered by IBD-related defects in intestinal barrier function, which favor bacterial translocation in the intestinal lamina propria, resulting in abnormal activation of both innate and adaptive mucosal immune responses [68].

and secretion of toxins [45]. The role of SCFAs in IBD pathogenesis is of special interest due to their involvement in the regulation of cellular processes (gene expression, differentiation, proliferation, chemotaxis and apoptosis) [46]. The aforementioned altered gut bacterial composition (dysbiosis) leads to minimized resistance to pathogen colonization and induction of pathobionts’ growth. Various studies have proposed that the microbiota related to IBD is enriched with pathobionts [47,48]. Nevertheless, there is no identification of a specific pathogen being an etiopathogenetic factor for IBD; some autochthonous pathobionts could have a pathogenic role in genetically predisposed individuals due to environmental or dietary changes that consequently promote the initiation of intestinal inflammation [47,49].

5.5. Dysbiosis and oxidative stress induction in IBD pathogenesis The induction of reactive oxygen species (ROS), which are associated with intestinal dysbiosis, plays a significant role in microbiotaassociated diseases, such as IBD [69,70]. The gut microbiota, during inflammation, can produce ROS directly or other enzymes which participate in endogenous ROS generation, such as nitric oxide synthase (NOS) through macrophage activation, promoting DNA damage [71]. Oxidative stress is caused by a disturbance in pro-oxidative molecules and antioxidant defenses, resulting to cellular impairments, including DNA damage, protein aggregation, and membrane abnormal function. The bacterial infection results in the alteration of the DNA repair system. Oxidative stress caused by ROS production promotes an initial inflammatory response through positive feedback, enhancing the ROS production and the consequent tissue damage [72].

5.2. Dysbiosis and dysregulation of T-cell differentiation in IBD pathogenesis Interaction of T cells with gut microbiota is very important for maintaining intestinal immunity. Th17 cell differentiation is partially defined by the composition of the endogenous gut microbiota. In a germ-free system or in the presence of antibiotics Th17 cell differentiation in the intestine is highly decreased [50]. Tregs play a critical role in maintaining immune homeostasis and establishing inflammation in response to commensal bacteria, and failure of their function results in the development of inflammation [50]. The dynamic balance regulated by the gut microbiome between Th17 and Tregs is thought to be an important aspect in the development of IBD as the developmental pathways of Th17 and Tregs are related with their differentiation and this balance is crucial in preserving intestinal homeostasis [51].

6. Gut microbiota as therapeutic strategy The perturbation of normal gut microbial communities has been implicated in IBD pathogenesis [20,73]. Recent advances evaluating the therapeutic potential of gut microbiota in treating IBD have supported the reconstitution of microbial populations through the administration of appropriate microbes. Gut microbiota exerts its effects on the host through the regulation of physiological, pathophysiological and immunological procedures [74–76]. After using experimental animal models and/or human data, studies have demonstrated the impact of gut microbiota in improving inflammation and highlighted its potential as a therapeutic strategy for treating inflammatory conditions [77–79]. Researches evaluating the anti-inflammatory effect of gut microbiota have shown promising results in treating gastric ulcers [80,81] and colorectal cancer [82–84]. In parallel, several therapeutic strategies have been developed to modulate and reconstruct the gut microbiota for the management of other gastrointestinal disorders [85]. Antibiotics, prebiotics, probiotics, postbiotics, synbiotics and fecal microbiota transplantation (FMT) are currently considered the most common treatment approaches.

5.3. Dysbiosis and altered regulation of intestinal epithelial cell death mechanisms in IBD pathogenesis In vivo and in vitro studies, have demonstrated the potential implication of cell death mechanisms in the pathogenesis of IBD. The occurrence of a complex crosstalk between autophagy, apoptosis, microbe sensing, and increased endoplasmic reticulum (ER) stress in the epithelium has been implicated in the pathogenesis of CD [52]. Studies have demonstrated that the ileal involvement in CD may be associated with Paneth cell dysfunction, suggesting a link between innate immunity, ER stress, and cell death [53,54]. Moreover, a novel necrosislike pathway called necroptosis, which is related to TNF receptor activation, is implicated to the pathogenesis of CD [55,56]. Lastly, in both animal models and IBD patients, amplification loops involving oxidative stress and inflammation mediated by damage-associated molecular pattern (DAMPS) have been associated with cell death in the intestinal mucosa [57,58].

6.1. Antibiotics

5.4. Dysbiosis and disruption of epithelial barrier integrity in IBD pathogenesis

Antibiotics can induce remission when disease is active and prevent relapse in IBD patients [86]. However, antibiotic use initiates a significant reaction on the gut microbiota. The imbalance caused in the composition of gut microbiota using antibiotics has been found to play a major role in the disease activity in both UC and CD patients. The exposure of gut bacterial populations to a short-term antibiotic use results in a decrease of susceptible bacteria, an overall reduction in their diversity and an increased probability of naturally resistant bacteria colonization [87,88]. The gut microbiota responds rapidly to antibiotics' exposure to avoid the antibacterial effects. Significant metabolic alterations occur at this stage such as the decline of the transport and metabolic capacity of bile acid, cholesterol, hormones and vitamins. However, the completion of antibiotic treatment results in the amelioration of microbial interactions. Data on the long-term effect of antibiotics’ use on the human gut microbiota are scarce. Nonetheless, studies using experimental animal models have proved that antibiotic

Dysfunction of the epithelial barrier along with alterations in paracellular permeability due to modified intercellular junctions may be a crucial factor in the pathogenesis of IBD [59]. Genome wide association studies (GWAS) have demonstrated several genes that link TJs' function to IBD [60,61]. Experimental studies including mice with genetic deficiencies similar to those found in human IBD patients have confirmed the importance of altering TJs and barrier integrity in IBD pathogenesis [62,63]. Specifically, intestinal epithelial cells act as a physical barrier, preventing the invasion of foreign pathogens [64]. Studies in human and experimental models with IBD have shown that prolonged inflammation combined with the disruption of TJs, result in the loss of intestinal epithelial cells’ integrity [65,66]. This process, facilitates the leakage of luminal pathogens across the epithelial barrier and the activation of TLRs, Dectin-1 and Caspase recruitment domaincontaining protein 9 (CARD9) in the lamina propria leading to a more 4

Microbial Pathogenesis 137 (2019) 103774

I. Aggeletopoulou, et al.

controlled studies are required [119]. Regarding the use of probiotics in UC patients, positive influence has been demonstrated in both induction and maintenance of remission. A new meta-analysis has shown that the use of VSL#3 is effective in inducing remission in active UC and that probiotics appeared to be safe and could be used as an alternative to 5‐aminosalicylates (5‐ASAs) for disease maintenance [118]. Another meta-analysis confirmed these results proving that probiotics and particularly VSL#3 have shown great effectiveness in UC patients [119]. Lastly, the results of a randomized, double-blind, placebo-controlled study assessing the efficacy of a multi-strain probiotic in IBD patients have reported positive outcomes for UC patients [120]. In particular, the multi-strain probiotic was related to reduced intestinal inflammation in UC patients and no serious adverse event was recorded [120]. In CD patients, there was no amelioration in intestinal inflammation [120].

exposure at early stages of life causes long term effects on the microbiota, which could affect body composition and contribute to the development of obesity [89]. Antibiotics use in treating IBD has been examined in 2 meta-analyses showing consistent results. The first reported that antibiotics may be beneficial in inducing remission in both UC and CD [90] and the second supported that antibiotics can ameliorate clinical outcomes in IBD [91]. On the contrary, another metaanalysis has shown that exposure to antibiotics, particularly in early childhood, increases the risk of being newly diagnosed with CD but not UC [92]. In the most recent ECCO guidelines, the use of antibiotics in CD patients is considered appropriate for septic complications, symptoms attributable to bacterial overgrowth or perineal disease [93], whereas in UC patients the existing data are insufficient to recommend antibiotics for maintenance of remission [94]. 6.2. Prebiotics

6.4. Postbiotics Prebiotics are nondigestible carbohydrates that are selectively fermented by intestinal bacteria which promote their development or activity with beneficiary results for the host [95]. Prebiotics typically include inulin, fructo-oligosaccharide (FOS), galacto-oligosaccharide (GOS), and lactulose which have been documented to increase commensal Lactobacillus and/or Bifidobacterium spp. in healthy populations [96]. Prebiotics have established some efficacy on IBD through several mechanisms of action, such as selective growth of native bacteria of the intestinal microbiota and increased SCFAs production (i.e. acetate, butyrate and propionate). Intestinal SCFAs increase results in decreased colonic pH and inhibition of pathogenic microorganisms adhesion to the intestinal cells, alterations in both colonocytes morphology and function with a consequent beneficial role in repairing inflamed intestinal epithelium in IBD patients, the stimulation of epidermal growth factor receptor (EGFR) to preserve intestinal homeostasis, the inhibition of proinflammatory cytokines, and lastly the suppression of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [97–101]. Studies evaluating the use of prebiotics in animal models, rats and mice have demonstrated positive outcomes [102–105]. A recent metaanalysis, which evaluated the effect of prebiotics on induced IBD, has highlighted their beneficial role in TNBS-induced colitis rats, regarding the growth of Lactobacillus and Bifidobacterium, the increase in SCFAs production, the decrease in macroscopic lesions to the colon and the amelioration in inflammatory markers [106]. In humans, despite the excellent safety profile, there is inadequate evidence to support prebiotic use in the clinical management of IBD [107–109].

Postbiotics refer to cell-wall components and/or metabolic byproducts, which are secreted by live bacteria or released following bacterial lysis that could contribute to health improvement of the host [121]. Postbiotics may stimulate anti-inflammatory immune responses and act as immunomodulators [121]. These properties suggest the use of postbiotics as an alternative therapeutic approach to probiotics for the treatment of intestinal inflammatory diseases. One study has evaluated the potential role of postbiotics in an ex-vivo organ culture model and concluded that this could be an effective and safe choice for the treatment of patients with acute IBD [122]. 6.5. Synbiotics The term synbiotics refers to a combination of probiotics and prebiotics. Synbiotics combine the beneficial effects of both probiotics and prebiotics improving the survival of live microbial dietary supplements in the gastrointestinal tract [123,124]. The most commonly used probiotics in symbiotic preparations include Lacbobacilli, Bifidobacteria spp., S. boulardii, B. coagulans, while the most typical prebiotics are oligosaccharides like FOS, GOS xyloseoligosaccharide (XOS) and inulin. It has been suggested that synbiotics contribute to 1) the reduction of undesirable microbial metabolic activities, such as the inhibition of the rate-limiting enzymes of different metabolic pathways [125], 2) the decrease of harmful microbiota, such as Clostridium and Enterobacterium and the 3) increase of beneficial strains such as Lactobacilli and Bifidobacteria [126,127], 4) the improvement of liver function in patients with liver disease [128,129] and 5) the prevention of bacterial translocation by restoring the gut epithelial barrier function through the upregulation of mucus production and induction of host immunomodulation activity [130]. A systematic review that examined the role of synbiotics in patients with IBD, suggested that synbiotics could be an effective treatment modality for acute and active CD [131]. Regarding UC patients, the use of synbiotics appears to have a positive outcome in maintenance of remission, with a concomitant reduction of proinflammatory cytokines expression and induction of anti-inflammatory cytokines expression [131]. Even though available data highlight the positive effects of certain bacterial species in the treatment of IBD, the conduction of further clinical trials is necessary for the determination of the role of synbiotics in patients with CD/UC.

6.3. Probiotics Another option for manipulating the gut microbiota is the administration of a single microorganism or a combination of bacteria as probiotic therapy [110]. Probiotics have been defined as “live microorganisms, which when administered in adequate amounts confer a health benefit on the host” [111]. Probiotics exert their effects by the exclusion of pathogens, maintenance of the gut barrier function and stimulation of mucosal and humoral immune responses [112]. In IBD patients, it has been suggested that specific - probiotics containing dietary supplements compete directly with pathogenic bacteria, leading to prevention of gut colonization. Moreover, they employ anti-inflammatory effects [37,113–115]. The most common bacteria used are the Lactobacillus, Bifidobacterium and Enterococcus strains [116,117]. ECCO guidelines have reported that there is no data to propose them for the maintenance of remission in CD patients [93]. A late meta-analysis has stated that probiotics may in overall have a significant impact on CD patients, especially in the post-surgical period [118]. Moreover, in children with IBD the use of mixed Lactobacillus and VSL#3 (a combination of probiotics) has shown high efficacy [118]. However, due to lack of evidence in CD patients, further high quality randomized

6.6. Fecal microbiota transplantation (FMT) FMT is the process of preparing a fecal suspension from a healthy individual and transferring it into the gastrointestinal tract of a diseased recipient [132]. This therapeutic approach has been established as a highly effective therapy for recurrent C. difficile infection (CDI) [133,134]. The use of FMT in patients with CDI aims to restore the gut microbial homeostasis in patients with dysbiosis, exhibiting a success 5

Microbial Pathogenesis 137 (2019) 103774

I. Aggeletopoulou, et al.

discomfort as the most common adverse event and death, severe infections and relapse of CDI and IBD as the most common serious adverse events [151]. The use of upper gastrointestinal routes resulted in a greater incidence of adverse events rate (43.6%) compared to lower gastrointestinal routes (17.7%) [151]. On the contrary, the respective incidences of serious adverse events rates were 2.0% and 6.1 [151]. In parallel, recent studies have raised some concerns about the efficacy and safety of FMT in IBD treatment [154]. The systematic review by Imdad et al., reported that no clear conclusion can be drawn due to the existence of small number of studies, low quality of evidence and lack of solid data on the rate of serious adverse events of FMT [154]. In parallel, there are scarce data on the efficacy of FMT for induction of remission in CD patients or in other specific populations (i.e. pediatric population) [154]. Lastly, there is lack of data on the long-term maintenance of remission in UC or CD [154]. In a recent review, additional concerns were raised on the use of FMT for the restoration of microbiota in IBD patients, highlighting a more variable response in this population compared to robust clinical outcomes in C. difficile infections [153]. Other limitations on the use of FMT could be the lack of identification of microbial community and the bacterial load administered from a healthy individual to an IBD patient for the prediction of the FMT outcome [153]. Lastly, as in most studies FMT is used combined with immunomodulatory drugs, FMT may be considered more efficacious as an adjuvant treatment [153]. The new ECCO guidelines state that FMT use in patients with active UC is promising [94]. On the other hand, they have focused on the need of additional studies to determine an optimized treatment protocol (route of administration, donor characteristics, frequency and duration of treatment) and to enhance the effectiveness and safety of this method [94].

rate exceeding 90% [135,136]. These very promising results have led to the introduction of FMT in the treatment guidelines of CDI by the American Society of Gastroenterology, the European Association of Clinical Microbiology, and the European Association of Infectious Diseases [137,138]. Beyond the use of FMT in CDI, a study presented the administration of sterile filtrates from donor stool (FFT) as an alternative approach for the restoration of normal microbiota [139]. This study has indicated that the use of bacterial constituents, metabolites, or bacteriophages has a prominent role in CDI treatment and may be used as a sufficient strategy especially for immunocompromised patients [139]. In parallel, the use of viruses has been supported in two more studies describing the impact of bacteriophages and eukaryotic virome in FMT [140,141]. Both studies have shown improved outcomes for CDI [141] and UC [140], highlighting that the virome community restoration may play a major role in FMT. The potential of the FMT therapeutic method was later evaluated for other diseases and has gained much interest as a novel therapy for IBD [142,143]. Numerous studies on the efficacy of FMT in patients with IBD have demonstrated conflicting results. The meta-analyses that compared the effectiveness of FMT to that of placebo are summarized in Table 1. Overall, 8 meta-analyses evaluated the efficacy of FMT in IBD disorders [142,144–150]. Three of them examined the role of FMT in both CD and UC [142,144,148] and 5 referred only to patients with UC [145–147,149,150]. Colman et al. and Paramsothy et al. have shown that FMT seems to be effective, particularly in UC patients, but they report that additional randomized controlled studies of FMT in IBD are needed, especially in patients with CD [144,148]. The most recent meta-analysis by Fang et al., on the role of FMT in IBD, suggests that FMT is an effective and safe treatment [142]. Moreover, it reports that factors such as the use of fresh or frozen donor stools, the delivery route, and previous treatment with antibiotics have no influence on the efficacy of FMT in IBD patients [142]. The data extracted from the meta-analyses regarding the efficacy of FMT in UC patients are consistent, suggesting that FMT provides a promising therapy for UC with few adverse events (100-102, 104, 105). Furthermore, the latter metaanalysis by Cao et al. concluded that colonoscopic administration of FMT and the existence of unrelated donor were significantly associated with higher efficacy in UC patients [150]. The major limitations of FMT concern safety issues and long-term [151] consequences in treating IBD [152–154]. A recent systematic review examined the occurrence of adverse effects due to FMT procedure [151]. The study showed an overall adverse events incidence of 28.5% and demonstrated abdominal

7. Conclusion The (side) effects of gut microbiota imbalance and the existence of defects in both innate and adaptive immunity have been implicated in the development of gut inflammation. In the last decade, it has been recognized that dysbiosis plays a substantial role in human pathophysiology and bacteria-specific targeted therapies are considered as powerful and promising approaches for IBD patients. The better understanding of the microbiota–host crosstalk has shown that microbes are key players for maintaining the homeostasis of immune system. Encouraging therapeutic advances for IBD management that involve gut microbiota regulation are antibiotics, prebiotics, probiotics, postbiotics, synbiotics and FMT. The choice of the optimal therapeutic

Table 1 Results from meta-analyses comparing fecal microbiota transplantation versus placebo in terms of clinical remission in patients with IBD. Study (reference)

Publication Year

Country

Type of Disease

Number of studies

Number of patients

Clinical remission [Pooled estimate (%) or OR or RR and 95% CI]

Study heterogeneity (I2 and p)

Colman et al. [144]

2014

USA

IBD

Shi et al. [145] Sun et al. [146]

2016 2016

China China

UC UC

13 4 13 11

79 UC 39 CD 141 133

I2 = 0%; p = 0.35 I2 = 37%; p = 0.05 I2 = 36.5%; p = 0.005 I2 = 33%; p = 0.139

Costello et al. [147] Paramsothy et al. [148] Narula et al.* [149]

2017 2017

Australia Australia

UC IBD

2017

Canada

UC

18 24 UC 6 CD 4

445 307 71 277

Cao et al. [150] Fang et al. [142]

2018 2018

China China

UC IBD

16 13 5

NR 178 74

24.1% (95% CI 11.1%-44.9%) 60.5% (95% CI 28.4%-85.6%) 40.5% (95% CI 24.7%-58.7%) 30.4% (95% CI 22.6–39.4%) OR: 3.67 (95%CI 1.82–7.39) 33% (95% CI 23%-43%) 52% (95% CI 31%-72%) RR: 0.76 (95% CI 0.62–0.93) 28.96 ± 22.39% (NR) 26% (95% CI 10%-48%) 22% (95% CI 3%-52%)

I2 = 0%; p < 0.01 I2 = 54%; p = 0.001 I2 = 52%; p = 0.063 I2 = 31%; p = 0.23 NR I2 = 88%; p ≤ 0.01 I2 = 85%; p ≤ 0.01

Abbreviations: IBD, Inflammatory Bowel Diseases; CD, Crohn's Disease; UC, Ulcerative Colitis; RR, risk ratio; OR, odds ratio; C.I., confidence interval; I2, study heterogeneity; NR, not reported. Note: The number of studies and patients included in each study are referred to those included in the meta-analysis. *This study includes only RCTs. *The RR and the CI refer to patients that did not achieve remission. 6

Microbial Pathogenesis 137 (2019) 103774

I. Aggeletopoulou, et al.

strategy depends on the type and stage of disease, including microbiome modulators aiming to change the host microbiota composition or microbial-based approaches to replace the defective microbes. Despite the conduct of numerous studies on the interplay between the gut microbiota and the host, major concerns remain regarding the time of treatment, the age of the host, the appropriate therapy, the suitable strain, and the development of personalized therapy. Future trials investigating these challenges will contribute greatly to understanding the underlying IBD pathologic mechanisms and will hopefully result in the development of novel therapeutic algorithms for the management of IBD.

Transl. Immunol. 5 (2016) e72, https://doi.org/10.1038/cti.2016.12. [19] P.B. Eckburg, E.M. Bik, C.N. Bernstein, et al., Diversity of the human intestinal microbial flora, Science 308 (2005) 1635–1638, https://doi.org/10.1126/science. 1110591. [20] S.M. Jandhyala, R. Talukdar, C. Subramanyam, H. Vuyyuru, M. Sasikala, D. Nageshwar Reddy, Role of the normal gut microbiota, World J. Gastroenterol. 21 (2015) 8787–8803, https://doi.org/10.3748/wjg.v21.i29.8787. [21] M.J. Morowitz, E. Carlisle, J.C. Alverdy, Contributions of intestinal bacteria to nutrition and metabolism in the critically Ill, Surg. Clin. N. Am. 91 (2011) 771–785, https://doi.org/10.1016/j.suc.2011.05.001. [22] S. Becattini, Y. Taur, E.G. Pamer, Antibiotic-induced changes in the intestinal microbiota and disease, Trends Mol. Med. 22 (2016) 458–478, https://doi.org/10. 1016/j.molmed.2016.04.003. [23] T.W. Shirkey, R.H. Siggers, B.G. Goldade, et al., Effects of commensal bacteria on intestinal morphology and expression of proinflammatory cytokines in the gnotobiotic pig, Exp. Biol. Med. 231 (2006) 1333–1345. [24] B.P. Willing, A.G. Van Kessel, Enterocyte proliferation and apoptosis in the caudal small intestine is influenced by the composition of colonizing commensal bacteria in the neonatal gnotobiotic pig, J. Anim. Sci. 85 (2007) 3256–3266, https://doi. org/10.2527/jas.2007-0320. [25] H. Kozakova, J. Kolinska, Z. Lojda, et al., Effect of bacterial monoassociation on brush-border enzyme activities in ex-germ-free piglets: comparison of commensal and pathogenic Escherichia coli strains, Microb. Infect. 8 (2006) 2629–2639, https://doi.org/10.1016/j.micinf.2006.07.008. [26] S. Kitajima, S. Takuma, M. Morimoto, Changes in colonic mucosal permeability in mouse colitis induced with dextran sulfate sodium, Exp. Anim. 48 (1999) 137–143, https://doi.org/10.1538/expanim.48.137. [27] H. Kamata, H. Hirata, Redox regulation of cellular signalling, Cell. Signal. 11 (1999) 1–14, https://doi.org/10.1016/S0898-6568(98)00037-0. [28] P.A. Swanson 2nd, A. Kumar, S. Samarin, et al., Enteric commensal bacteria potentiate epithelial restitution via reactive oxygen species-mediated inactivation of focal adhesion kinase phosphatases, Proc. Natl. Acad. Sci. U. S. A. 108 (2011) 8803–8808, https://doi.org/10.1073/pnas.1010042108. [29] S.F. Assimakopoulos, I. Papageorgiou, A. Charonis, Enterocytes' tight junctions: from molecules to diseases, World J. Gastrointest. Pathophysiol. 2 (2011) 123–137, https://doi.org/10.4291/wjgp.v2.i6.123. [30] L. Lu, W.A. Walker, Pathologic and physiologic interactions of bacteria with the gastrointestinal epithelium, Am. J. Clin. Nutr. 73 (2001) 1124S–1130S, https:// doi.org/10.1093/ajcn/73.6.1124S. [31] R. Mennigen, K. Nolte, E. Rijcken, et al., Probiotic mixture VSL#3 protects the epithelial barrier by maintaining tight junction protein expression and preventing apoptosis in a murine model of colitis, Am. J. Physiol. Gastrointest. Liver Physiol. 296 (2009) G1140–G1149, https://doi.org/10.1152/ajpgi.90534.2008. [32] L. Peng, Z.R. Li, R.S. Green, I.R. Holzman, J. Lin, Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers, J. Nutr. 139 (2009) 1619–1625, https:// doi.org/10.3945/jn.109.104638. [33] T. Ichinohe, I.K. Pang, Y. Kumamoto, et al., Microbiota regulates immune defense against respiratory tract influenza A virus infection, Proc. Natl. Acad. Sci. U. S. A. 108 (2011) 5354–5359, https://doi.org/10.1073/pnas.1019378108. [34] D. Kim, M.Y. Zeng, G. Nunez, The interplay between host immune cells and gut microbiota in chronic inflammatory diseases, Exp. Mol. Med. 49 (2017) 24, https://doi.org/10.1038/emm.2017.24. [35] D. Sheehan, C. Moran, F. Shanahan, The microbiota in inflammatory bowel disease, J. Gastroenterol. 50 (2015) 495–507, https://doi.org/10.1007/s00535-0151064-1. [36] R.B. Sartor, Microbial influences in inflammatory bowel diseases, Gastroenterology 134 (2008) 577–594, https://doi.org/10.1053/j.gastro.2007.11. 059. [37] A.D. Kostic, R.J. Xavier, D. Gevers, The microbiome in inflammatory bowel disease: current status and the future ahead, Gastroenterology 146 (2014) 1489–1499, https://doi.org/10.1053/j.gastro.2014.02.009. [38] X.C. Morgan, T.L. Tickle, H. Sokol, et al., Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment, Genome Biol. 13 (2012) 2012–2013, https://doi.org/10.1186/gb-2012-13-9-r79. [39] H. Sokol, P. Seksik, The intestinal microbiota in inflammatory bowel diseases: time to connect with the host, Curr. Opin. Gastroenterol. 26 (2010) 327–331, https:// doi.org/10.1097/MOG.0b013e328339536b. [40] B.P. Willing, J. Dicksved, J. Halfvarson, et al., A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes, Gastroenterology 139 (2010) 1844–1854, https://doi.org/10. 1053/j.gastro.2010.08.049. [41] D. Knights, K.G. Lassen, R.J. Xavier, Advances in inflammatory bowel disease pathogenesis: linking host genetics and the microbiome, Gut 62 (2013) 1505–1510, https://doi.org/10.1136/gutjnl-2012-303954. [42] M. Issa, A.N. Ananthakrishnan, D.G. Binion, Clostridium difficile and inflammatory bowel disease, Inflamm. Bowel Dis. 14 (2008) 1432–1442, https://doi.org/10. 1002/ibd.20500. [43] L.W. Lamps, K.T. Madhusudhan, J.M. Havens, et al., Pathogenic Yersinia DNA is detected in bowel and mesenteric lymph nodes from patients with Crohn's disease, Am. J. Surg. Pathol. 27 (2003) 220–227. [44] N. Rolhion, A. Darfeuille-Michaud, Adherent-invasive Escherichia coli in inflammatory bowel disease, Inflamm. Bowel Dis. 13 (2007) 1277–1283, https:// doi.org/10.1002/ibd.20176. [45] J.G. LeBlanc, F. Chain, R. Martín, L.G. Bermúdez-Humarán, S. Courau, P. Langella, Beneficial effects on host energy metabolism of short-chain fatty acids and

Grant support None to declare. Declaration of Competing Interest No conflict of interest to declare. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.micpath.2019.103774. References [1] Y.Z. Zhang, Y.Y. Li, Inflammatory bowel disease: pathogenesis, World J. Gastroenterol. 20 (2014) 91–99, https://doi.org/10.3748/wjg.v20.i1.91. [2] B. Ungar, U. Kopylov, Advances in the development of new biologics in inflammatory bowel disease, Ann. Gastroenterol. 29 (2016) 243–248, https://doi. org/10.20524/aog.2016.0027. [3] A. Geremia, P. Biancheri, P. Allan, G.R. Corazza, A. Di Sabatino, Innate and adaptive immunity in inflammatory bowel disease, Autoimmun. Rev. 13 (2014) 3–10, https://doi.org/10.1016/j.autrev.2013.06.004. [4] G.M. Cobrin, M.T. Abreu, Defects in mucosal immunity leading to Crohn's disease, Immunol. Rev. 206 (2005) 277–295, https://doi.org/10.1111/j.0105-2896.2005. 00293.x. [5] S.R. Targan, L.C. Karp, Defects in mucosal immunity leading to ulcerative colitis, Immunol. Rev. 206 (2005) 296–305, https://doi.org/10.1111/j.0105-2896.2005. 00286.x. [6] A. Schirbel, C. Fiocchi, Inflammatory bowel disease: established and evolving considerations on its etiopathogenesis and therapy, J Dig Dis 11 (2010) 266–276, https://doi.org/10.1111/j.1751-2980.2010.00449.x. [7] F. Sommer, F. Bäckhed, The gut microbiota — masters of host development and physiology, Nat. Rev. Microbiol. 11 (2013) 227, https://doi.org/10.1038/ nrmicro2974. [8] E. Thursby, N. Juge, Introduction to the human gut microbiota, Biochem. J. 474 (2017) 1823–1836, https://doi.org/10.1042/bcj20160510. [9] J.M. Manson, M. Rauch, M.S. Gilmore, The commensal microbiology of the gastrointestinal tract, Adv. Exp. Med. Biol. 635 (2008) 15–28, https://doi.org/10. 1007/978-0-387-09550-9_2. [10] D.N. Frank, N.R. Pace, Gastrointestinal microbiology enters the metagenomics era, Curr. Opin. Gastroenterol. 24 (2008) 4–10, https://doi.org/10.1097/MOG. 0b013e3282f2b0e8. [11] J. Qin, R. Li, J. Raes, et al., A human gut microbial gene catalogue established by metagenomic sequencing, Nature 464 (2010) 59–65, https://doi.org/10.1038/ nature08821. [12] R.E. Ley, M. Hamady, C. Lozupone, et al., Evolution of mammals and their gut microbes, Science 320 (2008) 1647–1651, https://doi.org/10.1126/science. 1155725. [13] L. Putignani, F. Del Chierico, A. Petrucca, P. Vernocchi, B. Dallapiccola, The human gut microbiota: a dynamic interplay with the host from birth to senescence settled during childhood, Pediatr. Res. 76 (2014) 2–10, https://doi.org/10.1038/ pr.2014.49. [14] K. Aagaard, J. Ma, K.M. Antony, R. Ganu, J. Petrosino, J. Versalovic, The placenta harbors a unique microbiome, Sci. Transl. Med. 6 (2014) 3008599, https://doi. org/10.1126/scitranslmed.3008599. [15] J.M. Rodriguez, K. Murphy, C. Stanton, et al., The composition of the gut microbiota throughout life, with an emphasis on early life, Microb. Ecol. Health Dis. 26 (2015), https://doi.org/10.3402/mehd.v26.26050. [16] C. Palmer, E.M. Bik, D.B. DiGiulio, D.A. Relman, P.O. Brown, Development of the human infant intestinal microbiota, PLoS Biol. 5 (2007) 26, https://doi.org/10. 1371/journal.pbio.0050177. [17] E.M.M. Quigley, Gut bacteria in health and disease, Gastroenterol. Hepatol. 9 (9) (2013 Sep) 560–569. [18] S. Shen, C.H.Y. Wong, Bugging inflammation: role of the gut microbiota, Clin.

7

Microbial Pathogenesis 137 (2019) 103774

I. Aggeletopoulou, et al.

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

[56]

[57]

[58]

[59]

[60]

[61] [62]

[63]

[64]

[65]

[66]

[67] [68]

[69]

[70]

[71]

[72]

[73]

vitamins produced by commensal and probiotic bacteria, Microb. Cell Factories 16 (2017), https://doi.org/10.1186/s12934-017-0691-z 79-79. R. Correa-Oliveira, J.L. Fachi, A. Vieira, F.T. Sato, M.A. Vinolo, Regulation of immune cell function by short-chain fatty acids, Clin. Transl. Immunol. 5 (2016), https://doi.org/10.1038/cti.2016.17. J. Chow, H. Tang, S.K. Mazmanian, Pathobionts of the gastrointestinal microbiota and inflammatory disease, Curr. Opin. Immunol. 23 (2011) 473–480, https://doi. org/10.1016/j.coi.2011.07.010. J.C. Gomes-Neto, H. Kittana, S. Mantz, et al., A gut pathobiont synergizes with the microbiota to instigate inflammatory disease marked by immunoreactivity against other symbionts but not itself, Sci. Rep. 7 (2017) 17707, https://doi.org/10.1038/ s41598-017-18014-5. N. Kamada, S.-U. Seo, G.Y. Chen, G. Núñez, Role of the gut microbiota in immunity and inflammatory disease, Nat. Rev. Immunol. 13 (2013) 321, https://doi. org/10.1038/nri3430. S.H. Lee, J.E. Kwon, M.-L. Cho, Immunological pathogenesis of inflammatory bowel disease, Int. Res. 16 (2018) 26–42, https://doi.org/10.5217/ir.2018.16. 1.26. S. Omenetti, T.T. Pizarro, The treg/Th17 Axis: a dynamic balance regulated by the gut microbiome, Front. Immunol. 6 (2015), https://doi.org/10.3389/fimmu.2015. 00639. T. Nunes, C. Bernardazzi, H.S. de Souza, Cell death and inflammatory bowel diseases: apoptosis, necrosis, and autophagy in the intestinal epithelium, BioMed Res. Int. 2014 (2014), https://doi.org/10.1155/2014/218493 218493-218493. A. Murthy, Y. Li, I. Peng, et al., A Crohn's disease variant in Atg16l1 enhances its degradation by caspase 3, Nature 506 (2014) 456–462, https://doi.org/10.1038/ nature13044. T.E. Adolph, M.F. Tomczak, L. Niederreiter, et al., Paneth cells as a site of origin for intestinal inflammation, Nature 503 (2013) 272–276, https://doi.org/10. 1038/nature12599. C. Gunther, E. Martini, N. Wittkopf, et al., Caspase-8 regulates TNF-alpha-induced epithelial necroptosis and terminal ileitis, Nature 477 (2011) 335–339, https:// doi.org/10.1038/nature10400. P.S. Welz, A. Wullaert, K. Vlantis, et al., FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation, Nature 477 (2011) 330–334, https://doi.org/10.1038/nature10273. A.R. Neves, M.T. Castelo-Branco, V.R. Figliuolo, et al., Overexpression of ATPactivated P2X7 receptors in the intestinal mucosa is implicated in the pathogenesis of Crohn's disease, Inflamm. Bowel Dis. 20 (2014) 444–457, https://doi.org/10. 1097/01.MIB.0000441201.10454.06. C.C. Marques, M.T. Castelo-Branco, R.G. Pacheco, et al., Prophylactic systemic P2X7 receptor blockade prevents experimental colitis, Biochim. Biophys. Acta 1 (2014) 65–78, https://doi.org/10.1016/j.bbadis.2013.10.012. J. Landy, E. Ronde, N. English, et al., Tight junctions in inflammatory bowel diseases and inflammatory bowel disease associated colorectal cancer, World J. Gastroenterol. 22 (2016) 3117–3126, https://doi.org/10.3748/wjg.v22.i11.3117. D.F. McCole, IBD candidate genes and intestinal barrier regulation, Inflamm. Bowel Dis. 20 (2014) 1829–1849, https://doi.org/10.1097/MIB. 0000000000000090. J. Meddings, What role does intestinal permeability have in IBD pathogenesis? Inflamm. Bowel Dis. 14 (2008) 20719, https://doi.org/10.1002/ibd.20719. H. Tanaka, M. Takechi, H. Kiyonari, G. Shioi, A. Tamura, S. Tsukita, Intestinal deletion of Claudin-7 enhances paracellular organic solute flux and initiates colonic inflammation in mice, Gut 64 (2015) 1529–1538, https://doi.org/10.1136/ gutjnl-2014-308419. L. Ding, Z. Lu, O. Foreman, et al., Inflammation and disruption of the mucosal architecture in claudin-7-deficient mice, Gastroenterology 142 (2012) 305–315, https://doi.org/10.1053/j.gastro.2011.10.025. T. Zuo, S.C. Ng, The gut microbiota in the pathogenesis and therapeutics of inflammatory bowel disease, Front. Microbiol. 9 (2018), https://doi.org/10.3389/ fmicb.2018.02247 2247-2247. P. Brun, I. Castagliuolo, V. Di Leo, et al., Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis, Am. J. Physiol. Gastrointest. Liver Physiol. 292 (2007) 5, https://doi.org/10.1152/ajpgi. 00024.2006. D.M. Underhill, I.D. Iliev, The mycobiota: interactions between commensal fungi and the host immune system, Nat. Rev. Immunol. 14 (2014) 405–416, https://doi. org/10.1038/nri3684. Y. Belkaid, T.W. Hand, Role of the microbiota in immunity and inflammation, Cell 157 (2014) 121–141, https://doi.org/10.1016/j.cell.2014.03.011. N. Kamada, G. Nunez, Role of the gut microbiota in the development and function of lymphoid cells, J. Immunol. 190 (2013) 1389–1395, https://doi.org/10.4049/ jimmunol.1203100. J.P. Nougayrede, S. Homburg, F. Taieb, et al., Escherichia coli induces DNA doublestrand breaks in eukaryotic cells, Science 313 (2006) 848–851, https://doi.org/10. 1126/science.1127059. T. Tian, Z. Wang, J. Zhang, Pathomechanisms of oxidative stress in inflammatory bowel disease and potential antioxidant therapies, Oxid Med Cell Longev 2017 (2017), https://doi.org/10.1155/2017/4535194 4535194-4535194. J.O. Lundberg, E. Weitzberg, J.A. Cole, N. Benjamin, Nitrate, bacteria and human health, Nat. Rev. Microbiol. 2 (2004) 593–602, https://doi.org/10.1038/ nrmicro929. A. Rezaie, R.D. Parker, M. Abdollahi, Oxidative stress and pathogenesis of inflammatory bowel disease: an epiphenomenon or the cause? Dig. Dis. Sci. 52 (2007) 2015–2021, https://doi.org/10.1007/s10620-006-9622-2. G.L. Hold, M. Smith, C. Grange, E.R. Watt, E.M. El-Omar, I. Mukhopadhya, Role of

[74]

[75]

[76]

[77]

[78]

[79]

[80]

[81]

[82]

[83]

[84]

[85]

[86]

[87]

[88]

[89]

[90]

[91]

[92]

[93]

[94]

[95]

[96]

[97]

[98]

[99]

[100]

8

the gut microbiota in inflammatory bowel disease pathogenesis: what have we learnt in the past 10 years? World J. Gastroenterol. 20 (2014) 1192–1210, https:// doi.org/10.3748/wjg.v20.i5.1192. J.C. Clemente, L.K. Ursell, L.W. Parfrey, R. Knight, The impact of the gut microbiota on human health: an integrative view, Cell 148 (2012) 1258–1270, https:// doi.org/10.1016/j.cell.2012.01.035. M.P. Francino, Antibiotics and the human gut microbiome: Dysbioses and accumulation of resistances, Front. Microbiol. 6 (2016), https://doi.org/10.3389/ fmicb.2015.01543. C.M. Guinane, P.D. Cotter, Role of the gut microbiota in health and chronic gastrointestinal disease: understanding a hidden metabolic organ, Therap Adv Gastroenterol 6 (2013) 295–308, https://doi.org/10.1177/1756283X13482996. P. Kiesler, I.J. Fuss, W. Strober, Experimental models of inflammatory bowel diseases, Cell Mol Gastroenterol Hepatol 1 (2015) 154–170, https://doi.org/10. 1016/j.jcmgh.2015.01.006. L.W. van den Elsen, H.C. Poyntz, L.S. Weyrich, W. Young, E.E. Forbes-Blom, Embracing the gut microbiota: the new frontier for inflammatory and infectious diseases, Clin. Transl. Immunol. 6 (2017), https://doi.org/10.1038/cti.2016.91. A. Reyes, M. Haynes, N. Hanson, et al., Viruses in the faecal microbiota of monozygotic twins and their mothers, Nature 466 (2010) 334–338, https://doi. org/10.1038/nature09199. G. Khoder, A.A. Al-Menhali, F. Al-Yassir, S.M. Karam, Potential role of probiotics in the management of gastric ulcer, Exp Ther Med 12 (2016) 3–17, https://doi. org/10.3892/etm.2016.3293. A.E. Foxx-Orenstein, W.D. Chey, Manipulation of the gut microbiota as a novel treatment strategy for gastrointestinal disorders, Am. J. Gastroenterol. 1 (2012) 41, https://doi.org/10.1038/ajgsup.2012.8. C. Ding, W. Tang, X. Fan, G. Wu, Intestinal microbiota: a novel perspective in colorectal cancer biotherapeutics, OncoTargets Ther. 11 (2018) 4797–4810, https://doi.org/10.2147/OTT.S170626. J. Gagniere, J. Raisch, J. Veziant, et al., Gut microbiota imbalance and colorectal cancer, World J. Gastroenterol. 22 (2016) 501–518, https://doi.org/10.3748/wjg. v22.i2.501. R. Gao, Z. Gao, L. Huang, H. Qin, Gut microbiota and colorectal cancer, Eur. J. Clin. Microbiol. Infect. Dis. 36 (2017) 757–769, https://doi.org/10.1007/s10096016-2881-8. A.T. Vieira, C. Fukumori, C.M. Ferreira, New insights into therapeutic strategies for gut microbiota modulation in inflammatory diseases, Clin. Transl. Immunol. 5 (2016) e87, https://doi.org/10.1038/cti.2016.38. O. Nitzan, M. Elias, A. Peretz, W. Saliba, Role of antibiotics for treatment of inflammatory bowel disease, World J. Gastroenterol. 22 (2016) 1078, https://doi. org/10.3748/wjg.v22.i3.1078. M. Ferrer, V.A. Martins dos Santos, S.J. Ott, A. Moya, Gut microbiota disturbance during antibiotic therapy: a multi-omic approach, Gut Microb. 5 (2014) 64–70, https://doi.org/10.4161/gmic.27128. A.E. Perez-Cobas, M.J. Gosalbes, A. Friedrichs, et al., Gut microbiota disturbance during antibiotic therapy: a multi-omic approach, Gut 62 (2013) 1591–1601, https://doi.org/10.1136/gutjnl-2012-303184. L.M. Cox, S. Yamanishi, J. Sohn, et al., Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences, Cell 158 (2014) 705–721, https://doi.org/10.1016/j.cell.2014.05.052. K.J. Khan, T.A. Ullman, A.C. Ford, et al., Antibiotic therapy in inflammatory bowel disease: a systematic review and meta-analysis, Am. J. Gastroenterol. 106 (2011) 661, https://doi.org/10.1038/ajg.2011.72. S.L. Wang, Z.R. Wang, C.Q. Yang, Meta-analysis of broad-spectrum antibiotic therapy in patients with active inflammatory bowel disease, Exp Ther Med 4 (2012) 1051–1056, https://doi.org/10.3892/etm.2012.718. R. Ungaro, C.N. Bernstein, R. Gearry, et al., Antibiotics associated with increased risk of new-onset Crohn's disease but not ulcerative colitis: a meta-analysis, Am. J. Gastroenterol. 109 (2014) 1728–1738, https://doi.org/10.1038/ajg.2014.246. F. Gomollon, A. Dignass, V. Annese, et al., European evidence-based consensus on the diagnosis and management of Crohn's disease 2016: Part 1: diagnosis and medical management, J Crohns Colitis 11 (2017) 3–25, https://doi.org/10.1093/ ecco-jcc/jjw168. M. Harbord, R. Eliakim, D. Bettenworth, et al., Third european evidence-based consensus on diagnosis and management of ulcerative colitis. Part 2: current management, J Crohns Colitis 11 (2017) 769–784, https://doi.org/10.1093/eccojcc/jjx009. G.R. Gibson, M.B. Roberfroid, Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics, J. Nutr. 125 (1995) 1401–1412, https://doi.org/10.1093/jn/125.6.1401. G.R. Gibson, R. Hutkins, M.E. Sanders, et al., Expert consensus document: the International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics, Nat. Rev. Gastroenterol. Hepatol. 14 (2017) 491–502, https://doi.org/10.1038/nrgastro.2017.75. R. Orel, T. Kamhi Trop, Intestinal microbiota, probiotics and prebiotics in inflammatory bowel disease, World J. Gastroenterol. 20 (2014) 11505–11524, https://doi.org/10.3748/wjg.v20.i33.11505. M.A. Looijer-van Langen, L.A. Dieleman, Prebiotics in chronic intestinal inflammation, Inflamm. Bowel Dis. 15 (2009) 454–462, https://doi.org/10.1002/ ibd.20737. D. Rios-Covian, P. Ruas-Madiedo, A. Margolles, M. Gueimonde, C.G. de Los ReyesGavilan, N. Salazar, Intestinal short chain fatty acids and their link with diet and human health, Front. Microbiol. 7 (2016), https://doi.org/10.3389/fmicb.2016. 00185. N. Kamada, G.Y. Chen, N. Inohara, G. Nunez, Control of pathogens and

Microbial Pathogenesis 137 (2019) 103774

I. Aggeletopoulou, et al.

[101]

[102]

[103]

[104]

[105]

[106]

[107]

[108]

[109]

[110]

[111]

[112]

[113]

[114]

[115]

[116]

[117]

[118]

[119]

[120]

[121]

[122]

[123]

[124]

[125] B.D. Wallace, M.R. Redinbo, The human microbiome is a source of therapeutic drug targets, Curr. Opin. Chem. Biol. 17 (2013) 379–384, https://doi.org/10. 1016/j.cbpa.2013.04.011. [126] S. Arai, Y. Morinaga, T. Yoshikawa, et al., Recent trends in functional food science and the industry in Japan, Biosci. Biotechnol. Biochem. 66 (2002) 2017–2029, https://doi.org/10.1271/bbb.66.2017. [127] A. Bomba, R. Nemcova, S. Gancarcikova, R. Herich, P. Guba, D. Mudronova, Improvement of the probiotic effect of micro-organisms by their combination with maltodextrins, fructo-oligosaccharides and polyunsaturated fatty acids, Br. J. Nutr. 88 (2002), https://doi.org/10.1079/BJN2002634. [128] S.M. Riordan, N.A. Skinner, C.J. McIver, et al., Synbiotic-associated improvement in liver function in cirrhotic patients: relation to changes in circulating cytokine messenger RNA and protein levels, Microb. Ecol. Health Dis. 19 (2007) 7–16, https://doi.org/10.1080/08910600601178709. [129] C. Buss, C. Valle-Tovo, S. Miozzo, A. Alves de Mattos, Probiotics and synbiotics may improve liver aminotransferases levels in non-alcoholic fatty liver disease patients, Ann. Hepatol. 13 (2014) 482–488. [130] I.Y. Hwang, E. Koh, A. Wong, et al., Engineered probiotic Escherichia coli can eliminate and prevent Pseudomonas aeruginosa gut infection in animal models, Nat. Commun. 8 (2017) 15028, https://doi.org/10.1038/ncomms15028. [131] M.J. Saez-Lara, C. Gomez-Llorente, J. Plaza-Diaz, A. Gil, The role of probiotic lactic acid bacteria and bifidobacteria in the prevention and treatment of inflammatory bowel disease and other related diseases: a systematic review of randomized human clinical trials, BioMed Res. Int. 505878 (2015) 22, https://doi. org/10.1155/2015/505878. [132] M.J. Grehan, T.J. Borody, S.M. Leis, J. Campbell, H. Mitchell, A. Wettstein, Durable alteration of the colonic microbiota by the administration of donor fecal flora, J. Clin. Gastroenterol. 44 (2010) 551–561, https://doi.org/10.1097/MCG. 0b013e3181e5d06b. [133] E. van Nood, A. Vrieze, M. Nieuwdorp, et al., Duodenal infusion of donor feces for recurrent Clostridium difficile, N. Engl. J. Med. 368 (2013) 407–415, https://doi. org/10.1056/NEJMoa1205037. [134] P. Moayyedi, Y. Yuan, H. Baharith, A.C. Ford, Faecal microbiota transplantation for < em > Clostridium difficile < /em > -associated diarrhoea: a systematic review of randomised controlled trials, Med. J. Aust. 207 (2017) 166–172, https:// doi.org/10.5694/mja17.00295. [135] D. Drekonja, J. Reich, S. Gezahegn, et al., Fecal microbiota transplantation for Clostridium difficile infection: a systematic review, Ann. Intern. Med. 162 (2015) 630–638, https://doi.org/10.7326/M14-2693. [136] A. Khoruts, M.J. Sadowsky, Understanding the mechanisms of faecal microbiota transplantation, Nat. Rev. Gastroenterol. Hepatol. 13 (2016) 508–516, https://doi. org/10.1038/nrgastro.2016.98. [137] C.M. Surawicz, L.J. Brandt, D.G. Binion, et al., Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections, Am. J. Gastroenterol. 108 (2013) 478–498, https://doi.org/10.1038/ajg.2013.4. [138] S.B. Debast, M.P. Bauer, E.J. Kuijper, European society of clinical microbiology and infectious diseases: update of the treatment guidance document for Clostridium difficile infection, Clin. Microbiol. Infect. 2 (2014) 1–26, https://doi.org/10.1111/ 1469-0691.12418. [139] S.J. Ott, G.H. Waetzig, A. Rehman, J. Moltzau-Anderson, R. Bharti, J.A. Grasis, L. Cassidy, A. Tholey, H. Fickenscher, D. Seegert, P. Rosenstiel, S. Schreiber, Efficacy of sterile fecal filtrate transfer for treating patients with Clostridium difficile infection, Gastroenterology 152 (2017) 799–811, https://doi.org/10.1053/j. gastro.2016.11.010. [140] N. Conceição-Neto, W. Deboutte, T. Dierckx, K. Machiels, J. Wang, K.C. Yinda, P. Maes, M. Van Ranst, M. Joossens, J. Raes, S. Vermeire, J. Matthijnssens, Low eukaryotic viral richness is associated with faecal microbiota transplantation success in patients with UC, Gut 67 (2018) 1558–1559, https://doi.org/10.1136/ gutjnl-2017-315281. [141] T. Zuo, S.H. Wong, K. Lam, R. Lui, K. Cheung, W. Tang, J.Y.L. Ching, P.K.S. Chan, M.C.W. Chan, J.C.Y. Wu, F.K.L. Chan, J. Yu, J.J.Y. Sung, S.C. Ng, Bacteriophage transfer during faecal microbiota transplantation in Clostridium difficile infection is associated with treatment outcome, Gut 67 (2018) 634–643, https://doi.org/10. 1136/gutjnl-2017-313952. [142] H. Fang, L. Fu, J. Wang, Protocol for fecal microbiota transplantation in inflammatory bowel disease: a systematic review and meta-analysis, BioMed Res. Int. 13 (2018), https://doi.org/10.1155/2018/8941340. eCollection 2018. [143] S.R. Jeon, J. Chai, C. Kim, C.H. Lee, Current evidence for the management of inflammatory bowel diseases using fecal microbiota transplantation, Curr. Infect. Dis. Rep. 20 (2018), https://doi.org/10.1007/s11908-018-0627-8 018-0627. [144] R.J. Colman, D.T. Rubin, Fecal microbiota transplantation as therapy for inflammatory bowel disease: a systematic review and meta-analysis, J Crohns Colitis 8 (2014) 1569–1581, https://doi.org/10.1016/j.crohns.2014.08.006. [145] Y. Shi, Y. Dong, W. Huang, D. Zhu, H. Mao, P. Su, Fecal microbiota transplantation for ulcerative colitis: a systematic review and meta-analysis, PLoS One 11 (2016), https://doi.org/10.1371/journal.pone.0157259. [146] D. Sun, W. Li, S. Li, Y. Cen, Q. Xu, Y. Li, Y. Sun, Y. Qi, Y. Lin, T. Yang, P. Xu, Q. Lu, Fecal microbiota transplantation as a novel therapy for ulcerative colitis: a systematic review and meta-analysis, Medicine 95 (23) (2016) 0000000000003765. [147] S.P. Costello, W. Soo, R.V. Bryant, V. Jairath, A.L. Hart, J.M. Andrews, Systematic review with meta-analysis: faecal microbiota transplantation for the induction of remission for active ulcerative colitis, Aliment. Pharmacol. Ther. 46 (2017) 213–224, https://doi.org/10.1111/apt.14173. [148] S. Paramsothy, R. Paramsothy, D.T. Rubin, et al., Faecal microbiota transplantation for inflammatory bowel disease: a systematic review and meta-analysis, J Crohns Colitis 11 (2017) 1180–1199, https://doi.org/10.1093/ecco-jcc/jjx063.

pathobionts by the gut microbiota, Nat. Immunol. 14 (2013) 685–690, https://doi. org/10.1038/ni.2608. M. Andrianifahanana, N. Moniaux, S.K. Batra, Regulation of mucin expression: mechanistic aspects and implications for cancer and inflammatory diseases, Biochim. Biophys. Acta 2 (2006) 189–222, https://doi.org/10.1016/j.bbcan.2006. 01.002. K. Abdelouhab, H. Rafa, R. Toumi, S. Bouaziz, O. Medjeber, C. Touil-Boukoffa, Mucosal intestinal alteration in experimental colitis correlates with nitric oxide production by peritoneal macrophages: effect of probiotics and prebiotics, Immunopharmacol. Immunotoxicol. 34 (2012) 590–597, https://doi.org/10. 3109/08923973.2011.641971. D. Camuesco, L. Peran, M. Comalada, A. Nieto, L.C. Di Stasi, M.E. RodriguezCabezas, A. Concha, A. Zarzuelo, J. Galvez, Preventative effects of lactulose in the trinitrobenzenesulphonic acid model of rat colitis, Inflamm. Bowel Dis. 11 (2005) 265–271, https://doi.org/10.1097/01.mib.0000160808.30988.d9. F. Lara-Villoslada, E. Debras, A. Nieto, A. Concha, J. Galvez, E. Lopez-Huertas, J. Boza, C. Obled, J. Xaus, Oligosaccharides isolated from goat milk reduce intestinal inflammation in a rat model of dextran sodium sulfate-induced colitis, Clin. Nutr. 25 (2006) 477–488, https://doi.org/10.1016/j.clnu.2005.11.004. K.L. Madsen, J.S. Doyle, L.D. Jewell, M.M. Tavernini, R.N. Fedorak, Lactobacillus species prevents colitis in interleukin 10 gene-deficient mice, Gastroenterology 116 (1999) 1107–1114, https://doi.org/10.1016/s0016-5085(99)70013-2. M.N. Rufino, G.F.P. Aleixo, I.E. Trombine-Batista, R. Giuffrida, R. Keller, H. Bremer-Neto, Systematic review and meta-analysis of preclinical trials demonstrate robust beneficial effects of prebiotics in induced inflammatory bowel disease, J. Nutr. Biochem. 62 (2018) 1–8, https://doi.org/10.1016/j.jnutbio.2018. 05.016. A. Laurell, K. Sjoberg, Prebiotics and synbiotics in ulcerative colitis, Scand. J. Gastroenterol. 52 (2017) 477–485, https://doi.org/10.1080/00365521.2016. 1263680. L.S. Celiberto, F.A. Graef, G.R. Healey, et al., Inflammatory bowel disease and immunonutrition: novel therapeutic approaches through modulation of diet and the gut microbiome, Immunology 155 (2018) 36–52, https://doi.org/10.1111/ imm.12939. T. Eom, Y.S. Kim, C.H. Choi, M.J. Sadowsky, T. Unno, Current understanding of microbiota- and dietary-therapies for treating inflammatory bowel disease, J. Microbiol. 56 (2018) 189–198, https://doi.org/10.1007/s12275-018-8049-8. P. Forsythe, J. Bienenstock, Immunomodulation by commensal and probiotic bacteria, Immunol. Investig. 39 (2010) 429–448, https://doi.org/10.3109/ 08820131003667978. J. Schlundt, Report of a Joint FAO/WHO Expert Consultation on Evaluation of Health and Nutritional Properties of Probiotics in Food Including Powder Milk with Live Lactic Acid Bacteria, FAO/WHO, 2002. F. Berrilli, D. Di Cave, S. Cavallero, S. D'Amelio, Interactions between parasites and microbial communities in the human gut, Front Cell Infect Microbiol 2 (2012), https://doi.org/10.3389/fcimb.2012.00141. S.E. Jones, J. Versalovic, Probiotic Lactobacillus reuteri biofilms produce antimicrobial and anti-inflammatory factors, BMC Microbiol. 9 (2009) 1471–2180, https://doi.org/10.1186/1471-2180-9-35. J. Plaza-Diaz, C. Gomez-Llorente, L. Campana-Martin, et al., Safety and immunomodulatory effects of three probiotic strains isolated from the feces of breastfed infants in healthy adults: SETOPROB study, PLoS One 8 (2013), https://doi. org/10.1371/journal.pone.0078111. E. Mortaz, I.M. Adcock, F.L. Ricciardolo, et al., Anti-inflammatory effects of Lactobacillus rahmnosus and Bifidobacterium breve on Cigarette smoke activated human macrophages, PLoS One 10 (2015), https://doi.org/10.1371/journal.pone. 0136455. L. Chen, Y. Zou, J. Peng, et al., Lactobacillus acidophilus suppresses colitis-associated activation of the IL-23/Th17 axis, J Immunol Res 909514 (2015) 20, https://doi.org/10.1155/2015/909514. L. Fontana, M. Bermudez-Brito, J. Plaza-Diaz, S. Munoz-Quezada, A. Gil, Sources, isolation, characterisation and evaluation of probiotics, Br. J. Nutr. 109 (2013), https://doi.org/10.1017/S0007114512004011. Y. Derwa, D.J. Gracie, P.J. Hamlin, A.C. Ford, Systematic review with meta-analysis: the efficacy of probiotics in inflammatory bowel disease, Aliment. Pharmacol. Ther. 46 (2017) 389–400, https://doi.org/10.1111/apt.14203. M. Ganji-Arjenaki, M. Rafieian-Kopaei, Probiotics are a good choice in remission of inflammatory bowel diseases: a meta analysis and systematic review, J. Cell. Physiol. 233 (2018) 2091–2103, https://doi.org/10.1002/jcp.25911. I. Bjarnason, G. Sission, B. Hayee, A randomised, double-blind, placebo-controlled trial of a multi-strain probiotic in patients with asymptomatic ulcerative colitis and Crohn's disease, Inflammopharmacology 27 (2019) 465–473, https://doi.org/ 10.1007/s10787-019-00595-4. J.E. Aguilar-Toalá, R. Garcia-Varela, H.S. Garcia, et al., Postbiotics: an evolving term within the functional foods field, Trends Food Sci. Technol. 75 (2018) 105–114, https://doi.org/10.1016/j.tifs.2018.03.009. K. Tsilingiri, T. Barbosa, G. Penna, et al., Probiotic and postbiotic activity in health and disease: comparison on a novel polarised ex-vivo organ culture model, Gut 61 (2012) 1007–1015, https://doi.org/10.1136/gutjnl-2011-300971. A. Wasilewski, M. Zielinska, M. Storr, J. Fichna, Beneficial effects of probiotics, prebiotics, synbiotics, and psychobiotics in inflammatory bowel disease, Inflamm. Bowel Dis. 21 (2015) 1674–1682, https://doi.org/10.1097/MIB. 0000000000000364. K.R. Pandey, S.R. Naik, B.V. Vakil, Probiotics, prebiotics and synbiotics- a review, J. Food Sci. Technol. 52 (2015) 7577–7587, https://doi.org/10.1007/s13197-0151921-1.

9

Microbial Pathogenesis 137 (2019) 103774

I. Aggeletopoulou, et al.

[152] T. Sunkara, P. Rawla, A. Ofosu, V. Gaduputi, Fecal microbiota transplant - a new frontier in inflammatory bowel disease, J. Inflamm. Res. 11 (2018) 321–328, https://doi.org/10.2147/JIR.S176190. [153] P.J. Basso, N.O.S. Câmara, H. Sales-Campos, Microbial-based therapies in the treatment of inflammatory bowel disease – an overview of human studies, Front. Pharmacol. 9 (2019) 1571, https://doi.org/10.3389/fphar.2018.01571. [154] A. Imdad, M.R. Nicholson, E.E. Tanner‐Smith, J.P. Zackular, O.G. Gomez‐Duarte, D.B. Beaulieu, S. Acra, Fecal transplantation for treatment of inflammatory bowel disease, Cochrane Database Syst. Rev. 11 (2018), https://doi.org/10.1002/ 14651858.CD012774.pub2.

[149] N. Narula, Z. Kassam, Y. Yuan, et al., Systematic review and meta-analysis: fecal microbiota transplantation for treatment of active ulcerative colitis, Inflamm. Bowel Dis. 23 (2017) 1702–1709, https://doi.org/10.1097/MIB. 0000000000001228. [150] Y. Cao, B. Zhang, Y. Wu, Q. Wang, J. Wang, F. Shen, The value of fecal microbiota transplantation in the treatment of ulcerative colitis patients: a systematic review and meta-analysis, Gastroenterol Res Pract 3 (2018), https://doi.org/10.1155/ 2018/5480961. [151] S. Wang, M. Xu, W. Wang, et al., Systematic review: adverse events of fecal microbiota transplantation, PLoS One 11 (2016), https://doi.org/10.1371/journal. pone.0161174.

10