REVIEW URRENT C OPINION
Inflammatory bowel disease and irritable bowel syndrome: similarities and differences Giovanni Barbara, Cesare Cremon, and Vincenzo Stanghellini
Purpose of review Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are classically viewed as dichotomous conditions. The former is perceived as a typical organic disease, and the latter is regarded as a disorder of gut function driven by mood. Recent research identified some shared contributing factors, which will be discussed here. Recent findings Mounting evidence shows the importance in both IBD and IBS of genetic, microbiological, epithelial, and immunological factors. In some instances, these factors overlap in the two conditions as shown by: involvement of brain–gut axis dysfunction in IBD, implication of TNFSF gene in Crohn’s disease and IBS, evidence of abnormal microbiota and its impact on host functions, identification of low-grade inflammation in subsets of IBS patients, and development of IBS symptoms in patients with IBD in remission. Summary IBD and IBS remain separate conditions although there are some overlapping mechanisms. Both research and clinical management would benefit from considering a functional approach for certain manifestations of IBD and accepting an organic view in subsets of IBS patients. Keywords epithelial barrier, genes, inflammatory bowel disease, irritable bowel syndrome, microbiota
INTRODUCTION Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are frequent gastrointestinal conditions associated with a marked socioeconomic burden and impairment of patients’ quality of life (QoL) [1 ,2 ]. IBD and IBS are clear paradigms of the dichotomy between organic and nonorganic gastrointestinal diseases. IBD is classically viewed as a peripheral condition characterized by intestinal inflammation, responding to therapies that primarily target the immune system. Conversely, IBS has been considered for a long time a centrally driven disorder diagnosed after exclusion of organic causes and manageable with lifestyle modifications and symptomatic treatment. However, several recent findings indicate that the boundaries between IBD and IBS are becoming blurred. There is epidemiologic, genetic, immune, and microbiological overlap. QoL is often similarly impaired in the two conditions, and it is not uncommon to verify that symptoms in patients with IBD surpass the severity of endoscopic lesions and objective markers of inflammation. The frequent experience of IBS-like symptoms in patients with IBD in remission further &
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substantiates points of contact and fuels the mounting evidence supporting a role for immunological dysfunction in the pathophysiology of IBS.
EPIDEMIOLOGICAL AND CLINICAL FEATURES IBD encompasses two main clinical entities, namely ulcerative colitis and Crohn’s disease, both presenting commonly with abdominal pain, diarrhea, and bloody stools. IBS is characterized by abdominal pain/discomfort and disordered defecation and further subtyped according to bowel habit characteristics. The main subtypes are IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), and IBS with Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy Correspondence to Giovanni Barbara, MD, Department of Medical and Surgical Sciences, Section of Internal Medicine and Gastroenterology, University of Bologna, St. Orsola–Malpighi Hospital, Building No. 5, Via Massarenti, 9, I-40138, Italy. E-mail: [email protected] Curr Opin Gastroenterol 2014, 30:352–358 DOI:10.1097/MOG.0000000000000070 Volume 30 Number 4 July 2014
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KEY POINTS IBD and IBS share some common features, including the involvement of genetic factors, disorders of immune system, and altered microbiota. Some genetic polymorphisms (TNFSF15), which regulate host–microbiota interactions, are more frequently observed both in Crohn’s disease and IBS. While low-grade intestinal inflammation has been widely described in IBS, the magnitude and nature of these responses is substantially different compared to that of IBD. IBS-like symptoms, which are frequently reported by patients with IBD, originate from a combination of psychological factors, low-grade inflammation, and enteric neuroplastic changes.
digestive disease with the greatest preponderance among females [11]. Mortality is almost nonexistent for IBS, but is also relatively rare for IBD, making gastroesophageal reflux disease a more commonly listed cause of death than IBD [11].
THE BRAIN–GUT AXIS The brain–gut axis involves interactions among the central and the autonomic nervous system, the hypothalamic–pituitary–adrenal axis, and the gastrointestinal tract, including the luminal microbiota, the epithelial barrier, and the intestinal immune system. Brain–gut axis interactions have been typically studied in the context of FGIDs and IBS in particular; however, several recent data suggest their relevance also in the pathophysiology of IBD [12 ]. An association between psychological factors and IBD flare-ups has been widely reported [12 ]. Depression has been shown to predispose to higher inflammatory responses to a stressor [13 ], and one third of patients report improvement of IBD with antidepressant therapy [14]. Compared to controls, patients taking antidepressants had reduced relapse rates, steroid use, and endoscopic procedures in the year after their introduction [15]. However, confirmation of these data in prospective, controlled studies is lacking. FGIDs have been widely linked to psychological factors, including anxiety, depression, fobia, and somatization. Koloski et al. [16 ] performed a 12-year longitudinal, prospective, population-based study to determine the directionality of brain–gut interactions in IBS and functional dyspepsia. As expected, higher levels of anxiety and depression at baseline were predictive of IBS at follow-up. However, FGID without mood disorders at baseline predisposed individuals to anxiety and depression at follow-up, suggesting that peripheral changes may be the trigger of mood disorders at least in a subgroup of IBS patients. Interestingly, disease activity status and severity of inflammation have also been linked to the severity of psychological symptoms associated with IBD (e.g. anxiety and depression) [12 ]. Regional cortical gray matter density changes have been detected in diverse inflammatory disorders, including IBD and IBS. The importance of female sex in brain neuroplastic changes has been described, particularly in IBS [17,18]. Recent data suggest that these changes could be the consequence of peripheral gut inflammation in ulcerative colitis, whereas they may represent a primary pathogenetic factor in IBS [17]. However, convincing cause–effect relationship in these disorders is still lacking. One major contributor of brain responses and symptom perception in IBS is visceral hypersensitivity, the increased &&
mixed bowel habit features (IBS-M), although this classification may be artificial as there is wide overlap between these different entities [3 ]. Abdominal pain, the cardinal symptom of IBS, is the first reported complaint that induces patients to consult a doctor and the key symptom impacting on QoL. Pain is also very frequently reported by IBD patients with active disease [4], but it is often neglected when the therapeutic focus is on mucosal healing. However, pain becomes central in patients who continue to complain of abdominal IBS-like symptoms in spite of resolution of inflammation [4]. Both IBD and IBS are associated with a significant impact on physical as well as mental components of healthrelated QoL [1 ,2 ,5 ,6]. The prevalence of IBD has been estimated to range between 1.5 and 294 cases per 100 000 people [7]. Frequency figures are much higher for IBS with around 10–20% of the population affected in Europe and the United States [8]. There have been similar trends of increasing prevalence of both IBD [5 ,9] and IBS [10] in the eastern world. It remains unknown whether this is a primary epidemiological shift of the disease or rather reflects higher consulting rates, improvements in diagnosis, or the result of increasing availability of therapeutic opportunities. Although most patients with IBD seek medical attention for their symptoms, there is an opposite trend for IBS with the majority of patients nonconsulting a physician. While IBD impacts on both outpatient and inpatient care, IBS is mainly seen in the outpatient setting [5 ]. Chronic constipation and IBS together account for 9.4 million of the 11.6 million outpatient diagnoses for functional gastrointestinal disorders (FGIDs) in the United States [11]. In the female population, the rate visit for IBS is 4.4 times that of males, making IBS the &&
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perception of stimuli arising from the gastrointestinal tract [19]. The role of visceral hypersensitivity and its correlation with the degree of active inflammation is controversial [20]. On the other hand, visceral hypersensitivity may become more evident in patients with IBD in clinical remission who show persistent symptoms including abdominal pain [21 ].
activation [25]. Although these data suggest that IBS, similarly to IBD, is linked to an abnormal mucosal immune response to luminal microbiota in genetically predisposed individuals, more work has to be done to confirm or discard this interesting hypothesis. Nonetheless, these data support the concept of a central role for organic changes in the pathogenesis of at least a subgroup of patients with IBS.
GENETIC FACTORS
MICROBIOTA
Gene hunting started over a decade ago in IBD research and led to identification of several genes contributing to IBD pathogenesis. These findings substantiate the known familiar aggregation in these patients. A recent meta-analysis of genomewide association studies identified 163 susceptibility loci in IBD. Many of these loci (e.g. NOD2, IRGM, ATG16L1, and IL23R) are involved in host–microbiota interactions [22]. The TNFSF15 gene encodes for TL1A, a member of the TNF ligand superfamily that is involved in defense against pathogens and modulates the interactions between host and microbiota in the gut. The TNFSF15 gene was first identified as a risk factor for Crohn’s disease and later reported to also contribute to the risk of ulcerative colitis [22]. On the basis of the observation that a subgroup of patients with IBS shows evidence of low-grade immune activation, the involvement of TNFSF15, previously linked to Crohn’s disease, has been recently investigated. A large IBS case–control study in 1992 individuals from two independent cohorts from Sweden and the United States identified that the Crohn’s disease-risk variant G from the rs4263839 single nucleotide polymorphism (SNP) in the TNFSF15 gene was more frequently observed in IBS (particularly IBS-C) than controls [23]. These data have been recently confirmed in a smaller study from the United Kingdom demonstrating also a higher tissue expression of TNFSF15 along with increased mRNA expression of several cytokines and chemokines [24]. As the disease risk alleles may be the same for Crohn’s disease and IBS, it has been hypothesized that common mechanisms could be involved in the predisposition to both conditions. It has also been hypothesized that IBS may represent an immunologically incomplete expression variant of Crohn’s disease [18]. Along the line of an involvement of genes in the pathogenesis of IBS, it was found that development of IBS following a waterborne outbreak of infectious gastroenteritis was associated with SNPs in toll-like receptor 9 (TLR9), the tight junction protein cadherin (CDH1), and the pro-inflammatory cytokine interleukin 6, which are involved in host–microbiota interactions, epithelial barrier, and immune
It is well established that IBD patients show reduced diversity and different compositions of intestinal microbiota, including reduction of bacteria involved in butyrate and propionate metabolism (e.g. Ruminococcus bromii et rel., Eubacterium rectale et rel., and Roseburia sp.) as well as mucus degradation (i.e. Akkermansia sp.) [26 –28 ]. Attention has been also directed to the potential role of specific bacterial strains including the reduction in tissue concentrations of the anti-inflammatory microbiota commensal Faecalibacterium prausnitzii [26 ]. The pathogenetic role of F. prausnitzii in IBD is supported by data showing that low tissue concentration of this bacterium was associated with an increased risk of postoperative recurrence of Crohn’s disease [26 ]. However, a recent study failed to find decreased tissue levels of F. prausnitzii at least in a pediatric group of Crohn’s disease patients [29]. The evidence linking microbiota to IBS is in its infancy, but it is already providing exciting results [30 ]. The clearest evidence of the participation of bacteria in the pathogenesis of IBS is provided by the fact that about 10% of individuals experiencing an acute episode of gastroenteritis (e.g. Shigella, Salmonella, and Campylobacter) develop persistent symptoms fulfilling the criteria for IBS [31]. A 16-year, prospective, controlled, culture-proven, follow-up study explored the association between a single episode of Salmonella gastroenteritis and new-onset FGIDs. In this long-term outcome study, it was shown that Salmonella gastroenteritis increased the risk for IBS, but only if the infection occurred during childhood [32 ]. Interestingly, acute infectious gastroenteritis is also a trigger for the development of IBD [33]. Porter et al. [33] demonstrated that acute infectious gastroenteritis was an independently associated risk factor for IBD [odds ratio (OR): 1.40] with ORs for Crohn’s disease slightly higher than those for ulcerative colitis (ORs: 1.54 and 1.36, respectively). The first compelling evidence of altered fecal microbiota composition in IBS comes from a Finnish study showing increased ratio of Firmicutes:Bacteroidetes and lower levels of Bifidobacteria [34]. A recent study investigated the correlation between microbiota profiles and psychological factors or
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bowel physiology [35 ]. It was found that microbiota abnormalities were associated with peripheral changes such as disturbances in gut transit, whereas individuals with no modifications of the microbiota correlated with anxiety and depression [35 ]. More recently, a bacterial profile of 27 genus-like groups significantly separated both postinfectious IBS and IBS-D from controls. The study also provided evidence of a correlation between changes in microbiota and expression of several host gene pathways involved in impaired epithelial barrier function [36 ]. Attention is being directed to the potential functional consequences of altered microbiota taxa. Diet is a major driving force in the control of microbiota composition and function. On the other hand, microbiota changes may lead to the abnormal fermentation of indigestible carbohydrates, with consequent production of gas and metabolites potentially involved in symptom generation. The effect of a challenge with a diet rich in fibers on microbiota composition and abdominal symptoms has been recently investigated. When patients complaining of flatulence were challenged with the fiber-rich diet, microbiota showed higher instability and reduction of microbial diversity compared to healthy controls. In addition, when challenged, both groups recorded more abdominal symptoms, number of gas evacuations, and more gas production [37 ]. Previous data demonstrated increased luminal and fecal protease activity in IBS. Proteases have been linked to the activation of receptors that are involved in pain transmission and bowel dysfunction. Specific intestinal bacterial groups (Lactobacillales, Lachnospiraceae, and Streptococcaceae) are linked to fecal protease activity. These data support the hypothesis that bacteria could be important contributors to higher fecal protease activity and support a link between bacteria and abdominal pain [38]. &&
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EPITHELIAL BARRIER The intestinal barrier represents a strategic site of the interplay between billions of bacteria, nutrients, and the host. A long-term change in epithelial barrier function has been suggested to play a role in the pathogenesis of IBD and predispose to IBD relapses [39]. Increased intestinal permeability has been recently suggested to participate in the pathogenesis of symptoms in IBS [40]. Higher paracellular permeability was demonstrated in colonic biopsies in Ussing chamber experiments [41]. In Caco-2 monolayers, the application of cleared supernatants of IBS colonic biopsies in culture induced downregulation of zonula occludens-1 mRNA expression and increased paracellular permeability, which
correlated with the severity of abdominal pain [41,42]. These functional observations are accompanied by elegant morphological studies showing that the jejunal mucosa of patients with IBS-D showed alterations in expression and phosphorylation of tight junctions and ultrastructural abnormalities such as perijunctional cytoskeleton condensation and enlarged apical intercellular distance between cells [43 ]. Interestingly, these alterations were correlated both with mast cell activation and clinical symptoms including diarrhea and pain severity [43 ]. The cause(s) of the described morphological and functional changes remain unknown, although previous episodes of infectious gastroenteritis, dysbiosis, allergy, genetic, and epigenetic factors may be involved. Low-grade inflammation described in subgroups of patients with IBS may have a role in the maintenance of increase of intestinal permeability. &
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INFLAMMATION Tissue inflammation is central to IBD pathogenesis and has been the starting point of mainstream research in this condition. Conversely, the concept that IBS pathogenesis involves peripheral organic changes and minimal inflammation is relatively new and represents a new concept resulting from recent research. Several studies showed increased numbers of immunocytes (e.g. mast cells and T cells) in both adult and pediatric IBS [44]. Low-grade inflammation has been mainly associated with postinfectious IBS; however, several studies demonstrate similar findings in IBS-D and IBS-C [45]. The fact that up to one third of patients with IBD in remission and around half of patients with microscopic colitis experience IBS-like symptoms further supports the involvement of low-grade inflammation in IBS [44]. Low-grade inflammation is coupled with increased expression of innate immunity to microbial molecular patterns (e.g. TLR) [46], suggesting a contributing role for gut microbiota. Biopsies obtained from the colonic mucosa of IBS patients released higher amounts of inflammatory mediators, including proteases, histamine, and prostaglandins compared with controls [47–49]. Caution should be used when comparing this inflammatory response with that of IBD, as marked quantitative and qualitative differences exist. As expected, the magnitude of the inflammatory response seen in IBS was much lower than that of active or quiescent ulcerative colitis, although it was widely overlapping with that of microscopic colitis [50]. In IBS, most data converge on the implication of mast cells. Activated mast cells in close proximity of enteric nerves were correlated with the intensity
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and frequency of abdominal pain [49]. Mucosal mediators of mast cell origin hyperexcited nociceptive visceral sensory pathways in recipient rodents [47,48,51 ] or enteric nervous system excitability in isolated gut tissues from guinea pigs [52]. Although immune cells are likely the major source of mediators impacting nerve function, a microbial origin of some of these factors has also been suggested [53]. Potential contributing factors of this low-grade inflammation include, among others, allergic reactions and stress. Acute psychological stress increased small intestinal permeability in humans and the mast cell stabilizer disodium chromoglycate blocked this effect. These findings provide new insights into the complex interplay between the central nervous system and the immune system in humans [54]. &
suggesting that central factors alone cannot justify completely the development of IBS-like symptoms in all patients [4]. The prevalence of IBS in the general population is relatively high (10–20%), hence coexistent IBS could be expected in a similar proportion of IBD patients in remission. However, the high prevalence of IBS-like symptoms in IBD in remission cannot be explained by casual overlap alone. Whether IBS-like symptoms reflect clinically undetected, low-grade inflammation is a matter of controversy. Fecal calprotectin was significantly higher in Crohn’s disease and ulcerative colitis patients with criteria for IBS than in those without IBS-type symptoms [55]. In addition, increased intraepithelial lymphocytes and tissue tumor necrosis factor alpha expression was associated with IBS-like symptoms in quiescent IBD, but not with IBS [56 ]. These findings suggest that occult inflammation could drive IBS-like symptoms in patients with IBD in remission and imply the possible need of further testing (e.g. fecal calprotectin) and potentiation of immunosuppressive therapy [55]. However, increased calprotectin levels have not been confirmed in more recent studies, suggesting a more complex pathogenesis [4,21 ]. A barostat study in patients with ulcerative colitis in remission indicated that IBS-like symptoms were associated with visceral hypersensitivity and mast cell infiltration [57]. In addition, Akbar et al. [58] showed a 3.9-fold to 5-fold increase of the sensory nerve receptor transient receptor potential vanilloid type 1 (TRPV1) associated with pain perception in the mucosa of IBD patients with IBS symptoms. TRPV1 expression correlated with the severity of abdominal pain, suggesting that postinflammatory neuroplastic changes occurring at least in a subgroup of patients with IBD may have potential consequences for bowel physiology, visceral hypersensitivity, and symptom generation. &&
EXPERIENCE OF IRRITABLE BOWEL SYNDROME SYMPTOMS IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE IN REMISSION Although a high proportion of patients with IBD frequently experiences symptoms, which are indistinguishable from IBS, the diagnosis is generally confirmed by additional laboratory and imaging studies. The clinical dilemma emerges when patients continue to experience symptoms (e.g. abdominal pain, bloating and changes in bowel habit) while in remission. Is this the expression of occult active disease or IBS? Should these patients receive more aggressive anti-inflammatory/immunosuppressive therapy? A meta-analysis of 1703 individuals showed that the prevalence of IBS-like symptoms in patients with IBD in remission was 35%. Crohn’s disease patients in remission had a higher risk of having IBS-like symptoms compared with ulcerative colitis in remission (OR: 1.74; 95% CI: 1.24 – 2.43) [4]. IBS-like symptoms in these individuals were associated with female sex, reduced well-being, and QoL as well as higher fatigue scores than those without [21 ]. Nonetheless, a comparative study reported that QoL was more severely affected in ‘true’ IBS compared with IBS occurring in IBD patients in remission. In a recent longitudinal 3-year follow-up study, it was observed that symptoms of IBS in ulcerative colitis in remission tended to fluctuate over time being present overall in 19% of patients at yearly visits [21 ]. A frequent finding is the detection of higher levels of mood disorders, including predominantly anxiety, in patients experiencing IBS-like symptoms compared with symptom-free individuals [4,21 ]. Although anxiety was independently associated with IBS symptoms, the risk seems moderate (OR: 1.11, CI: 1.01–1.21), &&
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CONCLUSION Recent research suggests that IBD and IBS share some common pathogenetic features. The possible implication of microbiota, inflammation, and genetic factors has received increasing attention in IBS research, although their relevance is far less defined in IBS compared with IBD. The overlap between IBD and IBS is particularly evident in patients who develop IBS-like symptoms while in remission. A better understanding of the role of pathogenetic factors and mechanisms underlying the development of persistent symptoms in patients with IBD in remission is now needed for the identification of more objective disease signatures and development of targeted therapies. Volume 30 Number 4 July 2014
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Acknowledgements G.B. and V.S. are supported in part by the Italian Ministry of Instruction, University and Research. Conflicts of interest G.B. and V.S. have served as consultants/advisory board members for Alfa Wassermann, Almirall, Italchimici, Ironwood, and Shire. G.B. and V.S. received research grant support from Alfa Wassermann, Italchimici, and Shire. G.B. received research grant support from Falk Pharma, Sofar, and Yakult. V.S. received research grant support from Almirall, Aptalis, Norgine, and Valeas. G.B. served as consultant/advisory board member for Danone, Falk Pharma, Malesci, Nestle`, Noos, Sofar, Synergy, and Yakult. V.S. served as consultant/advisory board member for Angelini, Aptalis, CM&D Pharma, Farmaderma, Janssen, Norgine, Takeda, Valeas, and Zeria. C.C. has been the recipient of a scholarship grant from Sofar.
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Gastroenterology 2010; 138:1502–1513. 26. Major G, Spiller R. Irritable bowel syndrome, inflammatory bowel disease & and the microbiome. Curr Opin Endocrinol Diabetes Obes 2014; 21:15– 21. Timely review describing the potential impact of gut microbiota in IBD and irritable bowel syndrome and the role of microbiota modulation in these disorders. 27. Cader MZ, Kaser A. Recent advances in inflammatory bowel disease: & mucosal immune cells in intestinal inflammation. Gut 2013; 62:1653– 1664. Up-to-date review highlighting the complex interplay of distinct intestinal immune cell types and discussing how mucosal immune system perturbations can lead to inflammation. 28. Rajilic-Stojanovic M, Shanahan F, Guarner F, de Vos WM. Phylogenetic analysis & of dysbiosis in ulcerative colitis during remission. Inflamm Bowel Dis 2013; 19:481–488. Interesting study assessing fecal microbiota composition in patients with ulcerative colitis. Results showed that fecal microbiota composition differs significantly in these patients in comparison with controls, but it is stable in time. This dysbiosis is characterized by significant reduction of members of the Clostridium cluster IV and significant reduction of bacteria involved in butyrate and propionate metabolism, including Ruminococcus bromii et rel., Eubacterium rectale et rel., Roseburia sp., and Akkermansia. 29. Hansen R, Russell RK, Reiff C, et al. Microbiota of de-novo pediatric IBD: increased Faecalibacterium prausnitzii and reduced bacterial diversity in Crohn’s but not in ulcerative colitis. Am J Gastroenterol 2012; 107:1913– 1922.
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Inflammatory bowel disease 30. Simren M, Barbara G, Flint HJ, et al. Intestinal microbiota in functional bowel disorders: a Rome foundation report. Gut 2013; 62:159–176. In depth review on the current knowledge on the role of intestinal microbiota in the pathophysiology of functional gastrointestinal disorders. The review explores also treatment implications including the use of prebiotics, probiotics, symbiotics, and antibiotics in these syndromes. 31. Spiller R, Garsed K. Postinfectious irritable bowel syndrome. Gastroenterology 2009; 136:1979–1988. 32. Cremon C, Stanghellini V, Pallotti F, et al. Salmonella gastroenteritis during & childhood is a risk factor for irritable bowel syndrome in adulthood. Gastroenterology 2014. [Epub ahead of print] Prospective, controlled, cohort study assessing functional digestive symptoms, psychological factors, and QoL 16 years after a single culture-proven foodborne Salmonella enteritidis outbreak involving 1811, mostly pediatric, patients in Bologna, Italy. Acute Salmonella gastroenteritis was identified as a risk factor for the development of long-term IBS symptoms (OR for IBS 1.92; 95% CI: 1.23– 2.98), but only if the infection occurs during childhood (OR for IBS in children 2.12; 95% CI: 1.21–3.71). 33. Porter CK, Tribble DR, Aliaga PA, et al. Infectious gastroenteritis and risk of developing inflammatory bowel disease. Gastroenterology 2008; 135:781– 786. 34. Rajilic´-Stojanovic´ M, Biagi E, Heilig HG, et al. Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome. Gastroenterology 2011; 141:1792–1801. ¨ hman L, et al. An irritable bowel syndrome subtype 35. Jeffery IB, O’Toole PW, O && defined by species-specific alterations in faecal microbiota. Gut 2012; 61:997–1006. Interesting study investigating the association between microbiota and the brain– gut axis in patients with IBS. Results showed that those with no modifications in fecal microbiota had more mood disorders while those with modification in microbiota had changes in bowel physiology. 36. Jalanka-Tuovinen J, Salojarvi J, Salonen A, et al. Faecal microbiota composi&& tion and host–-microbe cross-talk following gastroenteritis and in postinfectious irritable bowel syndrome. Gut 2013. [Epub ahead of print] First study to show that fecal microbiota of patients with postinfectious IBS differs from that of controls and shares similarities with that of patients with IBS with diarrhea, suggesting a common pathophysiology. Members of Bacteroidetes phylum were increased 12-fold in patients, while controls had 35-fold more uncultured Clostridia. Microbial dysbiosis correlates with the expression of several host gene pathways, including impaired epithelial barrier function. 37. Manichanh C, Eck A, Varela E, et al. Anal gas evacuation and colonic & microbiota in patients with flatulence: effect of diet. Gut 2014. [Epub ahead of print] Study analyzing the potential role of diet on digestive symptoms, anal gas evacuation, intestinal gas distribution, and colonic microbiota in 30 patients with flatulence. On a flatulogenic diet, both patients and controls recorded more abdominal symptoms, gas production, and evacuations. Interestingly, only microbiota of patients developed instability in composition, while that of controls was stable, suggesting that patients with flatulence have a poor tolerance of intestinal gas that is associated with microbiota instability. 38. Carroll IM, Ringel-Kulka T, Ferrier L, et al. Fecal protease activity is associated with compositional alterations in the intestinal microbiota. PLoS One 2013; 8:e78017. 39. Salim SY, Soderholm JD. Importance of disrupted intestinal barrier in inflammatory bowel diseases. Inflamm Bowel Dis 2011; 17:362–381. 40. Piche T. Tight junctions and IBS: the link between epithelial permeability, lowgrade inflammation, and symptom generation? Neurogastroenterol Motil 2014; 26:296–302. 41. Piche T, Barbara G, Aubert P, et al. Impaired intestinal barrier integrity in the colon of patients with irritable bowel syndrome: involvement of soluble mediators. Gut 2009; 58:196–201. 42. Camilleri M. Peripheral mechanisms in irritable bowel syndrome. N Engl J Med 2012; 367:1626–1635. &&
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43. Martinez C, Lobo B, Pigrau M, et al. Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier. Gut 2013; 62:1160–1168. Careful study assessing clinical symptoms and jejunal biopsies in 45 patients with IBS-D and 30 controls. Patients with IBS-D displayed increased mast cell counts and activation, increased protein expression of claudin-2, reduced occludin phosphorylation and enhanced redistribution from the membrane to the cytoplasm, increased myosin kinase expression, and enhanced phosphorylation of myosin. These alterations were associated with ultrastructural abnormalities at the apical junction complex which correlated both with mast cell activation and clinical symptoms. 44. Barbara G, Cremon C, Carini G, et al. The immune system in irritable bowel syndrome. J Neurogastroenterol Motil 2011; 17:349–359. 45. Matricon J, Meleine M, Gelot A, et al. Review article: associations between immune activation, intestinal permeability and the irritable bowel syndrome. Aliment Pharmacol Ther 2012; 36:1009–1031. 46. Belmonte L, Beutheu Youmba S, Bertiaux-Vandaele N, et al. Role of toll like receptors in irritable bowel syndrome: differential mucosal immune activation according to the disease subtype. PLoS One 2012; 7:e42777. 47. Cenac N, Andrews CN, Holzhausen M, et al. Role for protease activity in visceral pain in irritable bowel syndrome. J Clin Invest 2007; 117:636–647. 48. Barbara G, Wang B, Stanghellini V, et al. Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome. Gastroenterology 2007; 132:26–37. 49. Barbara G, Stanghellini V, De Giorgio R, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004; 126:693–702. 50. Cremon C, Gargano L, Morselli-Labate AM, et al. Mucosal immune activation in irritable bowel syndrome: gender-dependence and association with digestive symptoms. Am J Gastroenterol 2009; 104:392–400. 51. Valdez-Morales EE, Overington J, Guerrero-Alba R, et al. Sensitization of & peripheral sensory nerves by mediators from colonic biopsies of diarrheapredominant irritable bowel syndrome patients: a role for PAR2. Am J Gastroenterol 2013; 108:1634–1643. Study examining the impact of mediators from colonic biopsies of patients with IBS on intrinsic excitability of colonic nociceptive dorsal root ganglion neurons. Supernatants from patients with IBS-D but not IBS-C induced a marked increase in neuronal excitability by a protease-activated receptor 2-mediated mechanism. 52. Balestra B, Vicini R, Cremon C, et al. Colonic mucosal mediators from patients with irritable bowel syndrome excite enteric cholinergic motor neurons. Neurogastroenterol Motil 2012; 24:1118–e1570. 53. Steck N, Mueller K, Schemann M, Haller D. Bacterial proteases in IBD and IBS. Gut 2012; 61:1610–1618. 54. Vanuytsel T, van Wanrooy S, Vanheel H, et al. Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism. Gut 2013. [Epub ahead of print] 55. Keohane J, O’Mahony C, O’Mahony L, et al. Irritable bowel syndrome-type symptoms in patients with inflammatory bowel disease: a real association or reflection of occult inflammation? Am J Gastroenterol 2010; 105:1788; 1789–1794; quiz 1795. 56. Vivinus-Nebot M, Frin-Mathy G, Bzioueche H, et al. Functional bowel symp&& toms in quiescent inflammatory bowel diseases: role of epithelial barrier disruption and low-grade inflammation. Gut 2014; 63:744–752. Important study evaluating the role of colonic barrier defects and low-grade inflammation in cecal biopsies of 51 patients with IBS, 49 patients with quiescent IBD and 27 controls. Paracellular permeability was significantly increased in IBS and patients with quiescent IBD and IBS-like symptoms and associated with lower expression of ZO-1 and a-catenin. Intraepithelial lymphocytes and TNFa were significantly increased only in patients with quiescent IBD and IBS-like symptoms. 57. van Hoboken EA, Thijssen AY, Verhaaren R, et al. Symptoms in patients with ulcerative colitis in remission are associated with visceral hypersensitivity and mast cell activity. Scand J Gastroenterol 2011; 46:981–987. 58. Akbar A, Yiangou Y, Facer P, et al. Expression of the TRPV1 receptor differs in quiescent inflammatory bowel disease with or without abdominal pain. Gut 2010; 59:767–774. &
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Inflammatory bowel disease and irritable bowel syndrome: similarities and differences Giovanni Barbara, Cesare Cremon, and Vincenzo Stanghellini
Purpose of review Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are classically viewed as dichotomous conditions. The former is perceived as a typical organic disease, and the latter is regarded as a disorder of gut function driven by mood. Recent research identified some shared contributing factors, which will be discussed here. Recent findings Mounting evidence shows the importance in both IBD and IBS of genetic, microbiological, epithelial, and immunological factors. In some instances, these factors overlap in the two conditions as shown by: involvement of brain–gut axis dysfunction in IBD, implication of TNFSF gene in Crohn’s disease and IBS, evidence of abnormal microbiota and its impact on host functions, identification of low-grade inflammation in subsets of IBS patients, and development of IBS symptoms in patients with IBD in remission. Summary IBD and IBS remain separate conditions although there are some overlapping mechanisms. Both research and clinical management would benefit from considering a functional approach for certain manifestations of IBD and accepting an organic view in subsets of IBS patients. Keywords epithelial barrier, genes, inflammatory bowel disease, irritable bowel syndrome, microbiota
INTRODUCTION Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are frequent gastrointestinal conditions associated with a marked socioeconomic burden and impairment of patients’ quality of life (QoL) [1 ,2 ]. IBD and IBS are clear paradigms of the dichotomy between organic and nonorganic gastrointestinal diseases. IBD is classically viewed as a peripheral condition characterized by intestinal inflammation, responding to therapies that primarily target the immune system. Conversely, IBS has been considered for a long time a centrally driven disorder diagnosed after exclusion of organic causes and manageable with lifestyle modifications and symptomatic treatment. However, several recent findings indicate that the boundaries between IBD and IBS are becoming blurred. There is epidemiologic, genetic, immune, and microbiological overlap. QoL is often similarly impaired in the two conditions, and it is not uncommon to verify that symptoms in patients with IBD surpass the severity of endoscopic lesions and objective markers of inflammation. The frequent experience of IBS-like symptoms in patients with IBD in remission further &
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substantiates points of contact and fuels the mounting evidence supporting a role for immunological dysfunction in the pathophysiology of IBS.
EPIDEMIOLOGICAL AND CLINICAL FEATURES IBD encompasses two main clinical entities, namely ulcerative colitis and Crohn’s disease, both presenting commonly with abdominal pain, diarrhea, and bloody stools. IBS is characterized by abdominal pain/discomfort and disordered defecation and further subtyped according to bowel habit characteristics. The main subtypes are IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), and IBS with Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy Correspondence to Giovanni Barbara, MD, Department of Medical and Surgical Sciences, Section of Internal Medicine and Gastroenterology, University of Bologna, St. Orsola–Malpighi Hospital, Building No. 5, Via Massarenti, 9, I-40138, Italy. E-mail: [email protected] Curr Opin Gastroenterol 2014, 30:352–358 DOI:10.1097/MOG.0000000000000070 Volume 30 Number 4 July 2014
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KEY POINTS IBD and IBS share some common features, including the involvement of genetic factors, disorders of immune system, and altered microbiota. Some genetic polymorphisms (TNFSF15), which regulate host–microbiota interactions, are more frequently observed both in Crohn’s disease and IBS. While low-grade intestinal inflammation has been widely described in IBS, the magnitude and nature of these responses is substantially different compared to that of IBD. IBS-like symptoms, which are frequently reported by patients with IBD, originate from a combination of psychological factors, low-grade inflammation, and enteric neuroplastic changes.
digestive disease with the greatest preponderance among females [11]. Mortality is almost nonexistent for IBS, but is also relatively rare for IBD, making gastroesophageal reflux disease a more commonly listed cause of death than IBD [11].
THE BRAIN–GUT AXIS The brain–gut axis involves interactions among the central and the autonomic nervous system, the hypothalamic–pituitary–adrenal axis, and the gastrointestinal tract, including the luminal microbiota, the epithelial barrier, and the intestinal immune system. Brain–gut axis interactions have been typically studied in the context of FGIDs and IBS in particular; however, several recent data suggest their relevance also in the pathophysiology of IBD [12 ]. An association between psychological factors and IBD flare-ups has been widely reported [12 ]. Depression has been shown to predispose to higher inflammatory responses to a stressor [13 ], and one third of patients report improvement of IBD with antidepressant therapy [14]. Compared to controls, patients taking antidepressants had reduced relapse rates, steroid use, and endoscopic procedures in the year after their introduction [15]. However, confirmation of these data in prospective, controlled studies is lacking. FGIDs have been widely linked to psychological factors, including anxiety, depression, fobia, and somatization. Koloski et al. [16 ] performed a 12-year longitudinal, prospective, population-based study to determine the directionality of brain–gut interactions in IBS and functional dyspepsia. As expected, higher levels of anxiety and depression at baseline were predictive of IBS at follow-up. However, FGID without mood disorders at baseline predisposed individuals to anxiety and depression at follow-up, suggesting that peripheral changes may be the trigger of mood disorders at least in a subgroup of IBS patients. Interestingly, disease activity status and severity of inflammation have also been linked to the severity of psychological symptoms associated with IBD (e.g. anxiety and depression) [12 ]. Regional cortical gray matter density changes have been detected in diverse inflammatory disorders, including IBD and IBS. The importance of female sex in brain neuroplastic changes has been described, particularly in IBS [17,18]. Recent data suggest that these changes could be the consequence of peripheral gut inflammation in ulcerative colitis, whereas they may represent a primary pathogenetic factor in IBS [17]. However, convincing cause–effect relationship in these disorders is still lacking. One major contributor of brain responses and symptom perception in IBS is visceral hypersensitivity, the increased &&
mixed bowel habit features (IBS-M), although this classification may be artificial as there is wide overlap between these different entities [3 ]. Abdominal pain, the cardinal symptom of IBS, is the first reported complaint that induces patients to consult a doctor and the key symptom impacting on QoL. Pain is also very frequently reported by IBD patients with active disease [4], but it is often neglected when the therapeutic focus is on mucosal healing. However, pain becomes central in patients who continue to complain of abdominal IBS-like symptoms in spite of resolution of inflammation [4]. Both IBD and IBS are associated with a significant impact on physical as well as mental components of healthrelated QoL [1 ,2 ,5 ,6]. The prevalence of IBD has been estimated to range between 1.5 and 294 cases per 100 000 people [7]. Frequency figures are much higher for IBS with around 10–20% of the population affected in Europe and the United States [8]. There have been similar trends of increasing prevalence of both IBD [5 ,9] and IBS [10] in the eastern world. It remains unknown whether this is a primary epidemiological shift of the disease or rather reflects higher consulting rates, improvements in diagnosis, or the result of increasing availability of therapeutic opportunities. Although most patients with IBD seek medical attention for their symptoms, there is an opposite trend for IBS with the majority of patients nonconsulting a physician. While IBD impacts on both outpatient and inpatient care, IBS is mainly seen in the outpatient setting [5 ]. Chronic constipation and IBS together account for 9.4 million of the 11.6 million outpatient diagnoses for functional gastrointestinal disorders (FGIDs) in the United States [11]. In the female population, the rate visit for IBS is 4.4 times that of males, making IBS the &&
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perception of stimuli arising from the gastrointestinal tract [19]. The role of visceral hypersensitivity and its correlation with the degree of active inflammation is controversial [20]. On the other hand, visceral hypersensitivity may become more evident in patients with IBD in clinical remission who show persistent symptoms including abdominal pain [21 ].
activation [25]. Although these data suggest that IBS, similarly to IBD, is linked to an abnormal mucosal immune response to luminal microbiota in genetically predisposed individuals, more work has to be done to confirm or discard this interesting hypothesis. Nonetheless, these data support the concept of a central role for organic changes in the pathogenesis of at least a subgroup of patients with IBS.
GENETIC FACTORS
MICROBIOTA
Gene hunting started over a decade ago in IBD research and led to identification of several genes contributing to IBD pathogenesis. These findings substantiate the known familiar aggregation in these patients. A recent meta-analysis of genomewide association studies identified 163 susceptibility loci in IBD. Many of these loci (e.g. NOD2, IRGM, ATG16L1, and IL23R) are involved in host–microbiota interactions [22]. The TNFSF15 gene encodes for TL1A, a member of the TNF ligand superfamily that is involved in defense against pathogens and modulates the interactions between host and microbiota in the gut. The TNFSF15 gene was first identified as a risk factor for Crohn’s disease and later reported to also contribute to the risk of ulcerative colitis [22]. On the basis of the observation that a subgroup of patients with IBS shows evidence of low-grade immune activation, the involvement of TNFSF15, previously linked to Crohn’s disease, has been recently investigated. A large IBS case–control study in 1992 individuals from two independent cohorts from Sweden and the United States identified that the Crohn’s disease-risk variant G from the rs4263839 single nucleotide polymorphism (SNP) in the TNFSF15 gene was more frequently observed in IBS (particularly IBS-C) than controls [23]. These data have been recently confirmed in a smaller study from the United Kingdom demonstrating also a higher tissue expression of TNFSF15 along with increased mRNA expression of several cytokines and chemokines [24]. As the disease risk alleles may be the same for Crohn’s disease and IBS, it has been hypothesized that common mechanisms could be involved in the predisposition to both conditions. It has also been hypothesized that IBS may represent an immunologically incomplete expression variant of Crohn’s disease [18]. Along the line of an involvement of genes in the pathogenesis of IBS, it was found that development of IBS following a waterborne outbreak of infectious gastroenteritis was associated with SNPs in toll-like receptor 9 (TLR9), the tight junction protein cadherin (CDH1), and the pro-inflammatory cytokine interleukin 6, which are involved in host–microbiota interactions, epithelial barrier, and immune
It is well established that IBD patients show reduced diversity and different compositions of intestinal microbiota, including reduction of bacteria involved in butyrate and propionate metabolism (e.g. Ruminococcus bromii et rel., Eubacterium rectale et rel., and Roseburia sp.) as well as mucus degradation (i.e. Akkermansia sp.) [26 –28 ]. Attention has been also directed to the potential role of specific bacterial strains including the reduction in tissue concentrations of the anti-inflammatory microbiota commensal Faecalibacterium prausnitzii [26 ]. The pathogenetic role of F. prausnitzii in IBD is supported by data showing that low tissue concentration of this bacterium was associated with an increased risk of postoperative recurrence of Crohn’s disease [26 ]. However, a recent study failed to find decreased tissue levels of F. prausnitzii at least in a pediatric group of Crohn’s disease patients [29]. The evidence linking microbiota to IBS is in its infancy, but it is already providing exciting results [30 ]. The clearest evidence of the participation of bacteria in the pathogenesis of IBS is provided by the fact that about 10% of individuals experiencing an acute episode of gastroenteritis (e.g. Shigella, Salmonella, and Campylobacter) develop persistent symptoms fulfilling the criteria for IBS [31]. A 16-year, prospective, controlled, culture-proven, follow-up study explored the association between a single episode of Salmonella gastroenteritis and new-onset FGIDs. In this long-term outcome study, it was shown that Salmonella gastroenteritis increased the risk for IBS, but only if the infection occurred during childhood [32 ]. Interestingly, acute infectious gastroenteritis is also a trigger for the development of IBD [33]. Porter et al. [33] demonstrated that acute infectious gastroenteritis was an independently associated risk factor for IBD [odds ratio (OR): 1.40] with ORs for Crohn’s disease slightly higher than those for ulcerative colitis (ORs: 1.54 and 1.36, respectively). The first compelling evidence of altered fecal microbiota composition in IBS comes from a Finnish study showing increased ratio of Firmicutes:Bacteroidetes and lower levels of Bifidobacteria [34]. A recent study investigated the correlation between microbiota profiles and psychological factors or
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bowel physiology [35 ]. It was found that microbiota abnormalities were associated with peripheral changes such as disturbances in gut transit, whereas individuals with no modifications of the microbiota correlated with anxiety and depression [35 ]. More recently, a bacterial profile of 27 genus-like groups significantly separated both postinfectious IBS and IBS-D from controls. The study also provided evidence of a correlation between changes in microbiota and expression of several host gene pathways involved in impaired epithelial barrier function [36 ]. Attention is being directed to the potential functional consequences of altered microbiota taxa. Diet is a major driving force in the control of microbiota composition and function. On the other hand, microbiota changes may lead to the abnormal fermentation of indigestible carbohydrates, with consequent production of gas and metabolites potentially involved in symptom generation. The effect of a challenge with a diet rich in fibers on microbiota composition and abdominal symptoms has been recently investigated. When patients complaining of flatulence were challenged with the fiber-rich diet, microbiota showed higher instability and reduction of microbial diversity compared to healthy controls. In addition, when challenged, both groups recorded more abdominal symptoms, number of gas evacuations, and more gas production [37 ]. Previous data demonstrated increased luminal and fecal protease activity in IBS. Proteases have been linked to the activation of receptors that are involved in pain transmission and bowel dysfunction. Specific intestinal bacterial groups (Lactobacillales, Lachnospiraceae, and Streptococcaceae) are linked to fecal protease activity. These data support the hypothesis that bacteria could be important contributors to higher fecal protease activity and support a link between bacteria and abdominal pain [38]. &&
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EPITHELIAL BARRIER The intestinal barrier represents a strategic site of the interplay between billions of bacteria, nutrients, and the host. A long-term change in epithelial barrier function has been suggested to play a role in the pathogenesis of IBD and predispose to IBD relapses [39]. Increased intestinal permeability has been recently suggested to participate in the pathogenesis of symptoms in IBS [40]. Higher paracellular permeability was demonstrated in colonic biopsies in Ussing chamber experiments [41]. In Caco-2 monolayers, the application of cleared supernatants of IBS colonic biopsies in culture induced downregulation of zonula occludens-1 mRNA expression and increased paracellular permeability, which
correlated with the severity of abdominal pain [41,42]. These functional observations are accompanied by elegant morphological studies showing that the jejunal mucosa of patients with IBS-D showed alterations in expression and phosphorylation of tight junctions and ultrastructural abnormalities such as perijunctional cytoskeleton condensation and enlarged apical intercellular distance between cells [43 ]. Interestingly, these alterations were correlated both with mast cell activation and clinical symptoms including diarrhea and pain severity [43 ]. The cause(s) of the described morphological and functional changes remain unknown, although previous episodes of infectious gastroenteritis, dysbiosis, allergy, genetic, and epigenetic factors may be involved. Low-grade inflammation described in subgroups of patients with IBS may have a role in the maintenance of increase of intestinal permeability. &
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INFLAMMATION Tissue inflammation is central to IBD pathogenesis and has been the starting point of mainstream research in this condition. Conversely, the concept that IBS pathogenesis involves peripheral organic changes and minimal inflammation is relatively new and represents a new concept resulting from recent research. Several studies showed increased numbers of immunocytes (e.g. mast cells and T cells) in both adult and pediatric IBS [44]. Low-grade inflammation has been mainly associated with postinfectious IBS; however, several studies demonstrate similar findings in IBS-D and IBS-C [45]. The fact that up to one third of patients with IBD in remission and around half of patients with microscopic colitis experience IBS-like symptoms further supports the involvement of low-grade inflammation in IBS [44]. Low-grade inflammation is coupled with increased expression of innate immunity to microbial molecular patterns (e.g. TLR) [46], suggesting a contributing role for gut microbiota. Biopsies obtained from the colonic mucosa of IBS patients released higher amounts of inflammatory mediators, including proteases, histamine, and prostaglandins compared with controls [47–49]. Caution should be used when comparing this inflammatory response with that of IBD, as marked quantitative and qualitative differences exist. As expected, the magnitude of the inflammatory response seen in IBS was much lower than that of active or quiescent ulcerative colitis, although it was widely overlapping with that of microscopic colitis [50]. In IBS, most data converge on the implication of mast cells. Activated mast cells in close proximity of enteric nerves were correlated with the intensity
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and frequency of abdominal pain [49]. Mucosal mediators of mast cell origin hyperexcited nociceptive visceral sensory pathways in recipient rodents [47,48,51 ] or enteric nervous system excitability in isolated gut tissues from guinea pigs [52]. Although immune cells are likely the major source of mediators impacting nerve function, a microbial origin of some of these factors has also been suggested [53]. Potential contributing factors of this low-grade inflammation include, among others, allergic reactions and stress. Acute psychological stress increased small intestinal permeability in humans and the mast cell stabilizer disodium chromoglycate blocked this effect. These findings provide new insights into the complex interplay between the central nervous system and the immune system in humans [54]. &
suggesting that central factors alone cannot justify completely the development of IBS-like symptoms in all patients [4]. The prevalence of IBS in the general population is relatively high (10–20%), hence coexistent IBS could be expected in a similar proportion of IBD patients in remission. However, the high prevalence of IBS-like symptoms in IBD in remission cannot be explained by casual overlap alone. Whether IBS-like symptoms reflect clinically undetected, low-grade inflammation is a matter of controversy. Fecal calprotectin was significantly higher in Crohn’s disease and ulcerative colitis patients with criteria for IBS than in those without IBS-type symptoms [55]. In addition, increased intraepithelial lymphocytes and tissue tumor necrosis factor alpha expression was associated with IBS-like symptoms in quiescent IBD, but not with IBS [56 ]. These findings suggest that occult inflammation could drive IBS-like symptoms in patients with IBD in remission and imply the possible need of further testing (e.g. fecal calprotectin) and potentiation of immunosuppressive therapy [55]. However, increased calprotectin levels have not been confirmed in more recent studies, suggesting a more complex pathogenesis [4,21 ]. A barostat study in patients with ulcerative colitis in remission indicated that IBS-like symptoms were associated with visceral hypersensitivity and mast cell infiltration [57]. In addition, Akbar et al. [58] showed a 3.9-fold to 5-fold increase of the sensory nerve receptor transient receptor potential vanilloid type 1 (TRPV1) associated with pain perception in the mucosa of IBD patients with IBS symptoms. TRPV1 expression correlated with the severity of abdominal pain, suggesting that postinflammatory neuroplastic changes occurring at least in a subgroup of patients with IBD may have potential consequences for bowel physiology, visceral hypersensitivity, and symptom generation. &&
EXPERIENCE OF IRRITABLE BOWEL SYNDROME SYMPTOMS IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE IN REMISSION Although a high proportion of patients with IBD frequently experiences symptoms, which are indistinguishable from IBS, the diagnosis is generally confirmed by additional laboratory and imaging studies. The clinical dilemma emerges when patients continue to experience symptoms (e.g. abdominal pain, bloating and changes in bowel habit) while in remission. Is this the expression of occult active disease or IBS? Should these patients receive more aggressive anti-inflammatory/immunosuppressive therapy? A meta-analysis of 1703 individuals showed that the prevalence of IBS-like symptoms in patients with IBD in remission was 35%. Crohn’s disease patients in remission had a higher risk of having IBS-like symptoms compared with ulcerative colitis in remission (OR: 1.74; 95% CI: 1.24 – 2.43) [4]. IBS-like symptoms in these individuals were associated with female sex, reduced well-being, and QoL as well as higher fatigue scores than those without [21 ]. Nonetheless, a comparative study reported that QoL was more severely affected in ‘true’ IBS compared with IBS occurring in IBD patients in remission. In a recent longitudinal 3-year follow-up study, it was observed that symptoms of IBS in ulcerative colitis in remission tended to fluctuate over time being present overall in 19% of patients at yearly visits [21 ]. A frequent finding is the detection of higher levels of mood disorders, including predominantly anxiety, in patients experiencing IBS-like symptoms compared with symptom-free individuals [4,21 ]. Although anxiety was independently associated with IBS symptoms, the risk seems moderate (OR: 1.11, CI: 1.01–1.21), &&
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CONCLUSION Recent research suggests that IBD and IBS share some common pathogenetic features. The possible implication of microbiota, inflammation, and genetic factors has received increasing attention in IBS research, although their relevance is far less defined in IBS compared with IBD. The overlap between IBD and IBS is particularly evident in patients who develop IBS-like symptoms while in remission. A better understanding of the role of pathogenetic factors and mechanisms underlying the development of persistent symptoms in patients with IBD in remission is now needed for the identification of more objective disease signatures and development of targeted therapies. Volume 30 Number 4 July 2014
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Inflammatory bowel disease and irritable bowel syndrome Barbara et al.
Acknowledgements G.B. and V.S. are supported in part by the Italian Ministry of Instruction, University and Research. Conflicts of interest G.B. and V.S. have served as consultants/advisory board members for Alfa Wassermann, Almirall, Italchimici, Ironwood, and Shire. G.B. and V.S. received research grant support from Alfa Wassermann, Italchimici, and Shire. G.B. received research grant support from Falk Pharma, Sofar, and Yakult. V.S. received research grant support from Almirall, Aptalis, Norgine, and Valeas. G.B. served as consultant/advisory board member for Danone, Falk Pharma, Malesci, Nestle`, Noos, Sofar, Synergy, and Yakult. V.S. served as consultant/advisory board member for Angelini, Aptalis, CM&D Pharma, Farmaderma, Janssen, Norgine, Takeda, Valeas, and Zeria. C.C. has been the recipient of a scholarship grant from Sofar.
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Inflammatory bowel disease 30. Simren M, Barbara G, Flint HJ, et al. Intestinal microbiota in functional bowel disorders: a Rome foundation report. Gut 2013; 62:159–176. In depth review on the current knowledge on the role of intestinal microbiota in the pathophysiology of functional gastrointestinal disorders. The review explores also treatment implications including the use of prebiotics, probiotics, symbiotics, and antibiotics in these syndromes. 31. Spiller R, Garsed K. Postinfectious irritable bowel syndrome. Gastroenterology 2009; 136:1979–1988. 32. Cremon C, Stanghellini V, Pallotti F, et al. Salmonella gastroenteritis during & childhood is a risk factor for irritable bowel syndrome in adulthood. Gastroenterology 2014. [Epub ahead of print] Prospective, controlled, cohort study assessing functional digestive symptoms, psychological factors, and QoL 16 years after a single culture-proven foodborne Salmonella enteritidis outbreak involving 1811, mostly pediatric, patients in Bologna, Italy. Acute Salmonella gastroenteritis was identified as a risk factor for the development of long-term IBS symptoms (OR for IBS 1.92; 95% CI: 1.23– 2.98), but only if the infection occurs during childhood (OR for IBS in children 2.12; 95% CI: 1.21–3.71). 33. Porter CK, Tribble DR, Aliaga PA, et al. Infectious gastroenteritis and risk of developing inflammatory bowel disease. Gastroenterology 2008; 135:781– 786. 34. Rajilic´-Stojanovic´ M, Biagi E, Heilig HG, et al. Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome. Gastroenterology 2011; 141:1792–1801. ¨ hman L, et al. An irritable bowel syndrome subtype 35. Jeffery IB, O’Toole PW, O && defined by species-specific alterations in faecal microbiota. Gut 2012; 61:997–1006. Interesting study investigating the association between microbiota and the brain– gut axis in patients with IBS. Results showed that those with no modifications in fecal microbiota had more mood disorders while those with modification in microbiota had changes in bowel physiology. 36. Jalanka-Tuovinen J, Salojarvi J, Salonen A, et al. Faecal microbiota composi&& tion and host–-microbe cross-talk following gastroenteritis and in postinfectious irritable bowel syndrome. Gut 2013. [Epub ahead of print] First study to show that fecal microbiota of patients with postinfectious IBS differs from that of controls and shares similarities with that of patients with IBS with diarrhea, suggesting a common pathophysiology. Members of Bacteroidetes phylum were increased 12-fold in patients, while controls had 35-fold more uncultured Clostridia. Microbial dysbiosis correlates with the expression of several host gene pathways, including impaired epithelial barrier function. 37. Manichanh C, Eck A, Varela E, et al. Anal gas evacuation and colonic & microbiota in patients with flatulence: effect of diet. Gut 2014. [Epub ahead of print] Study analyzing the potential role of diet on digestive symptoms, anal gas evacuation, intestinal gas distribution, and colonic microbiota in 30 patients with flatulence. On a flatulogenic diet, both patients and controls recorded more abdominal symptoms, gas production, and evacuations. Interestingly, only microbiota of patients developed instability in composition, while that of controls was stable, suggesting that patients with flatulence have a poor tolerance of intestinal gas that is associated with microbiota instability. 38. Carroll IM, Ringel-Kulka T, Ferrier L, et al. Fecal protease activity is associated with compositional alterations in the intestinal microbiota. PLoS One 2013; 8:e78017. 39. Salim SY, Soderholm JD. Importance of disrupted intestinal barrier in inflammatory bowel diseases. Inflamm Bowel Dis 2011; 17:362–381. 40. Piche T. Tight junctions and IBS: the link between epithelial permeability, lowgrade inflammation, and symptom generation? Neurogastroenterol Motil 2014; 26:296–302. 41. Piche T, Barbara G, Aubert P, et al. Impaired intestinal barrier integrity in the colon of patients with irritable bowel syndrome: involvement of soluble mediators. Gut 2009; 58:196–201. 42. Camilleri M. Peripheral mechanisms in irritable bowel syndrome. N Engl J Med 2012; 367:1626–1635. &&
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43. Martinez C, Lobo B, Pigrau M, et al. Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier. Gut 2013; 62:1160–1168. Careful study assessing clinical symptoms and jejunal biopsies in 45 patients with IBS-D and 30 controls. Patients with IBS-D displayed increased mast cell counts and activation, increased protein expression of claudin-2, reduced occludin phosphorylation and enhanced redistribution from the membrane to the cytoplasm, increased myosin kinase expression, and enhanced phosphorylation of myosin. These alterations were associated with ultrastructural abnormalities at the apical junction complex which correlated both with mast cell activation and clinical symptoms. 44. Barbara G, Cremon C, Carini G, et al. The immune system in irritable bowel syndrome. J Neurogastroenterol Motil 2011; 17:349–359. 45. Matricon J, Meleine M, Gelot A, et al. Review article: associations between immune activation, intestinal permeability and the irritable bowel syndrome. Aliment Pharmacol Ther 2012; 36:1009–1031. 46. Belmonte L, Beutheu Youmba S, Bertiaux-Vandaele N, et al. Role of toll like receptors in irritable bowel syndrome: differential mucosal immune activation according to the disease subtype. PLoS One 2012; 7:e42777. 47. Cenac N, Andrews CN, Holzhausen M, et al. Role for protease activity in visceral pain in irritable bowel syndrome. J Clin Invest 2007; 117:636–647. 48. Barbara G, Wang B, Stanghellini V, et al. Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome. Gastroenterology 2007; 132:26–37. 49. Barbara G, Stanghellini V, De Giorgio R, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004; 126:693–702. 50. Cremon C, Gargano L, Morselli-Labate AM, et al. Mucosal immune activation in irritable bowel syndrome: gender-dependence and association with digestive symptoms. Am J Gastroenterol 2009; 104:392–400. 51. Valdez-Morales EE, Overington J, Guerrero-Alba R, et al. Sensitization of & peripheral sensory nerves by mediators from colonic biopsies of diarrheapredominant irritable bowel syndrome patients: a role for PAR2. Am J Gastroenterol 2013; 108:1634–1643. Study examining the impact of mediators from colonic biopsies of patients with IBS on intrinsic excitability of colonic nociceptive dorsal root ganglion neurons. Supernatants from patients with IBS-D but not IBS-C induced a marked increase in neuronal excitability by a protease-activated receptor 2-mediated mechanism. 52. Balestra B, Vicini R, Cremon C, et al. Colonic mucosal mediators from patients with irritable bowel syndrome excite enteric cholinergic motor neurons. Neurogastroenterol Motil 2012; 24:1118–e1570. 53. Steck N, Mueller K, Schemann M, Haller D. Bacterial proteases in IBD and IBS. Gut 2012; 61:1610–1618. 54. Vanuytsel T, van Wanrooy S, Vanheel H, et al. Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism. Gut 2013. [Epub ahead of print] 55. Keohane J, O’Mahony C, O’Mahony L, et al. Irritable bowel syndrome-type symptoms in patients with inflammatory bowel disease: a real association or reflection of occult inflammation? Am J Gastroenterol 2010; 105:1788; 1789–1794; quiz 1795. 56. Vivinus-Nebot M, Frin-Mathy G, Bzioueche H, et al. Functional bowel symp&& toms in quiescent inflammatory bowel diseases: role of epithelial barrier disruption and low-grade inflammation. Gut 2014; 63:744–752. Important study evaluating the role of colonic barrier defects and low-grade inflammation in cecal biopsies of 51 patients with IBS, 49 patients with quiescent IBD and 27 controls. Paracellular permeability was significantly increased in IBS and patients with quiescent IBD and IBS-like symptoms and associated with lower expression of ZO-1 and a-catenin. Intraepithelial lymphocytes and TNFa were significantly increased only in patients with quiescent IBD and IBS-like symptoms. 57. van Hoboken EA, Thijssen AY, Verhaaren R, et al. Symptoms in patients with ulcerative colitis in remission are associated with visceral hypersensitivity and mast cell activity. Scand J Gastroenterol 2011; 46:981–987. 58. Akbar A, Yiangou Y, Facer P, et al. Expression of the TRPV1 receptor differs in quiescent inflammatory bowel disease with or without abdominal pain. Gut 2010; 59:767–774. &
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