New Insights Into the Pathogenesis of Irritable

Bengi G. et al. Vol. 5, issue 10, October issue, 2017 Medical Research Archives

REVIEW ARTICLE NEW INSIGHTS INTO THE PATHOGENESIS OF IRRITABLE BOWEL SYNDROME Göksel Bengi1, İlkay Şimşek1 Affiliations: 1 Dokuz Eylul University, Medicine Faculty, Department of Gastroenterology, İzmir, Turkey * Corresponding author: Göksel Bengi, E-mail: [email protected]

Abstract: Irritable Bowel Syndrome is one of the most frequently seen functional bowel diseases. Despite its high prevalence, the etiology and pathogenesis of IBS could not still be explained completely and diagnosing is quite difficult in some cases. IBS, being a multisymptomatic functional gastrointestinal system disease, has a broad clinical spectrum and in general, the symptoms are associated with gastrointestinal dysmotility and visceral hypersensitivity. The true diagnosis is based on four key factors: medical history, physical examination, minimal laboratory tests and colonoscopy or other appropriate tests in some cases. However, a homogeneous pathophysiological pattern has not been defined for IBS and this situation, with a high degree of probability, reflects that IBS is a multifactorial disorder that involves abnormalities in brain-gut interactions, visceral hypersensitivity, intestinal motility and secretion, psychosocial factors, composition of the gut microbiota, disturbed intestinal permeability and low grade immune activity. Key Words: Irritable, bowel, gastrointestinal, IBS

Irritable Bowel Syndrome is one of the most predominant, constipation predominant, frequently seen functional bowel diseases mixed type and the ungroupable. characterized by recurrent abdominal pains Constipation predominant IBS diagnosis and change in bowel habits (IBS-C) is made if more than 25% of bowel (diarrhea/constipation). IBS is a long-term movements are type 1 or type 2 and less than illness in which patients suffer from chronic 25% is type 6 or 7. Whereas in the diarrhea- or recurrent gastrointestinal symptoms predominant IBS (IBS-D); while more than despite the fact that routine clinical 25% of the bowel movements are type 6 or investigations are normal. Although regional type 7, less than 25% are type 1 or type 2. In variation exists, the prevalence of IBS ranges mixed-type IBS (IBS-M); in more than 25% from 10–15% in population-based studies in of the bowel movements type 1 or type 2 and North America and Europe. The prevalence again in more than 25% type 6 or type 7 of IBS is most common between 20 and 40 coexistence is seen. The patients that do not years of age with a significant female fall into any of these three categories are predominance (1). Irritable bowel syndrome included to the unsubtyped group (IBS-U). is divided into four sub-groups by evaluation And in time, inter-type transitions may be of the patient’s stool according to BSFS observed in 75% of these patients. IBS is (Bristol Stool Form Scale) as diarrhea- associated with decreased quality of life,

impaired social function and loss of work amendment was the vague nature of the term productivity. Onset of symptoms is most ‘’discomfort’’ and the word ‘’discomfort’’ not common in young adults and IBS has a existing in every language or expressing global prevalence of around 11% (2). different meanings in different languages. Despite its high prevalence, the etiology and Besides that, it is not clear whether the pathogenesis of IBS can still not be discrimination between discomfort and pain is explained completely and diagnosing is quite qualitative or quantitative, the knowledge about difficult in some cases (3). IBS, being a the meaning of the word discomfort multisymptomatic functional gastrointestinal significantly varies among individuals and it is system disease, has a broad clinical spectrum thought to cover too many symptoms. The and in general, the symptoms are associated other major amendment contained the with gastrointestinal dysmotility and visceral modification made on the symptom frequency hypersensitivity (4). In this compilation, we threshold. Compared to the period indicated as will mention the diagnosis and main minimum 3 days in a month in Rome III, in pathophysiological bases of IBS. Rome IV, occurrence of abdominal pain at least 1 day in a week on average during the Diagnostic criteria and clinical previous month is regarded necessary. It is symptoms of IBS: possible for both amendments to decrease the IBS prevalence in population-based studies; Since the pathophysiology of IBS could not however, since most of the IBS patients be completely understood and the routine recognize pain as one of the main symptoms investigations show normal results, IBD (7) and appearance of the symptoms in most diagnosis is based on the combination of of the IBS patients in clinical samplings in a altered bowel habits and abdominal pain frequency higher than once a week (8), according to the Rome IV criteria (5). neither of these amendments will According to that, IBS diagnosis can be significantly affect the IBS prevalence in made when a patient has recurrent clinical populations. Besides that, with the abdominal pain complaint associated with 2 aim of emphasizing that a significant or more of the following criteria: (1) related proportion of IBS patients actually report with defecation; (2) associated with change worsening in pain with defecation and/or stool in defecation frequency; (3) associated with frequency and/or change in stool form, since it change in appearance of stool. Because of was regarded necessary for abdominal pain to the relationship with motility disorder, be described with the wording ‘’…related visceral hypersensitivity, change in mucosa with defecation…’’ (Rome IV) instead of function and immune function, bowel ‘’….recovering with defecation….’’ (Rome microbiota changes and the change III), a minor amendment made on the appearing in the central nervous system definition of the main IBS criteria was also (CNS) process, the Rome IV criteria were included to Rome IV. expanded according to this concept of these bowel-brain interaction disorders. In clinical practice, there are limited aspects in respect of use of Rome Criteria. These criteria When compared with the Rome III (6) criteria, may leave the patients who can be treated two changes in IBS diagnostic criteria stand successfully however who do not meet the out in Rome IV. First of these is exclusion of criteria out of scope. The subject patients’ abdominal discomfort from the scope of remaining out of scope may be originating identification criteria and this means that from the symptom duration being shorter than abdominal pain is not a prerequisite for IBS 6 months, symptoms appearing in frequency diagnosis anymore. The basis underlying this lower than 1 in a week or inability of meeting

2 of the 3 criteria. Besides that, some patients Faecal calprotectin is a non-invasive may have two or even more FGIDs and these screening method for intestinal mucosal concurrent symptoms are not included in the inflammation and it is seen to be more scope of Rome IV Criteria (9). effective than the standard test application such as C-reactive protein (14). It is accepted Premonitory symptoms suggest existence of an that IBS patients are under risk in respect of organic disease; however, some authors believe concurrent celiac disease existence. It is that the accuracy level provided by these estimated that celiac disease may develop in remains insufficient (10). The IBS patients’ a proportion reaching 4.7% of the patients complaining also of various other meeting IBS criteria (15). gastrointestinal (for example dyspepsia) symptoms and nongastrointestinal symptoms Stool analysis may prove to be useful in respect like migraine, fibromyalgia, chronic fatigue, of diarrhea symptom especially in developing chronic pelvic pain, sexual dysfunction, eating countries. When presence of warning disorders, food intolerances and other disorders symptoms or premonitory symptoms do not that provide additional support to diagnosis is a exist, colonoscopy for screening purposes situation worthy of notice. should be made if the patient is over the age of 50 . The correlation between IBS and small Some diseases such as inflammatory bowel intestinal bacterial overgrowth (SIBO) has disease (IBD), microscopic colitis, celiac been validated in many researches. This disease, lactulose and fructose intolerance, validation has been made mostly by using colon cancer, enteric infections, food allergy breath tests, however in about 60% of the and intolerance as well as neuroendocrine patients with IBS and diarrhea, quantitative tumors may show similarity to IBS and microbiological assessment of the duodenal therefore some diagnostic tests may be needed aspirate that confirmed SIBO was also used. for diagnosis. It can be seen that a series of Hydrogen glucose breath test is the most various diagnostic methods including common non-invasive SIBO diagnostic manometry, colonoscopy and enteroclysis method (16). (11,12) along with stool cultures and blood tests provide benefit in respect of excluding Different IBS biomarkers have been defined the organic disease. Routine laboratory and tested; however none of these is a practical analyses like complete blood count and indicator of the subject disease that can be blood enzyme panels are normal tests in IBS. commonly used. A short while ago, promising Diagnostic evaluation depends on whether results for faecal volatile organic metabolites the predominant symptom is diarrhea or (VOM) and colonic mucosal markers were constipation. The tests suggested for the obtained. It has been shown that in IBS patients who report symptoms with unclear patients, nerve growth factor, IFN-g, toll-like etiology are: faecal calprotectin or lactoferrin receptor 4 (TLR4), pre-haptoglobin 2 in stool, celiac disease serology, inflammatory expression increased seriously compared to disease markers (ESR, CRP, peripheral blood the control group and was specifically low smear), thyroid function tests and selective compared to the ulcerative colitis patients malabsorption markers (i.e. albumin, ferritin). (17). In special cases, gastroscopy and/or colonoscopy is needed. It is recommended to In conclusion, the true diagnosis is based exclude microscopic colitis or another low- on four key factors: medical history, grade chronic inflammation in patients mainly physical examination, minimal laboratory with diarrhea and even in patients with normal tests and colonoscopy or other appropriate mucosa biopsies (13). tests in some cases.

The pathogenesis of irritable bowel Brain-gut axis syndrome The brain-gut axis defines the bidirectional However, a homogeneous pathophysio- information exchange that happens between logical pattern has not been defined for IBS these two organs. This neuroanatomic and this situation, with a high degree of substrate is a complex integrated circuit that probability, reflects that IBS is a transmits the information it receives from the multifactorial disorder that involves cognitive and emotional centers to the abnormalities in brain-gut interactions (18), gastrointestinal system and provides data visceral hypersensitivity (19), intestinal transmission at the opposite direction as well motility and secretion (20), psychosocial (26). In our day, IBS is thought to be a factors (21), composition of the gut regulation disorder in the system named as microbiota (22), disturbed intestinal the brain-gut axis where abnormal function in permeability (23) and low grade immune the enteric, autonomic and/or central nervous activity (24). systems plays a role along with peripheral abnormalities that are probably predominant Disruption of the bidirectional brain-gut in some patients and that disturb processing communication which determines the of the signals coming from periphery at the changes in digestive secretion and motility center in the other patients (4). The and leads to visceral hypersensitivity is one gastrointestinal system is intensely innervated of most important elements of IBS etiology to provide information regarding the lumen (25). Another factor in FGID pathogenesis is contents, the processes that regulate digestion the change in the intestinal epithelial barrier and absorption and the potential threats. The which plays a critical role in preserving the gastrointestinal afferent sensory fibers that intestinal homeostasis. The permeability of terminate at the bowel wall express a series of this epithelium may increase depending on membrane receptors and ion channels that genetic factors, disturbances in gut receive the information about disruption of microbiota, diet, stress, infection and mucosal epithelium and lumen contents. These inflammation. neurons, besides activating local responses, The Rome IV criteria and the publications transmit the sensory information to the spinal about these criteria, although the emphasis cord or the brain stem through vagus nerve and on the term ‘’functional’’ used in their spinal afferents for its advanced processing and naming has been reduced, reflect a logical integration. However, it should be change made in conceptualization of the GI overemphasized that during normal disorders family they cover. In recent years, digestion lots of information coming from the opinion that many specific afferent ends are mostly not perceived and pathophysiological processes, altered is used in reflexes that control motility, immune function, increased intestinal secretion and blood flow (27). permeability and the imbalance between The signals that come from the bowel and different types of gut bacteria included, play ascend upwards, reach the brain from the a role gradually receives broader acceptance. spinal cord through anterolateral and dorsal Besides that, it is also accepted that the column pathways and here they are neural and hormonal interaction between transmitted to the ventral nuclei of the brain and gut carries importance in respect thalamus and to primary and secondary of formation and regulation of the symptoms somatosensory cortex regions for that appear in the disorders. localization, intensity and pain duration and finally to the limbic regions for the

emotional component of pain response. mucosal irritation; genetics; mast cell involvement that suggests low grade The immune system plays the role of an immune activation; food intolerance and important intermediary in the function of changes in bacterial flora and luminal brain-gut axis. As a result of injury, antigen(4). inflammation or ischemia, leukocytes, lymphocytes, thrombocytes, mast cells, macrophages, fibroblasts and the mediators Intestinal barrier released from blood vessels change the The intestinal barrier which protects us activities of the sensory nerves and increase against the threats originating from the their sensitivity by affecting them directly or intestinal lumen, plays a critical role in indirectly. Therefore, the abnormal preservation of the intestinal homeostasis. inflammatory response given to different Referring to animal researches, various events (stress, infection, food, etc.) can be factors that lead to intestinal barrier responsible for presence of pathological dysfunction have been defined. These factors cellularity and inflammatory cytokines in include the genetic and epigenetic changes, the colons of some IBS patients (27). decrease in glutamine synthetase activity, a The neuroendocrine system that potentially fall in proteolytic activity caused by the plays a role in IBS pathogenesis consists of pancreatic enzymes that appear in the two constituents: 14 types of endocrine cell intestinal lumen or bacterial proteases and spread on the intestinal mucosa and ENS stress-induced mast cell activation. In nerve fibers. This system, like serotonin, humans, the factor that leads to intestinal peptide YY(PYY), GIP, somatostatin, CCK, barrier dysfunction can be one of these ghrelin and other transmitters, changes mechanisms. In animal studies, it has been motility, secretion, absorption and intestinal shown that psychological stress has microcirculation by production of transmitter indirectly activated the mast cells through substances that relay signal to the corticotropin-releasing hormone (CRH) neighbouring cells (paracrine) through the secreted by eosinophils (31). Increase of the vascular system (endocrine) or the intestinal permeability and the consequent intrinsic/extrinsic nerves (28). Besides that, antigenic material translocation in IBS is characterized by the abnormal epithelium enables the stimulation of the synthesis, transport and inactivation of the intestinal immune system by production of peptides and amines which affect motility, inflammatory mediators that can maintain secretion, absorption in intestinal mucosa permeability and create abnormal neuron and the sensation in the organ (29). In responses (32). different IBS types, there are also changes in the intensity of ileal serotonin, PYY, GIP The effect of psychosomatic disorders and somatostatin cells (30). The close relationship of IBS with mental Therefore, the multifactorial patho- disorders is a quite established deep rooted physiology of IBS and FGID involves a belief in clinical practice. One of the most series of different factors that may contribute common psychiatric disorders associated with to the change of motility and symptom IBS is depression which appears in a great perception :psychosocial factors (also proportion like 30% of IBS patients. The includes sexual abuse in childhood relationship between depression and IBS may associated with higher IBS incidence in both originate from the IBS probability of IBS childhood); visceral hypersensitivity; being higher in patients with depression history gastrointestinal infection, inflammation or and may be linked to development of secondary

depression in patients who had been diagnosed reuptake of this amine (34). It has been FGID previously. It has been shown that shown that in IBS patients the SERT gene depressive syndrome, sleep disorders or expression has decreased and this decrease sexual dysfunctions may emerge in IBS may be responsible for appearance of patients with long lasting disease progress diarrheic symptoms originating from the (33). Anxiety often accompanies IBS (16% increased 5-HT level on the intestinal wall compared to the ratio which is 6% in the (37). The findings of Colucci et al.(38) have control group) and may worsen the IBS not validated this situation. In the study symptoms (34). made by these researchers, it is reported that lower SERT expression and decreased 5-HT In conclusion, although it is known that there intake activity originates from 5HTTLPR (5- is a connection between mental disorders and HT transporter long polymorphic region) IBS, it should be emphasized that the etiology polymorphism in the human SERT gene. of these is multifactorial and complex and has The examined gene has dominant –short (S) not gained complete clarity. Psychological and recessive – long (L) alleles. Presence of stress is an important risk factor in respect of allele S is associated with a lower SERT development of several diseases and when it is expression and decrease of 5-HT reception present, it may aggravate their symptoms. activity. Although the severity of IBS However, psychological stress may develop as symptoms in patients with LS/SS genotype a consequence of IBS also (35). was meaningfully higher compared to the LL genotype, generally in IBS patients and in Genetic susceptibility case of stratification, the frequency of 5HTTLPR genotypes in C-IBS and D-IBS Emergence of IBS more frequently in patients has not shown a meaningful monozygotic twins compared to dizygotic difference compared to the healthy control twins (33% compared to 13.3%, subjects. Thus, it is seen that 5HTTLPR respectively) shows that genetic polymorphism affects the course of the predispositions play a role in development of disease however it does not affect its this disease. Compared to the 2% of the emergence or clinical picture in respect of individuals in the control group, in a proportion the predominant bowel habit (38). greater than 33% of the patients, IBS family history is discovered. As shown in a recently The importance of the other polymorphisms made research, IBS may involve genetically is also accepted. Presence of these is related determined changes in serotonergic with the increase of proinflammatory transmission in the gastrointestinal system cytokine TNF-α expression and decrease of (36). A large portion of the intestinal the anti-inflammatory cytokines IL-10 ve serotonin is stored in the enterochromaffin TGF-β expression (33). cells (EC) found in the intestinal mucosa. It has been determined that the number of these Some data at limited level are also available cells and consequently the 5-HT level on the about the role of epigenetics in IBS intestinal wall is higher in IBS-D patients pathology. – In recent researches, the whereas it decreases in IBS-C patients (37). importance of the stress which causes the epigenome to be reshaped in the stress which On the surface of the enterocytes, serotonin causes visceral pain has been shown (39). reuptake transporters (SERT) are found. These inhibit the serotonergic transmission Stress and accelerate the motility of the gastrointestinal system by reducing the Chronic stress can create susceptibility for

IBS development by increasing the disorders both directly and through its metabolites. in gastrointestinal system motility, gut Although it is determined that more than microbiota, visceral sensation and mucosa 1200 different microbes exist in the GI function and also cause exacerbation of its system (43), these microbes are found in only symptoms (40). a small ratio in every healthy individual (44). The firm relationship between the host and Stress activates the hypothalamic, pituitary, intestinal microbiota is being explained by adrenal (HPA) axis and this may disrupt the showing the role of the naturally found, non- bidirectional communication between brain pathogenic commensal microbiota in and gut (41). It is also asserted that chronic intestine physiology, development of energy stress and increased glucocorticoid levels can metabolism (45) and mucosal immune cause a permanent increase in sensitivity system education (46) as example. against visceral stimuli by affecting the amygdala which is an important limbic In the experimental researches and structure and anxiety-like behaviour as well. observational studies made over the past decade, it was shown that the microbial Excessive catecholamine release that reduces composition in the Inflammatory Bowel the amount of acidic mucopolysaccharide in Disease (IBD) and Irritable Bowel Syndrome the intestinal mucosa and the mucin (IBS) patients can change compared to the production shows a negative effect on the healthy individuals. In the recent years it has mucosal barrier. Under stress conditions, been determined that the dysbiosis in the IgA production which prevents adhesion of microbiota related with lumen and mucosa is pathogens to intestinal epithelium decreases. associated with IBS (47). However, although These processes can lead to disorders in gut it has been shown that changes in gut microbiota and increase the permeability of microbiota appear in these disorders, the the intestinal wall against bacterial antigens importance that the microbial dysbiosis and toxins (37). detected in IBD and IBS carries has to be determined and the role of nutrition, The role of gut microbiota in IBS therapeutic and environmental factors in preservation of the gut microbiota and its role The gut microbiota contains 1000-1150 in disruption of gut microbiota composition in species of bacteria (1013–1014) (42) and these disorders should be specified. Finally, plays an important role in intestinal the potential of the altered intestinal development, processing and digestion of microbiota for curing and preventing GI food, immune system function, resistance disorders like IBD and IBS has not yet gained against pathogens, numerous metabolic clarity. It has been shown that bacterial pathways as well as in modulation of diversity decreased both in the lumen and the neurotransmitters, hormone production and mucosa specimens taken from IBS patients secretion. The changes in the count and (47-49). It has been reported that there was a composition of bacteria are defined as decrease in Lactobacillus and Biﬁdobacterium dysbiosis. In dysbiosis, many factors such as spp in IBS-D and even they did not exist at all drugs (antibiotics, nonsteroidal anti- and the pathogenic species like Enterobacter inflammatory drugs), high carbohydrate have increased (50). In IBS-C patients, it was containing diets, chronic mental or physical determined that the Veillonella species was stress, history of a past illness, climate predominant (40). changes or air pollution play a role. Humans live in a condition of close symbiosis with our intestinal microbiota which shows effect

Post-infectious IBS functional gastrointestinal symptoms can be explained with the abnormal modulatory Although the individuals in whom IBS mechanisms that arise as a response to various develops after a gastroenteritis disease (post- stimuli that nutrients mediate (31). In infectious IBS) constitutes only a subgroup gastrointestinal system nutrient presence of the IBS cases, the increase of the risk of modulates gastrointestinal motility, barrier IBS development after a previous GI function (secretion, absorption), sensitivity and infection seven times more strengthens the the intestinal microbiota. Some intestinal hypothesis that the abnormalities in the receptors are nutrient-specific and the immune interactions between the microbe stimulation of these lead to activation of the and host is related with IBS pathophysiology neurohumoral pathways that are related to the (51). Potentially, an altered microbiota composition of the meal. The strongest composition is associated with disruption of component of nutrients that affect motility, the microbe recognition property in IBS and sensitivity and intestinal barrier is fat; this may lead to a change in the capability of however, carbohydrates in low amounts and eradicating the microbial invaders. the wheat proteins such as gliadin or gluten are Therefore, indication of that the Toll-like also important (27). receptor expression change (52) in the mucosa and the increase in serum antibody Hypersensitivity to some nutrients may lead levels formed against flagellla which is a to disruption of intestinal mucosa, low-grade bacteria component (53) in IBS patients has inflammation in the gastrointestinal system, been shown attracts attention. Besides that, increase of intestinal epithelial permeability the intestinal microbiota can affect the other and visceral hypersensitivity (28). Although factors that are asserted to be in the scope of well-defined food allergies are not common IBS pathophysiology, also; for example, in IBS patients, it has been observed that IBS intestinal permeability (54), brain function symptoms intensify due to fructose (55), enteric nervous system (56) as well as malabsorption (60). Chemicals which have intestinal motility (57) and visceral pain (58). potential bioactivity such as salicylates, Moreover, it can create the key symptoms amines and glutamates may also cause like bloating and gas in IBS patients through abdominal pain, bloating or diarrhea and lumen microbiota carbohydrate fermentation these are associated with IBS (61). and gas production (59). In IBS patients, most of their symptoms are In conclusion, still a deficiency in the related with consumption of a specific type of information regarding what kind of a role meals and 63% of the patients know the intestinal microbiota plays in IBS products that must be avoided (62). It has been pathophysiology is in question. Therefore, to proved that in fermentation process excessive study the connection between microbiota and gas production and osmotic hypertension may IBS pathophysiology in detail, researches increase the IBS symptoms and this occurs that consider the heterogeneity of IBS through insufficiently absorbed nutrients that symptoms and the components of IBS are defined as FODMAP (fermentable pathophysiology other than the microbiota oligosaccharides, disaccharides, monosaccha- and evaluate the microbiota composition in rides and polyols). The aforesaid substances time should be made. include the short chain carbohydrates such as fructose, lactose, sugar alcohols which are Nutrition found in milk products, some vegetables and fruits (for example: onion, garlic, leek, cabbage, The relationship between nutrients and the Brussels sprouts, corn, apple, peach,

watermelon, plum, dried fruits), cereal products suggesting IBS may develop while gluten (wheat, rye) and honey (63). intolerance may also be seen in IBS patients. The role of gluten in IBS pathogenesis has not There is fructose malabsorption and dietary been clearly proved. NCGS (Non-Celiac fructose intolerance in about one third of the Gluten Sensitivity) is a syndrome that has patients with IBS suspicion. Lactase activity intestinal and extra-intestinal symptoms has decreased also in nearly 70% of the adult related to the ingestion of gluten containing population (64). In individuals who have food. This is a disease entity different from lactase deficiency, lactose is not absorbed by celiac disease or wheat allergy. Due to the being hydrolyzed in the small bowel, but similarity of the intestinal symptoms of NCGS passes through the gastrointestinal tract to to IBS symptoms, many patients who have the colon where gas that causes luminal NCGS complaint are misdiagnosed as IBS. In distension as a result of bacterial NCGS patients, extra-intestinal symptoms fermentation and generates the arise more frequently compared to IBS: gastrointestinal symptoms and the short- fatigue, headache, anxiety, numbness, chain fatty acids are produced (65). myalgia, weight loss and even autism or Dietary fiber deficiency is an important hallucinations (66). factor for IBS-C symptoms; however some patients may paradoxically complain of the Infections intensification of their symptoms after consumption of greater amount of water Especially being IBS-D, diagnosis in some soluble fiber. The gas produced during the patients can be associated with an acute decomposition of the water soluble fiber and gastrointestinal infection story in the past. FODMAPs by the intestinal bacteria causes This disorder is defined as post-infectious intestinal gas and discomfort. This process irritable bowel syndrome (PI-IBS). The depends on the composition of the intestinal factors that cause PI-IBS are protosoal microflora (36). (Trichinella sp.), parasitic (Giardia intestinalis) or viral (norovirus, Norwalk In summary, abnormality of the fermentation virus) infections as well as the bacterial of the substances taken by nutrition in the infections (Salmonella sp., Shigella sp., colon may lead to the development of GI Campylobacter jejuni, Escherichia coli – symptoms. The fructose containing ETEC, EAggEC, O157:H7) (33). FODMAP diet mostly constitutes a part of these arguments due to the present supportive It is thought that PI-IBS probability shows evidence that shows meaningful recovery of correlation with the severity of the IBS symptoms. However, since this kind of symptoms and the course of infection. This dietary changes may cause and aggravate disease can be seen even 6 years after acute microbial dysbiosis, in order to determine enteritis (67). PI-IBS mostly appears in the long-term effectiveness and reliability, young individuals whereas the risk decreases future studies that evaluate the long-term in the individuals over 60 years of age (68). effects shown by dietary changes on the PI-IBS is also characterized by the increase microbiota composition are needed. of T cell, neutrophil and mast cell counts in Gluten is a factor well known to affect the the colonic mucosa, hyperplasia of EC cells. permeability of the intestinal barrier, to create Stimulation of the immune system causes low-grade inflammation and to stimulate the chronic low-grade inflammatory state in the visceral and autonomic nervous system (28). gastrointestinal mucosa that leads to PI-IBS In individuals with celiac disease, symptoms (50).

Low-grade inflammation and other clinical and laboratory findings of the patient should be evaluated altogether. Based on the recent studies, it has been Despite all the effort spent in forming the asserted that the visceral hypersensitivity in diagnostic criteria concerning IBS, the IBS could be secondary to the activation of present criteria remain incapable in daily immune cells and development of low-grade practice. inflammation. In IBS patients, increase in incidence of mucosal hyperplasia, While IBS symptoms have traditionally been lymphocyte aggregation and increased count found associated with disturbed of EC cell, eosinophil and mast cell develops gastrointestinal motility, visceral compared to the healthy control subjects and hypersensitivity and psychological stress in this validates that low-grade inflammation general, in the recently made studies now the arises in intestines which have IBS (37). role of the changes in intestinal and colonic flora is also emphasized. It has been shown In some IBS patients, the serum levels of the both in experimental and observational proinflammatory factors such as IL-1b, IL-6, studies that in IBS patients, not only IL-8, IL-12, TNF-α, T and B cells and intestinal microbial dysbiosis occurred, but macrophages increase (69). The severity of at the same time bacterial diversity has the symptoms shows correlation with the decreased, too. The potential of the gut levels of inflammatory markers (40). microbiota to affect the brain-gut axis is There is an overlap in the clinical symptoms spoken of. It is still not clarified which that are present in functional disorders (such as mediators and pathways are at the forefront IBS) and in chronic inflammatory bowel in the patients who have visceral disorders (such as Crohn’s colitis). It has even hypersensitivity. It has been shown in been asserted that IBS may be an observational studies that especially inflammatory disorder type where low-grade infectious gastroenteritis cause risk increase non-specific intestinal inflammation is found in IBS development. Therefore, research (70). For example, it has been shown that should continue on gut microbiota, intestinal mucosal pro-inflammatory cytokine levels barrier permeability, neuroimmune functions have increased in many IBS patients, and and psychological stress and on their especially in post-infectious IBS (71). interaction with each other. In further Functional disorders may also constitute the studies, by revealing these cause for the symptoms to persist or for pathophysiological mechanisms, efficient clinical exacerbations in validated IBD treatment plans can be formed. patients. Determination of the faecal calprotectin concentration is accepted as the best non-invasive screening method for REFERENCES intestinal mucosal inflammation in these patients (72). 1. Saha L. Irritable bowel syndrome: pathogenesis, diagnosis, treatment, and In conclusion; IBS is a disease that has evidence-based medicine. World J complex etiological factors; where there are Gastroenterol 2014;20(22):6759–73. unanswered questions despite many studies made on its definition, pathophysiology, 2. Canavan C, West J, Card T. The diagnostic criteria and management. As epidemiology of irritable bowel recommended in the Rome IV criteria also, syndrome. Clin Epidemiol. when making a diagnosis in IBS patients, the 2014;4(6):71-80. age, characteristics of the primary symptom

3. O’swiecimska J, Szymlak A, Roczniak Neurogastroenterol. Motil. 2007, 19, W, Girczys-Polednik K, Kwiecien J. 188–195. New insights into the pathogenesis and treatment of irritable bowel syndrome. 12. Malik, A.; Lukaszewski, K.; Caroline, Adv Med Sci. 2017 Mar;62(1):17-30. D.; Parkman, H. A retrospective review of enteroclysis in patients with obscure 4. Şimşek İ. Irritable Bowel Syndrome and gastrointestinal bleeding and chronic other functional Gastrointestinal abdominal pain of undetermined disorders. J Clin Gastroenterol etiology. Dig. Dis. Sci. 2005,50, 649– 2011;45:86-88. 655. 5. Lacy BE, Mearin F, Chang L, Chey 13. Bellini M, Gambaccini D, Stasi C, WD, Lembo AJ, Simren M, Spiller R. Urbano MT, Marchi S, Usai-Satta P. Bowel Disorders. Gastroenterology. Irritable bowel syndrome: a disease still 2016; 150:1393–1407. searching for pathogenesis, diagnosis and therapy. World J Gastroenterol 6. Longstreth GF, Thompson WG, Chey 2014;20(27):8807–20. WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. 14. Hyams JS, Di Lorenzo C, Saps M, Gastroenterology. 2006;130(5):1480-91. Shulman RJ, Staiano A, van Tilburg M. Functional disorders: children and 7. Spiegel BM, Bolus R, Agarwal N, adolescents. Gastroenterology 2016; Sayuk G, Harris LA, Lucak S et al. 150:1456–68. Measuring symptoms in the irritable bowel syndrome: development of a 15. El-Salhy M, Gundersen D, Gilja OH, framework for clinical trials. Aliment Hatlebakk JG, Hausken T. Is irritable Pharmacol Ther. 2010;32(10):1275-91. bowel syndrome an organic disorder? World J Gastroenterol 2014;20(2): 384– 8. Palsson OS, Baggish J, Whitehead WE. 400. Episodic nature of symptoms in irritable bowel syndrome. Am J Gastroenterol. 16. Pyleris E, Giamarellos-Bourboulis EJ, 2014;109(9):1450-60. Tzivras D, Koussoulas V, Barbatzas C, Pimentel M. The prevalence of 9. Drossman DA. Functional overgrowth by aerobic bacteria in the gastrointestinal disorders: history, small intestine by small bowel culture: pathophysiology, clinical features relationship with irritable bowel and Rome IV. Gastroenterology syndrome. Dig Dis Sci 2016;150:1262–79. 2012;57(5):1321–9. 10. Black TP, Manolakis CS, Di Palma JA. 17. Sood R, Law GR, Ford AC. Diagnosis ‘‘Red ﬂag’’ evaluation yield in irritable of IBS: symptoms, symptom-based bowel syndrome. J Gastrointestin criteria, biomarkers or Liver Dis 2012;21(2):153–6. ‘psychomarkers’? Nat Rev 11. Desipio, J.; Friedenberg, F.K.; Gastroenterol Hepatol Korimilli, A.; Richter, J.E.; Parkman, 2014;11(11):683–91. H.P.; Fisher, R.S. High-resolution solid- 18. Moloney RD, Johnson AC, O'Mahony state manometry of the SM, Dinan TG, Greenwood-Van antropyloroduodenal region. Meerveld B, Cryan JF. Stress and the Microbiota-Gut-Brain Axis in Visceral

Pain: Relevance to Irritable Bowel Greenwood-Van Meer- veld B, Syndrome. CNS Neurosci Ther. Cryan JF. Stress and the microbiota- 2016;22(2):102-17. gut-brain axis in visceral pain: relevance to irritable bowel 19. Keszthelyi D, Troost FJ, Jonkers DM, syndrome. CNS Neurosci Ther van Eijk HM, Dekker J, Buurman WA, 2016;22(2): 102–17. Masclee AA. Visceral hypersensitivity in irritable bowel syndrome: evidence 26. Gaman A, Kuo B. Neuromodulatory for involvement of serotonin processes of the brain-gut axis. Neuro- metabolism--a preliminary study. modulation 2008;11(4):249–59. Neurogastroenterol Motil. 2015;27(8):1127-37. 27. Vanner S, Greenwood-Van Meerveld B, Mawe G, Shea-Donohue T, Verdu EF, 20. Sikander A, Rana SV, Prasad KK. Role Wood J, et al. Fundamentals of of serotonin in gastrointestinal motility neurogastroenterology: basic science. and irritable bowel syndrome. Clin Gastro-enterology 2016;150:1280–91. Chim Acta. 2009;403(1-2):47-55. 28. Barbara G, Feinle-Bisset C, Ghoshal 21. Van Oudenhove L, Tornblom H, UC, Quigley EM, Santos J, Vanner S, et Storsrud S, Tack J, Simren M. al. The intestinal microenvironment and Depression and Somatization Are functional gastrointestinal disorders. Associated With Increased Postprandial Gastroenterology 2016;150:11305–18. Symptoms in Patients With Irritable Bowel Syndrome. Gastroenterology. 29. Mearin F, Lacy BE, Chang L, Chey 2016;150(4):866-74. WD, Lembo AJ, Simren M, et al. Bowel disorders. Gastroenterology 22. Carroll IM, Ringel-Kulka T, Siddle JP, 2016;150:1393–407. Ringel Y. Alterations in composition and diversity of the intestinal microbiota 30. El-Salhy M, Gilja OH, Gundersen D, in patients with diarrhea-predominant Hatlebakk JG, Hausken T. Endocrine irritable bowel syndrome. cells in the ileum of patients with Neurogastroenterol Motil. irritable bowel syndrome. World J 2012;24(6):521-30, e248. Gastroenterol 2014;20(9):2383–91. 23. Scheppach W, Sommer H, Kirchner T, 31. Boeckxstaens G, Camilleri M, Sifrim D, Paganelli GM, Bartram P, Christl S, Houghton LA, Elsenbruch S, Lindberg Richter F, Dusel G, Kasper H. Effect of G, et al. Fundamentals of butyrate enemas on the colonic mucosa neurogastroenterology: in distal ulcerative colitis. physiology/motility – sensation. Gastroenterology. 1992;103(1):51-6. Gastroenterology 2016. http://dx.doi.org/10.1053/j.gastro.2016. 24. Spiller R, Lam C. An Update on Post- 02.030 infectious Irritable Bowel Syndrome: Role of Genetics, Immune Activation, 32. Matricon J, Meleine M, Gelot A, Serotonin and Altered Microbiome. J Piche T, Dapoigny M, Muller E, et al. Neurogastroenterol Motil. Review article: Associations between 2012;18(3):258-68. immune activation, intestinal permeability and the irritable bowel 25. Moloney RD, Johnson AC, syndrome. Aliment Pharmacol Ther O’Mahony SM, Dinan TG, 2012;36(11– 12):1009–31.

33. Nehring P, Mrozikiewicz-Rakowska system: a simple method of B, Krasnode˛bski P, Karnafel W. monitoring irritable bowel syndrome Zespo´ ł jelita draz˙ liwego - nowe and its progress. Aliment Pharmacol spojrzenie na etiopatogeneze˛. Prz Ther 1997;11(2):395–402. Gastroenterol 2011;6(1):17–22. 42. Hyland NP, Quigley EM, Brint E. 34. Grundmann O, Yoon SL. Irritable bowel Microbiota-host interactions in syndrome: epidemiology, diagnosis and irritable bowel syndrome: epithelial treatment:an update for health-care barrier, immune regulation and brain- practitioners. J Gastroenterol Hepatol gut interactions. World J 2010;25(4):691–9. Gastroenterol 2014;20(27):8859–66. 35. Van Oudenhove L, Crowell MD, 43. Rajilic-Stojanovic M, Smidt H, de Vos Drossman DA, Halpert AD, Keefer L, WM. Diversity of the human Lackner JM, et al. Biopsychosocial gastrointestinal tract microbiota aspects of functional gastrointestinal revisited. Environ Microbiol. disorders. Gastroenterology 2007;9(9):2125-36. 2016;150:1355–67. 44. Faith JJ, Guruge JL, Charbonneau M, 36. El-Salhy M. Irritable bowel syndrome: Subramanian S, Seedorf H, Goodman diagnosis and pathogenesis. World J AL, Clemente JC, Knight R, Heath AC, Gastroenterol 2012;18(37):5151–63. Leibel RL, Rosenbaum M, Gordon JI. The long-term stability of the human gut 37. Katiraei P, Bultron G. Need for a microbiota. Science. comprehensive medical approach to the 2013;341(6141):1237439. neuro-immuno-gastroenterology of irritable bowel syndrome. World J Gas- 45. Sommer F, Backhed F. The gut troenterol 2011;17(23):2791–800. microbiota--masters of host development and physiology. Nat Rev 38. Colucci R, Gambaccini D, Ghisu N, Microbiol. 2013;11(4):227-38. Rossi G, Costa F, Tuccori M, et al. Inﬂuence of the serotonin transporter 46. Helgeland L, Dissen E, Dai KZ, 5HTTLPR polymorphism on symptom Midtvedt T, Brandtzaeg P, Vaage JT. severity in irritable bowel syndrome. Microbial colonization induces PLoS One 2013;8(2):e54831. oligoclonal expansions of intraepithelial CD8 T cells in the gut. Eur J Immunol. 39. Weaver IC, Cervoni N, Champagne 2004;34(12):3389-400. FA, D’Alessio AC, Sharma S, Seckl JR, et al. Epigenetic programming by 47. Sundin J, Rangel I, Fuentes S, Heikamp- maternal behavior. Nat Neurosci de Jong I, Hultgren-Hörnquist E, de Vos 2004;7(8): 847–54. WM, Brummer RJ. Altered faecal and mucosal microbial composition in post- 40. Marlicz W, Zawada I, Starzyn´ ska T. infectious irritable bowel syndrome Zespo´ ł nadwraz˙ liwego jelita - patients correlates with mucosal nadwra- z˙ liwe jelito czy nadwraz˙ lymphocyte phenotypes and liwy umysł? Pol Merkur Lekarski psychological distress. Aliment 2012;32(187): 64–9. Pharmacol Ther. 2015;41(4):342-51. 41. Francis CY, Morris J, Whorwell PJ. 48. Carroll IM, Ringel-Kulka T, Keku TO, The irritable bowel severity scoring Chang YH, Packey CD, Sartor RB,

Ringel Y. Molecular analysis of the signs in a faecal transplantation model. J luminal- and mucosal-associated Med Microbiol. 2016;65(3):201-10. intestinal microbiota in diarrhea- predominant irritable bowel syndrome. 55. Rogers GB, Keating DJ, Young RL, Am J Physiol Gastrointest Liver Wong ML, Licinio J, Wesselingh S. Physiol. 2011;301(5):G799-807. From gut dysbiosis to altered brain function and mental illness: mechanisms 49. Giamarellos-Bourboulis E, Tang J, and pathways. Mol Psychiatry. 2016. Pyleris E, Pistiki A, Barbatzas C, Brown J, Lee CC, Harkins TT, Kim G, 56. Cossais F, Durand T, Chevalier J, Weitsman S, Barlow GM, Funari VA, Boudaud M, Kermarrec L, Aubert P, Pimentel M. Molecular assessment of Neveu I, Naveilhan P, Neunlist M. differences in the duodenal microbiome Postnatal development of the myenteric in subjects with irritable bowel glial network and its modulation by syndrome. Scand J Gastroenterol. butyrate. Am J Physiol Gastrointest 2015;50(9):1076-87. Liver Physiol. 2016:ajpgi 00232 2015. 50. Lee YJ, Park KS. Irritable bowel 57. Robinette ML, Colonna M. GI motility: syndrome: emerging paradigm in microbiota and macrophages join forces. pathophysiology. World J Cell. 2014;158(2):239-40. Gastroenterol 2014;20(10):2456–69. 58. Moloney RD, Johnson AC, O'Mahony 51. Spiller R, Lam C. An Update on Post- SM, Dinan TG, Greenwood-Van infectious Irritable Bowel Syndrome: Meerveld B, Cryan JF. Stress and the Role of Genetics, Immune Activation, Microbiota-Gut-Brain Axis in Visceral Serotonin and Altered Microbiome. J Pain: Relevance to Irritable Bowel Neurogastroenterol Motil. Syndrome. CNS Neurosci Ther. 2012;18(3):258-68. 2016;22(2):102-17. 52. Brint EK, MacSharry J, Fanning A, 59. Parkes GC, Brostoff J, Whelan K, Shanahan F, Quigley EM. Differential Sanderson JD. Gastrointestinal expression of toll-like receptors in microbiota in irritable bowel syndrome: patients with irritable bowel syndrom. their role in its pathogenesis and Am J Gastroenterol. 2011;106(2):329- treatment. Am J Gastroenterol. 36. 2008;103(6):1557-67. 53. Schoepfer AM, Schaffer T, Seibold- 60. Di Nicolantonio JJ, Lucan SC. Is Schmid B, Müller S, Seibold F. fructose malabsorption a cause of Antibodies to flagellin indicate irritable bowel syndrome? Med. reactivity to bacterial antigens in IBS Hypotheses 2015;85:295-297. patients. Neurogastroenterol Motil. 61. Niec AM, Frankum B, Talley NJ. Are 2008;20(10):1110-8. adverse food reactions linked to irritable 54. Souza EL, Elian SD, Paula LM, Garcia bowel syndrome? Am J Gastroenterol CC, Vieira AT, Teixeira MM, Arantes 1998;93(11):2184–90. RM, Nicoli JR, Martins FS. Escherichia 62. Heizer WD, Southern S, McGovern S. coli strain Nissle 1917 ameliorates The role of diet in symptoms of experimental colitis by modulating irritable bowel syndrome in adults: a intestinal permeability, the inflammatory response and clinical

narrative review. J Am Diet Assoc 68. Saha L. Irritable bowel syndrome: 2009;109(7):1204–14. pathogenesis, diagnosis, treatment, and evidence-based medicine. World J 63. El-Salhy M, Ostgaard H, Gundersen Gastroenterol 2014;20(22):6759–73. D, Hatlebakk JG, Hausken T. The role of diet in the pathogenesis and 69. Camilleri M. Evolving concepts of the management of irritable bowel pathogenesis of irritable bowel syn- syndrome (Review). Int J Mol Med drome: to treat the brain or the gut? J 2012;29(5):723–31. Pediatr Gastroenterol Nutr 2009;48(Suppl. 2):S46–8. 64. Savaiano DA, Levitt MD. Milk intolerance and microbe-containing 70. El-Salhy M. Recent developments in dairy foods. J Dairy Sci the pathophysiology of irritable bowel 1987;70(2):397–406. syndrome. World J Gastroenterol 2015;21(25):7621–36. 65. Lomer MC, Parkes GC, Sanderson JD. Review article: lactose intolerance 71. Saps M, Pensabene L, Turco R, Staiano in clinical practice – myths and A, Cupuro D, Di Lorenzo C. Rotavirus realities. Aliment Pharmacol Ther gastroenteritis: precursor of functional 2008;27(2): 93–103. gastrointestinal disorders? J Pediatr Gastroenterol Nutr 2009;49(5):580– 66. Catassi C, Elli L, Bonaz B, Bouma G, 3.ü Carroccio A, Castillejo G, et al. Diagnosis of non-celiac gluten 72. Henderson P, Casey A, Lawrence SJ, sensitivity (NCGS): the Salerno Kennedy NA, Kingstone K, Rogers P, et Experts’ Criteria. Nutrients al. The diagnostic accuracy of fecal 2015;7(6):4966–77. calprotectin during the investigation of suspected pediatric inﬂammatory bowel 67. Pimentel M, Chatterjee S, Chang C, disease. Am J Gastroenterol Low K, Song Y, Liu C, et al. A new rat 2012;107(6):941–9. model links two contemporary theories in irritable bowel syndrome. Dig Dis Sci 2008;53(4):982–9.