Out of all the FGIDs, perhaps IBS is the most researched diseases entity in terms of its patho-physiology. These studies have reported large number of different and possible patho-physiological mechanisms. However, at the moment all these studies have only possibly touched on the surface of this complicated disease entity and have failed to demonstrate an exact patho-physiological mechanism/s. The majority of the patho-physiological studies include small samples, sometimes do not included a control group and the reported mean differences are too small to provide a statistical power to obtain meaningful conclusions. In addition, some of the studies were conducted in a heterogeneous group of patients with chronic functional abdominal pain rather than in specifically in those with IBS and therefore could not be exactly applied to IBS. Several controversies exist in the proposed patho-physiology of IBS. Strangely, most of the proposed mechanisms do not correlate with the clinical symptoms.
In both models, a large number of patho-physiological mechanism have been suggested and interactions between these mechanisms are believed to result in the development of IBS in susceptible individuals. Main suggested patho-physiological mechanisms for IBS are illustrated in Figure 1 according to the top-down and bottom-up models.
Figure 1 Top-down and bottom-up models of patho-physiology of irritable bowel syndrome.
ENS: Enteric nervous system; 5-HT: 5-hydroxytryptamin; HPA axis: Hypothalamo-pituitary-adrenal axis.
Top-down model vs bottom-up model
In top-down model, the symptoms of IBS are believed to be caused by alternations in the central nervous system initiated by various stressors directed at the central nervous system (exteroceptive stress) such as adverse life events[11,45,46]. anxiety[1,41] and depression. It is believed that several neural networks of the brain interact with each other in an intricate manner to generate symptoms. Studies conducted in adult patients with IBS have reported interactions between central executive network (involving attention, working memory planning and response selection), salient network (responding to external and internal stimuli that reach to the brain), sensory motor network and autonomic networks (central control of autonomic function)[76,78,80]. These interactions are believed to alter the activity of the enteric nervous system through the autonomic nervous system and hypothalamo-pituitary-adrenal axis (HPA axis), causing physiological changes in the gut including visceral hypersensitivity and alteration in motility, permeability, secretion, immune reactions and the microbiome[78,80].
The bottom-up model suggests that various stressors directed at the gut can influence central nervous system and alter the cortical response to the visceral stimuli causing symptoms in IBS. Intestinal infections, mucosal inflammation, gut distension, immune mediated reactions, food allergy, alterations in gut microbial flora, increased intestinal permeability and abnormal responses of the enteric nervous system to gut stimuli (e.g., alterations in neurotransmitters such as serotonin) in combination or in isolation trigger symptom generation in this model. The gut may influence the brain via the intrinsic primary afferents neurons, whose cell bodies are located in cranial and dorsal nerve root ganglia. The sympathetic afferents from gut are believed to be the main mediator of nociceptive stimuli while vagal afferents are mainly believed to be involved in non-nociceptive sensations (e.g., local reflexes, gastric accommodation etc.).
The main problem is that the patho-physiological changes reported in the gut and the central nervous system in patients of IBS up to now can be attributed to both these models and identifying which comes first is like a chicken or the egg situation. However, the introduction of these two models has laid some foundations for direction of further research in the patho-physiology of IBS.
Communication between brain and the gut: brain-gut-axis
Both conceptual models recognize interactions between brain and the gut as the main patho-physiological mechanism in IBS. This bidirectional communication is called as the brain-gut axis and consists of the central and autonomic nervous systems, enteric nervous system and neuro-endocrine system and the neuro-immune system[23,81].
Autonomic nervous system: Autonomic nervous system has been considered to be one of the main communicators between the brain and the gut in both top-down and bottom-up models of pathogenesis of IBS. However, so far very few studies have been conducted to assess the autonomic nervous system in IBS and its exact role in generation of symptoms is not clear.
Studies conducted in adults have shown a correlation between vagal response and post-prandial abdominal symptoms of IBS-D and IBS-C. Some other studies have reported abnormal gastric motility and underlying vagal defects[83,84]. Another study has reported abnormal fingertip blood flow responses in subjects with IBS suggesting excess sympathetic activity. Findings of the above studies suggest that a shifting of sympathetic-parasympathetic balance may contributes to the pathogenesis of IBS. However, some other studies failed to demonstrate abnormalities in autonomic functions in patients with IBS.
However, all these studies have assessed either cardiovascular or ocular autonomic functions, but not the autonomic functions of the gut specifically. How these findings can be directly applied to the autonomic functions of the gastrointestinal tract is far from clear. Currently no exact technique is available to assess the gastrointestinal autonomic functions. Therefore, development of such a technique is a major challenge and will provide better opportunities to understand the role of the autonomic nervous system in gut functions in both health and disease.
Hypothalamo-pituitary-adrenal axis: The hypothalamic-pituitary-adrenal axis (HPA axis) is considered to be an important communicator in the brain-gut axis. HPA axis is activated by both exteroreceptive and interoceptive stress and therefore likely to be involved in both patho-physiological models. Activation of HPA axis ultimately results in increased release of corticotrophin releasing hormone (CRH), adrenocorticotrophic hormone (ACTH) and cortisol. Increased release of CRH is believed to promote central sensitization while ACTH and cortisol tend to activate resident immune cells and extrinsic primary afferents in the gastrointestinal tract causing peripheral sensitization.
Corticotrophin releasing factor (CRF) is increasingly recognized as an important factor in the development of FGIDs including IBS. However, only a few human studies have been conducted so far and most of the assumptions are based on results of animal studies. One study reported an upregulation of CRF-Receptor type 1 (CRF-R1) in patients with IBS. In addition, long-lasting epigenetic changes in the CRF expression have been reported in those exposed to neonatal stress, which results in the transcriptional responses to stress in adulthood. In contrast, another study assessed the diurnal rhythm of cortisol and stress reactivity and showed that cortisol as a marker of stress does not have a major role in abdominal pain in infants. Similar to humans, CRF-R1 upregulation, reversible mitochondrial damage and IBS like gut dysfunction were reported in rats after exposure to psychological stress. In this study, the increased CRF-R1 expression, reversible mucosal inflammation, increased epithelial permeability and conductance, and abnormal colonic response after exposure to stress lasted for a short duration (7 d) while visceral hypersensitivity observed after administration of exogenous CRF persisted for 30 d after exposure. In agreement, others have reported that CRF and its receptors play an important role in stress related alterations of visceral sensitivity and gastrointestinal motility[91-93].
Observed patho-physiological changes in IBS
Numerous studies have been conducted in adults and children with IBS and large number of possible patho-physiological mechanisms have been suggested. However, they are like individual pieces of a large jig-saw puzzle and we are far from solving this complicated problem. Fitting up available information on patho-physiology and finding the missing pieces of this puzzle is a major challenge.
Visceral hypersensitivity: Visceral hypersensitivity is defined as an enhanced perception of mechanical triggers applied to the bowel which seem as pain and discomfort. In normal individuals, physiological changes in the gastrointestinal tract such as motility and distension do not cause pain. When there is altered sensory response to physiological stimuli, it is called visceral hypersensitivity. Two main types of visceral hypersensitivity have been identified so far. They are hyperalgesia and allodynia. Hyperalgesia is defined as in intensified pain sensation in response to normal stimuli which usually do not provoke pain, while allodynia is the elevated nociceptive sensation in response to normal stimuli.
Visceral hypersensitivity is considered to be the cornerstone in the patho-physiology of IBS. One pediatric study has reported decreased rectal sensory threshold for pain in IBS and functional abdominal pain. Another study in children with IBS has demonstrated that abdominal pain is associated with abnormal perception of visceral sensations and hypersensitivity. Similar results have been reported in several other pediatric studies too[98-100]. Adults studies have also reported lowered rectal pain threshold in patients with IBS. Several factors such as psychological stress, gastrointestinal infections, alterations in gut microbiota, inflammation, immunological factors, food, as well as genes, have been suggested to induce visceral hypersensitivity[98,102,103]. Visceral hypersensitivity is believed to be results from pain modulation at both peripheral level as well as at central nervous system.
Modulation of pain: (1) At the enteric nervous system: Main function of the enteric nervous system is to regulate local gastrointestinal reflexes and to transmit sensory information to the central nervous system for processing and integration. A vast majority of afferent information received from the gut is used for regulation of normal functions such as motility and secretion. Information regarding the sensory perception and modulation at the level of enteric nervous system is limited. One study assessing mast cell-induced excitation of visceral nociceptive sensory neurons in adults with IBS has suggested the possibility of initiation and perpetuation of symptoms through modulation of sensory neurons in the enteric nervous system. (2) At the central nervous system: Increased pain perception in IBS is considered to be at least partly related to altered descending inhibition and pain affecting at the peripheral level and catastrophizing of pain at the central level. It is reported that increased pain perception in IBS is not due to the tendency to report more pain but because of increased spinal nociceptive transmission and impaired endogenous inhibition of somatic pain. When functional magnetic resonance imaging (fMRI) was used, insular cortex and pre-frontal cortex are recognized as the main areas of the central nervous system which are involved in the processing of visceral pain in IBS. It is also possible that alterations in pain appraisal, hypervigilance to interoceptive signals from the gut and engagement of emotional arousal could also contribute to the patho-physiology.
Alterations in neurotransmitters and receptors: More and more emerging evidence have recognized alterations in serotonin as important mediator in pathogenesis of IBS. Serotonin (5-hydrodytryptamine; 5-HT) is an important neurotransmitter in enteric neurons and paracrine signaling substance secreted by enterochromaffin (EC) cells in the intestinal mucosa. It mediates communication between the brain and the gut, and has been shown to be the responsible agent for bloating, nausea and vomiting[113,114]. In addition, it is considered to be an important signaling molecule in the central nervous system involved in mood, appetite, sleep, memory and learning. Alterations in serotonin is implicated in central nervous system disorders such as anxiety, depression and some psychiatric disorders. Serotonin is removed by a highly selective transporter called the serotonin transporter (SERT). Gene polymorphisms of SERT receptors have been shown to be associated with IBS[116-118]. In addition, some distinct changes in EC cell numbers and content as well as release and uptake of serotonin appear to have relevance to the patho-physiology of IBS[115,119,120].
Gastrointestinal dysmotility: A large number of studies have demonstrated abnormalities in gastric myoelectrical activity[121-124], gastric motility[123-130] and accommodation[131,132] and intestinal and colonic transit[125,133-135] in patients with IBS and other FAPDs. Few have reported an association between motility abnormalities and exposure to stress. It is suggested that stress can lead to alterations in central aminergic network involving serotonin and noradrenaline and therefore believed to play an important role in the pathogenesis of IBS, especially in the top-down model. However, so far no clear relationship has been demonstrated between motility abnormalities and symptoms in children with IBS. Therefore, whether the observed gastrointestinal motor abnormities are a cause for IBS or an effect of IBS is yet to be determined.
Immune mediated mechanisms: Increased prevalence of allergies and atopic disorders including asthma have been shown in patients with IBS[137-139]. But the small number of research ventures conducted up to now with small sample sizes have failed to demonstrate an exact link with immunoglobulin E (IgE )[140,141]. Increased numbers of mass cells have been reported throughout the gastrointestinal tract in patients with IBS[102,142,143]. It is suggested that serotonin is released during degranulation of these cells and stimulates peripheral nerves in the submucosa and increases visceral sensitivity.
Infection, inflammation and intestinal barrier functions: It is suggested that visceral hypersensitivity observed in patient with IBS can be secondary to the activation of immune cells and to the development of low-grade inflammation. Studies conducted in children with IBS have demonstrated an accumulation of inflammatory cells in the intestinal mucosa. A previous study conducted in children with FAP or IBS has reported an increased gut permeability and low grade inflammation. It has also been shown that the low grade inflammation was related to the degree to which pain interfered with activities. The increased permeability is attributed to the enlarged spaces between epithelial cells, cytoskeletal condensation, abnormal gene and protein expression in tight junction proteins of intestinal epithelial cells and reduction in the expression of occluding and zonula occludens protein 1[146,147]. Bacterial mediated and proteasome mediated alterations have also been suggested as possible triggers for low grade inflammation which ultimately leads to increase intestinal permeability (“leaky gut”).
IBS is common after gastroenteritis and it is often of the IBS-D type. In post-infectious IBS, gastrointestinal infections are believed to stimulate the immune system causing low-grade inflammation. Post-infectious IBS is associated with hyperplasia of EC cells, increased counts of neutrophils, mast cells and T cells in the colonic mucosa. It is believed that gastrointestinal infections stimulate the immune system causing low-grade inflammation leading to post-infectious IBS.
Microbiota: Gut microbiota is reported to be different in patients with IBS that in healthy individuals, with increased Firmicutes/Bacteroids ratio, increased relative abundance of fecal Ruminoccus torque like phenotypes and reduced bacterial diversity with increase in certain bacterial species (Enterobacteriaceae, Veillonella, Dorea) and reduction of other species (Bifidobacterium, Collinsella, Clostridiales)[110,151]. Children with IBS have significantly higher percentage of Haemophilus parainfluenzae in their gut[152-154]. Increasing visceral sensitivity, altered gastrointestinal transit and increase in permeability of the intestine is reported in experimental studies using germ free animals receiving gut microbiota of patients with IBS, indicating a potential pathogenic role of gut microbiota. Some other studies have reported an association between differences in short chain fatty acid production by colonic bacteria and the development of symptoms in diarrhea predominant IBS. Interactions between the gut microbiota and food (fermented protein products, generation of gases) are potential sources for cell damage, altered barrier function as well as symptoms such as bloating and distension. In addition, gut microbiota may influence other patho-physiological factors such as intestinal permeability, brain function, enteric nervous system, gastrointestinal motility and visceral pain, contributing to the patho-physiology of FGIDs. However, further studies are needed, especially in children, to confirm the role of gut microbiota in IBS.
Food: Even though children have identified a large number of food items which exacerbates their symptoms only a few have been reported to be associated with IBS. IBS has been shown to be associated with fermentable oligo-, di- and monosaccharides carbohydrates and polyols (FODMAPs). However, the exact relationship between lactose and fructose mal-digestion and IBS is not clear. Its relationship with fiber is rather controversial[160,161].
Genetic, epigenetic and environmental factors: Previous studies have reported that those with a family history of IBS or other bowel symptoms are more likely develop IBS[41,162]. Similarly, twin studies have suggested that there is a higher concordance of occurrence of IBS in monozygotic twins than in dizygotic twins. The concordance rate of IBS in monozygotic twins was 17.2% while that was 8.4% in dizygotic twins. However, if genetic factors play a major role in development of IBS, the concordance rate in monozygotic twins needs to be much higher. Therefore, it is possible that social and environmental factors also play an important role in development of IBS, in addition to the genetic predisposition. This finding is further strengthened by other studies which reported that parents of children with FAPDs have higher tendency to develop similar illnesses[37,164].
A large number of genetic polymorphisms were considered to be associated with IBS. However, overall there is limited evidence of a genetic association. The most frequently studied genetic associations are related to the serotonergic system, including serotonin transporter (SERT) gene polymorphisms[116,117]. MicroRNAs considered to play a role in the pathogenesis of IBS through regulating serotonin reuptake transport expression and single-nucleotide polymorphisms rs56109847 led to reduce microRNA binding and overexpression of the target gene in intestinal cells increasing IBS-D risk.
Other gene polymorphisms involved in IBS include mitochondrial DNA polymorphism, alpha 2 receptor gene C-1291G polymorphism, cytokine gene polymorphisms (e.g., IL-10 and IL 12 C (-1188) A)[170,171] and tumor necrosing factor super family (TNFSF) 15 polymorphism[172-174].
However, identification of a single gene polymorphism in patient with IBS alone would not possibly explain the complex nature of this disease. It is known that epigenetic changes in the genome play a crucial role in pathogenesis of diseases. It is possible that environmental factors, psychological stresses, exposure to child maltreatments and some of the Patho-physiological mechanisms interact with each other in a very intricate manner to alter epigenetic DNA (by DNA methylation, histone modification) and changes in micro-RNA which can alter the gene expression (inhibition of increase transcription) to produce IBS phenotype. However, further evidence needs to be generated in this vital area of association between epigenetic changes and IBS.