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Irritable Bowel Syndrome Pathophysiology .pptx
- 1. IBS – PATHOPHYSIOLOGY& TREATMENT Dr.N.A.Rajesh Professor & Head Department Of Medical GE SRM Medical College Hospital & RC
- 2. OBJECTIVES • WHAT ISIBS? • UNDERSTANDING THE PATHOPHYSIOLOGY • LIFESTYLE,HABITS & IBS • PREVENTION & TREATMENT
- 3. IBS- Introduction • Irritablebowel syndrome (IBS) is a chronic functional gastrointestinal disease • Abdominal pain & change in bowel function • Significant impact on patient’s quality of life and a high socioeconomic burden. • Prevalence varies greatly between countries because of differences in food, culture, and diagnosis • Rome Foundation Global Study reported that the overall prevalence of IBS was 3.8% • The highest prevalence observed in • Women, Educated, Wealthy, Students and Younger individuals
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- 6. OVERLAP OF IBSWITH OTHER FGIDs/DGBI • It tends to overlap with other functional gastrointestinal diseases (FGIDs)/DGBIs • 68% have overlap of 2 GI regions ( Esophageal, ,gastroduodenal, bowel & anorectal) • 55% have IBS-FD overlap • 2.3% have overlap of all 4 GI regions • Anxiety & Depression were common characteristics in the mechanism of FGIDs • 53% of IBS cases report pain in ≥ 3 non abdominal areas • Headache, Fibromyalgia, LBA etc
- 7. PATHOPHYSIOLOGY • In thepast, IBS could not be explained by a clear etiology • Traditionally been described as a disorder of visceral hypersensitivity and GI motor disturbances • Etiopathogenesis is Multidimensional • Peripheral factors • Abnormal GI motility • GI inflammation & altered gut permeability • Luminal microenvironment alteration • Microbiota dysbiosis • SIBO • Host-microbe interaction • Bile acid malabsorption • Pathogenic infection • Dietary factors • Neurohumoral dysregulation • Altered serotonergic transmission • Visceral hypersensitivity • Central factors • Psychological stress • Cognitive dysfunction • Abnormal emotional arousal system response • Sleep dysfunction • Genetic factors
- 8. PATHOPHYSIOLOGY • Genetic Factors •Complex polygenic, Atypical single gene aberrations (example - SCN5A) • Genetic polymorphism of IBS pathogenesis –related genes related to • Seratonin signalling • Immune regulation • Epithelial barrier function • Bile acid synthesis • DNA methylation changes • Gut Microbiota • Modulate gut brain axis & gut neuromuscular junction • Alter immunity & integrity of the gut
- 9. PATHOPHYSIOLOGY With the increasingresearch ,the pathophysiological mechanisms of IBS has changed from functional to brain-gut interaction. • Gut Brain Interactions • GI tract sends signals that affect the brain, resulting in alterations in immune function, secretion, and motility • Vagus nerve - main communication conduit between the brain and the microbiota • Gut permeability and the brain function is significantly altered in patients with IBS • Correcting the crosstalk between the ANS and CNS is an important in IBS prevention
- 10. PATHOPHYSIOLOGY • Gut BrainInteractions • CRF functions both centrally and peripherally & modulate body response to stress and stimulates IBS symptoms • The binding of CRF to its receptors induces changes in • smooth muscle contractility • mucosal transport • mucosal permeability • visceral pain sensitivity
- 11. PATHOPHYSIOLOGY • Gut BrainInteractions – Stress • Psychological stress have a critical influence on the gut-brain axis • Stress affect • intestinal motility and permeability • visceral sensitivity • immune responses, • gut microbiota composition • Stress Secretion of proinflammatory cytokines Activates the HPA and hypothalamic-ANS axis Induce release of CRF, adrenocorticotropic hormone, and cortisol Affects gut homeostasis
- 12. PATHOPHYSIOLOGY • Abdominal painin IBS patients has been shown to be associated with structural changes of the brain. • Rectal stimulation • Activate the anterior cingulate cortex, prefrontal cortex, insula, thalamus, and cerebellum, and is higher in IBS • Female IBS patients • Increase in gray matter volume and cortical thickness in the primary and secondary somatosensory cortex and subcortical regions • Decrease in the volume, surface, and cortical thickness of the gray matter in the posterior insula and superior frontal gyrus
- 13. PATHOPHYSIOLOGY • Abnormal Oroanal transit time (OATT) is related to hydrogen and methane concentration in the gut • More rapid OATT is associated with a higher severity of abdominal discomfort, rumbling, and nausea. • Gut endocrine cells are scattered throughout the gastrointestinal tract and have sensory microvilli that sense gut pressure and gut contents • microbial food metabolism in gut lumen stimulate the cells release hormones & neurotransmitters into the lamina propria • Histamine, 5-HT, glutamate, and noradrenalin strengthen visceral pain • γ-aminobutyric acid reduces gastrointestinal motility
- 14. PATHOPHYSIOLOGY • Visceral hypersensitivityand gut barrier disruption • Animal experiments have shown • Apelin activates CRF and TLR4, create a cycle of proinflammatory cytokine signaling - a key pathway for the pathological mechanism of IBS. • The disruption of the gut barrier leads to an increase in lipopolysaccharides (LPS) and proinflammatory cytokines - a vital pathological mechanism that causes abdominal pain in patients with IBS.
- 15. PATHOPHYSIOLOGY • Microbiome • Themicrobial diversity • a decrease in Coli, Lactobacilli, Collinsella, and Bifidobacteria • a increase in Enterobacteria, anaerobes, Escherichia coli, Ruminococcus gnavus, and Bacteroides in patients with IBS. • Microbiota-gut-brain axis • Dinan et al - Disturbances in the gut microbiota can affect brain function, behavior, and cognition • Studies have shown that in 2/3rd patients functional gastrointestinal symptoms preceded the mood disorder • Koloski et al showed higher baseline levels of anxiety and depression - significant predictors of developing IBS
- 16. DIAGNOSIS • No singleor specific diagnostic tests for IBS • Diagnosis is clinical & is based on Rome IV Criteria • Exclude organic diseases • Alarm symptoms • Rectal bleeding, Weight loss, Nocturnal symptoms • Recent change in bowel function • Exclude somatoform/psychological disorders • Screening tests • Hemoglobin, CRP • Fecal Calprotectin • Colonoscopy • Specialized tests if no response to primary treatment • Anorectal manometry and balloon expulsion, colonic transit • Tests for biochemical causes of diarrhea • Sugar malabsorption – Abnormal D-Xylose test , Fat malabsorption – Fecal fat • Bile acid diarrhea • SIBO – Glucose Hydrogen Breath Test
- 17. MANAGEMENT • The Asianexperts called DGBI pathophysiological mechanisms as micro-organic factors • Micro-organic factors • Slow colon transit and Fecal evacuation disorder may be hidden behind the diagnosis of a patient with IBS-C. • Dietary intolerance, including that of lactose and fructose, bile acid malabsorption, non-celiac wheat sensitivity, SIBO and GI infection may be the cause of symptoms in IBS-D. • Therefore a multi-modality care targeting various pathophysiological mechanisms of IBS is superior to standard care. • Personalized care - unrevealing these pathophysiological mechanisms in each patient through thorough • History taking • Physical examination and • Investigation
- 18. MANAGEMENT • IBS isa syndrome diagnosed by symptom-based criteria • Goal of treatment is to relieve patient’s symptoms and improve the quality of life (QOL) • All bothersome symptoms should be targeted while treating these patients rather than only the predominant symptoms • Counseling, reassurance and lifestyle modification are important in the management of IBS • Frequent counseling sessions and promoting physical activity (e.g. yoga, meditation) • Sleep disorders should be recognized & appropriately treated with pharmacotherapy • Dietary intervention – Low FODMAP diet
- 19. Management • Dietary FODMAPrestriction is useful in a proportion of IBS patients • A low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet is particularly useful for • Flatulence • Bloating • Abdominal pain • Diarrhea
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- 21. MANAGEMENT • The initialpharmacotherapy of IBS is primarily symptom based • Antispasmodics are the first-line treatment of abdominal pain in patients with IBS and non-responsive patients may benefit from visceral neuromodulators • Psychoactive pharmacotherapy (visceral neuromodulators) are useful to relieve abdominal pain in IBS patients • Work both through central and peripheral mechanisms. • These drugs work even in the absence of significant psychological comorbidity
- 23. MANAGEMENT • The initialpharmacotherapy of IBS is primarily symptom based. • Laxatives and Antidiarrheals are the first-line treatment for IBS-C and IBS-D, respectively • Fiber supplements • Water-soluble - psyllium, ispaghula, calcium polycarbophil, methylcellulose • Insoluble - wheat bran • Recommended dose - 20 g per day – improve constipation and abdominal pain • Stimulant drugs such as senna and bisacodyl • quite effective purgatives but may cause abdominal cramps • Loperamide, Diphenoxylate, Ramosetron & Visceral NM with anticholinergic activity like Amytriptyline – useful in IBS -D
- 24. MANAGEMENT • The initialpharmacotherapy of IBS is primarily symptom based • Probiotics may be helpful • Rifaximin • Methane-producing IBS-C patients • High breath methane on lactulose hydrogen breath test is seen in slow transit constipation • Non constipated IBS also benefit from Rifaximin • Psychological interventions are useful in those with psychiatric comorbidities or refractory IBS • Patients with severe symptoms, non-responding patients and overlap disorders more often have psychological comorbidity • Psychological interventions • Pharmacotherapy • Cognitive behavior therapy • Gut-directed hypnotherapy • Yoga and MBSRT
- 29. CONCLUSION • IBS isa complex disease with multiple pathophysiological mechanisms • A multidisciplinary approach that incorporates nonpharmacological and/or pharmacological treatments is emphasized. • Individualized treatment plans are necessary for effectively managing IBS.
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Editor's Notes
- #4 Rome III criteria may be preferred over Rome IV to diagnose IBS in India due to its higher sensitivity. However, Manning and Asian criteria were found to be even superior to Rome III criteria
- #6 Earlier, it was thought that FGIDs (currently called DGBI) are isolated disorders without any overlap. Pathologies exist in GIT on a continuum instead of as separate disorders & overlap may be a natural clinical symptom of FGIDs Overlaps between various FGIDs are common rather than exceptions . It must be emphasized that owing to busy work schedules, the overlaps may often be overlooked by physicians, particularly in India and the adjoining nations, as they may primarily focus on predominant symptoms instead of directing adequate attention to recognize the overlaps in their clinical practice ]. In a recent multicentric study by the Rome Foundation, patients with multiple FGIDs were found to have more psychological comorbidity, healthcare utilization and IBS severity
- #7 Traditionally,irritable bowel syndrome has been considered to be a disorder with no known underlying structural or biochemical explanation Several centrally mediated processes resulting in visceral hypersensitivity and peripheral mechanisms that initiate perturbations of gastrointestinal motor and sensory functions have been recognized and can lead to IBS symptoms.6
- #8 Numerous lines of evidence show that the genetic risk for IBS varies between complex polygenic individuals who have combinations of common variants and those with atypical single gene aberrations (15,16). For instance, a mutation in SC5NA, which is a sodium ion channel gene, was determined to be linked to abdominal pain in patients with IBS The pathogenesis of IBS is also associated with changes in the gut microbiota, which alter the immunity and integrity of the gut and further modulate the gut-brain axis and the gut neuromuscular junction Under normal circumstances, the mucosal epithelium, which is where the stimulation of homeostatic immune responses occurs, upholds the integrity of the barrier and maintains tolerance to commensal bacteria by restricting microbes to the surface or the intestinal lumen. This process permits bacteria to steadfastly colonize the intestine and undergo cooperative functions. However, when this barrier is broken by invading inflammatory agents, pathogens, or other factors which aggravate the immune response, severe inflammation occurs. This inflammatory reaction affects the intestinal milieu, because it alters the composition of the gut microbiota there is growing evidence to suggest that maintaining the appropriate diversity of gut microbiota is not only essential for gut health but is also critical for the normal physiological function of other organs, especially the brain. In neonates and older people, the occurrence of microbial imbalance, termed dysbiosis, has the potential to profoundly affect brain function. This is because the brain depends upon the metabolic products of gut microbes
- #9 The gut-brain axis (Figure 1) comprises the enteric nervous system (ENS), the CNS, the gut wall in the periphery, and the hypothalamo-pituitary-adrenal (HPA) axis (37). The communication between the gut and the CNS is bidirectional and is centered upon the neural, endocrine, and neuroimmune pathways this axis serves as a key communication hub in the regulation of food intake, digestion, and the sensation of adequate control of gut and bowel movements. Structural and functional disruptions of the gut-brain axis alter the nervous system’s reflexive and perceptual responses, which can potentially instigate GI disorders, such as IBS The vagus nerve encompasses thousands of nerve endings, among which 80% are afferent, carrying stimuli toward the CNS and brain. The pathways involved in this communication are also responsible for transmitting efferent signals from the CNS to the intestinal wall vagus nerve is an important component of the ANS, and the sympathoadrenomedullar axis is the specific component of the ANS that participates in acute stress response. The sympathoadrenal and HPA axes are considered to be the key constituents of the stress response system in vertebrates (41). Multiple anxiety-related psychiatric disorders and stress-sensitive pain syndromes arise due to alterations of this multifaceted system Disruption of the ANS at any level, including in the form of decreased parasympathetic and increased sympathetic activity, can cause patients with IBS to experience distorted autonomic reflexes, accounting for a degree of awareness when it comes to extraintestinal symptoms and GI stimuli Specifically, the connections between transcellular permeability (evaluated by live bacterial passage of Salmonella typhimurium) and paracellular permeability and resting-state functional connectivity in the default mode network brain region were examined. Ultimately, the women with moderate to severe IBS and the healthy women exhibited statistical differences in terms of paracellular and transcellular epithelial permeability, and structural and functional brain features. Furthermore, among the women with IBS, those with lower epithelial permeability reported more severe IBS symptoms, which was associated with increased functional and structural connectivity in endogenous pain facilitation regions. Figure 1 The gut-brain axis. The vagus nerve provides a link between the gut and the brain. This connection involves the ENS, the CNS, the gut wall at the periphery, and the HPA axis. Alterations in the gut microbiota can influence mood, behavior, stress, anxiety, and neurotransmitters. Imbalance of the gut microbiota affects the signals sent by the gut to the brain, resulting in alterations in secretion, motility, nutrient delivery, microbial balance, and immune function. Together, these disruptions contribute to IBS symptoms. ENS, enteric nervous system; CNS, central nervous system; HPA, hypothalamo-pituitary-adrenal; IBS, irritable bowel syndrome.
- #10 The binding of CRF to its receptors induces changes in smooth muscle contractility, mucosal transport, mucosal permeability, and visceral pain sensitivity, all of which are correlated with the colonic manifestations of IBS One study examined the HPA axis, colonic motility, and autonomic reactions following CRF administration, and also examined brain activity alterations in patients with IBS. After CRF administration, the male IBS group showed a greater increase in colonic motility than the male controls; in contrast, in comparison to their controls, the female IBS group displayed changes in sympathovagal balance and had a reduced basal parasympathetic tone. The study suggested that treatments that act centrally might aid in reducing the stress-induced physical symptoms of IBS (53). Ultimately, more studies into the mechanistic network of the central CRF system and the GI CRF system at a local level will improve our knowledge of the gut-brain axis.
- #11 One study examined the HPA axis, colonic motility, and autonomic reactions following CRF administration, and also examined brain activity alterations in patients with IBS. After CRF administration, the male IBS group showed a greater increase in colonic motility than the male controls; in contrast, in comparison to their controls, the female IBS group displayed changes in sympathovagal balance and had a reduced basal parasympathetic tone. The study suggested that treatments that act centrally might aid in reducing the stress-induced physical symptoms of IBS (53). Ultimately, more studies into the mechanistic network of the central CRF system and the GI CRF system at a local level will improve our knowledge of the gut-brain axis.
- #12 Pathology of irritable bowel syndrome in the intestinal. Food and microbial metabolism stimulate the gut's endocrine cells to release hormones and neurotransmitters, leading to visceral pain and reducing gastrointestinal motility. Apelin, corticotropin-releasing factor, and Toll-like receptor 4-proinflammatory cytokine signaling lead to visceral hypersensitivity and disruption of the gut barrier. The concentrations of hydrogen and methane are related to abnormal oroanal transit time (OATT), and a more rapid OATT was associated with a higher severity of abdominal discomfort, rumbling, and nausea. Decreasing miR-199 caused visceral hypersensitivity and augmented visceral pain in patients with irritable bowel syndrome (IBS) through translational upregulation of TRPV1. Colonic mucosal protein expression and faecal bile acids were correlated with the symptom severity of IBS-D patients. CRF: Corticotropin-releasing factor; TLR4: Toll-like receptor 4
- #13 Abnormal colonic transit and disorders of evacuation are important physiopathologies in patients with IBS, leading to constipation, bloating, and abdominal pain. The levels of colonic mucosal Short-chain fatty acid (SCFA), Fecal bile acids (FBA), Tryptophan, and Methane gas production are higher in patients with IBS
- #14 Abnormal colonic transit and disorders of evacuation are important physiopathologies in patients with IBS, leading to constipation, bloating, and abdominal pain.
- #15 Research progresses on the mechanism of action of the microbiota-gut-brain axis. Brain changes in patients with irritable bowel syndrome (IBS) are associated with abdominal pain. They have higher activation of the anterior cingulate cortex, prefrontal cortex, insula, thalamus, and cerebellum. They also mainly showed an increase of gray matter volume and cortical thickness in the primary somatosensory cortex, secondary somatic sensory cortex, and subcortical regions and a decrease of gray matter volume, surface area, and cortical thickness in the posterior insula and superior frontal gyrus. Specific changes in the intestinal flora of patients with IBS. The number of Coli, Lactobacilli, Collinsella, and Bifidobacteria in IBS patients decreased, while the number of Enterobacteria, Anaerobes, Escherichia coli, Ruminococcus gnavus, and Bacteroides increased.
- #16 . IBS represents a spectrum of symptoms that may arise from diverse dysfunctions of the gut-brain axis, including abnormal intestinal motility or transit, increased sensation or perception of abdominal symptoms such as pain or bloating (mediated in the gut or in the brain), and psychological disturbances including somatization or multiple somatic comorbidities In Asian consensus, Bristol stool forms 1–3 have been defned as constipation and 5–7 as diarrhea. Sub-classifcation of IBS, according to the bowel pattern, could be based on a modifcation of the Rome III criteria [82]. The BSFS demonstrated substantial validity and reliability [9, 83]. The Asian consensus on IBS suggested that in addition to Bristol types 1 and 2 stool, type 3 stool should also be considered as constipation in Asia [63, 82]. In a multicentre study from India, improvement in subtyping IBS using BSFS as suggested in the Asian consensus has been reported [71]; in this study, applying stool types 3 (as hard stool) and 5 (as a soft stool) as abnormal stool forms allowed more patients to be subtyped compared to the use of Rome subtyping system that considers type 3 to type 5 stools as normal stools Other constipation-associated symptoms such as straining, feeling of incomplete evacuation, patients’ perception and infrequent bowel movements (less than three bowel movements per week) should also be considered while sub-classifying IBS.
- #17 Slow colon transit may result from excess methane production in the gut due to methanogen overgrowth. In contrast, the patients with non-C-IBS may have lactose and fructose malabsorption, bile acid malabsorption, non-celiac wheat and FODMAP intolerance, gut microbiota dysbiosis including SIBO, immune activation, and post-infection including post-COVID-19 etiology. These are, however, not watertight compartments; IBS-C patients may also have some of the pathophysiological factors listed under IBS-D and vice versa
- #18 The urban lifestyle associated with fad diets (junk, fast food, fatty food, tea, cofee, aerated drinks, etc.), substance abuse (smoking, chewing tobacco), low levels of physical activity, and psychological stress (depression, anxiety, insomnia) has been associated with higher prevalence of IBS [ Typical FODMAP-rich foods include wheat, onions, chickpeas, lentils, apples, corn, milk, yogurt, and honey. Foods rich in these FODMAPs are difficult to decompose and absorb in the small intestine and continue to the large intestine without processing, where they are rapidly fermented and decomposed by intestinal bacteria. During the process, hydrogen gas and methane gas are generated, and they draw water into the intestinal tract due to their high osmotic pressure. In clinical trials, it has been reported that IBS patients who ate a low-FODMAP diet had fewer IBS symptoms than those who ate a normal diet
- #21 The urban lifestyle associated with fad diets (junk, fast food, fatty food, tea, cofee, aerated drinks, etc.), substance abuse (smoking, chewing tobacco), low levels of physical activity, and psychological stress (depression, anxiety, insomnia) has been associated with higher prevalence of IBS [
- #23 The urban lifestyle associated with fad diets (junk, fast food, fatty food, tea, cofee, aerated drinks, etc.), substance abuse (smoking, chewing tobacco), low levels of physical activity, and psychological stress (depression, anxiety, insomnia) has been associated with higher prevalence of IBS [ Soluble fibre forms a gel in the intestinal tract, thus facilitating the movement of stool masses. Insoluble fibre, however, absorbs water into its fibrous structure and swells, increasing the volume of the stool itself and stimulating intestinal peristalsis. Psyllium, a soluble fibre, is effective in ameliorating the common symptoms of IBS, as well as IBS-related constipation symptoms However, wheat bran, an insoluble fibre, has been reported to be effective for IBS-related constipation symptoms, but worsens general IBS symptoms and IBS-related abdominal pain
- #24 The urban lifestyle associated with fad diets (junk, fast food, fatty food, tea, cofee, aerated drinks, etc.), substance abuse (smoking, chewing tobacco), low levels of physical activity, and psychological stress (depression, anxiety, insomnia) has been associated with higher prevalence of IBS Since gut microbiota dysbiosis and SIBO are associated with IBS, drugs manipulating gut microbiota such as antibiotics (rifaximin) and probiotics have been evaluated in its treatment. Another form of manipulation of gut microbiota using fecal transplantation is not recommended to treat IBS at present, but this therapy is only undertaken in a research setting. In an earlier consensus, the review of pieces of evidence suggested that Lactobacillus strains ameliorated fatulence signifcantly and abdominal or global symptom scores were improved by Bifdobacterium and Escherichia and Streptococcus strains both provided persistent symptom reduction [135]. However, the current evidences are not enough to achieve a strong consensus on the use of specifc probiotics as a routine practice and its dose as the therapy of choice. More studies are needed on this issue from India. mindfulness-based stress reduction therapy [MBSRT]) directed against abnormal gut-brain interaction using visceral neuromodulators and various forms of psychotherapies have been found useful in the treatment of refractory IBS The fundamental basis for recommending a lowFODMAP diet is that bloating results from bacterial fermentation of intraluminal saccharides. monosaccharides, and polyol diet The low fermentable oligosaccharides, disaccharides, monosaccharides, and polyol (FODMAP) diet involve reducing the consumption of poorly absorbed short-chain carbohydrates and low gas-producing foods. Unabsorbed fructose, polyols, and lactose can increase small intestinal water content, while indigestible fructans and galacto-oligosaccharides may lead to microbial fermentation in the colon, triggering symptoms in IBS patients [49]. The low FODMAP diet is a dietary therapy that should be supervised by a nutritionist. Halmos et al. demonstrated that a low FODMAP diet can improve bloating, abdominal pain, and flatulence in IBS patients Ideally, the low FODMAP diet should be followed for 4–6 weeks, as long-term restrictions may increase the risk of inadequate nutrition.
- #29 Therefore, in the future, we should pay more attention to the influence of the brain-gut axis and the central nervous system on the entire gastrointestinal tract and understand FGIDs as a whole.