Irritable Bowel Syndrome (IBS): Contemporary Insights intoitsEpidemiology, Pathophysiology, and Therapeutic Approaches
Ahmed Alsolami1*
1Department of InternalMedicine, College of Medicine, University of Ha’il, Ha’il 55476, SaudiArabia.
*Email:[email protected]
ABSTRACT
Irritable Bowel Syndrome (IBS) continues to be a pervasive gastrointestinal disorder affecting millions worldwide, imposing a significant burden on healthcare systems and impacting the quality of life for those afflicted. This review aims to provide a comprehensive overview of the current understanding of IBS by exploring its epidemiology, detailing its complex pathophysiology, and examining contemporary therapeutic approaches. The paper discusses the prevalence and demographic factors associated with IBS, highlighting its global impact. Moving into the realm of pathophysiology, we delve into the multifactorial causes that contribute to the disorder, including altered gut microbiota, psychosocial factors, and gut-brain axis dysregulation. Finally, the review focuses on existing and emerging treatment modalities, from dietary adjustments and pharmacological interventions to psychological therapies. Particular attention is paid to groundbreaking medications like Eluxadoline, Tenapanor, Asimadoline, Linaclotide, and Plecanatide, which have the potential to revolutionize IBS management. Through this review, we seek to consolidate current knowledge on IBS and present avenues for future research and treatment innovation.
Key words:Irritable bowel syndrome, Gut-brain axis, Gut microbiota, Fecal microbiota transplant
INTRODUCTION
Irritable Bowel Syndrome (IBS), a term that has become widely used in the field of gastroenterology over the past few decades, represents a complex and multifaceted disorder that elicits significant interest and concern among clinicians, researchers, and patients alike [1]. IBS is a functional gastrointestinal disorder with a multifactorial etiology, including altered gut motility, visceral hypersensitivity, psychosocial factors, and low-grade inflammation [2, 3]. IBS is characterized by abdominal pain, bloating, and altered bowel habits [4]. It is one of the most diagnosed gastrointestinal disorders worldwide. The epidemiology and prevalence of IBS provide insights into its global impact and the affected populations. Irritable Bowel Syndrome (IBS) stands out as a prevalent functional gastrointestinal disorder, globally impacting a substantial portion of the population. Characterized by a cluster of symptoms such as abdominal pain, altered bowel habits, and bloating, IBS not only influences physical health but also plays a significant role in the diminishment of quality of life [5]. While IBS might not be a life-threatening ailment, its pervasive nature can markedly erode the quality of life, catalyze psychological distress, and usher in substantial economic implications both for affected individuals and the broader healthcare ecosystem [6]. The phenomenon of the increasing global incidence of IBS has become an imperative topic of investigation in gastrointestinal medicine. IBS, characterized by abdominal pain, bloating, and altered bowel habits without an identifiable organic cause, has been witnessing a surge in cases worldwide, affecting diverse populations across various geographical regions [7]. The movement of people and dietary habits across borders can merge different risk factors, thereby potentially escalating IBS cases worldwide. The global landscape of IBS is continually evolving. Variations in its prevalence across geographies and demographics underscore the significance of contextual factors, be they dietary, environmental, genetic, or psychosocial. These fluctuations are not merely statistical annotations; they are pivotal in guiding public health initiatives, resource allocation, and therapeutic research directions [8].
The pathophysiology of IBS is multifaceted, with various mechanisms and factors interplaying in its genesis [9]. The enigma of IBS pathophysiology is gradually unraveling, revealing a tapestry where diverse physiological, microbial, immunological, and psychological threads interweave [10]. Although strides have been made, the complexity and heterogeneity of IBS mandate continued exploration into its pathophysiology. This shall pave the way towards precision medicine approaches, providing more targeted and efficacious interventions to alleviate the burden of IBS [11]. Diagnosing IBS is largely a clinical endeavor, relying on symptom-based criteria in the absence of alarm features. This review elucidates the diagnostic approach to IBS [3, 12]. This review aims to explore the latest scientific understandings of the contemporary vistas of IBS, unearthing the latest epidemiological trends, dissecting the modern understanding of its pathophysiology, and evaluating the current and emerging therapeutic strategies. Through this exploration, we aim to foster a deeper comprehension of IBS, catalyze further research, and enhance patient care in this pivotal domain of gastroenterology.
Review
Irritable Bowel Syndrome (IBS) is a functional gastrointestinal disorder characterized by a constellation of symptoms such as abdominal pain, bloating, and altered bowel habits, which may manifest as constipation, diarrhea, or a combination of both [13]. Though prevalent and often debilitating, the underlying mechanisms contributing to IBS are not fully understood [14]. The pathophysiology of IBS is complex and multifactorial, involving an intricate interplay between psychological factors, the gut-brain axis, microbiota imbalances, and abnormalities in gut motility and secretion [15]. While traditionally viewed as a disorder predominantly influenced by psychological stressors, recent advances in research have unraveled more about the physiological aspects underpinning IBS.
Emerging evidence has pointed towards a role for genetic predisposition, altered gut microbiome, low-grade inflammation, and dysfunctional gut-brain interactions in the development and perpetuation of IBS symptoms [16].
The multifaceted impact of IBS: From physical symptoms to psychosocial consequences and financial burden
Physical discomfort and pain:One of the most recognizable hallmarks of IBS is abdominal pain and discomfort [14, 17]. The unpredictable nature of these symptoms can disrupt daily life activities, making it challenging to plan or commit to social and work-related engagements. Frequent episodes of cramping and bloating can lead to missed opportunities and a constant sense of unease [10, 18]. Altered bowel habits: IBS patients frequently experience altered bowel habits, including diarrhea, constipation, or alternating between the two [14, 19]. These symptoms not only cause physical discomfort but also contribute to anxiety and embarrassment. The fear of sudden urgent bowel movements can limit individuals' willingness to travel, engage in physical activities, or dine out, further isolating them from social interactions. Psychological distress:The psychosocial impact of IBS cannot be understated [20]. The chronic nature of the condition can lead to anxiety and depression, often exacerbating symptoms in a vicious cycle [21]. The uncertainty of when and where symptoms might strike can lead to anticipatory anxiety, which can, in turn, worsen IBS symptoms. This psychological toll can severely affect a person's quality of life, leading to social withdrawal and reduced participation in enjoyable activities [22]. Dietary restrictions: Many individuals with IBS find relief by adhering to specific diets, such as low-FODMAP or gluten-free diets [23]. While these dietary modifications can alleviate symptoms, they can also limit food choices and add a layer of complexity to meal planning and dining out [24]. The constant need to be vigilant about food choices can be mentally exhausting and restrict the enjoyment of food-related experiences [25]. Impact on work and relationships: IBS can disrupt professional life and strain personal relationships [26]. Frequent absenteeism due to severe symptoms can lead to decreased job performance and career advancement opportunities [27]. Additionally, the need to frequently excuse oneself from social gatherings or cancel plans with friends and family can strain relationships and lead to feelings of isolation. Financial burden: The costs associated with managing IBS, including doctor's visits, medications, dietary supplements, and alternative therapies, can be significant [28]. This financial burden adds stress to the lives of individuals with IBS, further impacting their overall quality of life [29].
Epidemiological evidence
Over the past few decades, many epidemiological studies have observed a marked increase in the number of IBS cases worldwide [30]. While historically considered more prevalent in Western countries, recent reports suggest a rising incidence in previously low-prevalence regions like Asia, Africa, and the Middle East [31]. Multiple factors contributing to the rise including, Increased awareness and reporting:With improved awareness among both medical professionals and the public, more cases are being diagnosed and reported [32]. Enhanced understanding of the Rome diagnostic criteria and increased healthcare-seeking behaviors have undoubtedly influenced the numbers [33]. Dietary changes:The global shift towards a more Westernized diet, rich in processed foods and low in fiber, may play a role [34]. Such diets can affect gut motility and the microbiome, potentially triggering or exacerbating IBS symptoms [35]. Antibiotic usage:The overuse of antibiotics, especially during early life, can disrupt the gut microbiota. Disruption in the delicate balance of gut flora might predispose individuals to IBS [36]. Stress and mental health:Modern lifestyles, often characterized by high stress and an increased prevalence of anxiety and depression, can be significant triggers for IBS [37]. The gut-brain axis plays a vital role in IBS, with stressors potentially leading to gastrointestinal symptom onset or exacerbation [38]. Infections: Gastrointestinal infections, sometimes termed post-infectious IBS, can lead to the onset of IBS symptoms [39]. With global travel on the rise, there's increased exposure to diverse pathogens that might contribute to IBS development [40]. Urbanization: Rapid urbanization, with associated lifestyle changes, might influence the rise in IBS [41]. Factors include altered dietary habits, increased stress, and reduced physical activity [42]. Changes in gut microbiota: increased antibiotic usage, reduced exposure to diverse environments, and decreased early childhood microbial exposures may influence the gut microbiota's composition, potentially impacting IBS risk [43]. Research: The rise emphasizes the need for more research into understanding IBS's etiology, pathophysiology, and potential preventive strategies.
Global prevalence
Overall impact: The global prevalence of IBS varies widely, typically ranging between 9% and 23% of the population depending on the region [44]. Regional variability: Different regions present varied prevalence rates, with some of the highest rates often reported in the United States, the United Kingdom, and certain Asian countries. Diagnostic criteria influence: The prevalence rates are also influenced by the diagnostic criteria employed, with the Rome IV criteria being widely utilized in recent times [30].
Demographic and social aspects
Age: IBS is commonly diagnosed in individuals under the age of 50, although it can occur at any age [45]. The onset is typically young adulthood. Gender: A consistent observation across various studies is the higher prevalence of IBS in females compared to males, with reasons likely being multifactorial involving biological, social, and psychological factors [46]. Socioeconomic status: Some studies have indicated a potential link between lower socioeconomic status and higher IBS prevalence, though this is not universally observed [47].
Risk factors and associated conditions
Psychological stress: There is a well-established connection between psychological stress and IBS onset and exacerbation [38]. Gastrointestinal infections: Post-infectious IBS (PI-IBS) is a recognized subtype that follows an episode of acute gastroenteritis [48]. Diet: Certain dietary components, such as FODMAPs (fermentable oligo-, di-, mono-saccharides, and polyols), have been implicated in triggering IBS symptoms in susceptible individuals [49]. Comorbidities: IBS often coexists with other functional disorders and psychiatric conditions like fibromyalgia and anxiety [50].
The pathophysiology of IBS
Altered gut motility: Motility Dysfunction: Discrepancies in gastrointestinal (GI) motility, including hypermotility and hypomotility, have been associated with IBS subtypes, IBS-D (diarrhea-predominant) and IBS-C (constipation-predominant) respectively [51]. Varying transit times and motility patterns influence stool consistency and frequency, embodying the divergent symptomatology seen among IBS subtypes. Visceral hypersensitivity:Sensation of Pain, IBS patients commonly exhibit visceral hypersensitivity, meaning a lowered threshold for pain or discomfort emanating from the GI tract [52]. An interplay of psychological factors and altered pain-signaling pathways might contribute to this amplified perception of visceral stimuli. Brain-gut axis dysregulation: Neurological Connections: The bidirectional communication between the gut and brain, mediated via neural, endocrine, and immune pathways, is pivotal for maintaining gastrointestinal homeostasis [15, 53]. Low-grade inflammation: Evidence has hinted at subtle, low-grade inflammation in the intestines of IBS patients, potentially emanating from an aberrant immune response. This inflammation might influence gut function and structure, thereby participating in the symptomatology of IBS. Gut microbiota dysbiosis and microbial community: The gut microbiota, influential in metabolic, immune, and barrier functions, has been spotlighted in IBS research. IBS patients often demonstrate altered gut microbial compositions (dysbiosis), which might influence gut function and immune responses, although causation remains to be definitively established [54, 55]. Genetic and epigenetic factors:Recent research has hinted at potential genetic predispositions to IBS, involving genes related to pain perception, inflammation, and stress responses. Epigenetic modifications, influenced by environmental factors, might also play a role in modulating IBS risk and its phenotypic expression [56]. Psychological factors: Psychological stress and mental health conditions are frequently intertwined with IBS and can potentially influence its onset and severity through mechanisms like stress-induced gut permeability and motility changes [57].
Nutritional implications
While IBS is often viewed in the context of its impact on quality of life and its symptomatology, it's important to recognize the potential nutritional implications of the disorder. Specifically, patients with IBS may be at an increased risk for micronutrient deficiencies. Multiple Factors Contributing to Micronutrient Deficiencies: Altered diet: Patients with IBS often modify their diet to avoid foods that trigger symptoms [58]. Such dietary restrictions can inadvertently lead to the exclusion of nutrient-rich foods, subsequently increasing the risk of micronutrient deficiencies. Malabsorption: In certain subtypes of IBS, particularly IBS-D (diarrhea predominant), the rapid transit of food can reduce the time available for the absorption of nutrients [59]. Intestinal inflammation: Although IBS is not primarily an inflammatory condition like Inflammatory Bowel Disease (IBD), some patients may exhibit low-grade inflammation, which can impair nutrient absorption [60]. Alteration in gut microbiota: The gut microbiota plays a role in the metabolism and absorption of certain nutrients [55]. IBS patients often have dysbiosis or an imbalance in their gut flora, which can affect the absorption and synthesis of certain micronutrients [54].
Several micronutrients have been studied in the context of IBS, with serum levels providing insights into their status in patients. Vitamin D: Vitamin D has a role in immune modulation and intestinal health. Its deficiency has been linked with several gastrointestinal disorders, including IBS. A notable number of studies have reported decreased serum vitamin D levels in IBS patients compared to controls [61]. The exact implications and causes (whether it's due to dietary habits, malabsorption, or reduced sun exposure) are still under research. Folate: Folate plays a role in DNA synthesis and repair. Folate deficiencies, although less commonly reported than vitamin D or B12 deficiencies, have been observed in some IBS populations. The cause often ties back to reduced intake of folate-rich foods or malabsorption [62]. Vitamin B12: Vitamin B12 is crucial for neurological function and red blood cell formation. Some IBS patients, particularly those on specific dietary restrictions or with malabsorption issues, may exhibit decreased serum vitamin B12 levels [62]. However, the data remains inconsistent, and not all IBS patients show this trend.
Therapeutic approaches
Dietary modifications: A low FODMAP (Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols) diet is often recommended. This involves eliminating certain carbohydrates that are difficult to digest and can ferment in the gut, leading to symptoms [8]. Regular exercise: Physical activity can improve gut motility and reduce stress, both of which can relieve IBS symptoms [63]. Stress management: Stress exacerbates IBS symptoms, so techniques such as mindfulness, deep breathing, and yoga may help [64]. Medication:antispasmodics, laxatives, antidiarrheals, and antibiotics [44]. Psychological treatments: Cognitive Behavioral Therapy (CBT): CBT has been shown to help manage the psychological aspects of IBS, such as stress and anxiety, which often exacerbate physical symptoms [65]. Probiotics: The use of beneficial bacteria can restore gut flora balance, though scientific backing is still inconclusive [66]. Herbal treatments: Peppermint oil, chamomile, and other herbal remedies have shown promise in small studies, but more research is needed [67]. Fecal microbiota transplant (FMT): This is still in the experimental phase but aims to reset the gut microbiota by introducing a healthy donor’s fecal matter [68]. Serotonin modulators: As serotonin plays a role in gut motility, medications that act on serotonin receptors are being investigated [69].
Emerging medications
The pharmaceutical landscape for IBS is rapidly evolving, with a focus on targeted therapies that address the underlying mechanisms of the disease rather than just treating symptoms. As research progresses, it is expected that these new agents will go through more rigorous clinical trials to confirm their efficacy and safety. It's an exciting time in the realm of IBS treatment, and these new medications could potentially revolutionize how the disorder is managed.
Eluxadoline: This mixed μ-opioid receptor agonist and δ-opioid receptor antagonist have been approved for the treatment of IBS-D (diarrhea-predominant IBS) [70]. It aims to regulate bowel movements and reduce abdominal pain. Tenapanor: An inhibitor of the sodium-hydrogen exchanger NHE3, tenapanor reduces water secretion in the bowel, offering promise for patients with IBS-C (constipation-predominant IBS) [71]. Asimadoline: This kappa-opioid receptor agonist has shown promise in Phase II trials for reducing visceral pain without impacting normal bowel function [72]. Linaclotide and plecanatide: These drugs are guanylate cyclase agonists that are used for IBS-C. They not only increase fluid secretion in the gut to alleviate constipation but also have the potential to reduce visceral pain [73].
CONCLUSION
Irritable Bowel Syndrome is not merely a gastrointestinal disorder; it is a condition that permeates all aspects of a person's life. The physical symptoms, coupled with the emotional and social challenges it presents, can significantly reduce the quality of life for those affected. Recognizing the holistic impact of IBS is crucial for healthcare providers and society at large to provide better support and understanding to individuals dealing with this chronic condition. Cultivating a thorough knowledge of its epidemiology aids healthcare professionals and policymakers in devising targeted strategies for prevention, management, and support mechanisms, thereby ameliorating the impact of IBS on affected individuals. Future research can deepen our understanding of how factors such as genetics, gut microbiome, and environmental exposures influence IBS prevalence and guide novel interventions.
ACKNOWLEDGMENTS : The authoracknowledges the InternalMedicineDepartment, College of Medicine, University of Ha'il, Ha'il, KSA for theircooperation
CONFLICT OF INTEREST : None
FINANCIAL SUPPORT : None
ETHICS STATEMENT : None
1. Mearin F, Lacy B, Chang L, Chey W, Lembo A, Simren M. Functional bowel disorders. Gas Troenterol. 2016. Press.
2. Bek S, Teo YN, Tan XH, Fan KH, Siah KT. Association between irritable bowel syndrome and micronutrients: A systematic review. J GastroenterolHepatol. 2022;37(8):1485-97.
3. Chey WD, Kurlander J, Eswaran SJJ. Irritable bowel syndrome: a clinical review. JAMA. 2015;313(9):949-58.
4. Sperber AD, Bangdiwala SI, Drossman DA, Ghoshal UC, Simren M, Tack J, et al. Worldwide prevalence and burden of functional gastrointestinal disorders, results of Rome Foundation Global Study. Gastroenterology. 2021;160(1):99-114.
5. Weaver KR, Melkus GD, Henderson WA. Irritable Bowel Syndrome. Am J Nurs. 2017;117(6):48-55.
6. Mönnikes H. Quality of life in patients with irritable bowel syndrome. J ClinGastroenterol. 2011;45 Suppl:S98-101.
7. Canavan C, West J, Card T. The epidemiology of irritable bowel syndrome. ClinEpidemiol. 2014:71-80.
8. Saha L. Irritable bowelsyndrome:pathogenesis, diagnosis, treatment, and evidence-basedmedicine. World J Gastroenterol. 2014;20(22):6759.
9. Drossman DA. Functional gastrointestinal disorders: history, pathophysiology, clinical features, and Rome IV. Gastroenterology. 2016;150(6):1262-79.
10. Lee YJ, Park KS. Irritable bowel syndrome: emerging paradigm in pathophysiology. World J Gastroenterol. 2014;20(10):2456-69.
11. Simrén M, Tack J. New treatments and therapeutic targets for IBS and other functional bowel disorders. Nat Rev GastroenterolHepatol. 2018;15(10):589-605.
12. Black CJ, Thakur ER, Houghton LA, Quigley EMM, Moayyedi P, Ford AC. Efficacy of psychological therapies for irritable bowel syndrome: systematic review and network meta-analysis. Gut. 2020;69(8):1441-51.
13. Lacy BE, Patel NK. Rome Criteria and a Diagnostic Approach to Irritable Bowel Syndrome. J Clin Med. 2017;6(11):99.
14. Mayer EA, Ryu HJ, Bhatt RR. The neurobiology of irritable bowel syndrome. Mol Psychiatry. 2023;28(4):1451-65.
15. Tang HY, Jiang AJ, Wang XY, Wang H, Guan YY, Li F, et al. Uncovering the pathophysiology of irritable bowel syndrome by exploring the gut-brain axis: a narrative review. Ann Transl Med. 2021;9(14):1187.
16. Baj A, Moro E, Bistoletti M, Orlandi V, Crema F, Giaroni C. Glutamatergic Signaling Along the Microbiota-Gut-Brain Axis. Int J Mol Sci. 2019;20(6):1482.
17. Camilleri M. Diagnosis and Treatment of Irritable Bowel Syndrome: A Review. JAMA. 2021;325(9):865-77.
18. Ng QX, Soh AYS, Loke W, Lim DY, Yeo WS. The role of inflammation in irritable bowel syndrome (IBS). J Inflamm Res. 2018;11:345-9.
19. Ahluwalia B, Iribarren C, Magnusson MK, Sundin J, Clevers E, Savolainen O, et al. A Distinct Faecal Microbiota and Metabolite Profile Linked to Bowel Habits in Patients with Irritable Bowel Syndrome. Cells. 2021;10(6):1459.
20. Simrén M, Törnblom H, Palsson OS, Van Oudenhove L, Whitehead WE, Tack J. Cumulative Effects of Psychologic Distress, Visceral Hypersensitivity, and Abnormal Transit on Patient-reported Outcomes in Irritable Bowel Syndrome. Gastroenterology. 2019;157(2):391-402.
21. Schaper SJ, Stengel A. Emotional stress responsivity of patients with IBS - a systematic review. J Psychosom Res. 2022;153:110694.
22. Barandouzi ZA, Lee J, Del Carmen Rosas M, Chen J, Henderson WA, Starkweather AR, et al. Associations of neurotransmitters and the gut microbiome with emotional distress in mixed type of irritable bowel syndrome. Sci Rep. 2022;12(1):1648.
23. Ali A, Weiss TR, McKee D, Scherban A, Khan S, Fields MR, et al. Efficacy of individualised diets in patients with irritable bowel syndrome: a randomised controlled trial. BMJ Open Gastroenterol. 2017;4(1):e000164.
24. Rej A, Aziz I, Tornblom H, Sanders DS, Simrén M. The role of diet in irritable bowel syndrome: implications for dietary advice. J Intern Med. 2019;286(5):490-502.
25. Whelan K, Martin LD, Staudacher HM, Lomer MCE. The low FODMAP diet in the management of irritable bowel syndrome: an evidence-based review of FODMAP restriction, reintroduction and personalisation in clinical practice. J HumNutr Diet. 2018;31(2):239-55.
26. Hod K, Melamed S, Dekel R, Maharshak N, Sperber AD. Burnout, but not job strain, is associated with irritable bowel syndrome in working adults. J Psychosom Res. 2020;134:110121.
27. Benitez-Rexach AM. Mediators Between Job Stress and Health Quality of Life Among Adults with Irritable Bowel Syndrome (Doctoral dissertation, Walden University). 2023.
28. Goodoory VC, Ng CE, Black CJ, Ford AC. Direct healthcare costs of Rome IV or Rome III-defined irritable bowel syndrome in the United Kingdom. Aliment PharmacolTher. 2022;56(1):110-20.
29. Tack J, Stanghellini V, Mearin F, Yiannakou Y, Layer P, Coffin B, et al. Economic burden of moderate to severe irritable bowel syndrome with constipation in six European countries. BMC Gastroenterol. 2019;19:1-3.
30. Oka P, Parr H, Barberio B, Black CJ, Savarino EV, Ford AC. Global prevalence of irritable bowel syndrome according to Rome III or IV criteria: a systematic review and meta-analysis. Lancet GastroenterolHepatol. 2020;5(10):908-17.
31. El-Salhy M, Patcharatrakul T, Gonlachanvit S. The role of diet in the pathophysiology and management of irritable bowel syndrome. Indian J Gastroenterol. 2021;40:111-9.
32. Elhosseiny D, Mahmoud NE, Manzour AF. Factors associated with irritable bowel syndrome among medical students at Ain Shams University. J Egypt Public Health Assoc. 2019;94:1-9.
33. Black CJ, Craig O, Gracie DJ, Ford AC. Comparison of the Rome IV criteria with the Rome III criteria for the diagnosis of irritable bowel syndrome in secondary care. Gut. 2021;70(6):1110-6.
34. Barber TM, Kabisch S, Pfeiffer AF, Weickert MO. The health benefits of dietary fibre. Nutrients. 2020;12(10):3209.
35. Schnedl WJ, Michaelis S, Mangge H, Enko D. A personalized management approach in disorders of the irritable bowel syndrome spectrum. ClinNutr ESPEN. 2023.
36. Zhou G, Huang M, Yu X, Zhang N, Tao S, Zhang M. Early life adverse exposures in irritable bowel syndrome: new insights and opportunities. Front Pediatr. 2023;11:1241801.
37. Jamalizadeh H, Ahmadi B, Setayesh M, Sharififar F, Ansari M, Shahesmaelli A, et al. Lifestyle and Health promotional Guidelines in Irritable Bowel Syndrome Patients from the Viewpoint of Persian Medicine. CurrTradit Med. 2021;7(4):478-81.
38. Labanski A, Langhorst J, Engler H, Elsenbruch S. Stress and the brain-gut axis in functional and chronic-inflammatory gastrointestinal diseases: A transdisciplinary challenge. Psychoneuroendocrinology. 2020;111:104501.
39. SvendsenAT, Bytzer P, Engsbro AL. Systematic review with meta-analyses: does the pathogen matter in post-infectious irritable bowel syndrome? Scand J Gastroenterol. 2019;54(5):546-62.
40. Ghoshal UC. Postinfection Irritable Bowel Syndrome. Gut Liver. 2022;16(3):331-40.
41. Zuo T, Kamm MA, Colombel JF, Ng SC. Urbanization and the gut microbiota in health and inflammatory bowel disease. Nat Rev GastroenterolHepatol. 2018;15(7):440-52.
42. Hajishafiee M, Keshteli AH, Saneei P, Feinle-Bisset C, Esmaillzadeh A, Adibi P. Healthy lifestyle score and irritable bowel syndrome: A cross-sectional study in adults. NeurogastroenterolMotil. 2020;32(5):e13793.
43. Vich Vila A, Imhann F, Collij V, Jankipersadsing SA, Gurry T, Mujagic Z, et al. Gut microbiota composition and functional changes in inflammatory bowel disease and irritable bowel syndrome. SciTransl Med. 2018;10(472):eaap8914.
44. Oświęcimska J, Szymlak A, Roczniak W, Girczys-Połedniok K, Kwiecień J. New insights into the pathogenesis and treatment of irritable bowel syndrome. Adv Med Sci. 2017;62(1):17-30.
45. Lovell RM, Ford AC. Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis. ClinGastroenterolHepatol. 2012;10(7):712-21.
46. Lovell RM, Ford AC. Effect of gender on prevalence of irritable bowel syndrome in the community:systematicreview and meta-analysis. Am J Gastroenterol. 2012;107(7):991-1000.
47. Silvernale C, Kuo B, Staller K. Lowersocioeconomicstatusisassociatedwith an increasedprevalence of comorbidanxiety and depressionamong patients with irritable bowelsyndrome:resultsfrom a multicentercohort. Scand J Gastroenterol. 2019;54(9):1070-4.
48. Lee YY, Annamalai C, Rao SSC. Post-Infectious Irritable Bowel Syndrome. CurrGastroenterol Rep. 2017;19(11):56.
49. Bellini M, Tonarelli S, Mumolo MG, Bronzini F, Pancetti A, Bertani L, et al. Low Fermentable Oligo- Di- and Mono-Saccharides and Polyols (FODMAPs) or Gluten Free Diet: What Is Best for Irritable Bowel Syndrome? Nutrients. 2020;12(11):3368.
50. Hausteiner-Wiehle C, Henningsen P. Irritable bowel syndrome: relations with functional, mental, and somatoform disorders. World J Gastroenterol. 2014;20(20):6024-30.
51. Gasbarrini A, Lauritano EC, Garcovich M, Sparano L, Gasbarrini G. New insights into the pathophysiology of IBS: intestinal microflora, gas production and gut motility. Eur Rev Med Pharmacol Sci. 2008;12 Suppl 1:111-7.
52. Kanazawa M, Hongo M, Fukudo S. Visceral hypersensitivity in irritable bowel syndrome. J GastroenterolHepatol. 2011;26 Suppl 3:119-21.
53. Holtmann GJ, Ford AC, Talley NJ. Pathophysiology of irritable bowel syndrome. Lancet GastroenterolHepatol. 2016;1(2):133-46.
54. Sciavilla P, Strati F, Di Paola M, Modesto M, Vitali F, Cavalieri D, et al. Gut microbiota profiles and characterization of cultivable fungal isolates in IBS patients. ApplMicrobiolBiotechnol. 2021;105:3277-88.
55. Chassard C, Dapoigny M, Scott KP, Crouzet L, Del'Homme C, Marquet P, et al. Functional dysbiosis within the gut microbiota of patients with constipated‐irritable bowel syndrome. Aliment PharmacolTher. 2012;35(7):828-38.
56. Mahurkar-Joshi S, Chang L. Epigeneticmechanisms in irritable bowel syndrome. Front Psychiatry. 2020;11:805.
57. Fircak M. Assessment of mental health in patients with irritable bowel syndrome. Gastroenterology. 2021;55(4):252-7.
58. Chey WD, Keefer L, Whelan K, Gibson PR. Behavioral and diet therapies in integrated care for patients with irritable bowel syndrome. Gastroenterology. 2021;160(1):47-62.
59. Jansson-Knodell CL, White M, Lockett C, Xu H, Shin A. Associations of food intolerance with irritable bowel syndrome, psychological symptoms, and quality of life. ClinGastroenterolHepatol. 2022;20(9):2121-31.
60. Uno Y. Hypothesis: mechanism of irritable bowel syndrome in inflammatory bowel disease. Med Hypotheses. 2019;132:109324.
61. Linsalata M, Riezzo G, Orlando A, D’Attoma B, Prospero L, Tutino V, et al. The relationshipbetweenlowserumvitamin D levels and altered intestinal barrierfunction in patients with IBS diarrhoeaundergoing a long-termlow-FODMAP diet:novel observations from a clinical trial. Nutrients. 2021;13(3):1011.
62. Roth B, Larsson E, Ohlsson B. Poor intake of vitamins and mineralsisassociatedwithsymptomsamong patients with irritable bowel syndrome. J GastroenterolHepatol. 2022;37(7):1253-62.
63. Zhou C, Zhao E, Li Y, Jia Y, Li F. Exercisetherapy of patients with irritable bowelsyndrome: A systematicreview of randomizedcontrolled trials. NeurogastroenterolMotil. 2019;31(2):e13461.
64. Shah K, Ramos-Garcia M, Bhavsar J, Lehrer P. Mind-body treatments of irritable bowel syndrome symptoms: An updatedmeta-analysis. BehavResTher. 2020;128:103462.
65. Jacobs JP, Gupta A, Bhatt RR, Brawer J, Gao K, Tillisch K, et al. Cognitive behavioraltherapy for irritable bowel syndrome inducesbidirectionalalterations in the brain-gut-microbiome axis associatedwithgastrointestinalsymptomimprovement. Microbiome. 2021;9(1):1-4.
66. Dahiya D, Nigam PS. BiotherapyUsingProbiotics as Therapeutic Agents to Restore the Gut Microbiota to RelieveGastrointestinal Tract Inflammation, IBD, IBS and Prevent Induction of Cancer. Int J Mol Sci. 2023;24(6):5748.
67. Nee J, Ballou S, Kelley JM, Kaptchuk TJ, Hirsch W, Katon J, et al. Peppermint oiltreatment for irritable bowelsyndrome: a randomized placebo-controlled trial. Am J Gastroenterol. 2021;116(11):2279-85.
68. Xu D, Chen VL, Steiner CA, Berinstein JA, Eswaran S, Waljee AK, et al. Efficacy of fecalmicrobiota transplantation in irritable bowelsyndrome:asystematicreview and meta-analysis. Am J Gastroenterol. 2019;114(7):1043.
69. Tack J, Broekaert D, Fischler B, Van Oudenhove L, Gevers AM, Janssens J. A controlledcrossoverstudy of the selectiveserotoninreuptakeinhibitorcitalopram in irritable bowel syndrome. Gut. 2006;55(8):1095-103.
70. Lembo AJ, Lacy BE, Zuckerman MJ, Schey R, Dove LS, Andrae DA, et al. Eluxadoline for irritable bowel syndrome withdiarrhea. N Engl J Med. 2016;374(3):242-53.
71. Markham A. Tenapanor: first approval. Drugs. 2019;79(17):1897-903.
72. Camilleri M. Novelpharmacology:asimadoline, a κ‐opioidagonist, and visceral sensation. NeurogastroenterolMotil. 2008;20(9):971-9.
73. Shah ED, Kim HM, Schoenfeld P. Efficacy and tolerability of guanylatecyclase-C agonists for irritable bowel syndrome with constipation and chronicidiopathicconstipation:asystematicreview and meta-analysis. Am J Gastroenterol. 2018;113(3):329.