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New treatments and therapeutic targets for IBS and other functional bowel disorders

Abstract

Functional bowel disorders (FBDs) are a spectrum of disorders characterized by combinations of symptoms attributable to the lower gastrointestinal tract. Most current first-line therapies for IBS and other FBDs target the predominant symptom and mainly affect one symptom in the symptom complex. Additional broadly effective treatment alternatives targeting the entire symptom complex are needed. New drugs for FBDs (such as lubiprostone, linaclotide, plecanatide, prucalopride, eluxadoline and rifaximin) target key mechanisms in the pathophysiology of these disorders and improve both the abnormal bowel habit and other key symptoms, such as abdominal pain and bloating. The current development of new treatment alternatives is focusing on different aspects of the complex pathophysiology of IBS and other FBDs: gut microenvironment (via diet and modulation of gut microbiota), enterohepatic circulation of bile acids, gastrointestinal secretion, motility and sensation, gut–brain interactions, gut barrier function and the immune system within the gastrointestinal tract. Studies also suggest that personalized treatment of IBS and other FBDs is possible using various diagnostic markers.

Key points

  • Treatment options for functional bowel disorders (FBDs) target key pathophysiological factors along the gut–brain axis, including altered gastrointestinal motility, visceral hypersensitivity, increased intestinal permeability, immune activation and altered gut microbiota.

  • Current first-line therapies for IBS and other FBDs mainly affect one symptom in the symptom complex, which is an inherent limitation.

  • New drugs for FBDs target key pathophysiological mechanisms and differ from current therapies by improving the abnormal bowel habit as well as other symptoms, such as abdominal pain and bloating.

  • Gut luminal factors, such as food, microbiota and bile acids, and their interaction with each other and the host might be important for symptom generation in at least a subset of patients with FBDs.

  • Treatments affecting gastrointestinal motility and sensitivity, as well as gut barrier function, are promising; medical foods have also been tested in small trials in IBS, with a good safety profile and some efficacy.

  • Personalized treatment strategies for patients with FBDs, based on various diagnostic markers, seem possible in the not so distant future.

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Fig. 1: The pathophysiology of functional bowel disorders.
Fig. 2: Symptom generation after intake of foods rich in fermentable oligosaccharides, disaccharides, monosaccharides and polyols.
Fig. 3: The enterohepatic circulation of bile acids.
Fig. 4: Mechanisms of action of agents used for treatment of IBS-D and functional diarrhoea.
Fig. 5: Mechanisms of action of agents used for treatment of IBS-C and chronic constipation.

References

  1. 1.

    Lacy, B. E. et al. Bowel disorders. Gastroenterology 150, 1393–1407 (2016).

    Google Scholar 

  2. 2.

    Ford, A. C. et al. Characteristics of functional bowel disorder patients: a cross-sectional survey using the Rome III criteria. Aliment. Pharmacol. Ther. 39, 312–321 (2014).

    CAS  PubMed  Google Scholar 

  3. 3.

    Wong, R. K. et al. Inability of the Rome III criteria to distinguish functional constipation from constipation-subtype irritable bowel syndrome. Am. J. Gastroenterol. 105, 2228–2234 (2010).

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Canavan, C., West, J. & Card, T. The epidemiology of irritable bowel syndrome. Clin. Epidemiol. 6, 71–80 (2014).

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Lovell, R. M. & Ford, A. C. Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis. Clin. Gastroenterol. Hepatol. 10, 712–721 (2012).

    PubMed  Google Scholar 

  6. 6.

    Sperber, A. D. et al. The global prevalence of IBS in adults remains elusive due to the heterogeneity of studies: a Rome foundation working team literature review. Gut 66, 1075–1082 (2017).

    PubMed  Google Scholar 

  7. 7.

    Locke, G. R. 3rd, Zinsmeister, A. R., Talley, N. J., Fett, S. L. & Melton, L. J. 3rd. Familial association in adults with functional gastrointestinal disorders. Mayo Clin. Proc. 75, 907–912 (2000).

    PubMed  Google Scholar 

  8. 8.

    Hungin, A. P., Whorwell, P. J., Tack, J. & Mearin, F. The prevalence, patterns and impact of irritable bowel syndrome: an international survey of 40,000 subjects. Aliment. Pharmacol. Ther. 17, 643–650 (2003).

    CAS  PubMed  Google Scholar 

  9. 9.

    Peery, A. F. et al. Burden of gastrointestinal, liver, and pancreatic diseases in the United States. Gastroenterology 149, 1731–1741 (2015).

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Whitehead, W. E., Palsson, O. & Jones, K. R. Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications? Gastroenterology 122, 1140–1156 (2002).

    PubMed  Google Scholar 

  11. 11.

    Longstreth, G. F. & Yao, J. F. Irritable bowel syndrome and surgery: a multivariable analysis. Gastroenterology 126, 1665–1673 (2004).

    PubMed  Google Scholar 

  12. 12.

    Chang, J. Y. et al. Impact of functional gastrointestinal disorders on survival in the community. Am. J. Gastroenterol. 105, 822–832 (2010).

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Simren, M., Tornblom, H., Palsson, O. S. & Whitehead, W. E. Management of the multiple symptoms of irritable bowel syndrome. Lancet Gastroenterol. Hepatol. 2, 112–122 (2017).

    PubMed  Google Scholar 

  14. 14.

    Manabe, N. et al. Lower functional gastrointestinal disorders: evidence of abnormal colonic transit in a 287 patient cohort. Neurogastroenterol Motil. 22, 293–e82 (2010).

    CAS  PubMed  Google Scholar 

  15. 15.

    Tornblom, H. et al. Colonic transit time and IBS symptoms: what’s the link? Am. J. Gastroenterol. 107, 754–760 (2012).

    PubMed  Google Scholar 

  16. 16.

    Simren, M. et al. Visceral hypersensitivity is associated with GI symptom severity in functional GI disorders: consistent findings from five different patient cohorts. Gut 67, 255–262 (2018).

    PubMed  Google Scholar 

  17. 17.

    Bednarska, O. et al. VIP and mast cells regulate increased passage of colonic bacteria in patients with irritable bowel syndrome. Gastroenterology 153, 948–960 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Ohman, L., Tornblom, H. & Simren, M. Crosstalk at the mucosal border: importance of the gut microenvironment in IBS. Nat. Rev. Gastroenterol. Hepatol. 12, 36–49 (2015).

    PubMed  Google Scholar 

  19. 19.

    Tap, J. et al. Identification of an intestinal microbiota signature associated with severity of irritable bowel syndrome. Gastroenterology 152, 111–123 (2017).

    PubMed  Google Scholar 

  20. 20.

    Drossman, D. A. et al. A prospective assessment of bowel habit in irritable bowel syndrome in women: defining an alternator. Gastroenterology 128, 580–589 (2005).

    PubMed  Google Scholar 

  21. 21.

    Engsbro, A. L., Simren, M. & Bytzer, P. Short-term stability of subtypes in the irritable bowel syndrome: prospective evaluation using the Rome III classification. Aliment. Pharmacol. Ther. 35, 350–359 (2012).

    CAS  PubMed  Google Scholar 

  22. 22.

    Awouters, F. et al. Loperamide. survey of studies on mechanism of its antidiarrheal activity. Dig. Dis. Sci. 38, 977–995 (1993).

    CAS  PubMed  Google Scholar 

  23. 23.

    Cann, P. A., Read, N. W., Holdsworth, C. D. & Barends, D. Role of loperamide and placebo in management of irritable bowel syndrome (IBS). Dig. Dis. Sci. 29, 239–247 (1984).

    CAS  PubMed  Google Scholar 

  24. 24.

    Ford, A. C. et al. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am. J. Gastroenterol. 109 (Suppl. 1), S2–26, quiz S27 (2014).

    PubMed  Google Scholar 

  25. 25.

    Bijkerk, C. J. et al. Soluble or insoluble fibre in irritable bowel syndrome in primary care? Randomised placebo controlled trial. BMJ 339, b3154 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    McRorie, J. W. Jr & McKeown, N. M. Understanding the physics of functional fibers in the gastrointestinal tract: an evidence-based approach to resolving enduring misconceptions about insoluble and soluble fiber. J. Acad. Nutr. Diet 117, 251–264 (2017).

    PubMed  Google Scholar 

  27. 27.

    Muller-Lissner, S. Pharmacokinetic and pharmacodynamic considerations for the current chronic constipation treatments. Expert Opin. Drug Metab. Toxicol. 9, 391–401 (2013).

    PubMed  Google Scholar 

  28. 28.

    Belsey, J. D., Geraint, M. & Dixon, T. A. Systematic review and meta analysis: polyethylene glycol in adults with non-organic constipation. Int. J. Clin. Pract. 64, 944–955 (2010).

    CAS  PubMed  Google Scholar 

  29. 29.

    Chapman, R. W., Stanghellini, V., Geraint, M. & Halphen, M. Randomized clinical trial: macrogol/PEG 3350 plus electrolytes for treatment of patients with constipation associated with irritable bowel syndrome. Am. J. Gastroenterol. 108, 1508–1515 (2013).

    CAS  PubMed  Google Scholar 

  30. 30.

    Annahazi, A., Roka, R., Rosztoczy, A. & Wittmann, T. Role of antispasmodics in the treatment of irritable bowel syndrome. World J. Gastroenterol. 20, 6031–6043 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Ford, A. C. et al. Effect of fibre, antispasmodics, and peppermint oil in the treatment of irritable bowel syndrome: systematic review and meta-analysis. BMJ 337, a2313 (2008).

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Camilleri, M. & Boeckxstaens, G. Dietary and pharmacological treatment of abdominal pain in IBS. Gut 66, 966–974 (2017).

    CAS  PubMed  Google Scholar 

  33. 33.

    Tack, J., Fried, M., Houghton, L. A., Spicak, J. & Fisher, G. Systematic review: the efficacy of treatments for irritable bowel syndrome—a European perspective. Aliment. Pharmacol. Ther. 24, 183–205 (2006).

    CAS  PubMed  Google Scholar 

  34. 34.

    Hills, J. M. & Aaronson, P. I. The mechanism of action of peppermint oil on gastrointestinal smooth muscle. An analysis using patch clamp electrophysiology and isolated tissue pharmacology in rabbit and guinea pig. Gastroenterology 101, 55–65 (1991).

    CAS  PubMed  Google Scholar 

  35. 35.

    Galeotti, N., Di Cesare Mannelli, L., Mazzanti, G., Bartolini, A. & Ghelardini, C. Menthol: a natural analgesic compound. Neurosci. Lett. 322, 145–148 (2002).

    CAS  PubMed  Google Scholar 

  36. 36.

    Juergens, U. R., Stober, M. & Vetter, H. The anti-inflammatory activity of L-menthol compared to mint oil in human monocytes in vitro: a novel perspective for its therapeutic use in inflammatory diseases. Eur. J. Med. Res. 3, 539–545 (1998).

    CAS  PubMed  Google Scholar 

  37. 37.

    Walstab, J. et al. Natural compounds boldine and menthol are antagonists of human 5-HT3 receptors: implications for treating gastrointestinal disorders. Neurogastroenterol Motil. 26, 810–820 (2014).

    CAS  PubMed  Google Scholar 

  38. 38.

    Liu, B. et al. TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain. Pain 154, 2169–2177 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Khanna, R., MacDonald, J. K. & Levesque, B. G. Peppermint oil for the treatment of irritable bowel syndrome: a systematic review and meta-analysis. J. Clin. Gastroenterol. 48, 505–512 (2014).

    PubMed  Google Scholar 

  40. 40.

    Drossman, D. A. et al. Neuromodulators for functional gastrointestinal disorders (disorders of gut-brain interaction): a Rome foundation working team report. Gastroenterology 154, 1140–1171 e1141 (2018).

    PubMed  Google Scholar 

  41. 41.

    Ford, A. C. et al. Effect of antidepressants and psychological therapies, including hypnotherapy, in irritable bowel syndrome: systematic review and meta-analysis. Am. J. Gastroenterol. 109, 1350–1365 (2014).

    CAS  PubMed  Google Scholar 

  42. 42.

    Gorard, D. A., Libby, G. W. & Farthing, M. J. Influence of antidepressants on whole gut and orocaecal transit times in health and irritable bowel syndrome. Aliment. Pharmacol. Ther. 8, 159–166 (1994).

    CAS  PubMed  Google Scholar 

  43. 43.

    Morgan, V., Pickens, D., Gautam, S., Kessler, R. & Mertz, H. Amitriptyline reduces rectal pain related activation of the anterior cingulate cortex in patients with irritable bowel syndrome. Gut 54, 601–607 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Poitras, P., Riberdy Poitras, M., Plourde, V., Boivin, M. & Verrier, P. Evolution of visceral sensitivity in patients with irritable bowel syndrome. Dig. Dis. Sci. 47, 914–920 (2002).

    PubMed  Google Scholar 

  45. 45.

    Van Oudenhove, L. et al. Biopsychosocial aspects of functional gastrointestinal disorders. Gastroenterology 150, 1355–1367 (2016).

    Google Scholar 

  46. 46.

    Tornblom, H. & Drossman, D. A. Centrally targeted pharmacotherapy for chronic abdominal pain. Neurogastroenterol Motil. 27, 455–467 (2015).

    CAS  PubMed  Google Scholar 

  47. 47.

    O’Leary, O. F. & Cryan, J. F. A ventral view on antidepressant action: roles for adult hippocampal neurogenesis along the dorsoventral axis. Trends Pharmacol. Sci. 35, 675–687 (2014).

    PubMed  Google Scholar 

  48. 48.

    Laird, K. T., Tanner-Smith, E. E., Russell, A. C., Hollon, S. D. & Walker, L. S. Short-term and Long-term efficacy of psychological therapies for irritable bowel syndrome: a systematic review and meta-analysis. Clin. Gastroenterol. Hepatol. 14, 937–947 (2016).

    PubMed  Google Scholar 

  49. 49.

    Lackner, J. M. et al. Self-administered cognitive behavior therapy for moderate to severe irritable bowel syndrome: clinical efficacy, tolerability, feasibility. Clin. Gastroenterol. Hepatol. 6, 899–906 (2008).

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Ljotsson, B. et al. Internet-delivered exposure-based treatment versus stress management for irritable bowel syndrome: a randomized trial. Am. J. Gastroenterol. 106, 1481–1491 (2011).

    PubMed  Google Scholar 

  51. 51.

    Moser, G. et al. Long-term success of GUT-directed group hypnosis for patients with refractory irritable bowel syndrome: a randomized controlled trial. Am. J. Gastroenterol. 108, 602–609 (2013).

    PubMed  Google Scholar 

  52. 52.

    Barbara, G. et al. The intestinal microenvironment and functional gastrointestinal disorders. Gastroenterology 150, 1305–1318 (2016).

    Google Scholar 

  53. 53.

    Lacy, B. E. The science, evidence, and practice of dietary interventions in irritable bowel syndrome. Clin. Gastroenterol. Hepatol. 13, 1899–1906 (2015).

    CAS  PubMed  Google Scholar 

  54. 54.

    Simren, M. et al. Intestinal microbiota in functional bowel disorders: a Rome foundation report. Gut 62, 159–176 (2013).

    PubMed  Google Scholar 

  55. 55.

    Bohn, L., Storsrud, S., Tornblom, H., Bengtsson, U. & Simren, M. Self-reported food-related gastrointestinal symptoms in IBS are common and associated with more severe symptoms and reduced quality of life. Am. J. Gastroenterol. 108, 634–641 (2013).

    PubMed  Google Scholar 

  56. 56.

    Le Neve, B. et al. A combined nutrient and lactulose challenge test allows symptom-based clustering of patients with irritable bowel syndrome. Am. J. Gastroenterol. 108, 786–795 (2013).

    PubMed  Google Scholar 

  57. 57.

    Posserud, I. et al. Symptom pattern following a meal challenge test in patients with irritable bowel syndrome and healthy controls. United European Gastroenterol. J. 1, 358–367 (2013).

    Google Scholar 

  58. 58.

    Spencer, M., Chey, W. D. & Eswaran, S. Dietary renaissance in IBS: has food replaced medications as a primary treatment strategy? Curr. Treat. Options Gastroenterol. 12, 424–440 (2014).

    PubMed  Google Scholar 

  59. 59.

    McKenzie, Y. A. et al. British Dietetic Association systematic review and evidence-based practice guidelines for the dietary management of irritable bowel syndrome in adults (2016 update). J. Hum. Nutr. Diet 29, 549–575 (2016).

    CAS  PubMed  Google Scholar 

  60. 60.

    Shepherd, S. J., Lomer, M. C. & Gibson, P. R. Short-chain carbohydrates and functional gastrointestinal disorders. Am. J. Gastroenterol. 108, 707–717 (2013).

    CAS  PubMed  Google Scholar 

  61. 61.

    Simren, M. Diet as a therapy for irritable bowel syndrome: progress at last. Gastroenterology 146, 10–12 (2014).

    PubMed  Google Scholar 

  62. 62.

    Staudacher, H. M., Irving, P. M., Lomer, M. C. & Whelan, K. Mechanisms and efficacy of dietary FODMAP restriction in IBS. Nat. Rev. Gastroenterol. Hepatol. 11, 256–266 (2014).

    CAS  PubMed  Google Scholar 

  63. 63.

    Shepherd, S. J., Parker, F. C., Muir, J. G. & Gibson, P. R. Dietary triggers of abdominal symptoms in patients with irritable bowel syndrome: randomized placebo-controlled evidence. Clin. Gastroenterol. Hepatol. 6, 765–771 (2008).

    CAS  PubMed  Google Scholar 

  64. 64.

    Halmos, E. P., Power, V. A., Shepherd, S. J., Gibson, P. R. & Muir, J. G. A diet low in FODMAPs reduces symptoms of irritable bowel syndrome. Gastroenterology 146, 67–75 (2014).

    CAS  PubMed  Google Scholar 

  65. 65.

    Staudacher, H. M. et al. Fermentable carbohydrate restriction reduces luminal bifidobacteria and gastrointestinal symptoms in patients with irritable bowel syndrome. J. Nutr. 142, 1510–1518 (2012).

    CAS  PubMed  Google Scholar 

  66. 66.

    Bohn, L. et al. Diet low in FODMAPs reduces symptoms of irritable bowel syndrome as well as traditional dietary advice: a randomized controlled trial. Gastroenterology 149, 1399–1407 (2015).

    PubMed  Google Scholar 

  67. 67.

    Eswaran, S. L., Chey, W. D., Han-Markey, T., Ball, S. & Jackson, K. A. Randomized controlled trial comparing the low FODMAP diet versus modified NICE guidelines in US adults with IBS-D. Am. J. Gastroenterol. 111, 1824–1832 (2016).

    CAS  PubMed  Google Scholar 

  68. 68.

    Krogsgaard, L. R., Lyngesen, M. & Bytzer, P. Systematic review: quality of trials on the symptomatic effects of the low FODMAP diet for irritable bowel syndrome. Aliment. Pharmacol. Ther. 45, 1506–1513 (2017).

    CAS  PubMed  Google Scholar 

  69. 69.

    Moayyedi, P. et al. The effect of dietary intervention on irritable bowel syndrome: a systematic review. Clin. Transl Gastroenterol. 6, e107 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Staudacher, H. M. et al. Diet low in FODMAPs reduces symptoms in patients with irritable bowel syndrome and probiotic restores bifidobacterium species: a randomized controlled trial. Gastroenterology 153, 936–947 (2017).

    CAS  PubMed  Google Scholar 

  71. 71.

    O’Keeffe, M. et al. Long-term impact of the low-FODMAP diet on gastrointestinal symptoms, dietary intake, patient acceptability, and healthcare utilization in irritable bowel syndrome. Neurogastroenterol. Motil. 30, e13154 (2017).

    Google Scholar 

  72. 72.

    Halmos, E. P. et al. Diets that differ in their FODMAP content alter the colonic luminal microenvironment. Gut 64, 93–100 (2015).

    CAS  PubMed  Google Scholar 

  73. 73.

    Biesiekierski, J. R. et al. Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am. J. Gastroenterol. 106, 508–514; quiz 515 (2011).

    CAS  PubMed  Google Scholar 

  74. 74.

    Biesiekierski, J. R. et al. No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates. Gastroenterology 145, 320–328 (2013).

    CAS  PubMed  Google Scholar 

  75. 75.

    Uhde, M. et al. Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease. Gut 65, 1930–1937 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Pimentel, M., Chow, E. J. & Lin, H. C. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am. J. Gastroenterol. 95, 3503–3506 (2000).

    CAS  PubMed  Google Scholar 

  77. 77.

    Posserud, I., Stotzer, P. O., Bjornsson, E. S., Abrahamsson, H. & Simren, M. Small intestinal bacterial overgrowth in patients with irritable bowel syndrome. Gut 56, 802–808 (2007).

    PubMed  Google Scholar 

  78. 78.

    Jalanka-Tuovinen, J. et al. Faecal microbiota composition and host-microbe cross-talk following gastroenteritis and in postinfectious irritable bowel syndrome. Gut 63, 1737–1745 (2014).

    PubMed  Google Scholar 

  79. 79.

    Pimentel, M., Chow, E. J. & Lin, H. C. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome. a double-blind, randomized, placebo-controlled study. Am. J. Gastroenterol. 98, 412–419 (2003).

    PubMed  Google Scholar 

  80. 80.

    Koo, H. L. & DuPont, H. L. Rifaximin: a unique gastrointestinal-selective antibiotic for enteric diseases. Curr. Opin. Gastroenterol. 26, 17–25 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Pimentel, M., Park, S., Mirocha, J., Kane, S. V. & Kong, Y. The effect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann. Intern. Med. 145, 557–563 (2006).

    PubMed  Google Scholar 

  82. 82.

    Sharara, A. I. et al. A randomized double-blind placebo-controlled trial of rifaximin in patients with abdominal bloating and flatulence. Am. J. Gastroenterol. 101, 326–333 (2006).

    CAS  PubMed  Google Scholar 

  83. 83.

    Pimentel, M. et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N. Engl. J. Med. 364, 22–32 (2011).

    CAS  PubMed  Google Scholar 

  84. 84.

    Lembo, A. et al. Repeat treatment with rifaximin is safe and effective in patients with diarrhea-predominant irritable bowel syndrome. Gastroenterology 151, 1113–1121 (2016).

    CAS  PubMed  Google Scholar 

  85. 85.

    Pimentel, M. et al. Repeat rifaximin for irritable bowel syndrome: no clinically significant changes in stool microbial antibiotic sensitivity. Dig. Dis. Sci. 62, 2455–2463 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Xu, D. et al. Rifaximin alters intestinal bacteria and prevents stress-induced gut inflammation and visceral hyperalgesia in rats. Gastroenterology 146, 484–496 (2014).

    CAS  PubMed  Google Scholar 

  87. 87.

    Hill, C. et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat. Rev. Gastroenterol. Hepatol. 11, 506–514 (2014).

    PubMed  Google Scholar 

  88. 88.

    Ford, A. C. et al. Efficacy of prebiotics, probiotics, and synbiotics in irritable bowel syndrome and chronic idiopathic constipation: systematic review and meta-analysis. Am. J. Gastroenterol. 109, 1547–1561; quiz 1546 (2014).

    PubMed  Google Scholar 

  89. 89.

    Hungin, A. P. S. et al. Systematic review: probiotics in the management of lower gastrointestinal symptoms - an updated evidence-based international consensus. Aliment. Pharmacol. Ther. 47, 1054–1070 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Quigley, E. M. Probiotics in irritable bowel syndrome: the science and the evidence. J. Clin. Gastroenterol. 49 (Suppl. 1), S60–S64 (2015).

    CAS  PubMed  Google Scholar 

  91. 91.

    Tillisch, K. et al. Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology 144, 1394–1401 (2013).

    CAS  PubMed  Google Scholar 

  92. 92.

    Pinto-Sanchez, M. I. et al. Probiotic bifidobacterium longum NCC3001 reduces depression scores and alters brain activity: a pilot study in patients with irritable bowel syndrome. Gastroenterology 153, 448–459 (2017).

    PubMed  Google Scholar 

  93. 93.

    Drossman, D. A. Functional gastrointestinal disorders: history, pathophysiology, clinical features & Rome IV. Gastroenterology 150, 1262–1279 (2016).

    Google Scholar 

  94. 94.

    Gibson, G. R. et al. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat. Rev. Gastroenterol. Hepatol. 14, 491–502 (2017).

    PubMed  PubMed Central  Google Scholar 

  95. 95.

    Alexea, O., Bacarea, V. & Pique, N. The combination of oligo- and polysaccharides and reticulated protein for the control of symptoms in patients with irritable bowel syndrome: results of a randomised, placebo-controlled, double-blind, parallel group, multicentre clinical trial. United European Gastroenterol. J. 4, 455–465 (2016).

    CAS  Google Scholar 

  96. 96.

    Azpiroz, F. et al. Effects of scFOS on the composition of fecal microbiota and anxiety in patients with irritable bowel syndrome: a randomized, double blind, placebo controlled study. Neurogastroenterol Motil. 9, e12911 (2017).

    Google Scholar 

  97. 97.

    Dimidi, E., Rossi, M. & Whelan, K. Irritable bowel syndrome and diet: where are we in 2018? Curr. Opin. Clin. Nutr. Metab. Care 20, 456–463 (2017).

    PubMed  Google Scholar 

  98. 98.

    Niv, E. et al. Randomized clinical study: partially hydrolyzed guar gum (PHGG) versus placebo in the treatment of patients with irritable bowel syndrome. Nutr. Metab. 13, 10 (2016).

    CAS  Google Scholar 

  99. 99.

    Halkjaer, S. I., Boolsen, A. W., Gunther, S., Christensen, A. H. & Petersen, A. M. Can fecal microbiota transplantation cure irritable bowel syndrome? World J. Gastroenterol. 23, 4112–4120 (2017).

    PubMed  PubMed Central  Google Scholar 

  100. 100.

    Pinn, D. M., Aroniadis, O. C. & Brandt, L. J. Is fecal microbiota transplantation (FMT) an effective treatment for patients with functional gastrointestinal disorders (FGID)? Neurogastroenterol Motil. 27, 19–29 (2015).

    CAS  PubMed  Google Scholar 

  101. 101.

    Cammarota, G. et al. European consensus conference on faecal microbiota transplantation in clinical practice. Gut 66, 569–580 (2017).

    PubMed  PubMed Central  Google Scholar 

  102. 102.

    Mizuno, S. et al. Bifidobacterium-rich fecal donor may be a positive predictor for successful fecal microbiota transplantation in patients with irritable bowel syndrome. Digestion 96, 29–38 (2017).

    PubMed  PubMed Central  Google Scholar 

  103. 103.

    Pinn, D. M., Aroniadis, O. C. & Brandt, L. J. Is fecal microbiota transplantation the answer for irritable bowel syndrome? A single-center experience. Am. J. Gastroenterol. 109, 1831–1832 (2014).

    PubMed  Google Scholar 

  104. 104.

    Tian, H. et al. Treatment of slow transit constipation with fecal microbiota transplantation: a pilot study. J. Clin. Gastroenterol. 50, 865–870 (2016).

    PubMed  Google Scholar 

  105. 105.

    Johnsen, P. H. et al. Faecal microbiota transplantation versus placebo for moderate-to-severe irritable bowel syndrome: a double-blind, randomised, placebo-controlled, parallel-group, single-centre trial. Lancet Gastroenterol. Hepatol. 3, 17–24 (2018).

    CAS  PubMed  Google Scholar 

  106. 106.

    Chang, B. W. & Rezaie, A. Irritable bowel syndrome-like symptoms following fecal microbiota transplantation: a possible donor-dependent complication. Am. J. Gastroenterol. 112, 186–187 (2017).

    PubMed  Google Scholar 

  107. 107.

    Mosinska, P., Storr, M. & Fichna, J. The role of AST-120 and protein-bound uremic toxins in irritable bowel syndrome: a therapeutic perspective. Therap Adv. Gastroenterol. 8, 278–284 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Tack, J. F., Miner, P. B. Jr., Fischer, L. & Harris, M. S. Randomised clinical trial: the safety and efficacy of AST-120 in non-constipating irritable bowel syndrome - a double-blind, placebo-controlled study. Aliment. Pharmacol. Ther. 34, 868–877 (2011).

    CAS  PubMed  Google Scholar 

  109. 109.

    Bharucha, A. E. & Waldman, S. A. Taking a lesson from microbial diarrheagenesis in the management of chronic constipation. Gastroenterology 138, 813–817 (2010).

    PubMed  PubMed Central  Google Scholar 

  110. 110.

    Corsetti, M. & Tack, J. Linaclotide: a new drug for the treatment of chronic constipation and irritable bowel syndrome with constipation. United European Gastroenterol. J. 1, 7–20 (2013).

    PubMed  PubMed Central  Google Scholar 

  111. 111.

    Andresen, V. et al. Effect of 5 days linaclotide on transit and bowel function in females with constipation-predominant irritable bowel syndrome. Gastroenterology 133, 761–768 (2007).

    CAS  PubMed  Google Scholar 

  112. 112.

    Chey, W. D. et al. Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety. Am. J. Gastroenterol. 107, 1702–1712 (2012).

    CAS  PubMed  Google Scholar 

  113. 113.

    Lembo, A. J. et al. Two randomized trials of linaclotide for chronic constipation. N. Engl. J. Med. 365, 527–536 (2011).

    CAS  PubMed  Google Scholar 

  114. 114.

    Rao, S. et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am. J. Gastroenterol. 107, 1714–1724 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Quigley, E. M. et al. Randomised clinical trials: linaclotide phase 3 studies in IBS-C - a prespecified further analysis based on European Medicines Agency-specified endpoints. Aliment. Pharmacol. Ther. 37, 49–61 (2013).

    CAS  PubMed  Google Scholar 

  116. 116.

    Castro, J. et al. Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 3′,5′-monophosphate. Gastroenterology 145, 1334–1346 (2013).

    CAS  PubMed  Google Scholar 

  117. 117.

    Bharucha, A. E., Locke, G. R. & Pemberton, J. H. Reply: To PMID 23261065. Gastroenterology 145, 488 (2013).

    PubMed  Google Scholar 

  118. 118.

    Johnston, J. M. et al. Linaclotide improves abdominal pain and bowel habits in a phase IIb study of patients with irritable bowel syndrome with constipation. Gastroenterology 139, 1877–1886 (2010).

    CAS  PubMed  Google Scholar 

  119. 119.

    Fukudo, S. et al. Linaclotide is effective and safe for patients with irritable bowel syndrome with constipation in Japan: a phase III randomized, double-blind, and placebo-controlled and long-term extension study. Gastroenterology 152, S714 (2017).

    Google Scholar 

  120. 120.

    Fukudo, S. et al. Determining an optimal dose of linaclotide for use in Japanese patients with irritable bowel syndrome with constipation: a phase II randomized, double-blind, placebo-controlled study. Neurogastroenterol Motil. 30, e13275 (2017).

    PubMed  Google Scholar 

  121. 121.

    Brenner, D. M. et al. Efficacy, safety, and tolerability of plecanatide in patients with irritable bowel syndrome with constipation: results of two phase 3 randomized clinical trials. Am. J. Gastroenterol. 113,735–745 (2018).

    CAS  PubMed  Google Scholar 

  122. 122.

    DeMicco, M., Barrow, L., Hickey, B., Shailubhai, K. & Griffin, P. Randomized clinical trial: efficacy and safety of plecanatide in the treatment of chronic idiopathic constipation. Therap Adv. Gastroenterol. 10, 837–851 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Miner, P. B. Jr. et al. A randomized phase III clinical trial of plecanatide, a uroguanylin analog, in patients with chronic idiopathic constipation. Am. J. Gastroenterol. 112, 613–621 (2017).

    CAS  PubMed  Google Scholar 

  124. 124.

    FDA. FDA approves trulance for chronic idiopathic constipation. FDA https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm537725.htm (2017).

  125. 125.

    Synergy Pharmaceuticals. Synergy Pharmaceuticals announces FDA approval of Trulance® (plecanatide) for the treatment of irritable bowel syndrome with constipation (IBS-C) in adults. Synergy Pharmaceuticals https://ir.synergypharma.com/press-releases/detail/1861/synergy-pharmaceuticals-announces-fda-approval-of (2018).

  126. 126.

    Rivkin, A. & Chagan, L. Lubiprostone: chloride channel activator for chronic constipation. Clin. Ther. 28, 2008–2021 (2006).

    CAS  PubMed  Google Scholar 

  127. 127.

    Barish, C. F., Drossman, D., Johanson, J. F. & Ueno, R. Efficacy and safety of lubiprostone in patients with chronic constipation. Dig. Dis. Sci. 55, 1090–1097 (2010).

    CAS  PubMed  Google Scholar 

  128. 128.

    Drossman, D. A. et al. Clinical trial: lubiprostone in patients with constipation-associated irritable bowel syndrome — results of two randomized, placebo-controlled studies. Aliment. Pharmacol. Ther. 29, 329–341 (2009).

    CAS  PubMed  Google Scholar 

  129. 129.

    Chey, W. D. et al. Safety and patient outcomes with lubiprostone for up to 52 weeks in patients with irritable bowel syndrome with constipation. Aliment. Pharmacol. Ther. 35, 587–599 (2012).

    CAS  PubMed  Google Scholar 

  130. 130.

    Spencer, A. G. et al. Intestinal inhibition of the Na+/H+ exchanger 3 prevents cardiorenal damage in rats and inhibits Na+ uptake in humans. Sci. Transl. Med. 6, 227ra236 (2014).

    Google Scholar 

  131. 131.

    Chey, W. D., Lembo, A. J. & Rosenbaum, D. P. Tenapanor treatment of patients with constipation-predominant irritable bowel syndrome: a phase 2, randomized, placebo-controlled efficacy and safety trial. Am. J. Gastroenterol. 112, 763–774 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Ardelyx. Ardelyx reports successful Phase 3 T3MPO-1 trial of tenapanor in patients with IBS-C. Ardelyx http://ir.ardelyx.com/news-releases/news-release-details/ardelyx-reports-successful-phase-3-t3mpo-1-trial-tenapanor (2017).

  133. 133.

    US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02686138?term=NCT02686138&rank=1 (2017).

  134. 134.

    Bagnol, D., Mansour, A., Akil, H. & Watson, S. J. Cellular localization and distribution of the cloned mu and kappa opioid receptors in rat gastrointestinal tract. Neuroscience 81, 579–591 (1997).

    CAS  PubMed  Google Scholar 

  135. 135.

    Bitar, K. N. & Makhlouf, G. M. Specific opiate receptors on isolated mammalian gastric smooth muscle cells. Nature 297, 72–74 (1982).

    CAS  PubMed  Google Scholar 

  136. 136.

    Lacy, B. E. Emerging treatments in neurogastroenterology: eluxadoline - a new therapeutic option for diarrhea-predominant IBS. Neurogastroenterol Motil. 28, 26–35 (2016).

    CAS  PubMed  Google Scholar 

  137. 137.

    Lembo, A. J. et al. Eluxadoline for irritable bowel syndrome with diarrhea. N. Engl. J. Med. 374, 242–253 (2016).

    CAS  PubMed  Google Scholar 

  138. 138.

    Chey, W. D., Dove, L. S., Andrae, D. A. & Covington, P. S. Early response predicts a sustained response to eluxadoline in patients with irritable bowel syndrome with diarrhoea in two phase 3 studies. Aliment. Pharmacol. Ther. 45, 1319–1328 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Lacy, B. E. et al. Eluxadoline efficacy in IBS-D patients who report prior loperamide use. Am. J. Gastroenterol. 112, 924–932 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Cash, B. D., Lacy, B. E., Schoenfeld, P. S., Dove, L. S. & Covington, P. S. Safety of eluxadoline in patients with irritable bowel syndrome with diarrhea. Am. J. Gastroenterol. 112, 365–374 (2017).

    CAS  PubMed  Google Scholar 

  141. 141.

    Gershon, M. D. & Tack, J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 132, 397–414 (2007).

    CAS  PubMed  Google Scholar 

  142. 142.

    Ford, A. C. et al. Efficacy of 5-HT3 antagonists and 5-HT4 agonists in irritable bowel syndrome: systematic review and meta-analysis. Am. J. Gastroenterol. 104, 1831–1843 (2009).

    CAS  PubMed  Google Scholar 

  143. 143.

    Tennis, P. et al. The relationship between dosing of alosetron and discontinuation patterns reported by patients participating in a follow-up programme. Aliment. Pharmacol. Ther. 25, 317–322 (2007).

    CAS  PubMed  Google Scholar 

  144. 144.

    Fukudo, S., Ida, M., Akiho, H., Nakashima, Y. & Matsueda, K. Effect of ramosetron on stool consistency in male patients with irritable bowel syndrome with diarrhea. Clin. Gastroenterol. Hepatol. 12, 953–959 (2014).

    CAS  PubMed  Google Scholar 

  145. 145.

    Fukudo, S. et al. Ramosetron reduces symptoms of irritable bowel syndrome with diarrhea and improves quality of life in women. Gastroenterology 150, 358–366 (2016).

    CAS  PubMed  Google Scholar 

  146. 146.

    Billio, A., Morello, E. & Clarke, M. J. Serotonin receptor antagonists for highly emetogenic chemotherapy in adults. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858.CD006272.pub2 (2010).

  147. 147.

    Garsed, K. et al. A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea. Gut 63, 1617–1625 (2014).

    CAS  PubMed  Google Scholar 

  148. 148.

    Holzer, P. & Holzer-Petsche, U. Tachykinins in the gut. Part I. expression, release and motor function. Pharmacol. Ther. 73, 173–217 (1997).

    CAS  PubMed  Google Scholar 

  149. 149.

    Corsetti, M., Akyuz, F. & Tack, J. Targeting tachykinin receptors for the treatment of functional gastrointestinal disorders with a focus on irritable bowel syndrome. Neurogastroenterol Motil. 27, 1354–1370 (2015).

    CAS  PubMed  Google Scholar 

  150. 150.

    Tack, J. et al. The neurokinin-2 receptor antagonist ibodutant improves overall symptoms, abdominal pain and stool pattern in female patients in a phase II study of diarrhoea-predominant IBS. Gut 66, 1403–1413 (2017).

    CAS  PubMed  Google Scholar 

  151. 151.

    US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02107196?term=NCT02107196&rank=1 (2017).

  152. 152.

    US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02120027?term=NCT02120027&rank=1 (2017).

  153. 153.

    Brown, P. M. et al. The tryptophan hydroxylase inhibitor LX1031 shows clinical benefit in patients with nonconstipating irritable bowel syndrome. Gastroenterology 141, 507–516 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154.

    Kulke, M. H. et al. Telotristat ethyl, a tryptophan hydroxylase inhibitor for the treatment of Carcinoid Syndrome. J. Clin. Oncol. 35, 14–23 (2017).

    CAS  PubMed  Google Scholar 

  155. 155.

    Mangel, A. W. & Hicks, G. A. Asimadoline and its potential for the treatment of diarrhea-predominant irritable bowel syndrome: a review. Clin. Exp. Gastroenterol. 5, 1–10 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156.

    Mangel, A. W. et al. Clinical trial: asimadoline in the treatment of patients with irritable bowel syndrome. Aliment. Pharmacol. Ther. 28, 239–249 (2008).

    CAS  PubMed  Google Scholar 

  157. 157.

    US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT01100684?term=asimadoline&cond=IBS+-+Irritable+Bowel+Syndrome&rank=1 (2013).

  158. 158.

    US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02475447?term=NCT02475447&rank=1 (2017).

  159. 159.

    Yamaguchi, O. et al. Randomized, double-blind, placebo- and propiverine-controlled trial of the once-daily antimuscarinic agent solifenacin in Japanese patients with overactive bladder. BJU Int. 100, 579–587 (2007).

    CAS  PubMed  Google Scholar 

  160. 160.

    Fukushima, Y., Suzuki, H., Matsuzaki, J., Kiyosue, A. & Hibi, T. Efficacy of solifenacin on irritable bowel syndrome with diarrhea: open-label prospective pilot trial. J. Neurogastroenterol Motil. 18, 317–323 (2012).

    PubMed  PubMed Central  Google Scholar 

  161. 161.

    Clave, P. & Tack, J. Efficacy of otilonium bromide in irritable bowel syndrome: a pooled analysis. Therap Adv. Gastroenterol. 10, 311–322 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162.

    Lee, K. N. et al. Efficacy and safety of tiropramide in the treatment of patients with irritable bowel syndrome: a multicenter, randomized, double-blind, non-inferiority trial, compared with octylonium. J. Neurogastroenterol Motil. 20, 113–121 (2014).

    PubMed  Google Scholar 

  163. 163.

    Aziz, I. et al. High prevalence of idiopathic bile acid diarrhea among patients with diarrhea-predominant irritable bowel syndrome based on rome III criteria. Clin. Gastroenterol. Hepatol. 13, 1650–1655 (2015).

    PubMed  Google Scholar 

  164. 164.

    Bajor, A., Tornblom, H., Rudling, M., Ung, K. A. & Simren, M. Increased colonic bile acid exposure: a relevant factor for symptoms and treatment in IBS. Gut 64, 84–92 (2015).

    CAS  PubMed  Google Scholar 

  165. 165.

    Mekjian, H. S., Phillips, S. F. & Hofmann, A. F. Colonic secretion of water and electrolytes induced by bile acids: perfusion studies in man. J. Clin. Invest. 50, 1569–1577 (1971).

    CAS  PubMed  Google Scholar 

  166. 166.

    Bampton, P. A., Dinning, P. G., Kennedy, M. L., Lubowski, D. Z. & Cook, I. J. The proximal colonic motor response to rectal mechanical and chemical stimulation. Am. J. Physiol. Gastrointest. Liver Physiol. 282, G443–449 (2002).

    CAS  PubMed  Google Scholar 

  167. 167.

    Mottacki, N., Simren, M. & Bajor, A. Review article: bile acid diarrhoea - pathogenesis, diagnosis and management. Aliment. Pharmacol. Ther. 43, 884–898 (2016).

    CAS  PubMed  Google Scholar 

  168. 168.

    Fernandez-Banares, F. et al. Randomised clinical trial: colestyramine versus hydroxypropyl cellulose in patients with functional chronic watery diarrhoea. Aliment. Pharmacol. Ther. 41, 1132–1140 (2015).

    CAS  PubMed  Google Scholar 

  169. 169.

    Orekoya, O. et al. Quantifying bile acid malabsorption helps predict response and tailor sequestrant therapy. Clin. Med. 15, 252–257 (2015).

    Google Scholar 

  170. 170.

    Wilcox, C., Turner, J. & Green, J. Systematic review: the management of chronic diarrhoea due to bile acid malabsorption. Aliment. Pharmacol. Ther. 39, 923–939 (2014).

    CAS  PubMed  Google Scholar 

  171. 171.

    Camilleri, M. et al. Effect of colesevelam on faecal bile acids and bowel functions in diarrhoea-predominant irritable bowel syndrome. Aliment. Pharmacol. Ther. 41, 438–448 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172.

    Appleby, R. N. et al. Effects of conventional and a novel colonic-release bile acid sequestrant, A3384, on fibroblast growth factor 19 and bile acid metabolism in healthy volunteers and patients with bile acid diarrhoea. United Eurpoean Gastroenterol. J. 5, 380–388 (2017).

    CAS  Google Scholar 

  173. 173.

    Walters, J. R. et al. A new mechanism for bile acid diarrhea: defective feedback inhibition of bile acid biosynthesis. Clin. Gastroenterol. Hepatol. 7, 1189–1194 (2009).

    CAS  PubMed  Google Scholar 

  174. 174.

    Keely, S. J. & Walters, J. R. The farnesoid X receptor: good for bad. Cell. Mol. Gastroenterol. Hepatol. 2, 725–732 (2016).

    PubMed  PubMed Central  Google Scholar 

  175. 175.

    Alawad, A. S. & Levy, C. FXR agonists: from bench to bedside, a guide for clinicians. Dig. Dis. Sci. 61, 3395–3404 (2016).

    PubMed  Google Scholar 

  176. 176.

    Walters, J. R. et al. The response of patients with bile acid diarrhoea to the farnesoid X receptor agonist obeticholic acid. Aliment. Pharmacol. Ther. 41, 54–64 (2015).

    CAS  PubMed  Google Scholar 

  177. 177.

    Odunsi-Shiyanbade, S. T. et al. Effects of chenodeoxycholate and a bile acid sequestrant, colesevelam, on intestinal transit and bowel function. Clin. Gastroenterol. Hepatol. 8, 159–165 (2010).

    CAS  PubMed  Google Scholar 

  178. 178.

    Simren, M., Bajor, A., Gillberg, P. G., Rudling, M. & Abrahamsson, H. Randomised clinical trial: the ileal bile acid transporter inhibitor A3309 versus placebo in patients with chronic idiopathic constipation — a double-blind study. Aliment. Pharmacol. Ther. 34, 41–50 (2011).

    CAS  PubMed  Google Scholar 

  179. 179.

    Rao, A. S. et al. Chenodeoxycholate in females with irritable bowel syndrome-constipation: a pharmacodynamic and pharmacogenetic analysis. Gastroenterology 139, 1549–1558 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180.

    Chey, W. D., Camilleri, M., Chang, L., Rikner, L. & Graffner, H. A randomized placebo-controlled phase IIb trial ofa3309, a bile acid transporter inhibitor, for chronic idiopathic constipation. Am. J. Gastroenterol. 106, 1803–1812 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. 181.

    Nakajima, A., Seki, M. & Taniguchi, S. Determining an optimal clinical dose of elobixibat, a novel inhibitor of the ileal bile acid transporter, in Japanese patients with chronic constipation: a phase II, multicenter, double-blind, placebo-controlled randomized clinical trial. J. Gastroenterol. 53, 525–534 (2017).

    PubMed  PubMed Central  Google Scholar 

  182. 182.

    Tack, J. et al. Systematic review: cardiovascular safety profile of 5-HT(4) agonists developed for gastrointestinal disorders. Aliment. Pharmacol. Ther. 35, 745–767 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. 183.

    Tack, J. & Corsetti, M. Prucalopride: evaluation of the pharmacokinetics, pharmacodynamics, efficacy and safety in the treatment of chronic constipation. Expert Opin. Drug Metab. Toxicol. 8, 1327–1335 (2012).

    CAS  PubMed  Google Scholar 

  184. 184.

    Tack, J., Quigley, E., Camilleri, M., Vandeplassche, L. & Kerstens, R. Efficacy and safety of oral prucalopride in women with chronic constipation in whom laxatives have failed: an integrated analysis. United European Gastroenterol. J. 1, 48–59 (2013).

    Google Scholar 

  185. 185.

    Tack, J. et al. Effect of prucalopride on symptoms of chronic constipation. Neurogastroenterol Motil. 26, 21–27 (2014).

    CAS  PubMed  Google Scholar 

  186. 186.

    Sanger, G. J. & Furness, J. B. Ghrelin and motilin receptors as drug targets for gastrointestinal disorders. Nat. Rev. Gastroenterol. Hepatol. 13, 38–48 (2016).

    CAS  PubMed  Google Scholar 

  187. 187.

    Camilleri, M. et al. Efficacy and safety of relamorelin in diabetics with symptoms of gastroparesis: a randomized, placebo-controlled study. Gastroenterology 153, 1240–1250 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. 188.

    Van der Ploeg, L. et al. Preclinical gastrointestinal prokinetic efficacy and endocrine effects of the ghrelin mimetic RM-131. Life Sci. 109, 20–29 (2014).

    PubMed  Google Scholar 

  189. 189.

    Acosta, A. et al. Relamorelin relieves constipation and accelerates colonic transit in a phase 2, placebo-controlled, randomized trial. Clin. Gastroenterol. Hepatol. 13, 2312–2319 (2015).

    CAS  PubMed  Google Scholar 

  190. 190.

    Acosta, A. et al. Short-term effects of relamorelin on descending colon motility in chronic constipation: a randomized, controlled trial. Dig. Dis. Sci. 61, 852–860 (2016).

    CAS  PubMed  Google Scholar 

  191. 191.

    Parkinson Study Group. Electronic address, p. o. e. A randomized trial of relamorelin for constipation in Parkinson’s disease (MOVE-PD): trial results and lessons learned. Parkinsonism Relat. Disord. 37, 101–105 (2017).

    Google Scholar 

  192. 192.

    Barbara, G. et al. Randomised controlled trial of mesalazine in IBS. Gut 65, 82–90 (2016).

    CAS  PubMed  Google Scholar 

  193. 193.

    Lam, C. et al. A mechanistic multicentre, parallel group, randomised placebo-controlled trial of mesalazine for the treatment of IBS with diarrhoea (IBS-D). Gut 65, 91–99 (2016).

    CAS  PubMed  Google Scholar 

  194. 194.

    Barbara, G. et al. Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome. Gastroenterology 132, 26–37 (2007).

    CAS  PubMed  Google Scholar 

  195. 195.

    Wouters, M. M. et al. Histamine receptor H1-mediated sensitization of TRPV1 mediates visceral hypersensitivity and symptoms in patients with irritable bowel syndrome. Gastroenterology 150, 875–887 (2016).

    CAS  PubMed  Google Scholar 

  196. 196.

    Klooker, T. K. et al. The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome. Gut 59, 1213–1221 (2010).

    CAS  PubMed  Google Scholar 

  197. 197.

    US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT01908465?term=ebastine&rank=2 (2017).

  198. 198.

    Ciampa, B. P., Reyes Ramos, E., Borum, M. & Doman, D. B. The emerging therapeutic role of medical foods for gastrointestinal disorders. Gastroenterol. Hepatol. 13, 104–115 (2017).

    Google Scholar 

  199. 199.

    Cash, B. D., Epstein, M. S. & Shah, S. M. A. Novel delivery system of peppermint oil is an effective therapy for irritable bowel syndrome symptoms. Dig. Dis. Sci. 61, 560–571 (2016).

    CAS  PubMed  Google Scholar 

  200. 200.

    Petschow, B. W., Burnett, B., Shaw, A. L., Weaver, E. M. & Klein, G. L. Serum-derived bovine immunoglobulin/protein isolate: postulated mechanism of action for management of enteropathy. Clin. Exp. Gastroenterol. 7, 181–190 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. 201.

    Good, L., Rosario, R. & Panas, R. New therapeutic option for irritable bowel syndrome: serum-derived bovine immunoglobulin. World J. Gastroenterol. 21, 3361–3366 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. 202.

    Wilson, D., Evans, M., Weaver, E., Shaw, A. L. & Klein, G. L. Evaluation of serum-derived bovine immunoglobulin protein isolate in subjects with diarrhea-predominant irritable bowel syndrome. Clin. Med. Insights Gastroenterol. 6, 49–60 (2013).

    PubMed  PubMed Central  Google Scholar 

  203. 203.

    Souba, W. W. et al. The role of glutamine in maintaining a healthy gut and supporting the metabolic response to injury and infection. J. Surg. Res. 48, 383–391 (1990).

    CAS  PubMed  Google Scholar 

  204. 204.

    Camilleri, M., Madsen, K., Spiller, R., Greenwood-Van Meerveld, B. & Verne, G. N. Intestinal barrier function in health and gastrointestinal disease. Neurogastroenterol Motil. 24, 503–512 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. 205.

    Zhou, Q., Souba, W. W., Croce, C. M. & Verne, G. N. MicroRNA-29a regulates intestinal membrane permeability in patients with irritable bowel syndrome. Gut 59, 775–784 (2010).

    CAS  PubMed  Google Scholar 

  206. 206.

    Bertrand, J. et al. Glutamine restores tight junction protein Claudin-1 expression in colonic mucosa of patients with diarrhea-predominant irritable bowel syndrome. JPEN J. Parenter. Enteral. Nutr. 40, 1170–1176 (2016).

    CAS  PubMed  Google Scholar 

  207. 207.

    Zhou, Q. & Verne, G. N. Reply: to PMID 25277410. Gastroenterology 148, 1080–1081 (2015).

    PubMed  PubMed Central  Google Scholar 

  208. 208.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01414244?term=glutamine&cond=Irritable+Bowel+Syndrome&rank=1 (2016).

    CAS  PubMed  Google Scholar 

  209. 209.

    Hesselink, J. M. Evolution in pharmacologic thinking around the natural analgesic palmitoylethanolamide: from nonspecific resistance to PPAR-alpha agonist and effective nutraceutical. J. Pain Res. 6, 625–634 (2013).

    PubMed  PubMed Central  Google Scholar 

  210. 210.

    Yang, B. et al. Polydatin attenuated food allergy via store-operated calcium channels in mast cell. World J. Gastroenterol. 19, 3980–3989 (2013).

    PubMed  PubMed Central  Google Scholar 

  211. 211.

    Camilleri, M. et al. Cannabinoid receptor 1 gene and irritable bowel syndrome: phenotype and quantitative traits. Am. J. Physiol. Gastrointest. Liver Physiol. 304, G553–G560 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. 212.

    Cremon, C. et al. Randomised clinical trial: the analgesic properties of dietary supplementation with palmitoylethanolamide and polydatin in irritable bowel syndrome. Aliment. Pharmacol. Ther. 45, 909–922 (2017).

    CAS  PubMed  Google Scholar 

  213. 213.

    Ottillinger, B., Storr, M., Malfertheiner, P. & Allescher, H. D. STW 5 (Iberogast(R)) — a safe and effective standard in the treatment of functional gastrointestinal disorders. Wien Med. Wochenschr. 163, 65–72 (2013).

    PubMed  Google Scholar 

  214. 214.

    Krueger, D. et al. The multi-herbal drug STW 5 (Iberogast) has prosecretory action in the human intestine. Neurogastroenterol Motil. 21, 1203–e1110 (2009).

    CAS  PubMed  Google Scholar 

  215. 215.

    Wegener, T. & Wagner, H. The active components and the pharmacological multi-target principle of STW 5 (Iberogast). Phytomedicine 13 (Suppl. 5), 20–35 (2006).

    CAS  PubMed  Google Scholar 

  216. 216.

    Madisch, A., Holtmann, G., Plein, K. & Hotz, J. Treatment of irritable bowel syndrome with herbal preparations: results of a double-blind, randomized, placebo-controlled, multi-centre trial. Aliment. Pharmacol. Ther. 19, 271–279 (2004).

    CAS  PubMed  Google Scholar 

  217. 217.

    Teschke, R., Wolff, A., Frenzel, C., Eickhoff, A. & Schulze, J. Herbal traditional Chinese medicine and its evidence base in gastrointestinal disorders. World J. Gastroenterol. 21, 4466–4490 (2015).

    PubMed  PubMed Central  Google Scholar 

  218. 218.

    Fan, H. et al. Tongxie formula reduces symptoms of irritable bowel syndrome. Clin. Gastroenterol. Hepatol. 15, 1724–1732 (2017).

    PubMed  Google Scholar 

  219. 219.

    Ahluwalia, B., Magnusson, M. K., Isaksson, S., Larsson, F. & Ohman, L. Effects of aloe barbadensis Mill. extract (AVH200(R)) on human blood T cell activity in vitro. J. Ethnopharmacol 179, 301–309 (2016).

    CAS  PubMed  Google Scholar 

  220. 220.

    Langmead, L., Makins, R. J. & Rampton, D. S. Anti-inflammatory effects of aloe vera gel in human colorectal mucosa in vitro. Aliment. Pharmacol. Ther. 19, 521–527 (2004).

    CAS  PubMed  Google Scholar 

  221. 221.

    Storsrud, S., Ponten, I. & Simren, M. A. Pilot study of the effect of aloe barbadensis Mill. Extract (AVH200(R)) in patients with irritable bowel syndrome: a randomized, double-blind, placebo-controlled study. J. Gastrointestin Liver Dis. 24, 275–280 (2015).

    PubMed  Google Scholar 

  222. 222.

    Davis, K., Philpott, S., Kumar, D. & Mendall, M. Randomised double-blind placebo-controlled trial of aloe vera for irritable bowel syndrome. Int. J. Clin. Pract. 60, 1080–1086 (2006).

    CAS  PubMed  Google Scholar 

  223. 223.

    Hutchings, H. A. et al. A randomised, cross-over, placebo-controlled study of aloe vera in patients with irritable bowel syndrome: effects on patient quality of life. ISRN Gastroenterol. 2011, 206103 (2011).

    CAS  PubMed  Google Scholar 

  224. 224.

    US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT01400048?term=aloe+vera&cond=IBS+-+Irritable+Bowel+Syndrome&rank=1 (2016).

  225. 225.

    Shishodia, S., Sethi, G. & Aggarwal, B. B. Curcumin: getting back to the roots. Ann. NY Acad. Sci. 1056, 206–217 (2005).

    CAS  PubMed  Google Scholar 

  226. 226.

    Ostad, S. N., Soodi, M., Shariffzadeh, M., Khorshidi, N. & Marzban, H. The effect of fennel essential oil on uterine contraction as a model for dysmenorrhea, pharmacology and toxicology study. J. Ethnopharmacol 76, 299–304 (2001).

    CAS  PubMed  Google Scholar 

  227. 227.

    Portincasa, P. et al. Curcumin and fennel essential oil improve symptoms and quality of life in patients with irritable bowel syndrome. J. Gastrointestin Liver Dis. 25, 151–157 (2016).

    PubMed  Google Scholar 

  228. 228.

    Chang, L., Tong, K. & Ameen, V. Ischemic colitis and complications of constipation associated with the use of alosetron under a risk management plan: clinical characteristics, outcomes, and incidences. Am. J. Gastroenterol. 105, 866–875 (2010).

    PubMed  Google Scholar 

  229. 229.

    Pasricha, P. J. Desperately seeking serotonin… A commentary on the withdrawal of tegaserod and the state of drug development for functional and motility disorders. Gastroenterology 132, 2287–2290 (2007).

    PubMed  Google Scholar 

  230. 230.

    Anderson, J. L. et al. Lack of association of tegaserod with adverse cardiovascular outcomes in a matched case-control study. J. Cardiovasc. Pharmacol. Ther. 14, 170–175 (2009).

    CAS  PubMed  Google Scholar 

  231. 231.

    Loughlin, J. et al. Tegaserod and the risk of cardiovascular ischemic events: an observational cohort study. J. Cardiovasc. Pharmacol. Ther. 15, 151–157 (2010).

    PubMed  Google Scholar 

  232. 232.

    Moayyedi, P. et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology 149, 102–109 (2015).

    PubMed  Google Scholar 

  233. 233.

    Bennet, S. M. P. et al. Multivariate modelling of faecal bacterial profiles of patients with IBS predicts responsiveness to a diet low in FODMAPs. Gut 67, 872–881 (2017).

    PubMed  Google Scholar 

  234. 234.

    Annahazi, A. et al. Luminal cysteine-proteases degrade colonic tight junction structure and are responsible for abdominal pain in constipation-predominant IBS. Am. J. Gastroenterol. 108, 1322–1331 (2013).

    CAS  PubMed  Google Scholar 

  235. 235.

    Cenac, N. et al. Role for protease activity in visceral pain in irritable bowel syndrome. J. Clin. Invest. 117, 636–647 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  236. 236.

    Vergnolle, N. Protease inhibition as new therapeutic strategy for GI diseases. Gut 65, 1215–1224 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  237. 237.

    Gadaleta, R. M. et al. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 60, 463–472 (2011).

    CAS  PubMed  Google Scholar 

  238. 238.

    Khaleghi, S., Ju, J. M., Lamba, A. & Murray, J. A. The potential utility of tight junction regulation in celiac disease: focus on larazotide acetate. Therap Adv. Gastroenterol. 9, 37–49 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  239. 239.

    Vanheel, H. et al. Impaired duodenal mucosal integrity and low-grade inflammation in functional dyspepsia. Gut 63, 262–271 (2014).

    CAS  Google Scholar 

  240. 240.

    Sweetser, S. et al. Do corticotropin releasing factor-1 receptors influence colonic transit and bowel function in women with irritable bowel syndrome? Am. J. Physiol. Gastrointest. Liver Physiol. 296, G1299–G1306 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  241. 241.

    Lobo, B. et al. Down-regulation of mucosal mast cell activation and immune response in diarrhea-irritable bowel syndrome by oral disodium cromoglicate. United European Gastroenterol. J. 5, 887–897 (2017).

    CAS  Google Scholar 

  242. 242.

    Wouters, M. M., Vicario, M. & Santos, J. The role of mast cells in functional GI disorders. Gut 65, 155–168 (2016).

    CAS  PubMed  Google Scholar 

  243. 243.

    Fabisiak, A., Wlodarczyk, J., Fabisiak, N., Storr, M. & Fichna, J. Targeting histamine receptors in irritable bowel syndrome: a critical appraisal. J. Neurogastroenterol Motil. 23, 341–348 (2017).

    PubMed  PubMed Central  Google Scholar 

  244. 244.

    Balemans, D., Boeckxstaens, G. E., Talavera, K. & Wouters, M. M. Transient receptor potential ion channel function in sensory transduction and cellular signaling cascades underlying visceral hypersensitivity. Am. J. Physiol. Gastrointest. Liver Physiol. 312, G635–G648 (2017).

    PubMed  Google Scholar 

  245. 245.

    Zhou, Q. et al. Decreased miR-199 augments visceral pain in patients with IBS through translational upregulation of TRPV1. Gut 65, 797–805 (2016).

    CAS  PubMed  Google Scholar 

  246. 246.

    Grinsvall, C., Tornblom, H., Tack, J., Van Oudenhove, L. & Simren, M. Psychological factors selectively upregulate rectal pain perception in hypersensitive patients with irritable bowel syndrome. Neurogastroenterol Motil. 27, 1772–1782 (2015).

    CAS  PubMed  Google Scholar 

  247. 247.

    Van Oudenhove, L., Tornblom, H., Storsrud, S., Tack, J. & Simren, M. Depression and somatization are associated with increased postprandial symptoms in patients with irritable bowel syndrome. Gastroenterology 150, 866–874 (2016).

    PubMed  Google Scholar 

  248. 248.

    Wilpart, K. et al. Coping skills are associated with gastrointestinal symptom severity and somatization in patients with irritable bowel syndrome. Clin. Gastroenterol. Hepatol. 15, 1565–1571 (2017).

    PubMed  Google Scholar 

  249. 249.

    Jones, M. P. et al. A biomarker panel and psychological morbidity differentiates the irritable bowel syndrome from health and provides novel pathophysiological leads. Aliment. Pharmacol. Ther. 39, 426–437 (2014).

    CAS  PubMed  Google Scholar 

  250. 250.

    Lembo, A. J. et al. Use of serum biomarkers in a diagnostic test for irritable bowel syndrome. Aliment. Pharmacol. Ther. 29, 834–842 (2009).

    CAS  PubMed  Google Scholar 

  251. 251.

    Pimentel, M. et al. Development and validation of a biomarker for diarrhea-predominant irritable bowel syndrome in human subjects. PLoS ONE 10, e0126438 (2015).

    PubMed  PubMed Central  Google Scholar 

  252. 252.

    Camilleri, M. et al. Effect of increased bile acid synthesis or fecal excretion in irritable bowel syndrome-diarrhea. Am. J. Gastroenterol. 109, 1621–1630 (2014).

    CAS  PubMed  Google Scholar 

  253. 253.

    Peleman, C. et al. Colonic transit and bile acid synthesis or excretion in patients with irritable bowel syndrome-diarrhea without bile acid malabsorption. Clin. Gastroenterol. Hepatol. 15, 720–727 e721 (2017).

    CAS  PubMed  Google Scholar 

  254. 254.

    Camilleri, M. et al. Serotonin-transporter polymorphism pharmacogenetics in diarrhea-predominant irritable bowel syndrome. Gastroenterology 123, 425–432 (2002).

    CAS  PubMed  Google Scholar 

  255. 255.

    Enck, P. et al. Irritable bowel syndrome. Nat. Rev. Dis. Primers 2, 16014 (2016).

    PubMed  PubMed Central  Google Scholar 

  256. 256.

    Gazouli, M. et al. Lessons learned—resolving the enigma of genetic factors in IBS. Nat. Rev. Gastroenterol. Hepatol. 13, 77–87 (2016).

    CAS  PubMed  Google Scholar 

  257. 257.

    Henstrom, M. et al. Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome. Gut 76, 263–270 (2016).

    Google Scholar 

  258. 258.

    Wong, B. S. et al. Pharmacogenetics of the effects of colesevelam on colonic transit in irritable bowel syndrome with diarrhea. Dig. Dis. Sci. 57, 1222–1226 (2012).

    CAS  PubMed  Google Scholar 

  259. 259.

    Boeckxstaens, G. E. et al. Phenotyping of subjects for large scale studies on patients with IBS. Neurogastroenterol Motil. 28, 1134–1147 (2016).

    CAS  PubMed  Google Scholar 

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Review criteria

This Review is based on literature searches performed in the PubMed database in August 2017 using the search terms “irritable bowel syndrome”, “functional bowel disorder”, “constipation”, “diarrhea”, “bloating”, “clinical trial”, “treatment”, “diet”, “probiotics”, “antibiotics”, “prebiotics”, “FMT”, “inflammation”, “prokinetics”, “microbiota”, “5-hydroxytryptamine”, “serotonin”, “secretagogue”, “herb” and “medical foods”. The reference lists of identified articles or linked articles were searched for further papers. English-language original research and review articles were considered. No publication date restrictions were applied. The Review is also based on the authors’ personal knowledge of ongoing clinical trials as well as on a search of Clinicaltrials.gov using the terms “irritable bowel syndrome”, “constipation” and “diarrhea”.

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Nature Reviews Gastroenterology & Hepatology thanks B. Niesler, E. Quigley and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Correspondence to Magnus Simrén.

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M.S. has received unrestricted research grants from Danone and Ferring Pharmaceuticals; he has served as a consultant and/or advisory board member for Albireo, Allergan, Almirall, AstraZeneca, Danone, Glycom, Menarini, Nestlé and Shire and as a speaker for Allergan, Almirall, Menarini, Shire, Takeda and Tillotts. J.T. has given scientific advice to Almirall, AstraZeneca, Danone, Menarini, Novartis, Nycomed, Ocera, Ono pharma, Shire, SK Life Sciences, Theravance, Tranzyme, XenoPort and Zeria and has been a member of the Speaker Bureau for Abbott, Alfa Wasserman, Almirall, AstraZeneca, Janssen, Menarini, Novartis, Nycomed, Shire and Zeria.

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Simrén, M., Tack, J. New treatments and therapeutic targets for IBS and other functional bowel disorders. Nat Rev Gastroenterol Hepatol 15, 589–605 (2018). https://doi.org/10.1038/s41575-018-0034-5

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