Functional dyspepsia

Abstract

Functional dyspepsia is one of the most prevalent functional gastrointestinal disorders. Functional dyspepsia comprises three subtypes with presumed different pathophysiology and aetiology: postprandial distress syndrome (PDS), epigastric pain syndrome (EPS) and a subtype with overlapping PDS and EPS features. Functional dyspepsia symptoms can be caused by disturbed gastric motility (for example, inadequate fundic accommodation or delayed gastric emptying), gastric sensation (for example, sensations associated with hypersensitivity to gas and bloating) or gastric and duodenal inflammation. A genetic predisposition is probable but less evident than in other functional gastrointestinal disorders, such as irritable bowel syndrome (IBS). Psychiatric comorbidity and psychopathological state and trait characteristics could also play a part, although they are not specific to functional dyspepsia and are less pronounced than in IBS. Possible differential diagnoses include Helicobacter pylori infection and peptic ulceration. Pharmacological therapy is mostly based on the subtype of functional dyspepsia, such as prokinetic and fundus-relaxing drugs for PDS and acid-suppressive drugs for EPS, whereas centrally active neuromodulators and herbal drugs play a minor part. Psychotherapy is effective only in a small subset of patients, whereas quality of life can be severely affected in nearly all patients. Future therapies might include novel compounds that attempt to treat the underlying gastric and duodenal inflammation.

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Figure 1: Putative mechanisms of functional dyspepsia symptoms at the macroscopic and microscopic level.
Figure 2: Proposed model for the interaction of factors involved in the generation of functional dyspepsia symptoms.
Figure 3: Diagnostic algorithm in functional dyspepsia.
Figure 4: Treatment algorithm in functional dyspepsia.
Figure 5: Foods and food groups frequently associated with symptom induction or exacerbation in functional dyspepsia.

References

  1. 1

    Barbara, L. et al. Definition and investigation of dyspepsia. Consensus of an international ad hoc working party. Dig. Dis. Sci. 34, 1272–1276 (1989).

    Google Scholar 

  2. 2

    Holtmann, G., Stanghellini, V. & Talley, N. J. Nomenclature of dyspepsia, dyspepsia subgroups and functional dyspepsia: clarifying the concepts. Baillieres Clin. Gastroenterol. 12, 417–433 (1998).

    Google Scholar 

  3. 3

    Stanghellini, V. et al. Gastroduodenal disorders. Gastroenterology 150, 1380–1392 (2016). This excellent publication defines the latest version of the Rome IV criteria (Rome IV) for gastroduodenal disorders and discusses the clinical features of functional dyspepsia.

    Google Scholar 

  4. 4

    Rodríguez-García, J. L. & Carmona-Sánchez, R. Functional dyspepsia and dyspepsia associated with Helicobacter pylori infection: do they have different clinical characteristics? Rev. Gastroenterol. Mex. 81, 126–133 (2016).

    Google Scholar 

  5. 5

    Sugano, K. et al. Kyoto global consensus report on Helicobacter pylori gastritis. Gut 64, 1353–1367 (2015).

    Google Scholar 

  6. 6

    Ford, A. C., Moayyedi, P., Jarbol, D. E., Logan, R. F. & Delaney, B. C. Meta-analysis: Helicobacter pylori ‘test and treat’ compared with empirical acid suppression for managing dyspepsia. Aliment. Pharmacol. Ther. 28, 534–544 (2008).

    Google Scholar 

  7. 7

    Ang, T. L. et al. Helicobacter pylori eradication versus prokinetics in the treatment of functional dyspepsia: a randomized, double-blind study. J. Gastroenterol. 41, 647–653 (2006).

    Google Scholar 

  8. 8

    Quigley, E. M. & Lacy, B. E. Overlap of functional dyspepsia and GERD — diagnostic and treatment implications. Nat. Rev. Gastroenterol. Hepatol. 10, 175–186 (2013).

    Google Scholar 

  9. 9

    Pleyer, C. et al. Overdiagnosis of gastro-esophageal reflux disease and underdiagnosis of functional dyspepsia in a USA community. Neurogastroenterol. Motil. 26, 1163–1171 (2014).

    Google Scholar 

  10. 10

    Friesen, C. A., Rosen, J. M. & Schurman, J. V. Prevalence of overlap syndromes and symptoms in pediatric functional dyspepsia. BMC Gastroenterol. 16, 75 (2016).

    Google Scholar 

  11. 11

    Mahadeva, S. & Ford, A. C. Clinical and epidemiological differences in functional dyspepsia between the east and the west. Neurogastroenterol. Motil. 28, 167–174 (2016).

    Google Scholar 

  12. 12

    Le Pluart, D. et al. Functional gastrointestinal disorders in 35,447 adults and their association with body mass index. Aliment. Pharmacol. Ther. 41, 758–767 (2015).

    Google Scholar 

  13. 13

    Suzuki, H. & Hibi, T. Overlap syndrome of functional dyspepsia and irritable bowel syndrome — are both diseases mutually exclusive? J. Neurogastroenterol. Motil. 17, 360–365 (2011).

    Google Scholar 

  14. 14

    Rasmussen, S. et al. Overlap of symptoms of gastroesophageal reflux disease, dyspepsia and irritable bowel syndrome in the general population. Scand. J. Gastroenterol. 50, 162–169 (2015).

    Google Scholar 

  15. 15

    Yao, X. et al. The overlap of upper functional gastrointestinal disorders with irritable bowel syndrome in Chinese outpatients: a multicenter study. J. Gastroenterol. Hepatol. 31, 1584–1593 (2016).

    Google Scholar 

  16. 16

    Talley, N. J., Weaver, A. L., Zinsmeister, A. R. & Melton, L. J. 3 rd Onset and disappearance of gastrointestinal symptoms and functional gastrointestinal disorders. Am. J. Epidemiol. 136, 165–177 (1992).

    Google Scholar 

  17. 17

    Olafsdottir, L. B., Gudjonsson, H., Jonsdottir, H. H. & Thjodleifsson, B. Natural history of functional dyspepsia: a 10-year population-based study. Digestion 81, 53–61 (2010). This is an excellent epidemiological study assessing onset and disappearance of functional dyspepsia in the general population.

    Google Scholar 

  18. 18

    Brook, R. A., Kleinman, N. L., Choung, R. S., Smeeding, J. E. & Talley, N. J. Excess comorbidity prevalence and cost associated with functional dyspepsia in an employed population. Dig. Dis. Sci. 57, 109–118 (2012).

    Google Scholar 

  19. 19

    Matsuzaki, J. et al. High frequency of overlap between functional dyspepsia and overactive bladder. Neurogastroenterol. Motil. 24, 821–827 (2012).

    Google Scholar 

  20. 20

    Jones, M. P., Walker, M. M., Ford, A. C. & Talley, N. J. The overlap of atopy and functional gastrointestinal disorders among 23,471 patients in primary care. Aliment. Pharmacol. Ther. 40, 382–391 (2014).

    Google Scholar 

  21. 21

    Persson, R. et al. The relationship between irritable bowel syndrome, functional dyspepsia, chronic fatigue and overactive bladder syndrome: a controlled study 6 years after acute gastrointestinal infection. BMC Gastroenterol. 15, 66 (2015).

    Google Scholar 

  22. 22

    Koloski, N. A. et al. The brain–gut pathway in functional gastrointestinal disorders is bidirectional: a 12-year prospective population-based study. Gut 61, 1284–1290 (2012). This 12-year, longitudinal, prospective, population-based study supports bi-directional interactions between the central nervous system and the gut in patients with IBS and functional dyspepsia.

    Google Scholar 

  23. 23

    Choung, R. S., Locke, G. R. 3rd, Schleck, C. D., Zinsmeister, A. R. & Talley, N. J. The effects of ageing on the onset and disappearance of unexplained abdominal pain: a population-based study. Aliment. Pharmacol. Ther. 39, 217–225 (2014).

    Google Scholar 

  24. 24

    Napthali, K., Koloski, N., Walker, M. M. & Talley, N. J. Women and functional dyspepsia. Women's health (Lond.) 12, 241–250 (2016).

    Google Scholar 

  25. 25

    Pike, B. L., Porter, C. K., Sorrell, T. J. & Riddle, M. S. Acute gastroenteritis and the risk of functional dyspepsia: a systematic review and meta-analysis. Am. J. Gastroenterol. 108, 1558–1563; quiz 1564 (2013).

    Google Scholar 

  26. 26

    Paula, H. et al. Non-enteric infections, antibiotic use, and risk of development of functional gastrointestinal disorders. Neurogastroenterol. Motil. 27, 1580–1586 (2015).

    Google Scholar 

  27. 27

    Holtmann, G., Gschossmann, J., Buenger, L., Gerken, G. & Talley, N. J. Do changes in visceral sensory function determine the development of dyspepsia during treatment with aspirin? Gastroenterology 123, 1451–1458 (2002).

    Google Scholar 

  28. 28

    Oshima, T., Fukui, H., Watari, J. & Miwa, H. Childhood abuse history is associated with the development of dyspepsia: a population-based survey in Japan. J. Gastroenterol. 50, 744–750 (2015).

    Google Scholar 

  29. 29

    Koloski, N. A. et al. Identification of early environmental risk factors for irritable bowel syndrome and dyspepsia. Neurogastroenterol. Motil. 27, 1317–1325 (2015).

    Google Scholar 

  30. 30

    Jones, M. P., Oudenhove, L. V., Koloski, N., Tack, J. & Talley, N. J. Early life factors initiate a ‘vicious circle’ of affective and gastrointestinal symptoms: a longitudinal study. United European Gastroenterol. J. 1, 394–402 (2013).

    Google Scholar 

  31. 31

    Fujiwara, Y. et al. Cigarette smoking and its association with overlapping gastroesophageal reflux disease, functional dyspepsia, or irritable bowel syndrome. Intern. Med. 50, 2443–2447 (2011).

    Google Scholar 

  32. 32

    Jung, J. G. et al. Visceral adiposity is associated with an increased risk of functional dyspepsia. J. Gastroenterol. Hepatol. 31, 567–574 (2016).

    Google Scholar 

  33. 33

    Deding, U., Torp-Pedersen, C. & Boggild, H. Perceived stress as a risk factor for dyspepsia: a register-based cohort study. Eur. J. Gastroenterol. Hepatol. 29, 560–567 (2017).

    Google Scholar 

  34. 34

    Ford, A. C., Marwaha, A., Sood, R. & Moayyedi, P. Global prevalence of, and risk factors for, uninvestigated dyspepsia: a meta-analysis. Gut 64, 1049–1057 (2015). This is an excellent meta-analysis of uninvestigated dyspepsia and its risk factors.

    Google Scholar 

  35. 35

    Ford, A. C. et al. Prevalence of uninvestigated dyspepsia 8 years after a large waterborne outbreak of bacterial dysentery: a cohort study. Gastroenterology 138, 1727–1736; quiz e1712 (2010).

    Google Scholar 

  36. 36

    Mearin, F. et al. Dyspepsia and irritable bowel syndrome after a Salmonella gastroenteritis outbreak: one-year follow-up cohort study. Gastroenterology 129, 98–104 (2005). This is the first and one of the largest investigations of post-infectious IBS and functional dyspepsia after a Salmonella outbreak in Spain.

    Google Scholar 

  37. 37

    Talley, N. J. & Ford, A. C. Functional dyspepsia. N. Engl. J. Med. 373, 1853–1863 (2015). This is a comprehensive review discussing the clinical management of functional dyspepsia, including diagnosis and treatment.

    Google Scholar 

  38. 38

    Aro, P., Talley, N. J., Johansson, S. E., Agreus, L. & Ronkainen, J. Anxiety is linked to new-onset dyspepsia in the Swedish population: a 10-year follow-up study. Gastroenterology 148, 928–937 (2015).

    Google Scholar 

  39. 39

    Koloski, N. A., Jones, M. & Talley, N. J. Evidence that independent gut-to-brain and brain-to-gut pathways operate in the irritable bowel syndrome and functional dyspepsia: a 1-year population-based prospective study. Aliment. Pharmacol. Ther. 44, 592–600 (2016).

    Google Scholar 

  40. 40

    Enck, P. et al. Irritable bowel syndrome. Nat. Rev. Dis. Primers 2, 16014 (2016). This is an excellent Primer on the other important and equally prevalent functional bowel disorder, IBS.

    Google Scholar 

  41. 41

    Porcelli, P., Leandro, G. & De Carne, M. Functional gastrointestinal disorders and eating disorders. Relevance of the association in clinical management. Scand. J. Gastroenterol. 33, 577–582 (1998).

    Google Scholar 

  42. 42

    Santonicola, A. et al. Prevalence of functional dyspepsia and its subgroups in patients with eating disorders. World J. Gastroenterol. 18, 4379–4385 (2012).

    Google Scholar 

  43. 43

    Brook, R. A. et al. Functional dyspepsia impacts absenteeism and direct and indirect costs. Clin. Gastroenterol. Hepatol. 8, 498–503 (2010).

    Google Scholar 

  44. 44

    Sander, G. B. et al. Influence of organic and functional dyspepsia on work productivity: the HEROES-DIP study. Value Health 14, S126–S129 (2011).

    Google Scholar 

  45. 45

    Tack, J., Bisschops, R. & Sarnelli, G. Pathophysiology and treatment of functional dyspepsia. Gastroenterology 127, 1239–1255 (2004).

    Google Scholar 

  46. 46

    Tack, J. et al. Functional gastroduodenal disorders. Gastroenterology 130, 1466–1479 (2006).

    Google Scholar 

  47. 47

    Tack, J., Piessevaux, H., Coulie, B., Caenepeel, P. & Janssens, J. Role of impaired gastric accommodation to a meal in functional dyspepsia. Gastroenterology 115, 1346–1352 (1998).

    Google Scholar 

  48. 48

    Farre, R. & Tack, J. Food and symptom generation in functional gastrointestinal disorders: physiological aspects. Am. J. Gastroenterol. 108, 698–706 (2013).

    Google Scholar 

  49. 49

    Vanheel, H. et al. Pathophysiological abnormalities in functional dyspepsia subgroups according to the Rome III criteria. Am. J. Gastroenterol. 112, 132–140 (2017).

    Google Scholar 

  50. 50

    Bisschops, R. et al. Relationship between symptoms and ingestion of a meal in functional dyspepsia. Gut 57, 1495–1503 (2008).

    Google Scholar 

  51. 51

    Kindt, S., Tertychnyy, A., de Hertogh, G., Geboes, K. & Tack, J. Intestinal immune activation in presumed post-infectious functional dyspepsia. Neurogastroenterol. Motil. 21, 832–e856 (2009).

    Google Scholar 

  52. 52

    Futagami, S. et al. Migration of eosinophils and CCR2-/CD68-double positive cells into the duodenal mucosa of patients with postinfectious functional dyspepsia. Am. J. Gastroenterol. 105, 1835–1842 (2010).

    Google Scholar 

  53. 53

    Mirbagheri, S. S. et al. Impact of microscopic duodenitis on symptomatic response to Helicobacter pylori eradication in functional dyspepsia. Dig. Dis. Sci. 60, 163–167 (2015).

    Google Scholar 

  54. 54

    Powell, N., Walker, M. M. & Talley, N. J. The mucosal immune system: master regulator of bidirectional gut-brain communications. Nat. Rev. Gastroenterol. Hepatol. 14, 143–159 (2017).

    Google Scholar 

  55. 55

    Furness, J. B. The enteric nervous system and neurogastroenterology. Nat. Rev. Gastroenterol. Hepatol. 9, 286–294 (2012).

    Google Scholar 

  56. 56

    Savidge, T. C. et al. Enteric glia regulate intestinal barrier function and inflammation via release of S-nitrosoglutathione. Gastroenterology 132, 1344–1358 (2007).

    Google Scholar 

  57. 57

    Oustamanolakis, P. & Tack, J. Dyspepsia: organic versus functional. J. Clin. Gastroenterol. 46, 175–190 (2012). This is an excellent systematic review discussing the differences between organic and functional dyspepsia.

    Google Scholar 

  58. 58

    Testoni, P. A., Bagnolo, F. & Tittobello, A. Interdigestive antro-duodenal motor disorders in functional dyspepsia. Associated chronic gastritis correlates with a further motor impairment. Ital. J. Gastroenterol. 24, 440–445 (1992).

    Google Scholar 

  59. 59

    Kellow, J. E. Motility-like dyspepsia. Current concepts in pathogenesis, investigation and management. Med. J. Aust. 157, 385–388 (1992).

    Google Scholar 

  60. 60

    Urbain, J. L. et al. Dynamic antral scintigraphy to characterize gastric antral motility in functional dyspepsia. J. Nucl. Med. 36, 1579–1586 (1995).

    Google Scholar 

  61. 61

    Holtmann, G., Goebell, H. & Talley, J. Impaired small intestinal peristaltic reflexes and sensory thresholds are independent functional disturbances in patients with chronic unexplained dyspepsia. Am. J. Gastroenterol. 91, 485–491 (1996).

    Google Scholar 

  62. 62

    Jebbink, R. J., vanBerge-Henegouwen, G. P., Akkermans, L. M. & Smout, A. J. Antroduodenal manometry: 24-hour ambulatory monitoring versus short-term stationary manometry in patients with functional dyspepsia. Eur. J. Gastroenterol. Hepatol. 7, 109–116 (1995).

    Google Scholar 

  63. 63

    Troncon, L. E., Thompson, D. G., Ahluwalia, N. K., Barlow, J. & Heggie, L. Relations between upper abdominal symptoms and gastric distension abnormalities in dysmotility like functional dyspepsia and after vagotomy. Gut 37, 17–22 (1995).

    Google Scholar 

  64. 64

    Gilja, O. H., Hausken, T., Wilhelmsen, I. & Berstad, A. Impaired accommodation of proximal stomach to a meal in functional dyspepsia. Dig. Dis. Sci. 41, 689–696 (1996).

    Google Scholar 

  65. 65

    Kim, D. Y. et al. Noninvasive measurement of gastric accommodation in patients with idiopathic nonulcer dyspepsia. Am. J. Gastroenterol. 96, 3099–3105 (2001).

    Google Scholar 

  66. 66

    Bortolotti, M. et al. Patterns of gastric emptying in dysmotility-like dyspepsia. Scand. J. Gastroenterol. 30, 408–410 (1995).

    Google Scholar 

  67. 67

    Coffin, B., Azpiroz, F., Guarner, F. & Malagelada, J. R. Selective gastric hypersensitivity and reflex hyporeactivity in functional dyspepsia. Gastroenterology 107, 1345–1351 (1994).

    Google Scholar 

  68. 68

    Mertz, H., Fullerton, S., Naliboff, B. & Mayer, E. A. Symptoms and visceral perception in severe functional and organic dyspepsia. Gut 42, 814–822 (1998).

    Google Scholar 

  69. 69

    Simren, M. et al. Visceral hypersensitivity is associated with GI symptom severity in functional GI disorders: consistent findings from five different patient cohorts. Guthttp://dx.doi.org/10.1136/gutjnl-2016-312361 (2017).

  70. 70

    Greydanus, M. P. et al. Neurohormonal factors in functional dyspepsia: insights on pathophysiological mechanisms. Gastroenterology 100, 1311–1318 (1991).

    Google Scholar 

  71. 71

    Bouin, M. et al. Intolerance to visceral distension in functional dyspepsia or irritable bowel syndrome: an organ specific defect or a pan intestinal dysregulation? Neurogastroenterol. Motil. 16, 311–314 (2004).

    Google Scholar 

  72. 72

    Bouin, M., Lupien, F., Riberdy-Poitras, M. & Poitras, P. Tolerance to gastric distension in patients with functional dyspepsia: modulation by a cholinergic and nitrergic method. Eur. J. Gastroenterol. Hepatol. 18, 63–68 (2006).

    Google Scholar 

  73. 73

    Gilja, O. H., Hausken, T., Bang, C. J. & Berstad, A. Effect of glyceryl trinitrate on gastric accommodation and symptoms in functional dyspepsia. Dig. Dis. Sci. 42, 2124–2131 (1997).

    Google Scholar 

  74. 74

    Lee, K. J. et al. A pilot study on duodenal acid exposure and its relationship to symptoms in functional dyspepsia with prominent nausea. Am. J. Gastroenterol. 99, 1765–1773 (2004).

    Google Scholar 

  75. 75

    Samsom, M., Verhagen, M. A., vanBerge Henegouwen, G. P. & Smout, A. J. Abnormal clearance of exogenous acid and increased acid sensitivity of the proximal duodenum in dyspeptic patients. Gastroenterology 116, 515–520 (1999).

    Google Scholar 

  76. 76

    Hammer, J., Fuhrer, M., Pipal, L. & Matiasek, J. Hypersensitivity for capsaicin in patients with functional dyspepsia. Neurogastroenterol. Motil. 20, 125–133 (2008).

    Google Scholar 

  77. 77

    Barbera, R., Feinle, C. & Read, N. W. Nutrient-specific modulation of gastric mechanosensitivity in patients with functional dyspepsia. Dig. Dis. Sci. 40, 1636–1641 (1995).

    Google Scholar 

  78. 78

    Feinle-Bisset, C. Upper gastrointestinal sensitivity to meal-related signals in adult humans — relevance to appetite regulation and gut symptoms in health, obesity and functional dyspepsia. Physiol. Behav. 162, 69–82 (2016).

    Google Scholar 

  79. 79

    Tanaka, F. et al. Concentration of glial cell line-derived neurotrophic factor positively correlates with symptoms in functional dyspepsia. Dig. Dis. Sci. 61, 3478–3485 (2016).

    Google Scholar 

  80. 80

    Choi, Y. J. et al. Upregulation of vanilloid receptor-1 in functional dyspepsia with or without Helicobacter pylori infection.. Medicine (Baltimore) 95, e3410 (2016).

    Google Scholar 

  81. 81

    Li, X. et al. The study on the role of inflammatory cells and mediators in post-infectious functional dyspepsia. Scand. J. Gastroenterol. 45, 573–581 (2010).

    Google Scholar 

  82. 82

    Ostertag, D. et al. Tryptase potentiates enteric nerve activation by histamine and serotonin: relevance for the effects of mucosal biopsy supernatants from irritable bowel syndrome patients. Neurogastroenterol. Motil. 95, e3410 (2017).

    Google Scholar 

  83. 83

    Witte, A. B. et al. Decreased number of duodenal endocrine cells with unaltered serotonin-containing cells in functional dyspepsia. Am. J. Gastroenterol. 111, 1852–1853 (2016).

    Google Scholar 

  84. 84

    Holtmann, G. & Talley, N. J. Functional dyspepsia. Curr. Opin. Gastroenterol. 31, 492–498 (2015).

    Google Scholar 

  85. 85

    Ishigami, H. et al. Endoscopy-guided evaluation of duodenal mucosal permeability in functional dyspepsia. Clin. Transl Gastroenterol. 8, e83 (2017).

    Google Scholar 

  86. 86

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

    Google Scholar 

  87. 87

    Witte, A. B. et al. Duodenal epithelial transport in functional dyspepsia: role of serotonin. World J. Gastrointest. Pathophysiol. 4, 28–36 (2013).

    Google Scholar 

  88. 88

    Krueger, D. et al. Neural influences on human intestinal epithelium in vitro. J. Physiol. 594, 357–372 (2016).

    Google Scholar 

  89. 89

    Vanuytsel, T. et al. Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism. Gut 63, 1293–1299 (2014). This study shows that in healthy individuals, acute psychological stress and peripheral corticotropin-releasing hormone increase small-intestinal permeability and suggests the involvement of mast cells.

    Google Scholar 

  90. 90

    Wauters, L., Nightingale, S., Talley, N. J., Sulaiman, B. & Walker, M. M. Functional dyspepsia is associated with duodenal eosinophilia in an Australian paediatric cohort. Aliment. Pharmacol. Ther. 45, 1358–1364 (2017).

    Google Scholar 

  91. 91

    Talley, N. J. et al. Non-ulcer dyspepsia and duodenal eosinophilia: an adult endoscopic population-based case-control study. Clin. Gastroenterol. Hepatol. 5, 1175–1183 (2007).

    Google Scholar 

  92. 92

    Cirillo, C. et al. Evidence for neuronal and structural changes in submucous ganglia of patients with functional dyspepsia. Am. J. Gastroenterol. 110, 1205–1215 (2015).

    Google Scholar 

  93. 93

    Du, L. et al. Increased duodenal eosinophil degranulation in patients with functional dyspepsia: a prospective study. Sci. Rep. 6, 34305 (2016).

    Google Scholar 

  94. 94

    Liebregts, T. et al. Small bowel homing T cells are associated with symptoms and delayed gastric emptying in functional dyspepsia. Am. J. Gastroenterol. 106, 1089–1098 (2011).

    Google Scholar 

  95. 95

    Walker, M. M. et al. Duodenal eosinophilia and early satiety in functional dyspepsia: confirmation of a positive association in an Australian cohort. J. Gastroenterol. Hepatol. 29, 474–479 (2014).

    Google Scholar 

  96. 96

    Wang, X. et al. Quantitative evaluation of duodenal eosinophils and mast cells in adult patients with functional dyspepsia. Ann. Diagn. Pathol. 19, 50–56 (2015).

    Google Scholar 

  97. 97

    Powell, N., Walker, M. M. & Talley, N. J. Gastrointestinal eosinophils in health, disease and functional disorders. Nat. Rev. Gastroenterol. Hepatol. 7, 146–156 (2010).

    Google Scholar 

  98. 98

    Shimura, S. et al. Small intestinal bacterial overgrowth in patients with refractory functional gastrointestinal disorders. J. Neurogastroenterol. Motil. 22, 60–68 (2016).

    Google Scholar 

  99. 99

    Costa, M. B., Azeredo, I. L. Jr, Marciano, R. D., Caldeira, L. M. & Bafutto, M. Evaluation of small intestine bacterial overgrowth in patients with functional dyspepsia through H2 breath test. Arq. Gastroenterol. 49, 279–283 (2012).

    Google Scholar 

  100. 100

    Hadizadeh, F. et al. Faecal microbiota composition associates with abdominal pain in the general population. Guthttp://dx.doi.org/10.1136/gutjnl-2017-314792 (2017).

  101. 101

    Nakae, H., Tsuda, A., Matsuoka, T., Mine, T. & Koga, Y. Gastric microbiota in the functional dyspepsia patients treated with probiotic yogurt. BMJ Open Gastroenterol. 3, e000109 (2016).

    Google Scholar 

  102. 102

    Igarashi, M. et al. Alteration in the gastric microbiota and its restoration by probiotics in patients with functional dyspepsia. BMJ Open Gastroenterol. 4, e000144 (2017).

    Google Scholar 

  103. 103

    Zhong, L. et al. Dyspepsia and the microbiome: time to focus on the small intestine. Gut 66, 1168–1169 (2016).

    Google Scholar 

  104. 104

    Lembo, A., Zaman, M., Jones, M. & Talley, N. J. Influence of genetics on irritable bowel syndrome, gastro-oesophageal reflux and dyspepsia: a twin study. Aliment. Pharmacol. Ther. 25, 1343–1350 (2007).

    Google Scholar 

  105. 105

    Holtmann, G., Goebell, H. & Talley, N. J. Functional dyspepsia and irritable bowel syndrome: is there a common pathophysiological basis? Am. J. Gastroenterol. 92, 954–959 (1997).

    Google Scholar 

  106. 106

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

    Google Scholar 

  107. 107

    Gathaiya, N. et al. Novel associations with dyspepsia: a community-based study of familial aggregation, sleep dysfunction and somatization. Neurogastroenterol. Motil. 21, 922–e969 (2009).

    Google Scholar 

  108. 108

    Holtmann, G., Liebregts, T. & Siffert, W. Molecular basis of functional gastrointestinal disorders. Best Pract. Res. Clin. Gastroenterol. 18, 633–640 (2004).

    Google Scholar 

  109. 109

    Holtmann, G. et al. G-Protein β3 subunit 825 CC genotype is associated with unexplained (functional) dyspepsia. Gastroenterology 126, 971–979 (2004).

    Google Scholar 

  110. 110

    Oshima, T. et al. The G-protein β3 subunit 825 TT genotype is associated with epigastric pain syndrome-like dyspepsia. BMC Med. Genet. 11, 13 (2010).

    Google Scholar 

  111. 111

    van Lelyveld, N., Linde, J. T., Schipper, M. & Samsom, M. Candidate genotypes associated with functional dyspepsia. Neurogastroenterol. Motil. 20, 767–773 (2008).

    Google Scholar 

  112. 112

    Tahara, T. et al. Homozygous 825T allele of the GNB3 protein influences the susceptibility of Japanese to dyspepsia. Dig. Dis. Sci. 53, 642–646 (2008).

    Google Scholar 

  113. 113

    Holtmann, G., van Rensburg, C., Schwan, T., Sander, P. & Siffert, W. Improvement of non-steroidal anti-inflammatory drug-induced gastrointestinal symptoms during proton pump inhibitor treatment: are G-protein β3 subunit genotype, Helicobacter pylori status, and environmental factors response modifiers?. Digestion 84, 289–298 (2011).

    Google Scholar 

  114. 114

    Saito, Y. A. et al. Polymorphisms of 5-HTT LPR and GNβ3 825C>T and response to antidepressant treatment in functional dyspepsia: a study from the functional dyspepsia treatment trial. Am. J. Gastroenterol. 112, 903–909 (2017).

    Google Scholar 

  115. 115

    Mawe, G. M. & Hoffman, J. M. Serotonin signalling in the gut — functions, dysfunctions and therapeutic targets. Nat. Rev. Gastroenterol. Hepatol. 10, 473–486 (2013).

    Google Scholar 

  116. 116

    Kerckhoffs, A. P., ter Linde, J. J., Akkermans, L. M. & Samsom, M. SERT and TPH-1 mRNA expression are reduced in irritable bowel syndrome patients regardless of visceral sensitivity state in large intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G1053–G1060 (2012).

    Google Scholar 

  117. 117

    Jones, R. H. et al. Alosetron relieves pain and improves bowel function compared with mebeverine in female nonconstipated irritable bowel syndrome patients. Aliment. Pharmacol. Ther. 13, 1419–1427 (1999).

    Google Scholar 

  118. 118

    Camilleri, C. E. et al. A study of candidate genotypes associated with dyspepsia in a U.S. community. Am. J. Gastroenterol. 101, 581–592 (2006).

    Google Scholar 

  119. 119

    Locke, G. R. 3 rd, Ackerman, M. J., Zinsmeister, A. R., Thapa, P. & Farrugia, G. Gastrointestinal symptoms in families of patients with an SCN5A-encoded cardiac channelopathy: evidence of an intestinal channelopathy. Am. J. Gastroenterol. 101, 1299–1304 (2006).

    Google Scholar 

  120. 120

    Van Oudenhove, L. & Aziz, Q. The role of psychosocial factors and psychiatric disorders in functional dyspepsia. Nat. Rev. Gastroenterol. Hepatol. 10, 158–167 (2013). This is a highly readable and comprehensive review on the role of psychological factors in functional dyspepsia.

    Google Scholar 

  121. 121

    Van Oudenhove, L. et al. Biopsychosocial aspects of functional gastrointestinal disorders. Gastroenterologyhttp://dx.doi.org/10.1053/j.gastro.2016.02.027 (2016).

  122. 122

    Padhy, S. K., Mishra, S., Sarkar, S., Bang, L. G. & Panigrahi, M. Comparison of psychiatric morbidity in patients with irritable bowel syndrome and non-ulcer dyspepsia. Ind. Psychiatry J. 25, 29–34 (2016).

    Google Scholar 

  123. 123

    Koloski, N. A., Talley, N. J. & Boyce, P. M. Predictors of health care seeking for irritable bowel syndrome and nonulcer dyspepsia: a critical review of the literature on symptom and psychosocial factors. Am. J. Gastroenterol. 96, 1340–1349 (2001).

    Google Scholar 

  124. 124

    Koloski, N. A., Talley, N. J. & Boyce, P. M. The impact of functional gastrointestinal disorders on quality of life. Am. J. Gastroenterol. 95, 67–71 (2000).

    Google Scholar 

  125. 125

    Kindt, S. et al. Longitudinal and cross-sectional factors associated with long-term clinical course in functional dyspepsia: a 5-year follow-up study. Am. J. Gastroenterol. 106, 340–348 (2011).

    Google Scholar 

  126. 126

    Wouters, M. M. & Boeckxstaens, G. E. Is there a causal link between psychological disorders and functional gastrointestinal disorders? Expert Rev. Gastroenterol. Hepatol. 10, 5–8 (2016).

    Google Scholar 

  127. 127

    Jones, M. P. et al. Mood and anxiety disorders precede development of functional gastrointestinal disorders in patients but not in the population. Clin. Gastroenterol. Hepatol. 15, 1014–1020 (2017).

    Google Scholar 

  128. 128

    Fang, Y. J. et al. Distinct aetiopathogenesis in subgroups of functional dyspepsia according to the Rome III criteria. Gut 64, 1517–1528 (2015).

    Google Scholar 

  129. 129

    Holtmann, G. et al. Clinical presentation and personality factors are predictors of the response to treatment in patients with functional dyspepsia; a randomized, double-blind placebo-controlled crossover study. Dig. Dis. Sci. 49, 672–679 (2004).

    Google Scholar 

  130. 130

    Wu, C. Y. et al. Effect of fluoxetine on symptoms and gastric dysrhythmia in patients with functional dyspepsia. Hepatogastroenterology 50, 278–283 (2003).

    Google Scholar 

  131. 131

    Geeraerts, B. et al. Influence of abuse history on gastric sensorimotor function in functional dyspepsia. Neurogastroenterol. Motil. 21, 33–41 (2009).

    Google Scholar 

  132. 132

    Van Oudenhove, L. et al. Abuse history, depression, and somatization are associated with gastric sensitivity and gastric emptying in functional dyspepsia. Psychosom. Med. 73, 648–655 (2011).

    Google Scholar 

  133. 133

    Ly, H. G., Weltens, N., Tack, J. & Van Oudenhove, L. Acute anxiety and anxiety disorders are associated with impaired gastric accommodation in patients with functional dyspepsia. Clin. Gastroenterol. Hepatol. 13, 1584–1591.e3 (2015).

    Google Scholar 

  134. 134

    Lorena, S. L., Tinois, E., Brunetto, S. Q., Camargo, E. E. & Mesquita, M. A. Gastric emptying and intragastric distribution of a solid meal in functional dyspepsia: influence of gender and anxiety. J. Clin. Gastroenterol. 38, 230–236 (2004).

    Google Scholar 

  135. 135

    Geeraerts, B. et al. Influence of experimentally induced anxiety on gastric sensorimotor function in humans. Gastroenterology 129, 1437–1444 (2005).

    Google Scholar 

  136. 136

    Sharma, A., Van Oudenhove, L., Paine, P., Gregory, L. & Aziz, Q. Anxiety increases acid-induced esophageal hyperalgesia. Psychosom. Med. 72, 802–809 (2010).

    Google Scholar 

  137. 137

    Lee, H. S., An, Y. S., Kang, J., Yoo, J. H. & Lee, K. J. Effect of acute auditory stress on gastric motor responses to a meal in healthy volunteers. J. Gastroenterol. Hepatol. 28, 1699–1704 (2013).

    Google Scholar 

  138. 138

    Lu, H. C. et al. Neuronal correlates in the modulation of placebo analgesia in experimentally-induced esophageal pain: a 3T-fMRI study. Pain 148, 75–83 (2010).

    Google Scholar 

  139. 139

    Chiarioni, G., Vantini, I., De Iorio, F. & Benini, L. Prokinetic effect of gut-oriented hypnosis on gastric emptying. Aliment. Pharmacol. Ther. 23, 1241–1249 (2006).

    Google Scholar 

  140. 140

    Coen, S. J. et al. Effects of attention on visceral stimulus intensity encoding in the male human brain. Gastroenterology 135, 2065–2074.e1 (2008).

    Google Scholar 

  141. 141

    Van Oudenhove, L. et al. Relationship between anxiety and gastric sensorimotor function in functional dyspepsia. Psychosom. Med. 69, 455–463 (2007).

    Google Scholar 

  142. 142

    Hausken, T. et al. Low vagal tone and antral dysmotility in patients with functional dyspepsia. Psychosom. Med. 55, 12–22 (1993).

    Google Scholar 

  143. 143

    Hveem, K., Hausken, T., Svebak, S. & Berstad, A. Gastric antral motility in functional dyspepsia. Effect of mental stress and cisapride. Scand. J. Gastroenterol. 31, 452–457 (1996).

    Google Scholar 

  144. 144

    Vanner, S. et al. Fundamentals of neurogastroenterology: basic science. Gastroenterologyhttp://dx.doi.org/10.1053/j.gastro.2016.02.018 (2016).

  145. 145

    Boeckxstaens, G. et al. Fundamentals of neurogastroenterology: physiology/motility — sensation. Gastroenterologyhttp://dx.doi.org/10.1053/j.gastro.2016.02.030 (2016). This is a critical review of normal physiology and pathophysiology of gastrointestinal function, detailing the processes underlying symptom generation in functional gastrointestinal disorders.

  146. 146

    Feinle-Bisset, C., Meier, B., Fried, M. & Beglinger, C. Role of cognitive factors in symptom induction following high and low fat meals in patients with functional dyspepsia. Gut 52, 1414–1418 (2003).

    Google Scholar 

  147. 147

    Al Omran, Y. & Aziz, Q. Functional brain imaging in gastroenterology: to new beginnings. Nat. Rev. Gastroenterol. Hepatol. 11, 565–576 (2014).

    Google Scholar 

  148. 148

    Mayer, E. A., Gupta, A., Kilpatrick, L. A. & Hong, J. Y. Imaging brain mechanisms in chronic visceral pain. Pain 156, S50–S63 (2015).

    Google Scholar 

  149. 149

    Lee, I. S., Wang, H., Chae, Y., Preissl, H. & Enck, P. Functional neuroimaging studies in functional dyspepsia patients: a systematic review. Neurogastroenterol. Motil. 28, 793–805 (2016).

    Google Scholar 

  150. 150

    Nan, J. et al. Anatomically related gray and white matter alterations in the brains of functional dyspepsia patients. Neurogastroenterol. Motil. 27, 856–864 (2015).

    Google Scholar 

  151. 151

    Zeng, F. et al. Regional brain structural abnormality in meal-related functional dyspepsia patients: a voxel-based morphometry study. PLoS ONE 8, e68383 (2013).

    Google Scholar 

  152. 152

    Liu, P. et al. Altered structural covariance of the striatum in functional dyspepsia patients. Neurogastroenterol. Motil. 26, 1144–1154 (2014).

    Google Scholar 

  153. 153

    Zhou, G. et al. White-matter microstructural changes in functional dyspepsia: a diffusion tensor imaging study. Am. J. Gastroenterol. 108, 260–269 (2013).

    Google Scholar 

  154. 154

    Ly, H. G. et al. Increased cerebral cannabinoid-1 receptor availability is a stable feature of functional dyspepsia: a [F]MK-9470 PET study. Psychother. Psychosom. 84, 149–158 (2015).

    Google Scholar 

  155. 155

    Ceccarini, J. et al. Association between cerebral cannabinoid 1 receptor availability and body mass index in patients with food intake disorders and healthy subjects: a [(18)F]MK-9470 PET study. Transl Psychiatry 6, e853 (2016).

    Google Scholar 

  156. 156

    Tominaga, K. et al. Regional brain disorders of serotonin neurotransmission are associated with functional dyspepsia. Life Sci. 137, 150–157 (2015).

    Google Scholar 

  157. 157

    Van Oudenhove, L. et al. Abnormal regional brain activity during rest and (anticipated) gastric distension in functional dyspepsia and the role of anxiety: a H(2)(15)O-PET study. Am. J. Gastroenterol. 105, 913–924 (2010).

    Google Scholar 

  158. 158

    Holtmann, G., Goebell, H., Jockenhoevel, F. & Talley, N. J. Altered vagal and intestinal mechanosensory function in chronic unexplained dyspepsia. Gut 42, 501–506 (1998).

    Google Scholar 

  159. 159

    Li, M. et al. Protein kinase C mediates the corticosterone-induced sensitization of dorsal root ganglion neurons innervating the rat stomach. J. Neurogastroenterol. Motil. 23, 464–476 (2017).

    Google Scholar 

  160. 160

    Carbone, F., Vandenberghe, A., Holvoet, T., Vanuytsel, T. & Tack, J. The impact of Rome IV criteria on functional dyspepsia subgroups in secondary care. Gastroenterology 152, S304 (2017).

    Google Scholar 

  161. 161

    Tack, J., Jones, M. P., Karamanolis, G., Coulie, B. & Dubois, D. Symptom pattern and pathophysiological correlates of weight loss in tertiary-referred functional dyspepsia. Neurogastroenterol. Motil. 22, 29–35; e4–e5 (2010).

    Google Scholar 

  162. 162

    Azpiroz, F. & Malagelada, J. R. Abdominal bloating. Gastroenterology 129, 1060–1078 (2005).

    Google Scholar 

  163. 163

    Bredenoord, A. J. & Smout, A. J. Physiologic and pathologic belching. Clin. Gastroenterol. Hepatol. 5, 772–775 (2007).

    Google Scholar 

  164. 164

    Tack, J., Caenepeel, P., Fischler, B., Piessevaux, H. & Janssens, J. Symptoms associated with hypersensitivity to gastric distention in functional dyspepsia. Gastroenterology 121, 526–535 (2001).

    Google Scholar 

  165. 165

    Lobo, B. et al. Effect of selective CCK1 receptor antagonism on accommodation and tolerance of intestinal gas in functional gut disorders. J. Gastroenterol. Hepatol. 31, 288–293 (2016).

    Google Scholar 

  166. 166

    Bendezu, R. A. et al. Colonic content in health and its relation to functional gut symptoms. Neurogastroenterol. Motil. 28, 849–854 (2016).

    Google Scholar 

  167. 167

    Bendezu, R. A. et al. Intestinal gas content and distribution in health and in patients with functional gut symptoms. Neurogastroenterol. Motil. 27, 1249–1257 (2015).

    Google Scholar 

  168. 168

    Burri, E. et al. Mechanisms of postprandial abdominal bloating and distension in functional dyspepsia. Gut 63, 395–400 (2014). This study shows that in patients with functional dyspepsia, a challenge meal can induce bloating and an abnormal postural tone, leading to abdominal distension.

    Google Scholar 

  169. 169

    Barba, E. et al. Abdominothoracic mechanisms of functional abdominal distension and correction by biofeedback. Gastroenterology 148, 732–739 (2015). This study shows that abdominal distension is produced by a behavioural response (with descent of the diaphragm, protrusion of the anterior abdominal wall and minor changes in the volume of intra-abdominal content) that can be corrected by biofeedback.

    Google Scholar 

  170. 170

    Barba, E., Accarino, A., Soldevilla, A., Malagelada, J. R. & Azpiroz, F. Randomized, placebo-controlled trial of biofeedback for the treatment of rumination. Am. J. Gastroenterol. 111, 1007–1013 (2016).

    Google Scholar 

  171. 171

    Talley, N. J., Vakil, N. & Practice Parameters Committee of the American College of Gastroenterology. Guidelines for the management of dyspepsia. Am. J. Gastroenterol. 100, 2324–2337 (2005).

    Google Scholar 

  172. 172

    Talley, N. J., Walker, M. M. & Holtmann, G. Functional dyspepsia. Curr. Opin. Gastroenterol. 32, 467–473 (2016).

    Google Scholar 

  173. 173

    Stanghellini, V. et al. Risk indicators of delayed gastric emptying of solids in patients with functional dyspepsia. Gastroenterology 110, 1036–1042 (1996).

    Google Scholar 

  174. 174

    Stanghellini, V. & Cogliandro, R. Review article: adherence to Rome criteria in therapeutic trials in functional dyspepsia. Aliment. Pharmacol. Ther. 40, 435–466 (2014).

    Google Scholar 

  175. 175

    Camilleri, M. & Stanghellini, V. Current management strategies and emerging treatments for functional dyspepsia. Nat. Rev. Gastroenterol. Hepatol. 10, 187–194 (2013).

    Google Scholar 

  176. 176

    Du, L. J. et al. Helicobacter pylori eradication therapy for functional dyspepsia: systematic review and meta-analysis. World J. Gastroenterol. 22, 3486–3495 (2016).

    Google Scholar 

  177. 177

    Xu, S. et al. Symptom improvement after helicobacter pylori eradication in patients with functional dyspepsia — a multicenter, randomized, prospective cohort study. Int. J. Clin. Exp. Med. 6, 747–756 (2013).

    Google Scholar 

  178. 178

    Pilichiewicz, A. N., Horowitz, M., Holtmann, G. J., Talley, N. J. & Feinle-Bisset, C. Relationship between symptoms and dietary patterns in patients with functional dyspepsia. Clin. Gastroenterol. Hepatol. 7, 317–322 (2009). This is the first prospective study to concurrently document dietary intake and occurrence of functional dyspepsia symptoms, and it demonstrates relationships between both energy and fat intakes and fullness and bloating.

    Google Scholar 

  179. 179

    Filipovic, B. F. et al. Laboratory parameters and nutritional status in patients with functional dyspepsia. Eur. J. Intern. Med. 22, 300–304 (2011).

    Google Scholar 

  180. 180

    Mullan, A. et al. Food and nutrient intakes and eating patterns in functional and organic dyspepsia. Eur. J. Clin. Nutr. 48, 97–105 (1994).

    Google Scholar 

  181. 181

    Carvalho, R. V., Lorena, S. L., Almeida, J. R. & Mesquita, M. A. Food intolerance, diet composition, and eating patterns in functional dyspepsia patients. Dig. Dis. Sci. 55, 60–65 (2010).

    Google Scholar 

  182. 182

    Cuperus, P., Keeling, P. W. & Gibney, M. J. Eating patterns in functional dyspepsia: a case control study. Eur. J. Clin. Nutr. 50, 520–523 (1996).

    Google Scholar 

  183. 183

    Saito, Y. A., Locke, G. R. 3rd, Weaver, A. L., Zinsmeister, A. R. & Talley, N. J. Diet and functional gastrointestinal disorders: a population-based case-control study. Am. J. Gastroenterol. 100, 2743–2748 (2005).

    Google Scholar 

  184. 184

    Hassanzadeh, S. et al. Meal frequency in relation to prevalence of functional dyspepsia among Iranian adults. Nutrition 32, 242–248 (2016).

    Google Scholar 

  185. 185

    Pilichiewicz, A. N. et al. Functional dyspepsia is associated with a greater symptomatic response to fat but not carbohydrate, increased fasting and postprandial CCK, and diminished PYY. Am. J. Gastroenterol. 103, 2613–2623 (2008).

    Google Scholar 

  186. 186

    Feinle-Bisset, C. & Azpiroz, F. Dietary and lifestyle factors in functional dyspepsia. Nat. Rev. Gastroenterol. Hepatol. 10, 150–157 (2013). This is a comprehensive review of the contribution of dietary factors to symptom occurrence in functional dyspepsia.

    Google Scholar 

  187. 187

    Goktas, Z. et al. Nutritional habits in functional dyspepsia and its subgroups: a comparative study. Scand. J. Gastroenterol. 51, 903–907 (2016).

    Google Scholar 

  188. 188

    Gibson, P. R. & Shepherd, S. J. Evidence-based dietary management of functional gastrointestinal symptoms: the FODMAP approach. J. Gastroenterol. Hepatol. 25, 252–258 (2010).

    Google Scholar 

  189. 189

    Houghton, L. A., Mangall, Y. F., Dwivedi, A. & Read, N. W. Sensitivity to nutrients in patients waith non-ulcer dyspepsia. Eur. J. Gastroenterol. 5, 109–114 (1993).

    Google Scholar 

  190. 190

    Suarez, F. L., Savaiano, D. A. & Levitt, M. D. A comparison of symptoms after the consumption of milk or lactose-hydrolyzed milk by people with self-reported severe lactose intolerance. N. Engl. J. Med. 333, 1–4 (1995).

    Google Scholar 

  191. 191

    Taggart, D. & Billington, B. P. Fatty foods and dyspersia. Lancet 2, 465–466 (1966).

    Google Scholar 

  192. 192

    Accarino, A. M., Azpiroz, F. & Malagelada, J. R. Attention and distraction: effects on gut perception. Gastroenterology 113, 415–422 (1997).

    Google Scholar 

  193. 193

    Tack, J. Prokinetics and fundic relaxants in upper functional GI disorders. Curr. Opin. Pharmacol. 8, 690–696 (2008).

    Google Scholar 

  194. 194

    Tack, J., Janssen, P., Masaoka, T., Farre, R. & Van Oudenhove, L. Efficacy of buspirone, a fundus-relaxing drug, in patients with functional dyspepsia. Clin. Gastroenterol. Hepatol. 10, 1239–1245 (2012).

    Google Scholar 

  195. 195

    Miwa, H. et al. Efficacy of the 5-HT1A agonist tandospirone citrate in improving symptoms of patients with functional dyspepsia: a randomized controlled trial. Am. J. Gastroenterol. 104, 2779–2787 (2009).

    Google Scholar 

  196. 196

    Matsueda, K., Hongo, M., Tack, J., Saito, Y. & Kato, H. A placebo-controlled trial of acotiamide for meal-related symptoms of functional dyspepsia. Gut 61, 821–828 (2012).

    Google Scholar 

  197. 197

    Tack, J. et al. Efficacy of mirtazapine in patients with functional dyspepsia and weight loss. Clin. Gastroenterol. Hepatol. 14, 385–392.e4 (2016).

    Google Scholar 

  198. 198

    Moayyedi, P., Delaney, B. C., Vakil, N., Forman, D. & Talley, N. J. The efficacy of proton pump inhibitors in nonulcer dyspepsia: a systematic review and economic analysis. Gastroenterology 127, 1329–1337 (2004).

    Google Scholar 

  199. 199

    Suzuki, H. et al. Effect of lansoprazole on the epigastric symptoms of functional dyspepsia (ELF study): a multicentre, prospective, randomized, double-blind, placebo-controlled clinical trial. United European Gastroenterol. J. 1, 445–452 (2013).

    Google Scholar 

  200. 200

    Ford, A. C. et al. Efficacy of psychotropic drugs in functional dyspepsia: systematic review and meta-analysis. Gut 66, 411–420 (2015).

    Google Scholar 

  201. 201

    Talley, N. J. et al. Effect of amitriptyline and escitalopram on functional dyspepsia: a multicenter, randomized controlled study. Gastroenterology 149, 340–349.e2 (2015).

    Google Scholar 

  202. 202

    Distrutti, E. et al. Effect of acute and chronic levosulpiride administration on gastric tone and perception in functional dyspepsia. Aliment. Pharmacol. Ther. 16, 613–622 (2002).

    Google Scholar 

  203. 203

    Melzer, J., Rosch, W., Reichling, J., Brignoli, R. & Saller, R. Meta-analysis: phytotherapy of functional dyspepsia with the herbal drug preparation STW 5 (Iberogast). Aliment. Pharmacol. Ther. 20, 1279–1287 (2004).

    Google Scholar 

  204. 204

    Pilichiewicz, A. N. et al. Effects of Iberogast on proximal gastric volume, antropyloroduodenal motility and gastric emptying in healthy men. Am. J. Gastroenterol. 102, 1276–1283 (2007).

    Google Scholar 

  205. 205

    Rosch, W., Vinson, B. & Sassin, I. A randomised clinical trial comparing the efficacy of a herbal preparation STW 5 with the prokinetic drug cisapride in patients with dysmotility type of functional dyspepsia. Z. Gastroenterol. 40, 401–408 (2002).

    Google Scholar 

  206. 206

    Suzuki, H. et al. Randomized clinical trial: rikkunshito in the treatment of functional dyspepsia — a multicenter, double-blind, randomized, placebo-controlled study. Neurogastroenterol. Motil. 26, 950–961 (2014).

    Google Scholar 

  207. 207

    Sakata, Y. et al. A randomized, placebo-controlled, double-blind clinical trial of the Japanese herbal medicine rikkunshito for patients with functional dyspepsia: the dream study. Gastroenterology 152, S120–S121 (2017).

    Google Scholar 

  208. 208

    Kusunoki, H. et al. Efficacy of rikkunshito, a traditional Japanese medicine (Kampo), in treating functional dyspepsia. Intern. Med. 49, 2195–2202 (2010).

    Google Scholar 

  209. 209

    Togawa, K. et al. Association of baseline plasma des-acyl ghrelin level with the response to rikkunshito in patients with functional dyspepsia. J. Gastroenterol. Hepatol. 31, 334–341 (2016).

    Google Scholar 

  210. 210

    Bates, S., Sjoden, P.-O. & Nyren, O. Behavioral treatment of non-ulcer dyspepsia. Scand. J. Behav. Ther. 17, 155–165 (1988).

    Google Scholar 

  211. 211

    Haug, T. T., Wilhelmsen, I., Svebak, S., Berstad, A. & Ursin, H. Psychotherapy in functional dyspepsia. J. Psychosom. Res. 38, 735–744 (1994).

    Google Scholar 

  212. 212

    Hamilton, J. et al. A randomized controlled trial of psychotherapy in patients with chronic functional dyspepsia. Gastroenterology 119, 661–669 (2000).

    Google Scholar 

  213. 213

    Calvert, E. L., Houghton, L. A., Cooper, P., Morris, J. & Whorwell, P. J. Long-term improvement in functional dyspepsia using hypnotherapy. Gastroenterology 123, 1778–1785 (2002).

    Google Scholar 

  214. 214

    Cheng, C., Yang, F. C., Jun, S. & Hutton, J. M. Flexible coping psychotherapy for functional dyspeptic patients: a randomized, controlled trial. Psychosom. Med. 69, 81–88 (2007).

    Google Scholar 

  215. 215

    Faramarzi, M. et al. The effect of psychotherapy in improving physical and psychiatric symptoms in patients with functional dyspepsia. Iran. J. Psychiatry 10, 43–49 (2015).

    Google Scholar 

  216. 216

    Orive, M. et al. A randomized controlled trial of a 10 week group psychotherapeutic treatment added to standard medical treatment in patients with functional dyspepsia. J. Psychosom. Res. 78, 563–568 (2015).

    Google Scholar 

  217. 217

    Lan, L. et al. Acupuncture for functional dyspepsia. Cochrane Database Syst. Rev. 10, CD008487 (2014).

    Google Scholar 

  218. 218

    Chang, X. R., Lan, L., Yan, J., Wang, X. J. & Chen, H. M. Efficacy of acupuncture at Foot-Yangming Meridian in the treatment of patients with functional dyspepsia: an analysis of 30 cases. World Chinese J. Digestol. 18, 839–844 (2010).

    Google Scholar 

  219. 219

    Park, Y. C., Kang, W., Choi, S. M. & Son, C. G. Evaluation of manual acupuncture at classical and nondefined points for treatment of functional dyspepsia: a randomized-controlled trial. J. Altern Complement Med. 15, 879–884 (2009).

    Google Scholar 

  220. 220

    Pang, B. et al. Acupuncture for functional dyspepsia: what strength does it have? A systematic review and meta-analysis of randomized controlled trials. Evid. Based Complement. Alternat. Med. 2016, 3862916 (2016). This is the latest meta-analysis of the efficacy of acupuncture therapy in functional dyspepsia.

    Google Scholar 

  221. 221

    Wang, C., Zhu, M., Xia, W., Jiang, W. & Li, Y. Meta-analysis of traditional Chinese medicine in treating functional dyspepsia of liver-stomach disharmony syndrome. J. Tradit. Chin. Med. 32, 515–522 (2012).

    Google Scholar 

  222. 222

    Ware, J. E., Snow, K. K. & Kosinski, M. SF-36 Health Survey and Interpretation Guide. (QualityMetric Inc., 2000).

    Google Scholar 

  223. 223

    Talley, N. J., Weaver, A. L. & Zinsmeister, A. R. Impact of functional dyspepsia on quality of life. Dig. Dis. Sci. 40, 584–589 (1995).

    Google Scholar 

  224. 224

    Wiklund, I., Glise, H., Jerndal, P., Carlsson, J. & Talley, N. J. Does endoscopy have a positive impact on quality of life in dyspepsia? Gastrointest. Endosc. 47, 449–454 (1998).

    Google Scholar 

  225. 225

    Mones, J. et al. Quality of life in functional dyspepsia. Dig. Dis. Sci. 47, 20–26 (2002).

    Google Scholar 

  226. 226

    Moayyedi, P. & Mason, J. Clinical and economic consequences of dyspepsia in the community. Gut 50 (Suppl. 4), 10–12 (2002). The strengths of this study are its large sample size and use of QOL instruments to estimate the personal and economic health burden of functional dyspepsia relative to more life-threatening diseases.

    Google Scholar 

  227. 227

    Talley, N. J. et al. Development of a new dyspepsia impact scale: the Nepean Dyspepsia Index. Aliment. Pharmacol. Ther. 13, 225–235 (1999).

    Google Scholar 

  228. 228

    Talley, N. J., Verlinden, M. & Jones, M. Quality of life in functional dyspepsia: responsiveness of the Nepean Dyspepsia Index and development of a new 10-item short form. Aliment. Pharmacol. Ther. 15, 207–216 (2001).

    Google Scholar 

  229. 229

    Jones, M. & Talley, N. J. Minimum clinically important difference for the Nepean Dyspepsia Index, a validated quality of life scale for functional dyspepsia. Am. J. Gastroenterol. 104, 1483–1488 (2009). This paper establishes the psychometric properties of a functional dyspepsia-specific QOL measure that can be implemented in both clinical and research settings.

    Google Scholar 

  230. 230

    Lackner, J. M. et al. The impact of physical complaints, social environment, and psychological functioning on IBS patients’ health perceptions: looking beyond GI symptom severity. Am. J. Gastroenterol. 109, 224–233 (2014).

    Google Scholar 

  231. 231

    Van Oudenhove, L. et al. The latent structure of the functional dyspepsia symptom complex: a taxometric analysis. Neurogastroenterol. Motil. 28, 985–993 (2016).

    Google Scholar 

  232. 232

    Grover, M. et al. Diabetic and idiopathic gastroparesis is associated with loss of CD206-positive macrophages in the gastric antrum. Neurogastroenterol. Motil.http://dx.doi.org/10.1111/nmo.13018 (2017).

  233. 233

    Friesen, C. A. et al. Montelukast in the treatment of duodenal eosinophilia in children with dyspepsia: effect on eosinophil density and activation in relation to pharmacokinetics. BMC Gastroenterol. 9, 32 (2009).

    Google Scholar 

  234. 234

    Tan, V. P. et al. Randomised clinical trial: rifaximin versus placebo for the treatment of functional dyspepsia. Aliment. Pharmacol. Ther. 45, 767–776 (2017).

    Google Scholar 

  235. 235

    Azpiroz, F. in Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management Vol. 2 (eds. Feldmann, M., Friedman, L. S. & Brand, L. J. ) 242–250 (Elsevier, 2015).

    Google Scholar 

  236. 236

    Ware, J. E. Jr & Sherbourne, C. D. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med. Care 30, 473–483 (1992).

    Google Scholar 

  237. 237

    Ware, J. Jr, Kosinski, M. & Keller, S. D. A 12-item short-form health survey: construction of scales and preliminary tests of reliability and validity. Med. Care 34, 220–233 (1996).

    Google Scholar 

  238. 238

    Dupuy, H. in Assessment of Quality of Life in Clinical Trials of Cardiovascular Therapies (eds Wenger, N. K., Mattson, M. E., Furberg, C. D. & Elinson, J. ) 170–183 (Le Jacq Publishing, 1984).

    Google Scholar 

  239. 239

    EuroQol Group. EuroQol — a new facility for the measurement of health-related quality of life. Health Policy 16, 199–208 (1990).

    Google Scholar 

  240. 240

    Goldberg, D. Manual of the General Health Questionnaire. (NFER-Nelson, 1978).

    Google Scholar 

  241. 241

    Beusenberg, M. & Orley, J. A. User's guide to the self reporting questionnaire (SRQ). World Health Organizationhttp://www.who.int/iris/handle/10665/61113 (1994).

  242. 242

    de la Loge, C. et al. Cross-cultural development and validation of a patient self-administered questionnaire to assess quality of life in upper gastrointestinal disorders: the PAGI-QOL. Qual. Life Res. 13, 1751–1762 (2004).

    Google Scholar 

  243. 243

    Chassany, O. et al. Validation of a specific quality of life questionnaire for functional digestive disorders. Gut 44, 527–533 (1999).

    Google Scholar 

  244. 244

    el-Omar, E. M., Banerjee, S., Wirz, A. & McColl, K. E. The Glasgow Dyspepsia Severity Score — a tool for the global measurement of dyspepsia. Eur. J. Gastroenterol. Hepatol. 8, 967–971 (1996).

    Google Scholar 

  245. 245

    Wiklund, I. K. et al. Quality of Life in Reflux and Dyspepsia patients. Psychometric documentation of a new disease-specific questionnaire (QOLRAD). Eur. J. Surg. Suppl. 1998, 41–49 (1998).

    Google Scholar 

  246. 246

    Eypasch, E. et al. Gastrointestinal Quality of Life Index: development, validation and application of a new instrument. Br. J. Surg. 82, 216–222 (1995).

    Google Scholar 

  247. 247

    Walker, M. M. & Talley, N. J. The role of duodenal inflammation in functional dyspepsia. J. Clin. Gastroenterol. 51, 12–18 (2017).

    Google Scholar 

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Acknowledgements

The research leading to these results has received funding from the People Programme of the European Union's Seventh Framework Programme under REA grant agreement no. 607652 (NeuroGUT), involving some of the authors (P.E., F.A., G.B. and M.S.). F.A. is supported by the Spanish Ministry of Economy (SAF 2016-76648-R). C.F.-B. is supported by a Senior Research Fellowship from the National Health and Medical Research Council of Australia (grant 1103020, 2016 - 21).

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Introduction (P.E. and J.R.); Epidemiology (P.E.); Mechanisms/pathophysiology (M.S., J.R., S.E., G.H., N.J.T. and J.T.); Diagnosis, screening and prevention (G.B.); Management (J.T., C.F.-B., A.S. and S.Z.); Quality of life (J.M.L.); Outlook (N.J.T., M.S. and P.E.); Overview of Primer (P.E.).

Corresponding author

Correspondence to Paul Enck.

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Competing interests

P.E. has received an unrestricted grant from SymbioPharm; has served as an adviser for Allergan, Almirall, AstraZeneca, Boehringer, Biocodex, Ferring, GA, Heel, SymbioPharm, TEVA and UCB; and has served as a speaker for Almirall, Bayer/Steigerwald, Boehringer, Chiesi, Heel and Sanofi. F.A. has received grant support from Danone, Clasado and Noventure; has served as an adviser for Danone, Clasado and Allergan; and has served as a speaker for Allergan. G.B. has served as an adviser for Reckitt-Benckiser and as speaker for Menarini. G.H. has received unrestricted grants from Bayer, Commonwealth Laboratories, the Falk Foundation and Takeda and has served as a speaker for Schwabe. M.S. has received unrestricted grants from Bayer/Steigerwald, Boehringer and Schwabe; has served as an adviser for Bionorica, Takeda and Almirall; and has served as a speaker for Almirall and Bayer/Steigerwald. J.T. has received research grants from Abide Therapeutics, Shire, Tsumura and Zeria; has given scientific advice to Abide Therapeutics, Alfa Wassermann, Allergan, Christian Hansen, Danone, Genfit, Ironwood, Janssen, Kiowa Kirin, Menarini, Mylan, Novartis, Nutricia, Ono Pharma, Rhythm, Shionogi, Shire, SK Life Sciences, Takeda, Theravance, Tsumura, Yuhan, Zealand and Zeria Pharmaceuticals; and has served as a speaker for Abbott, Allergan, AstraZeneca, Janssen, Kiowa Kirin, Menarini, Mylan, Novartis, Shire, Takeda and Zeria. N.J.T. has received grant support from Abbott, Commonwealth Diagnostic Laboratories, GI Therapies, Janssen, Pfizer, Prometheus and Salix and has served as a consultant for Adelphi Values, Allergan, Ardelyx, CJ Healthcare, Commonwealth Diagnostic Laboratories, Danone, Forest Laboratories, Furiex, GI Care, GI Therapies, Napo Pharmaceuticals, Outpost Medicine, Samsung, Synergy, Takeda and Yuhan. All other authors declare no competing interests.

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Enck, P., Azpiroz, F., Boeckxstaens, G. et al. Functional dyspepsia. Nat Rev Dis Primers 3, 17081 (2017). https://doi.org/10.1038/nrdp.2017.81

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