Dyspepsia pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Fahad Hasan, M.D.[2] Ajay Gade MD[3]]
Overview
Functional dyspepsia is now classified as a disorder of gut-brain interaction, affecting approximately 7% of the community, and is diagnosed by the presence of one or more of bothersome epigastric pain, epigastric burning, early satiation, and/or postprandial fullness, present for the last 3 months with symptom onset at least 6 months before diagnosis, in the absence of an identifiable organic cause on evaluation including upper endoscopy.[1] Functional dyspepsia is heterogeneous, with symptoms associated with several overlapping mechanisms: impaired gastric accommodation (~40%), visceral hypersensitivity to gastric distention (~40%), and mild delayed gastric emptying (~30%); approximately 30% of patients have none of these, and these abnormalities correlate poorly with symptoms and occur in asymptomatic controls. Increasing evidence implicates low-grade duodenal microinflammation (modestly increased eosinophils and mast cells with impaired barrier function) driving an aberrant type 2 helper T (Th2) immune response in a subgroup.[2][3] These mechanisms occur in patients who have acquired excessive responsiveness to stress as a result of the environment during early life, genetic abnormalities, residual inflammation after gastrointestinal infections, or other causes. The process may be modified by factors including psychophysiological abnormalities, abnormal secretion of gastric acid, Helicobacter pylori infection, impaired duodenal mucosal barrier integrity, diet, and lifestyle.
Pathophysiology
The pathophysiology of dyspepsia is as follows:[4][5][6][7][8][9][10][1][2]
Pathophysiology of functional dyspepsia
- The symptoms of functional dyspepsia (FD) are directly caused by multiple, overlapping physiological abnormalities, now understood to include:
- Abnormal gastric motility. Mild delayed gastric emptying is present in ∼30% of patients (associated with postprandial fullness, nausea, and vomiting), but emptying rate correlates inconsistently with symptoms and accelerating it does not reliably improve them. FD and gastroparesis are increasingly viewed as overlapping ends of a spectrum of gastric sensorimotor disorders rather than identical entities; the distinction remains clinically relevant because FD carries a better prognosis, and part of the reported overlap is an artifact of the low-calorie/low-fat emptying meal and the >10%-retention-at-4-h cutoff.[11][12][13]
- Impaired gastric accommodation. Failure of the proximal stomach to relax normally in response to a meal redistributes food to the distal stomach; impaired accommodation is present in up to ~40% of patients and is the abnormality most closely associated with early satiation, postprandial fullness, and unintentional weight loss.[2][3]
- Visceral hypersensitivity, characterized by heightened perception of normal gastric distension and duodenal chemosensitivity (particularly to lipids and acid), which correlates with meal-related symptom severity.[10][2]
- Low-grade duodenal mucosal inflammation and impaired barrier integrity. Duodenal biopsies in FD show increased intraepithelial and lamina propria eosinophil and mast cell infiltration, with associated downregulation of the tight-junction proteins occludin and claudin, increased paracellular permeability, and abnormal β-catenin and desmosomal protein expression. This "leaky gut" phenotype is thought to allow luminal antigens to activate submucosal immune and neural pathways, driving symptom generation.[14][15]
- Duodenal microinflammation and subtype controversy. A 2022 systematic review and meta-analysis confirmed higher duodenal eosinophil and mast cell counts in FD — most pronounced in post-infection FD — but found no significant association with FD subtype (PDS vs EPS), which challenges the concept of eosinophilia as a PDS-specific driver. Post-infection FD accounts for ~10% of cases, with roughly a 2.5–3-fold increased risk ≥6 months after acute gastroenteritis.[16][2]
- Altered gut-brain axis signaling. FD is now classified as a disorder of gut-brain interaction; peripheral duodenal signals (immune activation, chemosensitivity) are relayed via vagal and spinal afferent pathways to central pain-processing and emotional regulation centers, which are further modulated by psychological comorbidity, anxiety, and depression.[1][2]
- Helicobacter pylori infection and post-infectious states (following acute gastroenteritis) can trigger or perpetuate the above mechanisms through sustained low-grade mucosal inflammation.[8]
- These mechanisms occur in patients who have acquired excessive responsiveness to stress as a result of the environment during early life, genetic abnormalities, residual inflammation after gastrointestinal infections, or other causes, with the process modified by factors including psychophysiological abnormalities, abnormal secretion of gastric acid, Helicobacter pylori infection, diet, and lifestyle.
- If the basis of this model of FD pathogenesis is excessive responsiveness of gastrointestinal function to stress and external stimuli, psychosomatic approaches to alter stress perception could be important treatment options.[17]
Microscopic Pathology
- In functional dyspepsia, routine histology on standard staining is typically unremarkable; the microscopic correlates are quantitative. Case-control studies and meta-analysis show increased duodenal eosinophil and mast cell counts (most marked in post-infection FD), with impaired barrier integrity — reduced expression of tight-junction proteins including ZO-1 (TJP1), increased paracellular permeability, and eosinophils/mast cells located close to submucosal plexus neurones with associated fine-nerve-fibre sprouting. Eosinophil activation/degranulation may correlate with symptoms better than counts alone, and no consistent association with FD subtype has been demonstrated.[14][16][2]
References
- ↑ 1.0 1.1 1.2 Black CJ, Paine PA, Agrawal A, Alqahtani A, Anand B, Byrne P, Clark CE, Corr A, Doherty G, Excell L, Ford AC, Kemp K, Nwokolo C, Owen L, Paranandi B, Ritchie N, Robertson E, Whorwell P, Wright S, Hasan B (2022). "British Society of Gastroenterology guidelines on the management of functional dyspepsia". Gut. 71 (9): 1697–1723. doi:10.1136/gutjnl-2022-327737. PMID 35798375 Check
|pmid=value (help). - ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Ford AC, Mahadeva S, Carbone MF, Lacy BE, Talley NJ (2020). "Functional dyspepsia". Lancet. 396 (10263): 1689–1702. doi:10.1016/S0140-6736(20)30469-4. PMID 33049222 Check
|pmid=value (help). - ↑ 3.0 3.1 Törnblom H, Carbone F, Hasler WL, et al. (2026). "Gastroduodenal Disorders". Gastroenterology. 170 (6): 1240–1260. doi:10.1053/j.gastro.2026.01.038.
- ↑ Talley NJ, Ford AC (2015). "Functional Dyspepsia". N. Engl. J. Med. 373 (19): 1853–63. doi:10.1056/NEJMra1501505. PMID 26535514.
- ↑ Napthali K, Koloski N, Walker MM, Talley NJ (2016). "Women and functional dyspepsia". Womens Health (Lond). 12 (2): 241–50. doi:10.2217/whe.15.88. PMC 5375052. PMID 26901578.
- ↑ Talley NJ (2016). "Functional dyspepsia: new insights into pathogenesis and therapy". Korean J. Intern. Med. 31 (3): 444–56. doi:10.3904/kjim.2016.091. PMC 4855108. PMID 27048251.
- ↑ Ganesh M, Nurko S (2014). "Functional dyspepsia in children". Pediatr Ann. 43 (4): e101–5. doi:10.3928/00904481-20140325-12. PMID 24716560.
- ↑ 8.0 8.1 Fock KM (2011). "Functional dyspepsia, H. pylori and post infectious FD". J. Gastroenterol. Hepatol. 26 Suppl 3: 39–41. doi:10.1111/j.1440-1746.2011.06649.x. PMID 21443707.
- ↑ Oustamanolakis P, Tack J (2012). "Dyspepsia: organic versus functional". J. Clin. Gastroenterol. 46 (3): 175–90. doi:10.1097/MCG.0b013e318241b335. PMID 22327302.
- ↑ 10.0 10.1 Kindt S, Dubois D, Van Oudenhove L, Caenepeel P, Arts J, Bisschops R, Tack J (2009). "Relationship between symptom pattern, assessed by the PAGI-SYM questionnaire, and gastric sensorimotor dysfunction in functional dyspepsia". Neurogastroenterol. Motil. 21 (11): 1183–e105. doi:10.1111/j.1365-2982.2009.01374.x. PMID 19663903.
- ↑ Pasricha PJ, Grover M, Yates KP, et al. (2021). "Functional Dyspepsia and Gastroparesis in Tertiary Care Are Interchangeable Syndromes With Common Clinical and Pathologic Features". Gastroenterology. 160 (6): 2006–2017. doi:10.1053/j.gastro.2021.01.230. PMID 33548234 Check
|pmid=value (help). - ↑ Camilleri M, Kuo B, Nguyen L, et al. (2022). "ACG Clinical Guideline: Gastroparesis". Am J Gastroenterol. 117 (8): 1197–1220. doi:10.14309/ajg.0000000000001874.
- ↑ Carbone F, De Buysscher R, Van den Houte K, et al. (2022). "Relationship Between Gastric Emptying Rate and Simultaneously Assessed Symptoms in Functional Dyspepsia". Clin Gastroenterol Hepatol. 20 (3): e429–e437. doi:10.1016/j.cgh.2021.03.023.
- ↑ 14.0 14.1 Vanheel H, Vicario M, Vanuytsel T, Van Oudenhove L, Martinez C, Keita ÅV, Pardon N, Santos J, Söderholm JD, Tack J, Farré R (2014). "Impaired duodenal mucosal integrity and low-grade inflammation in functional dyspepsia". Gut. 63 (2): 262–71. doi:10.1136/gutjnl-2012-303857. PMID 23474421.
- ↑ Walker MM, Talley NJ, Prabhakar M, Pennaneac'h CJ, Aro P, Ronkainen J, Storskrubb T, Harmsen WS, Zinsmeister AR, Agréus L (2009). "Duodenal mastocytosis, eosinophilia and intraepithelial lymphocytosis as possible disease markers in the irritable bowel syndrome and functional dyspepsia". Aliment. Pharmacol. Ther. 29 (7): 765–73. doi:10.1111/j.1365-2036.2009.03937.x. PMID 19183150.
- ↑ 16.0 16.1 Shah A, Fairlie T, Brown G, et al. (2022). "Duodenal Eosinophils and Mast Cells in Functional Dyspepsia: A Systematic Review and Meta-Analysis of Case-Control Studies". Clin Gastroenterol Hepatol. 20 (10): 2229–2242.e29. doi:10.1016/j.cgh.2021.11.026.
- ↑ Miwa H (2012). "Why dyspepsia can occur without organic disease: pathogenesis and management of functional dyspepsia". J Gastroenterol. doi:10.1007/s00535-012-0625-9. PMID 22766746. Unknown parameter
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