Small Bowel Homing T Cells Are Associated With Symptoms and Delayed Gastric Emptying in Functional Dyspepsia

Liebregts, Tobias; Adam, Birgit; Bredack, Christoph; Gururatsakul, Montri; Pilkington, Katherine R.; Brierley, Stuart M.; Blackshaw, L. Ashley; Gerken, Guido; Talley, Nicholas J.; Holtmann, Gerald

doi:10.1038/ajg.2010.512

Cited by 167 publications

(184 citation statements)

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“…There is also evidence of aberrant immune activation in the peripheral blood of patients with FD. The levels of gut-homing T cells are increased, and cultured peripheral blood immune cells produce excess inflammatory cytokines that are linked to delayed gastric emptying [108]. This work suggests that a proportion of FD is an immune-mediated disease driven by allergic type T h 2 inflammation.…”

Section: Immunological Disorders In Fdmentioning

confidence: 87%

Therapeutic strategies for functional dyspepsia and irritable bowel syndrome based on pathophysiology

2015

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Functional gastrointestinal disorders (FGIDs) are common and distressing. They are so named because a defined pathophysiology in terms of structural or biochemical pathways is lacking. Traditionally FGIDs have been conceptualized as brain-gut disorders, with subgroups of patients demonstrating visceral hypersensitivity and motility abnormalities as well as psychological distress. However, it is becoming apparent that there are certain structural or biochemical gut alterations among subsets with the common FGIDs, most notably functional dyspepsia (FD) and irritable bowel syndrome (IBS). For example, a sodium channel mutation has been identified in IBS that may account for 2 % of cases, and subtle intestinal inflammation has been observed in both IBS and FD. Other research has implicated early life events and stress, autoimmune disorders and atopy and infections, the gut microbiome and disordered mucosal immune activation in patients with IBS or FD. Understanding the origin of symptoms in FGIDs will allow therapy to be targeted at the pathophysiological changes, not at merely alleviating symptoms, and holds hope for eventual cure in some cases.For example, there are promising developments in manipulating the microbiome through diet, prebiotics and antibiotics in IBS, and testing and treating patients for Helicobacter pylori infection remains a mainstay of therapy in patients with dyspepsia and this infection. Locally acting drugs such as linaclotide have been an advance in treating the symptoms of constipation-predominant IBS, but do not alter the natural history of the disease. A role for a holistic approach to patients with FGIDs is warranted, as brain-togut and gut-to-brain pathways appear to be activated.

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Section: Immunological Disorders In Fdmentioning

confidence: 87%

Therapeutic strategies for functional dyspepsia and irritable bowel syndrome based on pathophysiology

2015

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“…1) were increased in patients with functional dyspepsia and correlated with symptom intensity and impaired gastric emptying, suggesting that gastric disturbances in functional dyspepsia could, in fact, be secondary to duodenal inflammation 94 . Together with data of increased duodenal eosinophilia 90,91,95,96 , these studies have demonstrated that low-grade mucosal inflammation plays a key part in the pathogenesis of functional dyspepsia.…”

Section: Gastroduodenal Inflammationmentioning

confidence: 95%

“…T H 2 cells also express IL-4 and IL-13, which provide feedback to the stomach and can promote immunoglobulin (Ig) class-switching in B cells and induce the expression of pro-allergic IgE antibodies, which further stimulate eosinophil degranulation and increase epithelial permeability. The pro-inflammatory cytokines tumour necrosis factor (TNF) and IL-1β and the anti-inflammatory cytokine IL-10 can be released by immune cells into the blood and promote, along with small-intestinal-homing T cells (expressing T cell surface glycoprotein CD4, integrin β7 (α4β7) and CC-chemokine receptor type 9 (CCR9)), an anxiety or stress response, which in turn can lead to disordered motility and visceral hypersensitivity in the stomach and duodenum 37,94 .…”

Section: Gastroduodenal Sensitivitymentioning

confidence: 99%

Functional dyspepsia

Enck¹,

Azpiroz

Boeckxstaens

et al. 2017

Nat Rev Dis Primers

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| 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. NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | ARTICLE NUMBER 17081 | 1 PRIMER © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .standard therapy for gastro -oesophageal reflux disease. Paediatric dyspeptic symptoms are being addressed in a separate classification effort 10 . This Primer covers functional dyspepsia in adults only, although we sporadically refer to paediatric functional dyspepsia when similarities exist. EpidemiologyThe population prevalence of functional dyspepsia is quite variable across the globe, with overall high numbers (10-40%) in Western countries and low numbers (5-30%) in Asia, independent of the respective functional dyspepsia definitions 11 . A large-scale health and nutrition survey from France 12 (which involved >35,000 people) identified that 15% of individuals had suspected functional dyspepsia, 28% had irritable bowel syndrome (IBS) and 6% had both. The population of patients who are affected by both IBS and functional dyspepsia has been reported to range between 10% and 27% in previous studies 13 and to approach 30% in popu lation samples; it could be even higher in specific populations 14,15 . This observation has given rise to the term 'overlap syndrome' (REF. 13), which calls into question the sensitivity and specificity of the Rome criteria, at least for IBS and functional dyspepsia. This argument is also supported by the observation that patients with functional dyspepsia m...

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“…Classifi cation of patients according to the IBS subtype is rarely performed, but when this is done clear diff erences in immune profi le are observed with increased concentrations of T H 1-type cytokines, including TNF-α and IL-1 β , detected alongside typical T H 2 cytokines, such as IL-10, in IBS-D ( 85,87,88 ). Th e lack of polarization toward a T H 1 or T H 2 axis indicates the nature of immune activation in IBS is not straightforward but instead likely to be a complex pheno menon incorporating several distinct cell types and / or possibly cells with plasticity of function ( 97 ).…”

Section: -Htmentioning

confidence: 99%

Immune Activation in Irritable Bowel Syndrome: Can Neuroimmune Interactions Explain Symptoms?

Hughes

Zola

et al. 2013

American Journal of Gastroenterology

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Irritable bowel syndrome (IBS) is a functional disorder of the gastrointestinal (GI) tract characterized by pain or discomfort from the lower abdominal region, which is associated with altered bowel habit. Despite its prevalence, there is currently a lack of effective treatment options for patients. IBS has long been considered as a neurological condition resulting from alterations in the brain gut axis, but immunological alterations are increasingly reported in IBS patients, consistent with the hypothesis that there is a chronic, but low-grade, immune activation. Mediators released by immune cells act to either dampen or amplify the activity of GI nerves. Release of a number of these mediators correlates with symptoms of IBS, highlighting the importance of interactions between the immune and the nervous systems. Investigation of the role of microbiota in these interactions is in its early stages, but may provide many answers regarding the mechanisms underlying activation of the immune system in IBS. Identifying what the key changes in the GI immune system are in IBS and how these changes modulate viscerosensory nervous function is essential for the development of novel therapies for the underlying disorder.

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Small Bowel Homing T Cells Are Associated With Symptoms and Delayed Gastric Emptying in Functional Dyspepsia

Abstract: Cellular immune activation with increased small bowel homing T cells may be key factors in the clinical manifestations of H. pylori-negative FD.

Cited by 167 publications

References 56 publications

Therapeutic strategies for functional dyspepsia and irritable bowel syndrome based on pathophysiology

Therapeutic strategies for functional dyspepsia and irritable bowel syndrome based on pathophysiology

Functional dyspepsia

Immune Activation in Irritable Bowel Syndrome: Can Neuroimmune Interactions Explain Symptoms?

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