Mast Cell–Nerve Interactions in Children With Functional Dyspepsia

Schäppi, Michela; Borrelli, Osvaldo; Knafelz, D.; Williams, Sue; Smith, Virpi V.; Milla, Peter J.; Lindley, Keith

doi:10.1097/mpg.0b013e318186008e

Cited by 58 publications

(48 citation statements)

References 42 publications

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“…In the food-protein-induced enterocolitis syndrome (FPIES) the suggested immunological (or allergic) pathophysiology mainly involves T-cell-mediated reactions, as recently reviewed [1]. Other immunological responses suggested in the pathogenesis of the GI symptoms associating with cow’s milk protein allergy (CMPA) include increased mononuclear cell production of tumor necrosis factor-α (TNF-α) [2], eosinophilic inflammation [3,4] as well as activated submucosal mast cells [5]. Possible non-immunological etiologies include 1) the direct effect of cow’s milk protein on intestinal motility [6], 2) colonic bacterial dysbiosis (possibly enhanced by cow’s milk formulas) [7,8], and 3) effects caused by the non-protein parts of cow’s milk: carbohydrates [9] and fatty acids [10].…”

Section: Introductionmentioning

confidence: 99%

Markers of gut mucosal inflammation and cow's milk specific immunoglobulins in non‐IgE cow's milk allergy

Merras‐Salmio¹,

Kolho²,

Pelkonen³

et al. 2014

Clinical & Translational All

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BackgroundAllergy to cow’s milk protein (CMP) may cause gastrointestinal (GI) symptoms in the absence of CMP specific IgE. The immunological mechanisms involved in such disease are not fully understood. Therefore we examined markers of gut mucosal inflammation and the immunoglobulin profiles in children with Gl symptoms suspected of cow’s milk protein allergy (CMPA).Patients and methodsWe prospectively recruited infants and young children (n = 57; median age 8.7 months) with gastrointestinal complaints suspected of CMPA. The diagnosis of CMPA was made using the double-blind, placebo-controlled food challenge. Serum and stool samples were collected during CMP-free diet and after both placebo and active challenges. We analyzed the stool samples for calprotectin, human β-defensin 2 and IgA. In serum, we analyzed the levels of β-lactoglobulin and α-casein specific IgA, and IgG antibodies (total IgG and subclasses IgG1 and IgG4). Control group included children with e.g. dermatological or pulmonary problems, consuming normal diets.ResultsFecal calprotectin levels were higher in the challenge positive group (n = 18) than in the negative (n = 37), with respective geometric means 55 μg/g [95% confidence interval 38–81] and 29 [24–36] μg/g (p = 0.0039), during cow’s milk free diet. There were no significant inter-group differences in the fecal β-defensin and IgA levels. The CMP specific IgG and IgA were not elevated in patients with CMPA, but the levels of β-lactoglobulin-IgG4 (p = 0.0118) and α-casein-IgG4 (p = 0.0044), and total α-casein-IgG (p = 0.0054) and -IgA (p = 0.0050) in all patient samples (regardless of CMPA diagnosis) were significantly lower compared to the control group using dairy products.ConclusionsDespite cow’s milk elimination in children intolerant to cow’s milk there might be ongoing low-grade inflammation in the gut mucosa. CMP specific IgG or IgA should not be used to diagnose non-IgE CMPA. The observed frequency of impaired CMP specific total IgA, IgG and IgG4 production in patients following cow’s milk free diet warrants further studies.

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Section: Introductionmentioning

confidence: 99%

Markers of gut mucosal inflammation and cow's milk specific immunoglobulins in non‐IgE cow's milk allergy

Merras‐Salmio¹,

Kolho²,

Pelkonen³

et al. 2014

Clinical & Translational All

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“…Since most patients with symptomatic GERD have normal oesophageal biopsies, 6 documenting normalisation is both difficult and irrelevant.…”

Section: Acknowledgementmentioning

confidence: 99%

“…Studies have shown that children with atopy have duodenal eosinophilia and that challenge with cow's milk protein can generate dyspeptic symptoms. 6 Other studies have shown that inflammation, including eosinophilia, may be seen in patients with Helicobacter pylori infection. 7 The process by which extrinsic factors create duodenal eosinophilic infiltration is uncertain.…”

mentioning

confidence: 99%

Editorial: the diminishing returns of normalisation of the oesophageal mucosa

Genta¹

2017

Aliment Pharmacol Ther

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hampered by the lack of correlation between symptom improvement and changes in physiologic measures such as gastric emptying studies.A new direction in functional dyspepsia is the concept that the duodenum may be the source of symptoms. Observational studies show an increased number of eosinophils in duodenal biopsies obtained from adults and children with functional dyspepsia. [2][3][4] Other studies have shown an increase in mast cells in the mucosa and evidence of inflammation in the sub-mucosal nerves and ganglia in the upper gastrointestinal tract. 5An inflammatory reaction may trigger the accumulation of eosinophils in the duodenal mucosa. The trigger may be intrinsic through the brain-gut axis or extrinsic through ingested proteins or bacteria.During the inflammatory process, a number of cytokines are released and activate the eosinophils, which are then ready for degranulation.During the process of degranulation, nerve growth factor is released and may have an effect on the sensory nerves of the upper gastrointestinal tract. Other products of degranulation such as major basic proteins can affect smooth muscle function causing spasm. Studies have shown that children with atopy have duodenal eosinophilia and that challenge with cow's milk protein can generate dyspeptic symptoms. 6 Other studies have shown that inflammation, including eosinophilia, may be seen in patients with Helicobacter pylori infection. 7 The process by which extrinsic factors create duodenal eosinophilic infiltration is uncertain. One plausible postulate is that alterations in mucosal permeability allow food-based antigens and bacterial products exposure to the immune system. What are the implications for future treatments? Anti-inflammatory agents and drugs aimed at decreasing allergic reactions are already being studied in functional dyspepsia. 9,10 Observational studies, while confirming the original observation of duodenal eosinophilia, need to give way to mechanistic studies that help us understand the pathogenesis of duodenal eosinophilia. Future studies will help determine if treating the eosinophilia, much as we treat eosinophilic oesophagitis, or restricting the diet will alleviate dyspeptic symptoms. ACKNOWLEDGEMENTDeclaration of personal interests: Consultant Ironwood Pharmaceuticals.

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“…19,20 Thus, the accumulation and degranulation of eosinophils gives rise to neural stimulation and smooth muscle contraction, which consequently produces gastrointestinal symptoms, such as abdominal cramps, abdominal discomfort, and flatulence. 16,19,20,48 According to a study by Schappi et al, 49 children with atopic FD demonstrated increased eosinophils and mast cells within the antrum, and these cells degranulated rapidly after a cow's milk challenge unlike in children with non-atopic FD. Duodenal eosinophilia can be associated with an allergy, 20 and eosinophils in the duodenum can be activated in patients with allergy-related disorders, including asthma and atopic eczema, which can induce gastrointestinal symptoms in these groups of patients.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Gastric and Duodenal Eosinophils in Children with Abdominal Pain Related Functional Gastrointestinal Disorders According to Rome III Criteria

Lee

Yang

Lee

2016

J Neurogastroenterol Motil

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Background/AimsAbdominal pain-related functional gastrointestinal disorder (AP-FGID) is common in children and adults. However, the mechanism of AP-FGID is not clearly known. Recently, micro-inflammation, especially eosinophilia in the gastrointestinal tract, was suggested in the pathophysiology of AP-FGID in adults. The aim of this study was to evaluate the association of gastric and duodenal eosinophilia with pediatric AP-FGID. MethodsIn total, 105 pediatric patients with AP-FGID were recruited and classified into 4 subgroups based on the Rome III criteria. Eosinophil counts in the gastric and duodenal tissues of children with AP-FGID were compared to those from normal pathology references or those of children with Helicobacter pylori infection. Tissue eosinophil counts were also compared among the 4 subtypes of AP-FGID. ResultsEosinophil counts in the gastric antrum and body were significantly higher in children with AP-FGID than normal reference values. Duodenal eosinophil counts were higher in children with AP-FGID, but not significantly when compared with normal reference values. There were no significant differences in eosinophil counts of the stomach or duodenum among the 4 subtypes of AP-FGID. Eosinophils counts in the gastric antrum and body were significantly higher in children with H. pylori infection than in those with AP-FGID. Duodenal eosinophilia was prominent in cases of H. pylori infection, but not statistically significant when compared with AP-FGID. ConclusionsOur study revealed that gastric eosinophilia is associated with AP-FGID in children, regardless of the subtype of functional abdominal pain. This suggests some contribution of gastrointestinal eosinophils in the development of pediatric AP-FGID.

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Mast Cell–Nerve Interactions in Children With Functional Dyspepsia

Abstract: Early-onset neuroimmune interactions induced by cow's milk in the gastric mucosa of atopic children are associated with rapid disturbance of gastric myoelectrical activity and dyspeptic symptoms.

Cited by 58 publications

References 42 publications

Markers of gut mucosal inflammation and cow's milk specific immunoglobulins in non‐IgE cow's milk allergy

Markers of gut mucosal inflammation and cow's milk specific immunoglobulins in non‐IgE cow's milk allergy

Editorial: the diminishing returns of normalisation of the oesophageal mucosa

Analysis of Gastric and Duodenal Eosinophils in Children with Abdominal Pain Related Functional Gastrointestinal Disorders According to Rome III Criteria

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