Pylori-negative Functional Dyspepsia Research Articles

Diversity recovery and probiotic shift of gastric microbiota in functional dyspepsia patients after Helicobacter pylori eradication therapy.

The effects of Helicobacter pylori eradication on gastric mucosa-colonizing microbes in patients with functional dyspepsia (FD) remain unclear. Here, we explored microbial variation induced by H. pylori infection and eradication treatment in FD patients. Gastric microbial abundance and diversity were significantly reduced in the H. pylori-infected FD patients. Eradication treatment increased alpha and beta diversity of gastric mucosa-colonizing microbes, and promoted the expansion of several probiotic microbes, such as Leuconostoc mesenteroides, which exhibited a matched antagonistic performance against H. pylori. Significant variation was observed in gastric mucosa-colonizing microbes between H. pylori-positive and H. pylori-negative FD patients. Eradication treatment induced microbial diversity recovery and may provide sufficient nutrition and space for probiotic microbes, such as Leuconostoc mesenteroides.

Comparison of CD4+ and CD8+ T- lymphocyte in Helicobacter pylori-negative functional dyspepsia.

Background:Functional dyspepsia (FD) is the most common gastrointestinal disorder with several symptoms such as stomach pain and abdominal bloating. The aim of this study was to investigate and compare CD4+ and CD8+ in the Helicobacter pylori-negative functional dyspepsia and control groups.Methods:Sixty one patients (35 patients with stomach pain and 26 with abdominal bloating), and 30 controls were reviewed based on the quantity of CD4+ and CD8+ T-cells isolated from gastric mucosa biopsy samples. The comparison between variables was analyzed with a chi-square or Fisher’s exact test and logistic regression analyses. P<0.05 and odds ratio (OR) with a 95% confidence interval demonstrated statistical significance.Results:A significant difference was observed between two-group patients and control group based on CD4+ and CD8+ presence, respectively (P=0.003, P=0.008). Furthermore, there was a significant difference between stomach pain-patients and control group with regard to CD4 count (P=0.01) and between abdominal bloating-patients and control group with regard to CD8 count (P=0.002). There was a decrease in both CD4+ and CD8+ T-cells in gastric mucosa in patients with FD with a significant reduction in the stomach pain-patients and abdominal bloating-patients in the number of CD4+ and CD8+ T-cells, respectively.Conclusion:These results indicated that the role of immunology in the absence of the CD4+ and CD8+ T-cells in the gastric mucosa may have a protective role against FD.

Impaired gastric mucosal integrity identified by confocal endomicroscopy in Helicobacter pylori-negative functional dyspepsia.

Low-grade inflammation may be involved in the pathogenesis of functional dyspepsia (FD). We hypothesis that altered gastric permeability is involved in the onset and persistence of this disorder. Therefore, our aim was to evaluate gastric mucosal integrity and mast cell numbers in patients with FD. We enrolled 58 patients with FD fulfilling the Rome III criteria (H Pylori negative), 20 inflammatory control subjects (H Pylori positive), and 20 healthy controls (H Pylori negative). Probe-based confocal endomicroscopy was performed using intravenous fluorescein to assess the paracellular fluorescein leakage and cell shedding. Mast cells were identified with quantitative immunohistochemistry on mucosal biopsies. Endomicroscopic score of paracellular permeability was significantly higher in H pylori-negative FD patients compared with healthy controls (1.45±1.27 vs 3.69±3.18, P=.006). However, FD patients and healthy controls did not show differences in cell shedding score (0.75±0.79 vs 1.29±1.14, P=.069). Mast cell numbers were significantly increased compared with healthy control samples (18.91±5.47 vs 14.1±3.88, P<.001). The magnitude of increase in permeability was positively correlated with mast cell numbers of FD patients (rs=.6588, P<.0001), but not dyspepsia symptom scores. Impaired gastric barrier function is present in FD patients. This might provide a new pathophysiological mechanism and therapeutical target in FD.

On the importance of developing a new generation of breath tests for Helicobacter pylori detection

State-of-the-art methods for non-invasive detection of the Helicobacter pylori (H. pylori) infection have been considered. A reported global tendency towards a non-decreasing prevalence of H. pylori worldwide could be co-influenced by the functional limitations of urea breath tests (UBTs), currently preferred for the non-invasive recognition of H. pylori in a clinical setting. Namely, the UBTs can demonstrate false-positive or false-negative results. Within this context, limitations of conventional clinically exploited H. pylori tests have been discussed to justify the existing need for the development of a new generation of breath tests for the detection of H. pylori and the differentiation of pathogenic and non-pathogenic strains of the bacterium. This paper presents the results of a pilot clinical study aimed at evaluating the development and diagnostic potential of a new method based on the detection of the non-urease products of H. pylori vital activity in exhaled gas. The characteristics of breath of adolescents with H. pylori-positive and H. pylori-negative functional dyspepsia, together with a consideration of the cytotoxin-associated gene A (CagA) status of H. pylori-positive subjects, have been determined for the first time using innovative point-contact nanosensor devices based on salts of the organic conductor tetracyanoquinodimethane (TCNQ). The clinical and diagnostic relevance of the response curves of the point-contact sensors was assessed. It was found that the recovery time of the point-contact sensors has a diagnostic value for differentiation of the H. pylori-associated peptic ulcer disease. The diagnostically significant elongation of the recovery time was even more pronounced in patients infected with CagA-positive H. pylori strains compared to the CagA-negative patients. Taking into account the operation of the point-contact sensors in the real-time mode, the obtained results are essential prerequisites for the development of a fast and portable breath test for non-invasive detection of cytotoxic CagA strains of H. pylori infection. The relaxation time of the point-contact nanosensors could be selected as a diagnostic criterion for non-invasive determination of H. pylori-associated destructive lesions of the gastroduodenal area in adolescents, using the point-contact spectroscopic concept of breath analysis. This can subsequently be implemented into a ‘test-and-treat’ approach for the management of uninvestigated dyspepsia in populations with a high prevalence of H. pylori (according to the Maastricht III and IV Consensus recommendations).

Relationship between headache and mucosal mast cells in pediatric Helicobacter pylori-negative functional dyspepsia

Although many patients with functional dyspepsia experience headache concurrently with dyspeptic symptoms, studies suggesting mechanisms underlying this phenomenon are limited. Herein, we explore the relationship between gastrointestinal inflammatory cells and presence of headache associated with dyspeptic symptoms in children with HELICOBACTER PYLORI -negative functional dyspepsia. Fifty-six patients with H. PYLORI -negative functional dyspepsia underwent upper endoscopy with biopsy to investigate recurrent epigastric pain or discomfort. Patients were divided into two groups according to self-reported presence of headache associated with dyspeptic symptoms. Inflammatory cells including mast cells, and enteroendocrine cells in the gastroduodenal mucosa were evaluated. Associations between headache presence and cellular changes in the gastroduodenal mucosa were examined. Headache was not associated with the grade of lymphocytes, neutrophil infiltration, or enteroendocrine cell density in the gastroduedenal mucosa. However, headache was significantly associated with high mast cell density in the body (27.81 ± 8.71 vs. 20.30 ± 8.16, P < 0.01) and duodenum (23.16 ± 10.40 vs. 14.84 ± 5.88, P < 0.01). Presence of headache associated with dyspeptic symptoms is strongly related to mucosal mast cell density in pediatric patients with H. PYLORI -negative functional dyspepsia. Thus, our results may help clinicians understand and treat headache during dyspeptic symptoms in such pediatric patients.

The Preproghrelin 3056 TT Genotype is Associated with the Feeling of Hunger and Low Acylated Ghrelin Levels in Japanese Patients with &lt;i&gt;Helicobacter pylori&lt;/i&gt;-negative Functional Dyspepsia

An impairment of gastric motility is strongly associated with the pathophysiology of functional dyspepsia (FD). Plasma ghrelin is one of the key molecules linked to gastric motility. Therefore, this study aimed to evaluate whether ghrelin (GHRL) gene polymorphisms are associated with clinical symptoms, the plasma ghrelin levels and gastric emptying in patients with FD as defined by the Rome III classification. We enrolled 74 Helicobacter pylori-negative patients presenting with typical symptoms of FD (epigastric pain syndrome (EPS), n=23; postprandial distress syndrome (PDS), n=51) and 102 healthy volunteers. Gastric motility was evaluated according to the Tmax value and T1/2 using the (13)C-acetate breath test. We used the Rome III criteria to evaluate upper abdominal symptoms and SRQ-D scores to determine the depression status. The Arg51Gln(346G->A), preproghrelin3056T->C, Leu72Met(408C->A) and Gln90Leu(3412T->A) polymorphisms were analyzed in DNA in blood samples obtained from the enrolled subjects. Genotyping was performed using polymerase chain reaction. There was a significant relationship (p=0.048) between the preproghrelin 3056TT genotype and the serum levels of acylated ghrelin in the H. pylori-negative FD patients. The preproghrelin 3056TT genotype was significantly (p=0.047) associated with the feeling of hunger in the H. pylori-negative FD patients. The preproghrelin 3056TT genotype is significantly associated with the acylated ghrelin levels and the feeling of hunger in H. pylori-negative FD patients. Further studies are needed to clarify the association between the preproghrelin 3056TT genotype and lower plasma acylated ghrelin levels and the impact of this relationship on the feeling of hunger in H. pylori-negative FD patients.

Review article: current treatment options and management of functional dyspepsia.

Functional dyspepsia (FD), a common functional gastrointestinal disorder, is defined by the Rome III criteria as symptoms of epigastric pain or discomfort (prevalence in FD of 89-90%), postprandial fullness (75-88%), and early satiety (50-82%) within the last 3 months with symptom onset at least 6 months earlier. Patients cannot have any evidence of structural disease to explain symptoms and predominant symptoms of gastroesophageal reflux are exclusionary. Symptoms of FD are non-specific and the pathophysiology is diverse, which explains in part why a universally effective treatment for FD remains elusive. To present current management options for the treatment of FD (therapeutic gain/response rate noted when available). The utility of Helicobacter pylori eradication for the treatment of FD is modest (6-14% therapeutic gain), while the therapeutic efficacy of proton pump inhibitors (PPI) (7-10% therapeutic gain), histamine-type-2-receptor antagonists (8-35% therapeutic gain), prokinetic agents (18-45%), tricyclic antidepressants (TCA) (response rates of 64-70%), serotonin reuptake inhibitors (no better than placebo) is limited and hampered by inadequate data. This review discusses dietary interventions and analyses studies involving complementary and alternative medications, and psychological therapies. A reasonable treatment approach based on current evidence is to initiate therapy with a daily PPI in H. pylori-negative FD patients. If symptoms persist, a therapeutic trial with a tricyclic antidepressant may be initiated. If symptoms continue, the clinician can possibly initiate therapy with an anti-nociceptive agent, a prokinetic agent, or some form of complementary and alternative medications, although evidence from prospective studies to support this approach is limited.

What Is the Difference Between -Associated Dyspepsia and Functional Dyspepsia?

Advances in basic and clinical research have revealed that Helicobacter pylori (H. pylori) infection plays an important role in the development of gastroduodenal dysmotility and hypersensitivity, as also in dyspepsia symptoms. In addition, recent studies have proposed an inflammation-immunological model for the pathogenesis of functional dyspepsia. Since H. pylori is the major microbe that provokes a gastroduodenal inflammatory response, it should not be overlooked when considering the pathophysiology of dyspepsia symptoms. In fact, population-based studies have demonstrated that H. pylori is detected more frequently in dyspepsia patients. However, although many clinical studies tried to reveal the association of H. pylori infection with gastric motility dysfunction or hypersensitivity, the results have been conflicting. On the other hand, many etiological features were revealed for the development of H. pylori-associated dyspepsia, such as abnormal ghrelin or leptic secretion, altered expression of muscle-specific microRNAs, and duodenal inflammatory cell infiltration. In addition, therapeutic strategy for H. pylori-associated dyspepsia would be different from H. pylori-negative functional dyspepsia. This review focuses the issue of whether H. pylori-associated dyspepsia should be considered as a different disease entity from functional dyspepsia.

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

Immune activation may have an important pathogenic role in the irritable bowel syndrome (IBS). While little is known about immunologic function in functional dyspepsia (FD), we have observed an association between cytokine secretion by peripheral blood mononuclear cells (PBMCs) and symptoms in IBS. Upper gastrointestinal inflammatory diseases are characterized by enhanced small bowel homing α4-, β7-integrin, chemokine receptor 9 (CCR9) positive T lymphocytes. We hypothesized that increased cytokine release and elevated circulating small bowel homing T cells are linked to the severity of symptoms in patients with FD. Thus, we aimed to (i) compare cytokine release in FD and healthy controls (HCs), (ii) quantify "gut homing" T cells in FD compared with HC and patients with IBS, and (iii) correlate the findings to symptom severity and gastric emptying. PBMC from 45 (Helicobacter pylori negative) patients with FD (Rome II) and 35 matched HC were isolated by density gradient centrifugation and cultured for 24 h. Cytokine production (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-10) was measured by enzyme-linked immunosorbent assay. CD4+ α4β7+CCR9+ T cells were quantified by flow cytometry in FD, HC and 23 patients with IBS. Gastric emptying was measured by scintigraphy. Symptom severity was assessed utilizing the standardized Gastrointestinal Symptom Score. FD patients had significantly higher TNF-α (107.2 ± 42.8 vs. 58.7 ± 7.4 pg/ml), IL-1β (204.8 ± 71.5 vs. 80.2 ± 17.4 pg/ml), and IL-10 (218 ± 63.3 vs. 110.9 ± 18.5 pg/ml) levels compared with HC, and enhanced gut homing lymphocytes compared with HC or IBS. Cytokine release and CD4+α4β7+CCR9+ lymphocytes were correlated with the symptom intensity of pain, cramps, nausea, and vomiting. Delayed gastric emptying was significantly associated (r = 0.78, P = 0.021) with CD4+α4β7+CCR9+ lymphocytes and IL-1β, TNF-α, and IL-10 secretion. Cellular immune activation with increased small bowel homing T cells may be key factors in the clinical manifestations of H. pylori-negative FD.

A prospective study of oesophageal 24-h ambulatory pH monitoring in patients with functional dyspepsia

Background. The diagnostic utility of 24-h oesophageal ambulatory pH monitoring in patients with functional dyspepsia has not been well established. Aims. We performed a prospective study of oesophageal pH monitoring in patients with functional dyspepsia in order to assess whether a positive pH test might predict response to proton pump inhibitor therapy in a subset of functional dyspepsia patients. Patients. Forty Helicobacter pylori-negative functional dyspepsia patients (35 males and 5 females, mean age (±S.E.M.) of 54 ± 2.4 years) with predominantly unspecified dyspepsia subtype and normal distal oesophageal biopsies. Methods. All subjects were randomised in a double-blind fashion to either omeprazole 20 mg/day or placebo daily for four weeks after 24-h pH monitoring. Results: Twenty-four-hour pH monitoring was abnormal in 9 of the 21 patients (43%) in the omeprazole group and 5/19 (26%) of the placebo group ( p = NS). Patients who reported symptomatic improvement on the Gastrointestinal Symptom Rating Scale were no more likely to have abnormal scores on pH monitoring than patients who did not have symptomatic response. Conclusions. Although approximately one-third of functional dyspepsia patients will have abnormal profiles on 24-h ambulatory oesophageal pH monitoring, an abnormal score does not appear to predict response to proton pump inhibitor therapy in patients with unspecified functional dyspepsia.

Gastric mucosal mast cells are increased in Helicobacter pylori-negative functional dyspepsia

Background & Aims : Mast cells might be involved in pathogenesis of functional dyspepsia because they can release a wide range of potent mediators, capable of altering gastric nerve and muscle function. This study aimed to determine whether mast cell numbers were increased in the gastric mucosa of patients with functional dyspepsia compared to control subjects. Methods : Biopsy samples were taken from the antrum and corpus of 111 patients: 20 asymptomatic control subjects, 62 patients with Rome criteria functional dyspepsia (33 Helicobacter pylori positive, 29 H. pylori negative), and 29 inflammatory control subjects ( H. pylori positive). Mast cells were detected immunohistochemically by using a mouse monoclonal antibody specific for tryptase. Quantification was performed with light microscopy, and results were expressed as mast cells/mm 2 ± standard error of mean. Results : Mast cells were significantly increased in H. pylori negative functional dyspepsia samples compared to normal control samples in the antrum (230.1 ± 11.3 vs. 94.8 ± 8.4, P < 0.001) and corpus (264.1 ± 27.1 vs. 123.9 ± 11.5, P = 0.001). Mast cells were also significantly increased in the antrum of patients with H. pylori positive functional dyspepsia compared to asymptomatic control subjects (166.5 ± 17.0 vs. 94.8 ± 8.4, P < 0.03). However, there was no significant difference between mast cell numbers in patients with H. pylori positive functional dyspepsia compared to inflammatory control subjects. Conclusions : Mast cells are increased in functional dyspepsia, independently of inflammation. This might contribute to the pathogenesis of functional dyspepsia by altering signaling in the brain-gut axis.