Pathogenesis Of Functional Dyspepsia Research Articles

Effects of Saikosaponin D on Apoptosis, Autophagy, and Morphological Structure of Intestinal Cells of Cajal with Functional Dyspepsia.

Functional dyspepsia (FD) is one of the most common gastrointestinal diseases, with a global prevalence of 10%-30%. However, the specific pathogenesis of FD has not yet been determined. As such, the aim of this study was to investigate the effects of saikosaponin D (SSD) administration on the apoptosis, autophagy, and morphological structure of the intestinal cells of Cajal (ICCs) in FD. Methods：A rat model of FD was constructed by stimulating the rat tail with a sponge clamp at one-third of the distal tail length. An autophagy model was constructed for ICCs using glutamate. The apoptosis rate in each group of cells was determined using flow cytometry. The expressions of ghrelin and substance P (SP) were detected using ELISA. The body weight and food intake of male and female rats in the SSD group were consistently higher than those in the model group. The SSD group showed substantial improvement compared with the model group, with no inflammatory cell infiltration and normal gastric mucosal structures. After intervention with SSD, the ultrastructure of the ICCs considerably improved and was clear. Compared with the model group, the expressions of LC3 I/II, ghrelin, and SP proteins in the SSD group were significantly upregulated, and the apoptosis rate was significantly reduced. The administration of SSD improved ICC morphology and structure, inhibited excessive autophagy, and improved FD, a gastrointestinal motility disorder, by regulating ghrelin and SP levels.

Mast cells disrupt the duodenal mucosal integrity: Implications for the mechanisms of barrier dysfunction in functional dyspepsia

Background Functional dyspepsia (FD) is a common functional gastrointestinal (GI) disorder, but its pathophysiology is poorly understood. Mast cells (MCs) may play a critical role in the development of FD. Therefore, the aim of this study was to investigate the effect of MCs on barrier function, tight junction (TJ) proteins and related signaling pathways. Methods The expression of the TJ proteins claudin-8, ZO-1 and occludin in biopsy tissues from seven FD patients and five controls was assessed. Based on the in vivo results, we further investigated the effect of (1) MC degranulation in a coculture model of Caco-2/RBL-2H3 cells and tryptase in Caco-2 monolayers, (2) MC degranulation in the presence or absence of a PAR-2 antagonist and (3) MC degranulation in the presence or absence of an ERK1/2 signaling pathway inhibitor. The epithelial integrity of Caco-2 cell monolayers was assessed by measuring the transepithelial electrical resistance (TEER). The expression of TJ proteins was evaluated by western blotting, QT-PCR and immunostaining. Results Epithelial claudin-8, ZO-1 and occludin protein expression were significantly reduced in tissues from FD patients compared with controls. MC degranulation and tryptase decreased the TEER and reduced the expression of TJ proteins in Caco-2 cell monolayers. A PAR-2 antagonist and an ERK1/2 signaling pathway inhibitor significantly reduced the effect of MC degranulation on the TEER and TJ protein expression in Caco-2 cell monolayers. Conclusions MCs disrupt duodenal barrier function by modulating the levels of TJ proteins, and the PAR-2 and ERK1/2 signaling pathways may mediate the pathogenesis of FD.

Multi-omics analysis reveals the metabolic regulators of duodenal low-grade inflammation in a functional dyspepsia model.

Several gastrointestinal phenotypes and impairment of duodenal mucosal barrier have been reported in clinical studies in patients with functional dyspepsia (FD). Due to the preferential colonization of the mucosa, intestinal microbes and their metabolites are commonly involved in host metabolism and immune responses. However, there are no studies on the intertwined correlation among multi-level data. For more comprehensive illustrating, a multi-omics analysis focusing on the duodenum was performed in the FD rat model. We found that differential microbiomes in the duodenum were significantly correlated with the biosynthesis of lipopolysaccharide and peptidoglycan. The innate immune response-related genes, which were upregulated in the duodenum, were associated with the TLR2/TLR4-NFκB signaling pathway. More importantly, arachidonyl ethanolamide (anandamide, AEA) and endocannabinoid analogues showed linear relationships with the FD phenotypes. Taken together, multi-level data from microbiome, transcriptome and metabolome reveal that AEA may regulate duodenal low-grade inflammation in FD. These results suggest an important cue of gut microbiome–endocannabinoid system axis in the pathogenesis of FD.

Pancreatic Dysfunction and Duodenal Inflammatory Responses Coordinate with Refractory Epigastric Pain Including Functional Dyspepsia: A Narrative Review.

Some patients with functional dyspepsia (FD) have abnormalities in pancreatic enzymes and chronic pancreatitis. Since 2009, when the idea of early chronic pancreatitis (ECP) first emerged, the utility of endoscopic ultrasonography gained attention, as it can help identify early chronic pancreatitis in patients with dyspepsia. Although the symptoms associated with pancreatic enzyme abnormalities and pancreatic dysfunction overlap with those of dyspepsia, no available data explain the direct relationships and linkages between pancreatic dysfunction and dyspeptic symptoms. Disturbance of exocrine pancreatic enzyme function and reduction in pancreatic endocrine levels, such as insulin, may be associated with dyspeptic symptoms through impaired gastric emptying and duodenal inflammation. Some recent studies have examined the role of duodenal pathophysiology in gastric motility, bicarbonate secretion, and digestion. Because reduced bicarbonate secretion, which is caused by pancreatic dysfunction, leads to a failure to neutralize gastric acid in the proximal duodenum, impaired bicarbonate secretion in turn fails to protect the duodenal mucosa against gastric acid influx, thereby inducing duodenal inflammation. In addition, elevated trypsin levels might be associated in part with duodenal inflammatory responses through PAR2-related immunomodulatory cells. This review describes how duodenal inflammation might affect the pathogenesis of FD and examines whether pancreatic dysfunction is associated with FD through intestinal inflammation.

Role of the duodenal microbiota in functional dyspepsia.

Functional dyspepsia (FD) is a common and debilitating gastrointestinal disorder attributed to altered gut-brain interactions. While the etiology of FD remains unknown, emerging research suggests the mechanisms are likely multifactorial and heterogenous among patient subgroups. Small bowel motor disturbances, visceral hypersensitivity, chronic microinflammation, and increased intestinal tract permeability have all been linked to the pathogenesis of FD. Recently, alterations to the gut microbiome have also been implicated to play an important role in the disease. Changes to the duodenal microbiota may either trigger or be a consequence of immune and neuronal disturbances observed in the disease, but the mechanisms of influence of small intestinal flora on gastrointestinal function and symptomatology are unknown. This review summarizes and synthesizes the literature on the link between the microbiota, low-grade inflammatory changes in the duodenum and FD. This review is not intended to provide a complete overview of FD or the small intestinal microbiota, but instead outline some of the key conceptual advances in understanding the interactions between altered gastrointestinal bacterial communities; dietary factors; host immune activation; and stimulation of the gut-brain axes in patients with FD versus controls. Current and emerging treatment approaches such as dietary interventions and antibiotic or probiotic use that have demonstrated symptom benefits for patients are reviewed, and their role in modulating the host-microbiota is discussed. Finally, suggested opportunities for diagnostic and therapeutic improvements for patients with this condition are presented.

Functional dyspepsia: A critical appraisal of the European consensus from a global perspective.

The European Society for Neurogastroenterology and Motility's (ESNM) consensus document on functional dyspepsia (FD) has provided a critical review of the evidence for 36statements highly relevant to the diagnosis and treatment of FD. We provide here our expert opinion on the North American, Australian and Asian assessments of the same topics discussed, and provide evidence where the ESNM consensus may deviate from those in the other continents. New and exciting data about the pathogenesis of FD are emerging including the possible central role of duodenal micro-inflammation (most notably eosinophilic duodenitis and intestinal mast cell disease), but this is a very dynamic field with several gaps remaining in our understanding that are summarized in this review. Identification of non-invasive biomarkers and testing of targeted therapies, including assessing the benefits of multidisciplinary teams in the management of FD, should be future priorities.

Succinate‐Induced Tuft Cell Hyperplasia Enhances FFA2/5‐HT Mediated Anion Secretion in Mouse Duodenum

Tuft cells are one of luminal chemosensing components in the small intestine, while the role of tuft cell in mucosal secretory responses to luminal chemicals such as short-chain fatty acids (SCFA) has not been elucidated. We thus hypothesized that tuft cell hyperplasia may increase the secretory responses to luminal SCFA due to the increased cholinergic signals since tuft cells express choline acetyltransferase (ChAT). Tuft cell hyperplasia was induced by oral sodium succinate (NaSuc, 100 mM) in the drinking water for 7 days. Sodium propionate (NaP, 10 mM, m), the selective free fatty acid receptor 2 (FFA2) agonist 4-CMTB (10 µM, s), or the TRPA1 agonist allyl isothiocyanate (AITC, 1 mM, m) were applied to the mucosal (m) or serosal (s) baths of an Ussing chamber mounted with muscle-stripped mucosa-submucosa preparations of mouse proximal duodenum or jejunum. The density of tuft cells (doublecortin-like kinase 1; DCLK1), enteroendocrine L cells (proglucagon, glucagon-like peptide-2), and enterochromaffin (EC) cells (5-HT, tryptophan hydroxylase 1; TPH1) were assessed by real-time PCR and immunostaining. NaSuc treatment significantly increased the number of DCLK1-positive tuft cells in the duodenal and jejunal villi. mRNA expression of DCLK1 and FFA2 were increased in the duodenal and jejunal mucosa, whereas TPH1 was increased only in the duodenal mucosa, and ChAT was increased in the jejunal mucosa, but proglucagon was unchanged in both. 5-HT-positive mast cell density rather than EC cell density was increased in the duodenum. Isc in response to luminal NaP was enhanced in the jejunum, which was atropine sensitive. In contrast, Isc responses to serosal 4-CMTB and luminal AITC were enhanced in the duodenum, which were mediated by 5-HT3 and 5-HT4 receptors. These results suggest that NaSuc differentially enhances secretory responses, with 5-HT signals in the duodenum and with cholinergic signals in the jejunum. These data may be implicated in the pathogenesis of functional dyspepsia (FD), since increased duodenal mast cell density and enhanced 5-HT signals are present in FD patients.

The effect of prucalopride on gastric sensorimotor function and satiation in healthy volunteers.

Gastric motor function alterations have been implicated in the pathogenesis of functional dyspepsia with postprandial distress syndrome (PDS). Prucalopride, a 5-TH4 agonist, is known to stimulate gastrointestinal motility. We aimed to evaluate the effect of prucalopride on gastric sensorimotor function in healthy subjects (HV). Barostat and intragastric pressure (IGP) measurements were performed in 17 HV (59% females, age 29.4±2.7y) after treatment with placebo or prucalopride (2mg) (single-blind cross-over). Isobaric stepwise distensions and gastric sensations were assessed to determine gastric compliance and sensitivity. Gastric accommodation (GA) with the barostat was quantified before and after ingestion of 200ml of a nutrient drink (ND). GA measured by IGP was quantified as the drop of IGP from baseline during the intragastric infusion of ND until maximal satiation (60ml/min). Prucalopride did not affect barostat assessed gastric compliance or sensitivity. No differences were observed in GA after prucalopride. During the barostat study, 10min after the meal, 7 HVs reported significantly higher ratings for nausea after prucalopride (p<0.001), and vomiting was induced in 4 of the HVs. A positive correlation was observed between the delta mean perception of nausea with the delta mean increase of intra-balloon volume before and after meal ingestion (r=0.37, p=0.03). During IGP measurements, no effect on nutrient tolerance was observed and increased cramp severity scores were observed which were associated with a significant increase of distal IGP (r=0.78, p<0.0001). Prucalopride does not enhances gastric accommodation but it might increase sensitivity to gastric distention. Furthermore, the increase in sensitivity seems to be related to an increase in nausea with distension. Clinicaltrials.gov: NCT04429802.

D-galacturonic acid ameliorates the intestinal mucosal permeability and inflammation of functional dyspepsia in rats.

Functional dyspepsia (FD) is a gastrointestinal disease caused by imbalanced gastrointestinal function. Traditional treatments are deemed to be limited, and new therapeutic drugs are required. New study suggested that duodenal low-grade inflammation and increased intestinal permeability play an important role in the pathogenesis of FD. Previous studies have shown that polysaccharides containing D-galacturonic acid (GA) could modulate intestinal immune activity in vitro and in animal models. However, the ability of GA monomer to improve intestinal mucosal permeability and inflammation in FD has not been clearly elucidated. A FD rat model was established using iodoacetamide (IA). FD Rats were administrated different doses of GA. Subsequently, the body weight and behavioral sensitivity of the rats were measured and evaluated; the permeability of the intestinal barrier was measured by determining D-lactose, lactulose/mannitol ratio (LMR), and permeability-related genes [desmocollin-2 (DSC2), TJP1, and OCLN] in FD rats. Also, inflammatory cells [cluster of differentiation (CD)3+ cells and mast cells] were assessed by immunohistochemistry, and the levels of immune-related factors, such as the Toll-like receptor-nuclear factor kappa B (TLR/NF-κB) pathway, were monitored by reverse transcription quantitative polymerase chain reaction (RT-qPCR) or western blot assays. Our results suggested that GA could markedly increase the body weight and attenuate the behavioral sensitivity of FD rats. Moreover, GA also has an obvious ameliorating effect on the intestinal mucosal permeability and inflammatory response of FD rats. Furthermore, we found that GA could markedly downregulate TLR2, TLR4, and NF-κB in FD rats. These findings indicate that GA could significantly attenuate the intestinal mucosal permeability and inflammation FD rats. The effect of GA was partially mediated by the TLR/NF-κB signaling pathway.

Evidence of Duodenal Epithelial Barrier Impairment and Increased Pyroptosis in Patients With Functional Dyspepsia on Confocal Laser Endomicroscopy and "Ex Vivo" Mucosa Analysis.

Duodenal epithelial barrier impairment and immune activation may play a role in the pathogenesis of functional dyspepsia (FD). This study was aimed to evaluate the duodenal epithelium of patients with FD and healthy individuals for detectable microscopic structural abnormalities. This is a prospective study using esophagogastroduodenoscopy enhanced with duodenal confocal laser endomicroscopy (CLE) and mucosal biopsies in patients with FD (n = 16) and healthy controls (n = 18). Blinded CLE images analysis evaluated the density of epithelial gaps (cell extrusion zones), a validated endoscopic measure of the intestinal barrier status. Analyses of the biopsied duodenal mucosa included standard histology, quantification of mucosal immune cells/cytokines, and immunohistochemistry for inflammatory epithelial cell death called pyroptosis. Transepithelial electrical resistance (TEER) was measured using Ussing chambers. Epithelial cell-to-cell adhesion proteins expression was assessed by real-time polymerase chain reaction. Patients with FD had significantly higher epithelial gap density on CLE in the distal duodenum than that of controls (P = 0.002). These mucosal abnormalities corresponded to significant changes in the duodenal biopsy samples of patients with FD, compared with controls, including impaired mucosal integrity by TEER (P = 0.009) and increased number of epithelial cells undergoing pyroptosis (P = 0.04). Reduced TEER inversely correlated with the severity of certain dyspeptic symptoms. Furthermore, patients with FD demonstrated altered duodenal expression of claudin-1 and interleukin-6. No differences in standard histology were found between the groups. This is the first report of duodenal CLE abnormalities in patients with FD, corroborated by biopsy findings of epithelial barrier impairment and increased cell death, implicating that duodenal barrier disruption is a pathogenesis factor in FD and introducing CLE a potential diagnostic biomarker in FD.

Management of functional dyspepsia in 2020: a clinical point of view.

Dyspepsia is a disorder that refers mainly to central upper abdominal pain or discomfort. When a cause of this symptom is not identified the condition is termed functional dyspepsia (FD), that affects a large part of the general population. The relevance of FD is due to its high prevalence, but also to its chronic or intermittent course. This induces a significant burden for each national healthcare system. The pathogenesis of FD is complex and multifactorial, depending on cultural, environmental, and biological factors. Although considered of main importance in the pathophysiology of several gastroduodenal diseases, in the context of FD Helicobacter pylori (H. pylori) infection plays a limited role. The diagnosis of FD requires the exclusion of organic gastroduodenal diseases as well as H. pylori infection. Thus, the diagnostic workup includes a complete anamnesis, biochemical tests, and endoscopy with biopsy (when requested), and the satisfaction of clinic criteria recommended by the Rome IV consensus. The treatment of FD is also challenging, in fact more and more studies focused on a wide range of different therapies, with a multitude of results. The aim of this literature review is to provide an update of the new evidences useful for diagnosis and management of FD.

Gut Microbiota Dysbiosis in Functional Dyspepsia.

Functional dyspepsia (FD) is one of the most prevalent chronic functional gastrointestinal disorders. Several distinct pathophysiological mechanisms, including gastro duodenal motor disorders, visceral hypersensitivity, brain-gut interactions, duodenal subtle inflammation, and genetic susceptibility, have been implicated in the pathogenesis of the disease, so far. However, emerging evidence suggests that both quantitative and qualitative disturbances of the gastrointestinal microbiota may also be implicated. In this context, several studies have demonstrated differences of the commensal bacterial community between patients with FD and healthy controls, while others have shown that intestinal dysbiosis might associate with disease’s symptoms severity. Elucidating these complex interactions constituting the microbiota and host crosstalk, may eventually lead to the discovery of novel, targeted therapeutic approaches that may be efficacious in treating the multiple aspects of the disorder. In this review, we summarize the data of the latest research with focus on the association between gut microbiota alterations and host regarding the pathogenesis of FD.

Usefulness of the hydrogen breath test in patients with functional dyspepsia

IntroductionThe pathogenesis of functional dyspepsia is complex and not well understood. Therefore, in this disease there should be considered involvement of different pathogenic factors, including intestinal bacteria.AimTo evaluate the results of the hydrogen breath test in relation to the clinical picture of functional dyspepsia.Material and methodsThe study included 40 healthy subjects (group I), 72 patients with postprandial distress syndrome (PDS, group II), and 84 patients with epigastric pain syndrome (EPS, group III). The diagnosis of functional dyspepsia was based on Rome Criteria IV. The urea breath test (13C-UBT) and lactulose hydrogen breath test (LHBT) were performed in all subjects. Patients with a positive urea breath test were excluded from the study. Patients with a positive LHBT test were assigned to antibiotic therapy (1200 mg daily for 14 days). Before treatment and 6 weeks after the end of antibiotic therapy the LHBT was performed, and severity of dyspeptic symptoms was assessed using a 10-points visual analogue scale.ResultsA positive LHBT test was found in 35 (48.6%) patients in the group with PDS, and in 40 (47.6%) patients with EPS (p > 0.05). A positive correlation between the results of the LHBT test and severity of dyspeptic symptoms was found in both group (p < 0.001). After treatment with rifaximin the mean LHBT result and the index of severity of dyspeptic complaints were significantly decreased (p < 0.001).ConclusionsQuantitative and/or qualitative changes in the gut microbiota may be the cause of functional dyspepsia.

Nerve growth factor and Tropomyosin receptor kinase A are increased in the gastric mucosa of patients with functional dyspepsia

BackgroundNerve growth factor (NGF) and enteric glial cells (EGCs) are associated with visceral hypersensitivity and gastrointestinal motility disorder, which may represent the pathogenesis of functional dyspepsia (FD). This study aimed to investigate the expression of NGF, its high affinity receptor tropomyosin receptor kinase A (TrkA) and the EGC activation marker glial fibrillary acidic protein (GFAP) in the gastric mucosa of patients with FD and the association of these proteins with dyspeptic symptoms.MethodsGastric mucosal biopsies taken from 27 FD patients (9 epigastric pain syndrome (EPS) patients, 7 postprandial distress syndrome (PDS) patients and 11 EPS overlap PDS patients) and 26 control subjects were used for analysis. The expression of NGF, TrkA and GFAP was examined, and the association of these proteins with dyspeptic symptoms, including epigastric pain, postprandial fullness, early satiation and epigastric burning, was analysed.ResultsThe expression levels of NGF, TrkA, and GFAP in the gastric mucosa were significantly higher in the EPS group, the PDS group, and the EPS overlap PDS group than in the healthy control group. There was no significant difference between the FD subgroups. TrkA colocalized with GFAP, which indicated that TrkA was localized to EGCs, and the expression of TrkA in EGCs was significantly higher in the FD group than in the control group. Changes in the expression of NGF, TrkA, and GFAP were positively correlated with epigastric pain, postprandial fullness and early satiation but had no significant relationship with epigastric burning.ConclusionsThe increased expression of gastric NGF, TrkA and GFAP might be involved in FD pathophysiology and symptom perception.

Shen-Ling-Bai-Zhu-San alleviates functional dyspepsia in rats and modulates the composition of the gut microbiota

The pathogenesis of functional dyspepsia (FD) is multifactorial, and the gut microbiota may play a significant role. Shen-Ling-Bai-Zhu-San (SLBZS), a traditional Chinese herbal medicine, has been widely used in the treatment of FD, and appears to influence the gut microbiota. Therefore, we hypothesized that SLBZS would alleviate dyspeptic symptoms by adjusting the composition of the gut microbiota. To test this hypothesis, we aimed to evaluate the effects of SLBZS on FD and elucidate the mechanism that underlies the interactions between gut microbiota and FD during SLBZS treatment. We employed a rat model of FD induced by multiple forms of chronic mild stimulation. 16S rRNA gene sequencing and shotgun metagenomic sequencing were used to analyze the microbial communities in fecal samples from the rats. We found that the SLBZS improved dyspeptic symptoms in FD rats, such as weight loss, decreased intestinal motility, reduced absorptive capacity. Moreover, the SLBZS treatment reversed gut dysbiosis in FD. With SLBZS treatment, FD biomarkers including Prevotella, Mucispirillum and Akkermansia were decreased while SCFA-producing bacteria such as Adlercreutzia and Clostridium, and sulfate-reducing bacteria Desulfovibrio were enriched. Additionally, SLBZS normalized the dysregulated function of the microbiome, upregulating the pathways of energy metabolism and decreasing the oxidative stress as well as bacterial pathogenesis. Our study demonstrated that SLBZS could ameliorate dyspepsia, and amend the dysregulated composition and function of the gut microbial community, providing insight into the mechanism of SLBZS treatment for FD from the perspective of gut microbiota.

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.

Gene Polymorphisms and Susceptibility to Functional Dyspepsia: A Systematic Review and Meta-Analysis.

Functional dyspepsia (FD) is a common chronic gastrointestinal disorder with a complex, undefined mechanism. Clustering of patients with FD in families highlights the role of genetic factors in the pathogenesis of FD. We performed a systematic review and meta-analysis to clarify the associations between specific gene polymorphisms and FD susceptibility. PubMed, EMBASE, the Cochrane Library, and HuGE database were searched. An additive model was adopted to determine whether previous studied genes are associated with FD susceptibility. Carriers of minor allele in GNB3 825C>T (OR = 1.15, 95% CI 0.99-1.34, P = 0.07), SCL6A4 5HTTLPR (OR = 0.92, 95% CI 0.75-1.12, P = 0.40), and CCK-1R 779T>C (OR = 0.86, 95% CI 0.72-1.03, P = 0.09) genes failed to demonstrate susceptibility to FD. In a subgroup analysis, only minor allele (T) in GNB3 825C>T was associated with an increased susceptibility to the epigastric pain syndrome subtype (OR = 1.34, 95% CI 1.10-1.63, P = 0.003). Our meta-analysis based on available studies using an additive model failed to show that GNB3, SCL6A4, and CCK-1R polymorphisms are associated with FD susceptibility.

The Altered Mucosal Barrier Function in the Duodenum Plays a Role in the Pathogenesis of Functional Dyspepsia.

An altered gastrointestinal barrier function is reportedly associated with the pathogenesis of functional dyspepsia (FD); however, the pathogenesis of FD has not yet been fully elucidated. The objective of the present study was to determine whether the mucosal barrier function is impaired in patients with FD and to investigate the mechanisms underlying FD. The present study included patients with FD (FD group, n = 24), non-FD patients with abdominal symptoms (symptomatic control group, n = 14), and patients with no abdominal symptoms (asymptomatic control group, n = 20). The groups were compared regarding the mucosal electrical impedance (MI) values of the stomach and duodenum, which were measured using a tissue conductance meter during esophagogastroduodenoscopy. There were no significant differences between the three groups in the MI of the stomach. In contrast, the duodenal MI of the FD group (17.8 ± 4.3Ω) was significantly lower than those of the symptomatic control group (27.2 ± 6.4Ω, p < 0.0001) and asymptomatic control group (23.0 ± 7.4Ω, p = 0.016). The expression of zonula occludens-1 (ZO-1) was significantly lower in the FD group than in the symptomatic control group (p = 0.011), where ZO-1 was positively correlated with the duodenal MI (β = 0.513, p = 0.017). The interleukin (IL)-1β expression was significantly higher in the FD group than in the symptomatic control group (p = 0.041), where IL-1β was inversely correlated with the duodenal MI (β = - 0.600, p = 0.004). The mucosal barrier function of the duodenum was altered in patients with FD. Both a decreased ZO-1 and increased IL-1β may play a role in the pathogenesis of FD.

Gastric corticotropin-releasing factor influences mast cell infiltration in a rat model of functional dyspepsia.

Functional gastrointestinal disorders (FGIDs) are characterized by dysregulated gut-brain interactions. Emerging evidence shows that low-grade mucosal inflammation and immune activation contribute to FGIDs, including functional dyspepsia (FD). Stress plays an important role in the onset of FD symptoms. In human subjects with FD, presence of gastric mast cells has been reported, but factors that influence mast cell infiltration remain uncharacterized. Corticotropin-releasing factor (CRF) initiates the body’s stress response and is known to degranulate mast cells. In this study, we delineated the role of the CRF system in the pathogenesis of FD in a rat model. Gastric irritation in neonate rat pups with iodoacetamide (IA) was used to induce FD-like symptoms. RNA interference (RNAi) was used to silence gastric CRF expression. Mast cell infiltrate in the stomach increased by 54% in IA-treated rats compared to controls and CRF-RNAi tended to decrease gastric mast cell infiltrate. Sucrose intake decreased in IA-treated rats and mast cell numbers showed a negative association with sucrose intake. IA treatment and transient silencing of gastric CRF increased hypothalamic CRF levels. In IA-treated rats, gastric levels of CRF receptor 2 (CRF2) decreased by ~76%, whereas hypothalamic CRF receptor 1 (CRF1) levels increased. Plasma levels of TNF-α showed a positive correlation with plasma CRF levels. Levels of phosphorylated p38 and ERK1/2 in the stomach showed a positive correlation with gastric CRF levels. Thus, CRF may contribute to low grade inflammation via modulating mast cell infiltration, cytokine levels, MAPK signaling, and the gut-brain axis.

Role of the Duodenum in the Pathogenesis of Functional Dyspepsia: A Paradigm Shift.

Functional dyspepsia (FD) is a common disorder characterized by chronic epigastric pain or burning, or bothersome postprandial fullness or early satiation, without a definitive organic cause. The pathogenesis of FD is likely heterogeneous. Classically, motor disorders, visceral hypersensitivity, and brain-gut interactions have been implicated in the pathophysiology of FD, but recently an important role for chronic low-grade inflammation and infection in FD has been reported and confirmed. Duodenal low-grade inflammation is frequently observed in FD in those with and without documented previous gastroenteritis. Duodenal eosinophils and in some cases mast cells may together or separately play a key role, and immune activation (eg, circulating homing small intestinal T cells) has been observed in FD. Low-grade intestinal inflammation in patients with FD may provoke impairment in motor-sensory abnormalities along the gastrointestinal neural axis. Among FD patients, the risk of developing dyspeptic symptoms after a bout of gastroenteritis is 2.54 (95% CI, 1.76–3.65) at more than 6 months after acute gastroenteritis. Gut host and microbial interactions are likely important, and emerging data demonstrate both quantitative and qualitative changes of duodenal mucosal and fecal microbiota in FD. Food antigens (eg, wheat proteins) may also play a role in inducing duodenal inflammation and dyspepsia. While causation is not established, the hypothesis that FD is a disorder of microscopic small intestinal inflammation in a major subset is gaining acceptance, opening the possibility of novel treatment approaches that may be able to alter the natural history of the disorder.