Association between genetic polymorphisms of NOD1, Interleukin-1B, and cagA strain with low-grade duodenal eosinophilia in Helicobacter pylori-related dyspepsia.

BACKGROUND: Functional dyspepsia (FD) is a multifactorial disorder. Helicobacter pylori (H. pylori)-related dyspepsia (HpD) may be considered a separate entity. Duodenal eosinophilia is a potential pathogenic mechanism in FD. However, the impact of duodenal eosinophilia and host genetic polymorphism of innate and pro-inflammatory cascade, nucleotide-binding oligomerization domain 1 (NOD-1), and interleukin-1 beta (IL-1ß) in HpD was not explored. AIM: To evaluate the association of NOD1-796G>A and IL-1B-511C>T gene variants and low-grade duodenal eosinophilia in HpD. METHODS: A multicenter cross-sectional study was conducted. A total of 253 patients who met Rome-IV criteria were selected before upper endoscopy and 98 patients were included after unremarkable upper endoscopy and positive H. pylori in gastric biopsies were assessed. Clinical parameters, H. pylori cagA and duodenal histology, were evaluated. RESULTS: Sixty-four (65%) patients had epigastric pain syndrome (EPS), 24 (25%) postprandial distress syndrome (PDS), and 10 (10%) EPS/PDS overlap. FD subtypes were not associated with NOD1-796G>A and IL-1B-511C>T gene variants. Low-grade duodenal eosinophilia was significantly increased in NOD1-796 GG versus single A-allele, but not in IL-1B-511 single T-allele or CC-allele. This association is dependent of cagA infection, since harboring cagA strain was significantly associated with low-grade duodenal eosinophilia with isolated variants NOD1-796 GG and IL-1B-511 single T-allele, but not without cagA. When we performed combined polymorphism analysis with NOD1-796 GG/IL-1B-511 single T-allele, a synergistic effect on low-grade duodenal eosinophilia was found between these two loci irrespective of cagA strain status in HpD. CONCLUSION: Our findings suggest that low-grade duodenal eosinophilia is significantly associated with NOD1-796 GG allele specially in cagA strain and with allelic combination NOD1-796 GG/IL-1B-511 single T-allele independent of cagA strain infection in HpD patients.

[Research progress in signaling pathways related to treatment of functional dyspepsia with traditional Chinese medicine].

Functional dyspepsia(FD) is a prevalent functional gastrointestinal disease characterized by recurrent and long-lasting symptoms that significantly impact the quality of life of patients. Currently, western medicine treatment has not made breakthrough progress and mainly relies on symptomatic therapies such as gastrointestinal motility agents, acid suppressants, antidepressants/anxiolytics, and psychotherapy. However, these treatments have limitations in terms of insufficient effectiveness and safety. Traditional Chinese medicine(TCM) possesses unique advantages in the treatment of FD. Through literature search in China and abroad, it has been found that the mechanisms of TCM in treating FD is associated with various signaling pathways, and research on these signaling pathways and molecular mechanisms has gradually become a focus. The main signaling pathways include the SCF/c-Kit signaling pathway, 5-HT signaling pathway, CRF signaling pathway, AMPK signaling pathway, TRPV1 signaling pathway, NF-κB signaling pathway, and RhoA/ROCK2/MYPT1 signaling pathway. This series of signaling pathways can promote gastrointestinal motility, alleviate anxiety, accelerate gastric emptying, reduce visceral hypersensitivity, and improve duodenal micro-inflammation in the treatment of FD. This article reviewed the research on TCM's regulation of relevant signaling pathways in the treatment of FD, offering references and support for further targeted TCM research in the treatment of FD.

Cannabidiol for Functional Dyspepsia With Normal Gastric Emptying: A Randomized Controlled Trial.

INTRODUCTION: Cannabidiol (CBD), a CBR2 agonist with limited psychic effects, antagonizes CB1/CB2 receptors. Allelic variation CNR1 (gene for CBR1) rs806378 and FAAH rs324420 were associated with altered gut motility and sensation. This study aimed to compare the pharmacodynamics and clinical effects of a 4-week treatment with pharmaceutical-grade CBD vs placebo and assess the interactions of FAAH and CNR1 gene variants on the effects of CBD in patients with functional dyspepsia (FD). METHODS: We performed a randomized, double-blinded, placebo-controlled (1:1 ratio) study of CBD b.i.d. (20 mg/kg/d according to the US Food and Drug Administration escalation guidance) in FD patients with nondelayed gastric emptying (GE) at baseline. Symptoms were assessed by validated daily symptom diary (0-4 scale for upper abdominal pain, nausea, and bloating), weekly assessment of adequate relief, Leuven Postprandial Distress Scale (8 symptoms, adjectival scores rated 0-4 for severity), and quality of life (Short-Form Nepean Dyspepsia Index [average of 10 dimensions each on a 5-point scale]). After the 4-week treatment, all patients underwent measurements of GE of solids, gastric volumes, and Ensure nutrient satiation test. Statistical analysis compared 2 treatments for all endpoints and the effects of CBD in association with FAAH rs324420 and CNR1 rs806378. RESULTS: CBD and placebo effects on physiological functions and patient response outcomes were not significantly different. There were borderline CBD treatment-by-genotype interactions: rs806378 CNR1 with Leuven Postprandial Distress Scale ( P = 0.06) and GE solids ( P = 0.12). DISCUSSION: Approved doses of CBD used off-label do not relieve FD with normal baseline GE of solids or alter gastric motor functions and satiation. CBD treatment-by-gene interactions suggest potential benefits for postprandial distress with CNR1 rs806378 T allele.

Moxibustion Regulates Gastrointestinal Motility via HCN1 in Functional Dyspepsia Rats.

BACKGROUND Moxibustion therapy has been found to ameliorate clinical symptoms of functional dyspepsia (FD). We aimed to examine the regulatory effect of moxibustion on the gastrointestinal (GI) motility in FD and explore the underlying mechanism based on the hyperpolarization-activated cyclic nucleotide-gated cation channel 1 (HCN1). MATERIAL AND METHODS Moxibustion therapy was used in FD rats induced by using classic tail-pinch and irregular feeding. Weight gain and food intake were recorded weekly, followed by detecting gastric residual rate (GRR) and small intestine propulsion rate (IPR). Next, western blotting was performed to determine the expression levels of HCN1 in the gastric antrum. qRT-PCR was used to detect HCN1 in the small intestine and hypothalamic satiety center. Double immunolabeling was used for HCN1 and ICCs in gastric antrum and small intestine. RESULTS The obtained results suggested that moxibustion treatment could increase weight gain and food intake in FD rats. The GRR and IPR were compared among the groups, which showed that moxibustion treatment could decrease GRR and increase IPR. Moxibustion increased the expression of HCN1 in the gastric antrum, small intestine, and hypothalamic satiety center. Histologically, the co-expressions of HCN1 and ICCs tended to increase in gastric antrum and small intestine. Meanwhile, HCN channel inhibitor ZD7288 prevented the above-mentioned therapeutic effects of moxibustion. CONCLUSIONS The results of the present study suggest that moxibustion can effectively improve the GI motility of FD rats, which may be related to the upregulation of HCN1 expression in gastric antrum, small intestine, and satiety center.

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

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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.

Analysis of the Influence of Interleukin-1ß Gene Polymorphism on Gastric Inflammatory Response and Precancerous Lesions Development in Patients with Functional Dyspepsia.

The present study aimed to evaluate the influence of the IL1B -31C/T polymorphism on gastric inflammatory response and precancerous lesions development - atrophic gastritis (AG) and intestinal metaplasia (IM) - in patients positive for Helicobacter pylori infection with functional dyspepsia (FD). The diagnosis of FD followed the Rome III criteria, and the H. pylori infection was evaluated by urease test and histological examination of gastric biopsies (corpus, antrum, and incisura). The severity of chronic inflammation and inflammatory activity, as well as the presence of precancerous lesions were evaluated accordingly to the updated Sydney System. Genotyping of the IL1B -31C/T polymorphism (rs1143627) was performed by polymerase chain reaction-restriction fragment length polymorphism. A total of 303 patients positive for H. pylori infection with FD were analyzed (81.8% women; mean age of 46.3 ± 12.3 years). No differences were observed in overall genotype frequencies among outcomes evaluated. However, in the dominant -31C allele model (CC+CT vs. TT), the frequency of the TT genotype was significantly higher among patients with moderate/severe chronic inflammation of the antrum than the frequency of the CC+CT genotypes (80.8% vs. 65.2%; OR = 2.25; 95% CI = 1.23-4.24; P = .005). The presence of AG and IM in the gastric mucosa of patients was of 19.5% and 19.1%, respectively. No significant association was observed concerning the frequencies of the genotypes of IL1B -31C/T polymorphism with development of precancerous lesions. In conclusion, our data suggest that genetic variants of the IL1B -31C/T polymorphism play a role in chronic inflammation of the gastric mucosa in H. pylori-infected FD patients.

Exosomal hsa-miR-933 in Gastric Juice as a Potential Biomarker for Functional Dyspepsia.

BACKGROUND: MicroRNAs (miRNAs) in exosomes represent disease-specific profiles and are applied as biomarkers in oncology. However, in functional dyspepsia (FD), the role of exosomal miRNAs has not been fully elucidated. AIMS: To investigate exosomal miRNAs as potential biomarkers of FD using liquid biopsy. METHODS: This retrospective cohort study included 11 subjects with FD and 11 age- and sex-matched healthy controls (HCs). We collected gastric juice and isolated exosomal miRNAs. In a discovery cohort, expression levels of 2565 miRNAs were evaluated by 3D-Gene® microarray. miRNA expression profiles from exosomes of subjects with FD and HCs were compared by two normalization methods: (1) global normalization and (2) normalization by internal control. Subsequently, in a validation cohort, the expression levels of miRNAs were validated by quantitative reverse transcription PCR (RT-qPCR). RESULTS: Through microarray analysis using the two methods, we identified 39 miRNAs that were consistently and significantly downregulated in FD cases compared with those in HCs. Of these, 12 miRNAs (hsa-miR-933, hsa-miR-345-5p, hsa-miR-708-5p, hsa-miR-203a-3p, hsa-miR-619-5p, hsa-miR-4294, hsa-miR-4481, hsa-miR-196a-5p, hsa-miR-3918, hsa-miR-372-3p, hsa-miR-658, and hsa-miR-3654) were further validated by RT-qPCR. Our results indicated that hsa-miR-933 was significantly downregulated in FD compared with HCs (0.317 ± 0.205-fold, P = 0.0317). Furthermore, the expression level of hsa-miR-933 was negatively associated with dyspepsia score and the frequency of epigastric pain and/or burning (P < 0.01, r = - 0.835; P = 0.0280, r = - 0.688, respectively). CONCLUSIONS: Exosomal hsa-miR-933 in gastric juice could be a candidate biomarker for FD.

New Medical Approach to Functional Dyspepsia, from Core Symposium 3, Japan Gastroenterological Association 2015-2017.

In the annual meeting of the Japan Gastroenterological Association (JGA), the scientific organizing committee selected the serial topics for the core symposium. One of the core symposia held during 2015-2017 was entitled "New medical approach to functional dyspepsia (FD)." In 2015, the subtitle of this symposium was "Helicobacter pylori gastritis and FD." In 2016, the subtitle of this symposium was "overlap with other functional GI disorders." In 2017, the subtitle was "therapeutic approach to FD." During these 3 years, a total of 24 presentations were included in Core Symposium 3 and deep and intensive discussions were carried out.

Polymorphisms of 5-HTT LPR and GNß3 825C>T and Response to Antidepressant Treatment in Functional Dyspepsia: A Study from The Functional Dyspepsia Treatment Trial.

OBJECTIVES: The Functional Dyspepsia Treatment Trial reported that amitriptyline (AMI) was associated with adequate relief of functional dyspepsia (FD) symptoms, but the pharmacogenetics of antidepressant response in FD are not known. GNß3 825C>T CC genotype has been previously linked to FD and TT genotype to antidepressant response in depression. The ss genotype of the 5-HTT LPR variant of the serotonin transporter gene (SLC6A4) has been linked to selective serotonin reuptake inhibitor (SSRI) response. We aimed to examine whether GNß3 825C>T and 5-HTT LPR polymorphisms result in differential treatment effects in FD patients receiving antidepressant therapy. METHODS: Participants were randomized to receive placebo, 50 mg AMI, or 10 mg escitalopram (ESC). The primary end point was adequate relief for ≥5 weeks of the last 10 weeks. Genotyping of GNß3 825C>T and 5-HTT LPR was performed utilizing PCR-based methods. RESULTS: GNß3 825C>T and 5-HTT LPR genotype data were available for 256 (88%) and 246 (84%) patients, respectively. Both polymorphisms were in Hardy-Weinberg equilibrium. In tests for differential treatment, neither 5-HTT LPR nor GNß3 825C>T genotype influenced response to therapy (P=0.89 and P=0.54, respectively). Although there was a tendency for a more favorable response to ESC in the SS/LS genotype compared to the LL genotype groups (40% vs. 31% reporting adequate relief of FD symptoms) among those in the ESC treatment arm, this was not significant (P=0.43). CONCLUSIONS: GNß3 825C>T and 5-HTT LPR genetic variants do not alter treatment response to tricyclic and SSRI antidepressants in FD.

Overlap between irritable bowel syndrome and functional dyspepsia including subtype analyses.

BACKGROUND AND AIM: Coexistent gastrointestinal symptom profiles and prevalence or associated factors for the overlap between each functional dyspepsia (FD) and irritable bowel syndrome (IBS) group remain unclear. Thus, the aim of the present study was to evaluate the clinicodemographic features of FD, IBS, and IBS-FD overlap and assess the risk factors thereof, including subtype and genetic polymorphisms for IBS-FD. METHODS: Consecutive patients were enrolled from the outpatient Gastroenterology clinics of Bundang Seoul National University Hospitals in Korea. All gastrointestinal symptoms occurring at least once per week in the previous 3 months were recorded. Diagnostic criteria of functional gastrointestinal disorders were based on the Rome III criteria. Risk factors including genetic polymorphisms of 5-HTTLPR and ADRA2A 1291 G alleles and CCK-1R intron 779T>C were assessed using a multivariate logistic regression model. RESULTS: A total of 632 subjects (278 control subjects, 308 FD, 156 IBS, and 110 who met the criteria for both FD and IBS) were included in this study. Patients with IBS-FD overlap had more severe symptoms (such as bloating, nausea, vomiting, hard or lumpy stools, defecation straining, and a feeling of incomplete bowel movement) and higher depression scores compared with non-overlap patients. Single/divorced or widowed marital status, nausea, bloating, and a feeling of incomplete emptying after bowel movements were independent risk factors for IBS-FD overlap among IBS patients. In contrast, young age, depression, bloating, and postprandial distress syndrome were positively associated with IBS-FD overlap among FD patients. 5-HTTLPR L/L was a risk factor for the co-occurrence of IBS-C among FD patients (OR: 12.47; 95% CI: 2.00-77.75; P = 0.007). CONCLUSIONS: Bloating was a risk factor for IBS-FD overlap. Patients with postprandial distress syndrome have a higher risk of coexisting IBS, particularly constipation-dominant IBS.

Sini-san improves duodenal tight junction integrity in a rat model of functional dyspepsia.

BACKGROUND: Recent reports have demonstrated that impaired barrier function and local microinflammation in the duodenal mucosa contribute to the pathogeneses of functional dyspepsia (FD). Thus, restoring normal barrier integrity becomes a potential therapeutic strategy in the treatment of FD. Sini-San (SNS) is a traditional Chinese prescription that exhibits therapeutic effects in FD, but the underlying mechanisms remain not well understood. METHODS: FD rats were established by tail clamping method and the therapeutic effect of SNS was evaluated by measuring the visceral sensitivity and gastric compliance. Transepithelial electrical resistance (TEER) that reveals epithelial barrier integrity was measured by Ussing chamber. The expression of tight junction (TJ) proteins, occludin and claudin-1, in the duodenum was determined by Western blot and immunofluorescence. The amount of tumor necrosis factor alpha (TNF-α) and interferon gamma (INF-γ) in duodenal mucosa was detected by enzyme-linked immune sorbent assay (ELISA). The mRNA level of transient receptor potential vanilloid type 1 (TRPV1) was measured by quantitative real time-polymerase chain reaction (qPCR). RESULTS: SNS could improve gastric compliance and attenuate visceral hypersensitivity (VH) in FD rats. TEER was decreased in FD rats, but treatment with SNS restored normal level of TEER and the expression of occludin and claudin-1 in FD rats. In addition, SNS administration ameliorated FD-associated increase in the production of TNF-α, IFN-γ and the expression of TRPV1. CONCLUSIONS: The therapeutic effect of SNS on FD is at least partially through improvement of TJ integrity and attenuation of FD-associated low-grade inflammation in the duodenum. Our findings highlight the molecular basis of SNS-based treatment of FD in human patients.

Functional dyspepsia.

PURPOSE OF REVIEW: Functional dyspepsia affects 10% of the population. Emerging data are beginning to unravel the pathogenesis of this heterogeneous disorder, and new data on treatment are helping to guide evidence-based practice. In this review, the latest advances are summarized and discussed. RECENT FINDINGS: The Rome IV criteria were published in 2016 and are similar to Rome III but further emphasize the subtypes (postprandial distress syndrome and epigastric pain syndrome) rather than focussing on the syndrome as a whole, and conclude that gastroesophageal reflux disease and irritable bowel syndrome are part of the functional dyspepsia spectrum. Environment is dominant in the pathogenesis. New data implicate herbivore pets and antibiotic exposure for a nongastrointestinal infection but require confirmation. Further experimental data suggest duodenal eosinophils and mast cells can alter enteric neuronal structure and function in functional dyspepsia. SUMMARY: Advances in our understanding of functional dyspepsia are changing clinical practice.

Influence of CYP2C19 on Helicobacter pylori eradication in Brazilian patients with functional dyspepsia.

The aim of this study was to examine the effect of polymorphisms in the cytochrome P450 (CYP) 2C19 gene (CYP2C19) on the Helicobacter pylori eradication rate in Brazilian patients with functional dyspepsia. Adults diagnosed with functional dyspepsia based on the ROME III criteria and infected with H. pylori were recruited to this study. The patients were subjected to gastrointestinal endoscopy and the H. pylori status was defined when both urease test and histopathology results were negative or positive. The patients were treated with proton pump inhibitor-based triple therapy (omeprazole, amoxicillin, and clarithromycin). CYP2C19*2 and CYP2C19*3 were genotyped by polymerase chain reaction-restriction fragment length polymorphism. One hundred and forty-eight patients (81.8% women) with a mean (± SD) age of 46.1 (12.2) years were included in this study. Based on the CYP2C19 genotypes, the patients were classified as homozygous extensive metabolizer (HomEM; 67.6%), heterozygous extensive metabolizer (HetEM; 26.3%), or poor metabolizer (PM; 6.1%). The H. pylori eradication rates in patients with HomEM, HetEM, and PM were 85.0, 89.7, and 100.0% (P = 0.376), respectively. The included study population comprised a high frequency of patients carrying the HomEM genotype. Although the genotypes of CYP2C19 variants were not statistically significant, the results of this study suggest a possible effect of the PM genotype on the efficacy of H. pylori eradication.

Association of SLC6A4 5-HTTLPR and TRPV1 945G>C with functional dyspepsia in Korea.

BACKGROUND AND AIM: The association of various genetic polymorphisms with functional dyspepsia (FD) has been suggested, but the results were still controversial. The aim of the present study was to assess the association of GNB3 825C>T, SLC6A4 5-HTTLPR, ADRA2A-1291C>G, CCK-1R intron 779T>C, and TRPV1 945G>C polymorphisms with FD based on Rome III criteria in Korea. METHODS: Study subjects were prospectively recruited from visitors to Seoul National University Bundang Hospital between 2009 and 2012. One hundred and twelve FD patients and 269 controls were enrolled. RESULTS: In SLC6A4 5-HTTLPR polymorphism, the frequency of S/S genotype was significantly lower than that of L/L + L/S genotype in FD compared to controls (P < 0.05). After stratification according to Helicobacter pylori infection, the S/S genotype was significantly associated with H. pylori-positive epigastric pain syndrome (EPS) patients (adjusted odds ratio (OR) 0.46; 95% confidence interval (CI) 0.22-0.99; P = 0.048). In TRPV1 945G>C polymorphism, the frequency of C/C genotype was lower in FD compared to controls (P = 0.057). The C carrier and C/C genotype was significantly associated with postprandial distress syndrome (PDS) and EPS, respectively (adjusted OR 0.47 and 0.43; 95% CI 0.25-0.90 and 0.20-0.93; P = 0.021 and 0.033). After stratification, the significant associations remained in H. pylori-positive PDS and EPS patients (adjusted OR 0.37 and 0.28; 95% CI 0.16-0.88 and 0.09-0.85; P = 0.024 and 0.025). CONCLUSIONS: The genetic polymorphism of SLC6A4 5-HTTLPR and TRPV1 945G>C could be one of the pathophysiological factors of FD, especially in the case of H. pylori-positive patients in Korea.

Association of genetic variants in GNß3 with functional dyspepsia: a meta-analysis.

BACKGROUND: Functional dyspepsia (FD) is a functional upper gastrointestinal disorder. The etiology and pathogenesis of FD remain unclear, with genetic factors playing an important role. Previous studies investigated the association of C825T in GNß3 with FD, with conflicting results reported. AIMS: The aim of this meta-analysis is to assess the association of genetic variants in GNß3 with FD. METHODS: We performed a systematic literature search in PubMed, Cochrane Library, Google Scholar, and Web of Knowledge, and conducted a meta-analysis to assess the association of C825T in GNß3 with FD. For sensitivity analysis, we analyzed the association between C825T and subtypes of FD. We also performed meta-analyses separately for individual ethnic groups/countries of origin. RESULTS: A total of eight studies met the eligibility criteria and were included in our analyses. Our meta-analysis finds no association between 825CC and FD (OR 1.19, 95% CI 0.84-1.67, p = 0.328). However, the association is significant under an additive model (OR 0.59, 95% CI 0.38-0.92, p = 0.018). Sensitivity analysis indicated a significant association of C825T with FD in participants from Korea but not in those from Japan, Europe, or the United States. We also detected a significant association of this SNP with dysmotility. CONCLUSIONS: The genetic variant C825T in GNß3 is significantly associated with FD under an additive model and the association is race-specific. Further studies with larger samples sizes are needed to validate our findings and to explore the potential mechanism underlying the association.

Nitric oxide synthase gene polymorphisms in functional dyspepsia.

OBJECTIVE: Nitrinergic control is important in meal-induced satiety. The aim of this study was to assess functional polymorphisms in nitric oxide synthase (NOS) genes in the susceptibility to functional dyspepsia (FD). METHODS: Genomic DNA from 89 patients with FD and 180 healthy subjects matched for age and gender were typed for the gene of neuronal NOS (nNOS, rs2682826), inducible NOS (iNOS, rs2297518) and a variable number tandem repeat in intron 4 of endothelial NOS (eNOS). Patients ingested 500 mL of Ensure(®) during a 20 min period and dyspeptic symptoms were scored. RESULTS: Genotype frequencies of eNOS and iNOS were not significantly different between FD patients and controls. The frequency of the T allele in nNOS was significantly higher in FD patients compared to the controls (49 vs. 16 %; odds ratio 5.01; 95 % confidence interval 2.83-9.01; p < 0.05). Patients with the T allele in the nNOS polymorphism reported a higher satiation score than those with the CC genotype during the nutrition drink test (median 179 vs. 117; p < 0.05). CONCLUSION: The nNOS gene polymorphism is associated with susceptibility to FD and influences satiation in FD patients. Our data support the importance of NOS gene polymorphisms in the pathogenesis of FD.

Physical activity, sedentary behavior, and the risk of functional gastrointestinal disorders: A two-sample Mendelian randomization study.

OBJECTIVES: Functional dyspepsia (FD) and irritable bowel syndrome (IBS) are prevalent functional gastrointestinal disorders (FGIDs). In this study we aimed to explore the causal association between physical activity or sedentary behavior and the risk of FD and IBS. METHODS: Mendelian randomization (MR) analysis was employed. Candidate genetic instruments for physical activity and sedentary behavior were retrieved from the latest published Genome-Wide Association Study (GWAS), which included up to 703 901 participants. Summary-level GWAS data for FD (8 875 cases and 320 387 controls) and IBS (9 323 cases and 301 931 controls) were obtained from the FinnGen study. The causal effects were mainly estimated by inverse variance weighted (IVW) method. Sensitivity analyses were implemented with Cochran's Q test, MR-Egger intercept test, leave-one-out analysis, and the funnel plot. RESULTS: No significant association of moderate-to-vigorous intensity physical activity (MVPA), leisure screen time (LST), sedentary behavior at work (SDW), and sedentary commuting (SDC) with the risk of FD was found. However, there was a suggestive correlation between MVPA and the decreased risk of FD (odds ratio [OR] 0.63, 95% confidence interval [CI] 0.39-0.99, P = 0.047). Genetically predicted MVPA decreased the risk of IBS (OR 0.58, 95% CI 0.40-0.84, P = 0.004), while increased LST was positively associated with IBS risk (OR 1.33, 95% CI 1.15-1.53, P < 0.001). No causal effects of SDW or SDC on IBS risk were observed. CONCLUSION: MVPA and LST are causally linked to the development of IBS, which will facilitate primary prevention of IBS.

The associations between functional dyspepsia and potential risk factors: A comprehensive Mendelian randomization study.

BACKGROUND: Previous cross-sectional studies have identified multiple potential risk factors for functional dyspepsia (FD). However, the causal associations between these factors and FD remain elusive. Here we aimed to fully examine the causal relationships between these factors and FD utilizing a two-sample MR framework. METHODS: A total of 53 potential FD-related modifiable factors, including those associated with hormones, metabolism, disease, medication, sociology, psychology, lifestyle and others were obtained through a comprehensive literature review. Independent genetic variants closely linked to these factors were screened as instrumental variables from genome-wide association studies (GWASs). A total of 8875 FD cases and 320387 controls were available for the analysis. The inverse variance weighted (IVW) method was employed as the primary analytical approach to assess the relationship between genetic variants of risk factors and the FD risk. Sensitivity analyses were performed to evaluate the consistency of the findings using the weighted median model, MR-Egger and MR-PRESSO methods. RESULTS: Genetically predicted depression (OR 1.515, 95% confidence interval (CI) 1.231 to 1.865, p = 0.000088), gastroesophageal reflux disease (OR 1.320, 95%CI 1.153 to 1.511, p = 0.000057) and years of education (OR 0.926, 95%CI 0.894 to 0.958, p = 0.00001) were associated with risk for FD in univariate MR analyses. Multiple medications, alcohol consumption, poultry intake, bipolar disorder, mood swings, type 1 diabetes, elevated systolic blood pressure and lower overall health rating showed to be suggestive risk factors for FD (all p<0.05 while ≥0.00167). The positive causal relationship between depression, years of education and FD was still significant in multivariate MR analyses. CONCLUSIONS: Our comprehensive MR study demonstrated that depression and lower educational attainment were causal factors for FD at the genetic level.

Meta-Analysis of the Association Between 5-Hydroxytryptamine Transporter Gene-Linked Polymorphic Region and Functional Dyspepsia and its Subtypes.

Background: Association studies of variations in the 5-hydroxytryptamine (5-HT, serotonin) transporter gene-linked polymorphic region (5-HTTLPR) and functional dyspepsia (FD) have yielded contradictory results. Hence, we performed a meta-analysis to clarify inconsistencies between the 5-HTTLPR polymorphism with FD and it subtypes. Methods: We performed a literature search in PubMed, Embase, Web of Science, Cochrane Library, and CNKI, including articles published until March 2022. We calculated and pooled odds ratios (ORs) with their 95% confidence intervals (CIs) in Stata 15.0. Data extraction was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and Cochrane Handbook for Systematic Reviews of Interventions. Results: The meta-analysis included six studies, comprising 488 cases and 1513 healthy controls. We did not observe a significant association between the 5-HTTLPR polymorphism and FD in the overall population. In subgroup analyses, the 5-HTTLPR polymorphism was significantly associated with FD-subtype epigastric pain syndrome (EPS) (SS vs. LL+LS, OR = 0.620, 95% CI: 0.414-0.930; SS vs. LS, OR = 0.640, 95% CI: 0.417-0.980; S vs. L, OR = 0.655, 95% CI: 0.471-0.911). However, no association was observed with the other subtype, postprandial distress syndrome (PDS). Conclusion: While the 5-HTTLPR polymorphism had no relationship with FD overall, splitting the disease into its subtypes revealed a clear association with EPS.