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.

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.

[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.

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.

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.

Research progress in signaling pathways related to treatment of functional dyspepsia with traditional Chinese medicine / 中国中药杂志

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.

Overexpression of microRNA-211 in Functional Dyspepsia via Downregulation of the Glial Cell Line-Derived Neurotrophic Factor (GDNF) by Increasing Phosphorylation of p38 MAPK Pathway.

Background: Overexpression of miRNA-211 suppresses the differentiation of bone marrow stem cells into intestinal ganglion cells via downregulation of GDNF, a regulator of intestine barrier function. The study aimed to investigate the interaction between miR-211 and GDNF on intestinal epithelial cells. Methods: The expression levels of miR-211 and GDNF in duodenal biopsy specimens from FD patients and healthy controls were compared. Enteric glia cell (EGCs) cell line transfected with miR-211 mimics and inhibitors were used to clarify the expression levels of GDNF were analyzed by qRT-PCR and ELISA. Intestine epithelial cell (IECs) cell line cultured in medium from ECGs in different transfection conditions were used in wound healing assay, cell proliferation assay, and western blotting for evaluation of p38 MAPK phosphorylation level. Results: MiR-211 expression was significantly upregulated in the duodenal tissue of patients with FD compared to healthy subjects, whereas GDNF expression was significantly downregulated (both p < 0.05). Transfection with miR-211 mimics significantly decreased GDNF mRNA expression and protein secretion (p < 0.001). An inhibited intestinal epithelial cell wound healing (p < 0.05) and increased expression levels of phosphorylated p38 MAPK (p < 0.05) were found in IECs cultured with medium from EGCs transfected with miR-211 mimics. Conclusions: MiR-211 may downregulates GDNF mRNA and protein expression via activation of the pp38 MAPK signaling pathway. Targeting miR-211 or the MAPK pathway may be a potential intervention for FD.

[Influence of electroacupuncture of"Zusanli"(ST36)on mast cells/TRPV1 signaling pathway in visceral hypersensitivity rats with functional dyspepsia].

OBJECTIVE: To explore the interventional mechanism of electroacupuncture (EA) of "Zusanli"(ST36)based on the involvement of mast cells/ transient receptor potential vanilloid type1 (TRPV1) signaling pathway in relieving visceral hypersensitivity in functional dyspepsia (FD) rats. METHODS: Sixty SD rats (half male and half female, 10 days in age) were randomly divided into normal control, model, medication (ketotifen) and EA groups, with 15 rats in each group. The FD model was established by gavage of iodoacetamide combined with tail clamping (stress stimulation). Rats of the medication group received intraperitoneal injection of ketotifen (1 mg·kg-1·d-1) for 14 d, and those of the EA group received EA of ST36 for 20 min, once a day for 14 d. An air-balloon was inserted into the rat's stomach for recording changes of the intragastric pressure (mL/mm Hg) via a pressure transducer. The visceral hypersensitivity was assessed using abdominal withdrawal reflex (AWR) score and the number and degranulation of mast cells of gastric mucosa were observed using toluidine blue staining. The expression levels of TRPV1 and proteinase activated receptor 2 (PAR2) in the stomach were observed using immunofluorescence histochemistry and Western blot, separately, and the contents of SP and CGRP in the stomach detected using ELISA. RESULTS: When the intragastric pressure was at 50, 60 and 70 mm Hg, the gastric compliance was significantly decreased (P<0.01), and the levels of visceral sensitivity increased in the model group （P<0.01）。 TRPV1 immunofluorescence tensity, expression of PAR2 and TRPV1 proteins, and contents of SP and CGRP in the stomach were considerably up-regulated in the model group compared with the normal control group (P<0.01). In comparison with the model group, under intragastric pressure of 50，60 and 70 mm Hg, the gastric compliance was obviously increased, and the visceral hypersensitivity decreased in the EA group （P<0.01,P<0.05）. TRPV1 immunofluorescence intensity, expression levels of PAR2 and TRPV1 proteins, and the contents of SP and CGRP in the stomach were considerably down-regulated in both medication and EA groups compared with the model group (P<0.01, P<0.05). The therapeutic effect of EA was significantly superior to that of medication in up-regulating the gastric compliance （at 70 mm Hg）, and down-regulating the contents of SP and CGRP (P<0.05). No significant differences were found between the EA and medication groups in up-regulating gastric compliance at intragastric pressure of 50 and 60 mm Hg, and in down-regulating the visceral sensitivity, TRPV1 fluorescence intensity, and expression of PAR2 and TRPV1 proteins (P>0.05). Toluidine blue staining showed an apparent increase of mast cell number with obvious degranulation in the gastric mucosa of rats in the model group, which was milder in the EA and medication groups. CONCLUSION: EA of ST36 can suppress visceral hypersensitivity and increase the gastric compliance in FD rats, which may be related with its effects in inhibiting the activation of gastric mast cells, and down-regulating the expression of gastric PAR2 and TRPV1 proteins and SP and CGRP contents.

[Effect of electroacupuncture at "Zusanli" (ST 36) on duodenal mast cells, NGF and NTRK1 in rats with functional dyspepsia].

OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Zusanli" (ST 36) on duodenal mast cells, nerve growth factor (NGF) and neurotrophic tyrosine kinase receptor type 1 (NTRK1), and to explore the mechanism of electroacupuncture at Zusanli (ST 36) on functional dyspepsia (FD). METHODS: Sixty SPF-grade 10-day-old SD rats were randomly divided into a normal group, a model group, a ketotifen group and an EA group, 15 rats in each group. The FD model was prepared by iodoacetamide combined with rat tail clamping method in the model group, the ketotifen group and the EA group. The rats in the ketotifen group were injected intraperitoneally with ketotifen (1 mg•kg-1•d-1) for 7 days; the rats in the EA group were treated with EA at bilateral "Zusanli" (ST 36), with disperse-dense wave, frequency of 2 Hz/50 Hz and intensity of 0.5 mA, 20 min each time, once a day for 14 days. The gastric emptying rate and small intestinal propulsion rate in each group were observed; the morphology of duodenal mucosa was observed by HE staining; the toluidine blue staining was used to observe the number and degranulation of mast cells in duodenal mucosa; the protein and mRNA expressions of NGF, NTRK1 in duodenum were detected by Western blot and real-time PCR; the level of interleukin-1ß (IL-1ß) in duodenum was measured by ELISA. RESULTS: Compared with the normal group, the gastric emptying rate and small intestinal propulsion rate in the model group were decreased (P<0.01); compared with the model group, the gastric emptying rate and small intestinal propulsion rate in the ketotifen group and the EA group were increased (P<0.01); the small intestinal propulsion rate in the EA group was higher than that in the ketotifen group (P<0.01). In the model group, local defects in duodenal mucosa were observed with a small amount of inflammatory cell infiltration; no obvious abnormality was found in duodenal mucosa of the other groups. Compared with the normal group, the mast cells of duodenal mucosa in the model group were increased significantly with significant degranulation; compared with the model group, the mast cells of duodenal mucosa in the ketotifen group and the EA group were decreased significantly, and the degranulation was not obvious. Compared with the normal group, the protein and mRNA expressions of NGF, NTRK1 as well as the level of IL-1ß in duodenum in the model group were increased (P<0.01); compared with the model group, the protein and mRNA expressions of NGF, NTRK1 as well as the levels of IL-1ß in duodenum in the ketotifen group and the EA group were decreased (P<0.01, P<0.05); compared with the ketotifen group, the mRNA expression of NGF, as well as the protein and mRNA expressions of NTRK1 in duodenum in the EA group were decreased (P<0.05, P<0.01). CONCLUSION: EA at "Zusanli" (ST 36) could inhibit the activation of duodenal mast cells and regulate the expressions of NGF and its receptor to improve the low-grade inflammatory response of duodenum, resulting in treatment effect on FD.

[Transcutaneous auricular vagus nerve stimulation promotes gastric motility by up-rgulating α7nAChR and suppressing NF-κB p65 expression in duodenum in rats with functional dyspepsia].

OBJECTIVE: To study the effect of transcutaneous auricular vagus nerve stimulation (taVNS) on gastric sensitivity and motility in rats with functional dyspepsia (FD), so as to explore its underlying mechanism in improving FD. METHODS: A total of 48 young SD rats were randomly divided into control (n=10), model (n=9), taVNS (n=9), subdiaphragmatic vagus nerve stimulation (SDVNS, n=9) and sham SDVNS (n=7) groups. The FD model was established by gavage of 0.1% iodoa-cetamide+2% glucose, once daily for 6 days. Rats in the taVNS group received taVNS (0.5 mA) of optopoint "Heart" and "Stomach" for 30 min, once daily for 14 days, while rats in the SDVNS group received subdiaphragmatic vagus nerve stimulation through the implanted electrode, and those of the sham SDVNS group received only application of the same electrodes without electrical stimulation. Electromyogram (EMG) of the cervical trapezius muscle (reflecting gastric sensitivity) was recorded before and after intragastric expansion via an air ballon and the gastric emptying rate was calculated for assessing the gastric motility. The contents of acetylcholine (ACh), nicotinic acetylcholine receptor α7 subunit (α7nAChR), interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) in the duodenum tissue were detected by enzyme-linked immunosorbent assay (ELISA). The expression of nuclear factor kappa B (NF-κB) p65 in the duodenum tissue was determined by Western blot. RESULTS: In comparison with the control group, the EMG change rate at intragastric pressure levels of 40, 60 and 80 mm Hg, expression of NF-κB p65 protein, and contents of IL-6, IL-1ß and TNF-α were significantly increased (P<0.05,P<0.01, P<0.001), while the gastric emptying rate, ACh and α7nAChR contents considerably decreased (P<0.05, P<0.001) in the model group. After interventions, the EMG change rate, contents of IL-6, IL-1ß and TNF-α, and expression of NF-κB p65 were notably decreased (P<0.05, P<0.01, P<0.001), and the gastric emptying rate, ACh and α7nAChR contents obviously increased (P<0.05, P<0.001) in both taVNS and SDVNS groups relevant to the model group. In comparison with the sham SDVNS group, the EMG change rate, contents of IL-6, IL-1ß and TNF-α, and expression of NF-κB p65 were notably decreased (P<0.01, P<0.05,P<0.001), and the gastric emptying rate, ACh and α7nAChR contents obviously increased (P<0.01, P<0.001) in the both SDVNS and taVNS groups. CONCLUSION: taVNS can reduce gastric sensitivity and promote gastric emptying in FD model rats, which may be closely related to its functions in up-regulating ACh and α7nAChR contents and inhibiting the activation of NF-κB p65 signaling in the duodenum.

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.

Duodenal Mucosal Expression of COVID-19-Related Genes in Health, Diabetic Gastroenteropathy, and Functional Dyspepsia.

CONTEXT: SARS-CoV-2 infects the gastrointestinal tract and may be associated with symptoms that resemble diabetic gastroparesis. Why patients with diabetes who contract COVID-19 are more likely to have severe disease is unknown. OBJECTIVE: We aimed to compare the duodenal mucosal expression of SARS-CoV-2 and inflammation-related genes in diabetes gastroenteropathy (DGE), functional dyspepsia (FD), and healthy controls. METHODS: Gastrointestinal transit, and duodenal mucosal mRNA expression of selected genes were compared in 21 controls, 39 DGE patients, and 37 FD patients from a tertiary referral center. Pathway analyses were performed. RESULTS: Patients had normal, delayed (5 FD [13%] and 13 DGE patients [33%]; P = 0.03 vs controls), or rapid (5 FD [12%] and 5 DGE [12%]) gastric emptying (GE). Compared with control participants, 100 SARS-CoV-2-related genes were increased in DGE (FDR < 0.05) vs 13 genes in FD; 71 of these 100 genes were differentially expressed in DGE vs FD but only 3 between DGE patients with normal vs delayed GE. Upregulated genes in DGE include the SARS-CoV2 viral entry genes CTSL (|Fold change [FC]|=1.16; FDR < 0.05) and CTSB (|FC|=1.24; FDR < 0.05) and selected genes involved in viral replication (eg, EIF2 pathways) and inflammation (CCR2, CXCL2, and LCN2, but not other inflammation-related pathways eg, IL-2 and IL-6 signaling). CONCLUSION: Several SARS-CoV-2-related genes were differentially expressed between DGE vs healthy controls and vs FD but not between DGE patients with normal vs delayed GE, suggesting that the differential expression is related to diabetes per se. The upregulation of CTSL and CTSB and replication genes may predispose to SARS-CoV2 infection of the gastrointestinal tract in diabetes.

A survey of functional dyspepsia in 361,360 individuals: Phenotypic and genetic cross-disease analyses.

BACKGROUND: Functional dyspepsia (FD) is a common gastrointestinal condition of poorly understood pathophysiology. While symptoms' overlap with other conditions may indicate common pathogenetic mechanisms, genetic predisposition is suspected but has not been adequately investigated. METHODS: Using healthcare, questionnaire, and genetic data from three large population-based biobanks (UK Biobank, EGCUT, and MGI), we surveyed FD comorbidities, heritability, and genetic correlations across a wide spectrum of conditions and traits in 10,078 cases and 351,282 non-FD controls of European ancestry. KEY RESULTS: In UK Biobank, 281 diagnoses were detected at increased prevalence in FD, based on healthcare records. Among these, gastrointestinal conditions (OR = 4.0, p < 1.0 × 10-300 ), anxiety disorders (OR = 2.3, p < 1.4 × 10-27 ), ischemic heart disease (OR = 2.2, p < 2.3 × 10-76 ), and infectious and parasitic diseases (OR = 2.1, p = 1.5 × 10-73 ) showed strongest association with FD. Similar results were obtained in an analysis of self-reported conditions and use of medications from questionnaire data. Based on a genome-wide association meta-analysis of genotypes across all cohorts, FD heritability was estimated close to 5% ( hSNP2  = 0.047, p = 0.014). Genetic correlations indicate FD predisposition is shared with several other diseases and traits (rg  > 0.344), mostly overlapping with those also enriched in FD patients. Suggestive (p < 5.0 × 10-6 ) association with FD risk was detected for 13 loci, with 2 showing nominal replication (p < 0.05) in an independent cohort of 192 FD patients. CONCLUSIONS & INFERENCES: FD has a weak heritable component that shows commonalities with multiple conditions across a wide spectrum of pathophysiological domains. This new knowledge contributes to a better understanding of FD etiology and may have implications for improving its treatment.

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.

Characterizing clinical features and location-specific gene expression profiles associated with pain burden in children with functional dyspepsia.

BACKGROUND: In children with functional dyspepsia (FD), genes involved in pain modulation may be differentially expressed contributing to chronic pain. METHODS: Children with suspected FD (cases) and known eosinophilic esophagitis (controls) undergoing esophagogastroduodenoscopy completed the Rome IV Diagnostic, Pain Burden and Frequency Severity-Duration questionnaires. Two antral and two duodenal biopsies were collected and relative fold differences in gene expression for 84 pain-associated genes compared to pain-free controls were calculated. RESULTS: Sixty-six subjects with FD (postprandial distress syndrome = 34, epigastric pain syndrome = 7, both = 25; 65% female; mean age 13.7 years) and 13 pain-free controls (8% female; mean age 12.7) were studied. There were no significant differences in antral and duodenal eosinophilic counts or distribution between the pain and pain-free groups. Pain severity and burden did not differ significantly between FD subgroups and neither measure significantly correlated with eosinophil counts in the antrum or duodenum. Analysis of 47 antral and 39 duodenal biospecimens revealed 5 candidate genes significantly associated with pain burden: antral EDN1, PTGES3 and duodenal HTR1A, P2Y1, SCN3A (p < 0.01). Subsequent stringent statistical analysis comparing those with significant pain versus no pain revealed antral PTGES3 and duodenal SCN3A were the highest priority candidate genes (p < 0.001). CONCLUSIONS: Pain burden in pediatric FD may be linked to antral EDN1, PTGES3 and duodenal HTR1A, P2Y1, SCN3A differential expression. These genes are known to be involved in pain conduction, modulation, and neurotransmission, suggesting potential therapeutic targets for managing pain in FD.

Aedes aegypti dyspepsia encodes a novel member of the SLC16 family of transporters and is critical for reproductive fitness.

As a key vector for major arthropod-borne viruses (arboviruses) such as dengue, Zika and chikungunya, control of Aedes aegypti represents a major challenge in public health. Bloodmeal acquisition is necessary for the reproduction of vector mosquitoes and pathogen transmission. Blood contains potentially toxic amounts of iron while it provides nutrients for mosquito offspring; disruption of iron homeostasis in the mosquito may therefore lead to novel control strategies. We previously described a potential iron exporter in Ae. aegypti after a targeted functional screen of ZIP (zinc-regulated transporter/Iron-regulated transporter-like) and ZnT (zinc transporter) family genes. In this study, we performed an RNAseq-based screen in an Ae. aegypti cell line cultured under iron-deficient and iron-excess conditions. A subset of differentially expressed genes were analyzed via a cytosolic iron-sensitive dual-luciferase reporter assay with several gene candidates potentially involved in iron transport. In vivo gene silencing resulted in significant reduction of fecundity (egg number) and fertility (hatch rate) for one gene, termed dyspepsia. Silencing of dyspepsia reduced the induction of ferritin expression in the midgut and also resulted in delayed/impaired excretion and digestion. Further characterization of this gene, including a more direct confirmation of its substrate (iron or otherwise), could inform vector control strategies as well as to contribute to the field of metal biology.

Prevalence of CYP2C19 polymorphism in Bogotá, Colombia: The first report of allele *17.

INTRODUCTION: Proton pump inhibitors (PPIs) are a group of drugs that are essential for the treatment of acid-related disorders, such as gastroesophageal reflux (GERD), dyspepsia, gastric ulcers and Helicobacter pylori (H. pylori) infection. PPIs such as omeprazole, esomeprazole, pantoprazole and lansoprazole are metabolized by the CYP2C19 enzyme, which is encoded by a polymorphic gene. Four polymorphisms have an impact on the speed of PPI metabolism: CYP2C19*1/*1 (extensive metabolizers), CYP2C19*2/*2 (intermediate metabolizers), CYP2C19*3/*3 (poor metabolizers) and CYP2C19*17/*17 (ultrarapid metabolizers). Extensive and ultrarapid metabolizers inactivate PPIs quickly, which consequently causes low plasma concentrations of PPIs, while intermediate or poor metabolizers have higher plasma concentrations of PPIs and, therefore, PPIs have greater therapeutic efficacy in individuals with these polymorphisms. OBJECTIVE: To determine the frequency of genetic polymorphisms of the CPY2C19 enzyme in Bogotá, Colombia. METHODS: This observational study was conducted in Bogotá between 2012 and 2015 and was part of a clinical trial (ID: NCT03650543). It included 239 subjects with dyspepsia, H. pylori infection, or GERD symptoms. CYP2C19 genotyping was performed on gastric biopsy samples. Polymorphisms *1, *2, and *3 were analyzed by real-time PCR (Roche®), and PCR-RFLP was used to determine the presence of polymorphism *17. RESULTS: The distribution of different types of PPI metabolizers was as follows: extensive (70.7%), ultrarapid (12.9%), intermediate (8.8%) and poor (0.8%). CONCLUSION: The population studied consisted mainly of extensive and ultrarapid PPI metabolizers. These findings show that it is necessary to increase PPI doses in this group of subjects or to use PPIs that are not metabolized by CYP2C19 (rabeprazole). This is the first Colombian work to identify ultrarapid metabolizers.

Impaired Duodenal Palmitoylethanolamide Release Underlies Acid-Induced Mast Cell Activation in Functional Dyspepsia.

BACKGROUND & AIMS: Acid hypersensitivity is claimed to be a symptomatic trigger in functional dyspepsia (FD); however, the neuroimmune pathway(s) and the mediators involved in this process have not been investigated systematically. Palmitoylethanolamide (PEA) is an endogenous compound, able to modulate nociception and inflammation, but its role in FD has not been assessed. METHODS: Duodenal biopsy specimens from FD and control subjects, and peroxisome proliferator-activated receptor-α (PPARα) null mice were cultured at a pH of 3.0 and 7.4. Mast cell (MC) number, the release of their mediators, and the expression of transient receptor potential vanilloid receptor (TRPV)1 and TRPV4, were evaluated. All measurements also were performed in the presence of a selective blocker of neuronal action potential (tetradotoxin). FD and control biopsy specimens in acidified medium also were incubated in the presence of different PEA concentrations, alone or combined with a selective PPARα or PPAR-γ antagonist. RESULTS: An acid-induced increase in MC density and the release of their mediators were observed in both dyspeptic patients and controls; however, this response was amplified significantly in FD. This effect was mediated by submucosal nerve fibers and up-regulation of TRPV1 and TRPV4 receptors because pretreatment with tetradotoxin significantly reduced MC infiltration. The acid-induced endogenous release of PEA was impaired in FD and its exogenous administration counteracts MC activation and TRPV up-regulation. CONCLUSIONS: Duodenal acid exposure initiates a cascade of neuronal-mediated events culminating in MC activation and TRPV overexpression. These phenomena are consequences of an impaired release of endogenous PEA. PEA might be regarded as an attractive therapeutic strategy for the treatment of FD.

Duodenal mucosal secretory disturbances in functional dyspepsia.

BACKGROUND: There is increased recognition of duodenal disturbances (inflammation, altered mucosal protein expression, and chemosensitivity) in functional dyspepsia (FD). Besides sensorimotor functions, enteric submucosal neurons also regulate epithelial ion transport. We hypothesized that duodenal mucosal ion transport and expression of associated genes are altered in FD. METHODS: Duodenal mucosal ion transport (basal and acetylcholine- and glucose-evoked changes in short-circuit current [Isc]) and expression of associated genes and regulatory miRNAs were evaluated in 40 FD patients and 24 healthy controls. RESULTS: Basal Isc (FD: 88.2 [52.6] µA/cm2 vs healthy: 20.3 [50.2] µA/cm2 ; P ≤ .0001), acetylcholine-evoked Isc (FD: Emax 50.4 [35.8] µA/cm2 vs healthy: 16.6 [15] µA/cm2 ; P ≤ .001), and glucose-evoked Isc responses (FD: Emax 69.8 [42.1] µA/cm2 vs healthy: 40.3 [24.6] µA/cm2 ; P = .02) were greater in FD than in controls. The Emax for glucose was greater in FD patients on selective serotonin reuptake inhibitors. In FD, the mRNA expression of SLC4A7 and SLC4A4, which transport bicarbonate into cells at the basolateral surface, and the apical anion exchanger SLC26A3 were reduced (false discovery rate <0.05), the serotonin receptor HTR4 was increased, and the serotonin transporter SLC6A4 was decreased. Selected miRNAs (hsa-miR-590-3p, hsa-miR-32-5p) that target genes associated with ionic transport were upregulated in FD. CONCLUSIONS: Compared to controls, FD patients had greater baseline and agonist-evoked duodenal mucosal secretory responses. These findings may be explained by reduced gene expression, which would be anticipated to reduce luminal bicarbonate secretion. The upregulated miRNAs may partly explain the downregulation of these genes in FD.

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.