Effect of sex on chronic stress induced alterations in hindbrain catecholaminergic system and autonomic dysfunction resulting in gastrointestinal dysmotility.

It has been reported that the clinical symptoms of functional dyspepsia (FD) exacerbate upon stress while the gender-related factors have been incompletely understood. This study aims to investigate the role of sex in chronic heterotypic stress (CHS)-induced autonomic and gastric motor dysfunction. For CHS, the rats were exposed to the combination of different stressors for 7 consecutive days. Subsequently, electrocardiography was recorded in anesthetized rats to evaluate heart rate variability (HRV) for the determination of autonomic outflow and sympathovagal balance. Solid gastric emptying (GE) was measured in control and CHS-loaded male and female rats. The immunoreactivities of catecholaminergic cell marker tyrosine hydroxylase (TH), choline acetyltransferase (ChAT), corticotropin releasing factor (CRF), and estrogen receptor (ER-α/ß) were evaluated in medullary and pontine brainstem sections by immunohistochemistry. Compared with the controls, CHS significantly delayed GE in males but not in females. There was no significant sex-related difference in parasympathetic indicator HF under either control or CHS conditions. Sympathetic indicator LF was significantly higher in control females compared to the males. The higher sympathetic output in females was found to be attenuated upon CHS; in contrast, the elevated sympathetic output was detected in CHS-loaded males. No sex- or stress-related effect was observed on ChAT immunoreactivity in the dorsal motor nucleus of N.vagus (DMV). In males, greater number of TH-ir cells was observed in the caudal locus coeruleus (LC), while they were more densely detected in the rostral LC of females. Regardless of sex, CHS elevated immunoreactivity of TH throughout the LC. Under basal conditions, greater number of TH-ir cells was detected in the rostral ventrolateral medulla (RVLM) of females. In contrast, CHS remarkably increased the number of TH-ir cells in the RVLM of males which was found to be decreased in females. There was no sex-related alteration in TH immunoreactivity in the nucleus tractus solitarius (NTS) of control rats, while CHS affected both sexes in a similar manner. Compared with females, CRF immunoreactivity was prominently observed in control males, while both of which were stimulated by CHS. ER-α/ß was found to be co-expressed with TH in the NTS and LC which exhibit no alteration related to either sex or stress status. These results indicate a sexual dimorphism in the catecholaminergic and the CRF system in brainstem which might be involved in the CHS-induced autonomic and visceral dysfunction occurred in males.

Breaking Barriers in Functional Dyspepsia: A Systematic Review and Meta-analysis on Duodenal Tight Junction Protein Expression.

Background/Aims: Disruptions in tight junction (TJ) protein expression leading to duodenal epithelial barrier impairment may contribute to increased intestinal permeability, potentially playing a role in functional dyspepsia (FD) pathophysiology. Currently published studies evaluated the role of several TJ proteins in FD patients with inconsistent results. Therefore, we conducted this systematic review and metaanalysis to evaluate the duodenal mucosal expression of several TJ proteins in FD. Methods: We performed a systematic electronic search on PubMed, EMBASE, and Scopus using predefined keywords. Diagnosis of FD by Rome III or Rome IV criteria was considered acceptable. Full articles satisfying our inclusion and exclusion criteria were included. The principal summary outcome was the mean difference of several TJ proteins in FD patients and control subjects. Results: A total of 8 and 5 studies were included in our qualitative and quantitative synthesis, respectively, with a total population of 666 participants, out of which 420 were FD patients. No significant differences were observed between FD patients and controls in the expression of claudin-1 (-0.102 [95% CI, -0.303, 0.099]), claudin-2 (0.161 [95% CI, -0.134, 0.456)], claudin-3 (0.278 [95% CI, -0.280, 0.837]), claudin-4 (0.045 [95% CI, -0.264, 0.354]), ZO-1 (-0.221 [95% CI, -0.683, 0.241]), ZO-2 (-0.070 [95% CI, -0.147, 0.007]), ZO-3 (-0.129 [95% CI, -0.376, 0.118]), ß-catenin (-0.135 [95% CI, -0.484, 0.214]), E-cadherin (-0.083 [95% CI, -0.229, 0.063]), and occludin (-0.158 [95% CI, -0.409, 0.093]). Conclusions: The expressions of all evaluated proteins including claudin-1, claudin-2, claudin-3, claudin-4, ZO-1, ZO-2, ZO-3, ß-catenin, E-cadherin, and occludin did not significantly differ between FD patients and controls. However, due to the limited number of included studies, results should be interpreted with caution.

The gut microbiome in disorders of gut-brain interaction.

Functional gastrointestinal disorders (FGIDs), chronic disorders characterized by either abdominal pain, altered intestinal motility, or their combination, have a worldwide prevalence of more than 40% and impose a high socioeconomic burden with a significant decline in quality of life. Recently, FGIDs have been reclassified as disorders of gut-brain interaction (DGBI), reflecting the key role of the gut-brain bidirectional communication in these disorders and their impact on psychological comorbidities. Although, during the past decades, the field of DGBIs has advanced significantly, the molecular mechanisms underlying DGBIs pathogenesis and pathophysiology, and the role of the gut microbiome in these processes are not fully understood. This review aims to discuss the latest body of literature on the complex microbiota-gut-brain interactions and their implications in the pathogenesis of DGBIs. A better understanding of the existing communication pathways between the gut microbiome and the brain holds promise in developing effective therapeutic interventions for DGBIs.

Determining the frequency of Helicobacter pylori in children with chronic kidney failure and its relationship to gastrointestinal symptoms.

Key Clinical Message: As there is no significant mutual relationship between Helicobacter pylori infection and chronic kidney disease in children, its routine study is not justified and is recommended only in symptomatic cases. Abstract: Children suffering from chronic kidney disease (CKD) often complain of indigestion but, if it is accompanied by abdominal pain, it is necessary to investigate and rule out Helicobacter pylori infection to confirm functional dyspepsia. Epidemiological studies in adults have conflicting results regarding the association between Helicobacter pylori infection and CKD. In this study, we determined the prevalence of H. pylori in children with kidney failure and its relationship to their gastrointestinal symptoms. In this retrospective study, 54 children with chronic kidney failure admitted to the hemodialysis ward of the Children's Medical Center, Tehran, Iran between 2012 and 2020 were studied. The mean age of our patients was 11.89 ± 3.99 years and their sex distribution was equal. H. pylori infection was reported in only three patients with 5.6%. Based on our findings, epigastric pain in children was the most common gastrointestinal symptom (70.4%). Among all patients, three patients (5.6%) died, all of them were male (P = 0.075). The most prevalent underlying cause of kidney failure in our patients was neurogenic bladder. We did not find any significant relationship between the increased risk of chronic kidney failure and co-infection with H. pylori. Investigating the cause of epigastric pain and looking for H. pylori is very important in CKD children under hemodialysis because if they receive a transplant the possibility of gastrointestinal complications will be increased with the use of steroid and immunosuppressive drugs.

Psychological Characteristics and Quality of Life of Patients With Functional Dyspepsia.

OBJECTIVE: The objective of this study is to compare the psychosocial characteristics of functional dyspepsia (FD) with its subgroups, epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS), against a healthy control group, and to investigate the quality of life (QoL). METHODS: All of the subjects were 210 adults, 131 patients with FD were diagnosed by gastroenterologist and 79 adults with no observable symptoms of FD were selected as the normal control group. Demographic factors were investigated. The Korean-Beck Depression Inventory-II, Korean-Beck Anxiety Inventory, Korean-Childhood Trauma Questionnaire, Multidimensional Scale of Perceived Social Support, Connor-Davidson Resilience Scale, and WHO Quality of Life Assessment Instrument Brief Form were used to assess psychological factors. A one-way analysis of variance was used to compare differences among the groups. Further, a stepwise regression analysis was conducted to determine factors affecting the QoL of the FD group. RESULTS: Between-group differences in demographic characteristics were not significant. Depression (F=37.166, p<0.001), anxiety (F=30.261, p<0.001), and childhood trauma (F=6.591, p<0.01) were all significantly higher in FD group compared to the normal control. Among FD subgroups, EPS exhibited higher levels of both depression and anxiety than PDS. Social support (F=17.673, p<0.001) and resilience (F=8.425, p<0.001) were significantly lower in FD group than in other groups, and the values were higher in PDS than in EPS. Resilience (ß=0.328, p<0.001) was the most important explanatory variable. The explained variance was 46.6%. CONCLUSION: Significantly more symptoms of depression, anxiety, childhood trauma was observed for both FD sub-group. These groups also had less social support, resilience, and QoL than the control groups.

Low Vitamin D Levels in Patients with Symptoms of Gastroparesis: Relationships with Nausea and Vomiting, Gastric Emptying and Gastric Myoelectrical Activity.

Patients with gastroparesis (Gp) often have diets deficient in calories, electrolytes, and vitamins. Vitamin D levels have been reported to be low in some patients with Gp but has not been systematically studied. AIMS: To determine vitamin D levels and relationships among symptoms, gastric emptying and gastric myoelectrical activity (GMA) in patients with symptoms of Gp. METHODS: 25-hydroxy-vitamin D was measured in patients at enrollment in the Gastroparesis Clinical Consortium Registry. Gastroparesis Cardinal Symptoms Index (GCSI), gastric emptying, and GMA before and after water load satiety test (WLST) were measured. GMA, expressed as percentage distribution of activity in normal and dysrhythmic ranges, was recorded using electrogastrography. RESULTS: Overall, vitamin D levels were low (< 30 ng/ml) in 288 of 513 (56.1%) patients with symptoms of Gp (206 of 376 (54.8%) patients with delayed gastric emptying (Gp) and 82 of 137 (59.9%) patients with symptoms of Gp and normal gastric emptying). Low vitamin D levels were associated with increased nausea and vomiting (P < 0.0001), but not with fullness or bloating subscores. Low vitamin D levels in patients with Gp were associated with greater meal retention at four hours (36% retention) compared with Gp patients with normal vitamin D levels (31% retention; P = 0.05). Low vitamin D in patients with normal gastric emptying was associated with decreased normal 3 cpm GMA before (P = 0.001) and increased tachygastria after WLST (P = 0.01). CONCLUSIONS: Low vitamin D levels are present in half the patients with symptoms of gastroparesis and are associated with nausea and vomiting and gastric neuromuscular dysfunction.

Comparative Assessment of the Anti-Helicobacter pylori Activity and Gastroprotective Effects of Three Herbal Formulas for Functional Dyspepsia In Vitro.

Helicobacter pylori has been implicated in various gastrointestinal disorders, including functional dyspepsia. This study aimed to compare the anti-H. pylori activity and gastroprotective effects of three typical herbal formulas used for gastrointestinal disorders in Korea: Shihosogan-tang (ST), Yijung-tang (YT), and Pyeongwi-san (PS). Firstly, we assessed the total phenolic and flavonoid contents, as well as the antioxidative capacity. Additionally, we evaluated the antibacterial effect on H. pylori using an ammonia assay, minimum inhibitory concentration (MIC) test, and the disk agar diffusion method. Furthermore, we examined alterations in the gene expression of tight junction proteins, pro-inflammatory cytokines, and cellular vacuolation using an AGS cell model infected with H. pylori. While ST exhibited a higher total phenolic content, superior free radical scavenging, and inhibition of H. pylori compared to YT and PS, YT more evidently inhibited gastric cellular morphological changes such as vacuolation. All formulations significantly ameliorated changes in inflammatory and gastric inflammation-related genes and cellular morphological alterations induced by H. pylori infection. Overall, the present in vitro study suggests that all three herbal formulas possess potential for ameliorating gastrointestinal disorders, with ST relatively excelling in inhibiting H. pylori infection and inflammation, while YT potentially shows greater efficacy in directly protecting the gastric mucosa.

The effectiveness and safety of natural food and food-derived extract supplements for treating functional gastrointestinal disorders-current perspectives.

Functional gastrointestinal disorders (FGIDs) were highly prevalent and involve gastrointestinal discomfort characterized by non-organic abnormalities in the morphology and physiology of the gastrointestinal tract. According to the Rome IV criteria, irritable bowel syndrome and functional dyspepsia are the most common FGIDs. Complementary and alternative medicines are employed by increasing numbers of individuals around the world, and they include herbal and dietary supplements, acupuncture, and hypnosis. Of these, herbal and dietary supplements seem to have the greatest potential for relieving FGIDs, through multiple modes of action. However, despite the extensive application of natural extracts in alternative treatments for FGIDs, the safety and effectiveness of food and orally ingested food-derived extracts remain uncertain. Many randomized controlled trials have provided compelling evidence supporting their potential, as detailed in this review. The consumption of certain foods (eg, kiwifruit, mentha, ginger, etc) and food ingredients may contribute to the alleviation of symptoms associated with FGID,. However, it is crucial to emphasize that the short-term consumption of these components may not yield satisfactory efficacy. Physicians are advised to share both the benefits and potential risks of these alternative therapies with patients. Furthermore, larger randomized clinical trials with appropriate comparators are imperative.

Comorbid functional dyspepsia reflects IL-33-mediated airway neuronal dysfunction in asthma.

BACKGROUND: Neuronal dysfunction is implicated in the pathophysiology of asthma and functional dyspepsia (FD). However, the relationship between these diseases remains unclear. OBJECTIVE: This study aimed to clarify the clinical implications of comorbid FD in asthma and to explore the unified pathway between asthma and FD by focusing on airway neuronal dysfunction. METHODS: Clinical indices and biomarkers, including capsaicin cough sensitivity (C-CS), were compared between patients with asthma with and without FD. C-CS was determined based on the capsaicin concentration that induced at least two (C2) or five coughs (C5). Additionally, the associations of airway inflammation with airway innervation and gastrointestinal motility were evaluated in mouse models of type 2 airway inflammation. RESULTS: Patients with asthma with FD had worse asthma control and cough severity and lower C2 and C5 thresholds than those without FD. The severity of FD symptoms was negatively correlated with C2 and C5 thresholds. FD and poor asthma control were predictors of heightened C-CS (defined as C5 of ≤ 2.44 µM) in asthma. A mouse model of papain-induced airway inflammation developed airway hyperinnervation and gastrointestinal dysmotility, and both pathologies were ameliorated by an anti-interleukin (IL)-33 antibody. Moreover, papain-induced gastrointestinal dysmotility was mitigated by silencing the airway sensory neurons using QX-314, a sodium channel blocker. Furthermore, sputum IL-33 levels were significantly elevated in patients with asthma with FD or heightened C-CS compared with those in their counterparts. CONCLUSION: FD is significantly associated with airway neuronal dysfunction in asthma. IL-33-mediated airway neuronal dysfunction may contribute to the interaction between asthma and FD.

Association between gut microbiota and common overlapping gastrointestinal disorders: a bidirectional two-sample Mendelian randomization study.

Background: The main functional gastrointestinal disorders (FGIDs) include functional dyspepsia (FD) and irritable bowel syndrome (IBS), which often present overlapping symptoms with gastroesophageal reflux disease (GERD), posing a challenge for clinical diagnosis and treatment. The gut microbiota is closely associated with FGIDs and GERD, although the causal relationship has not been fully elucidated. Therefore, we aimed to investigate the potential causal relationship using bidirectional two-sample Mendelian randomization (MR) analysis. Materials and methods: The genetic data of the 211 gut microbiota were obtained from the MiBioGen consortium (N = 14,306, from phylum to genus level) and species level of gut microbiota were acquired from the Dutch Microbiome Project (N = 7,738). For FD and IBS, we utilized the FinnGen consortium, whereas, for GERD data analysis, we obtained the IEU OpenGWAS project. The inverse-variance weighted (IVW) method was used as the primary method to calculate causal effect values. Sensitivity analyses were also performed to confirm the robustness of the primary findings of the MR analyses. Moreover, a reverse MR analysis was conducted to assess the likelihood of reverse causality. Results: Combining the results of the preliminary and sensitivity analyses, we identified that 8 gut microbial taxa were associated with FD. Genus Lachnospiraceae NK4A136 group (p = 3.63 × 10-3) and genus Terrisporobacter (p = 1.13 × 10-3) were strongly associated with FD. At the same time, we found that 8 gut microbial taxa were associated with IBS. Family Prevotellaceae (p = 2.44 × 10-3) and species Clostridium leptum (p = 7.68 × 10-3) display a robust correlation with IBS. In addition, 5 gut microbial taxa were associated with GERD using the IVW approach. In the reverse MR analysis, 2 gut microbial taxa were found to be associated with FD, 5 gut microbial taxa were found to be associated with IBS, and 21 gut microbial taxa were found to be associated with GERD. Conclusion: The study reveals the potential causal effects of specific microbial taxa on FD, IBS, and GERD and may offer novel insights into the diagnosis and treatment of these conditions.

Alterations in gastrointestinal motility assessed by high-resolution antroduodenal manometry in patients with severe disorders of gut-brain interaction.

INTRODUCTION: Data are limited regarding gastrointestinal motility disturbance in disorders of gut-brain interaction (DGBI). This study aimed to characterize antroduodenal motor alterations in patients using high-resolution antroduodenal manometry (HR-ADM). METHODS: HR-ADM was performed in patients with severe DGBI and compared with healthy volunteers (HV). HR-ADM used a commercially available probe composed of 36 electronic sensors spaced 1 cm apart and positioned across the pylorus. Antral and duodenal motor high-resolution profiles were analyzed, based on the frequency, amplitude, and contractile integral/sensor (CI/s) calculated for each phase of the migrating motor complex (MMC). RESULTS: Eighteen HV and 64 patients were investigated, 10 with irritable bowel syndrome (IBS), 24 with functional dyspepsia (FD), 15 with overlap IBS-FD, and 15 with other DGBI. Compared with HV, patients had a lower frequency of phase II duodenal contractions (27 per hour vs 51; p=0.002) and a lower duodenal phase II contraction amplitude (70 mmHg vs 100; p=0.01) resulting in a lower CI/s of phase II (833 mmHg.cm.s vs 1901; p<0.001) in the duodenum. In addition, the frequency of phase II propagated antroduodenal contractions was lower (5 per hour vs 11; p<0.001) in patients, as compared to HV. Interestingly, the antral CI/s of phase III was decreased in FD patients, but not in IBS patients. CONCLUSION: Patients with severe DGBI display alterations in antral and intestinal motility assessed using commercially available HR-ADM. Whether these alterations may explain symptom profiles in such patients remains to be confirmed. (NCT04918329 and NCT01519180).

Gut microbiota and functional dyspepsia: a two-sample Mendelian randomization study.

Background: Numerous studies have established that alterations in the gut microbiota (GM) constitute an embedded mechanism in functional dyspepsia (FD). However, the specific GM taxa implicated in the pathological process of FD have remained unclear. Methods: A two-sample Mendelian randomization analysis was initially conducted to examine the causal relationships between GM and FD, utilizing GWAS data from the MiBioGen Consortium (18,340 cases) and FinnGenn (8,875 cases vs. 320,387 controls). The MR study primarily employed the inverse-variance weighted (IVW) method. Sensitivity analyses were performed to test for heterogeneity and pleiotropy. Single-nucleotide polymorphisms of causal GM taxa were mapped to genes, which were subsequently assessed for causal relationships with FD employing the same methodology. Results: IVW results revealed that the genus Clostridium innocuum group (OR: 1.12, 95% CI: 1.02-1.24, P = 0.020) and genus Ruminiclostridium 9 were positively associated with FD risk (OR: 1.27, 95% CI: 1.03-1.57, P = 0.028), while the genus Lachnospiraceae FCS020 group tended to exert a negative effect on FD risk (OR = 0.84, 95% CI: 0.73-0.98, P = 0.023). Among GM-related genes, a notable association was observed between RSRC1 and increased FD risk (OR = 1.13, 95% CI: 1.07-1.20, P < 0.001). In sensitivity analyses, no significant pleiotropy or heterogeneity of the results was found. Conclusions: This study furnished evidence for distinct effects of specific GM taxa on FD risk and hinted at a potential biological mechanism, thereby offering theoretical underpinning for future microbiotherapy of FD.

The effect of mindfulness-based cognitive therapy on the Clinical efficacy and psychological state in patients with functional dyspepsia.

BACKGROUND AND AIM: To observe the clinical therapeutic effect and mental state of mindfulness-based cognitive therapy (MBCT) in patients with functional dyspepsia (FD). METHODS: In this study, 80 patients suffering from FD in an outpatient clinic were enrolled from January to December 2020. Patients were randomly allocated into the control group (conventional treatment) and observation group (MBCT treatment). Patients in the control group were prescribed rabeprazole and mosapiride, and patients in the observation group were given MBCT therapy in addition to the above drugs. After treatment for 8 weeks, the changes in gastrointestinal symptom scores, anxiety, depression, mindfulness and sleep quality and gastric emptying testing were compared between these two groups. RESULTS: The observation group showed strikingly lower gastrointestinal symptom scores, SAS, SDS, PSQI, and SCL-90 scale scores, and higher FFMQ scale scores than the control group (p < 0.05). There was no conspicuous change in gastric emptying monitoring (p > 0.05). CONCLUSIONS: MBCT therapy can improve patients' gastrointestinal symptoms, attenuate their anxiety and depression levels, and ameliorate their sleep quality.

Comparing the prevalence and association between anxiety, depression and gastrointestinal symptoms in gastroparesis versus functional dyspepsia: A systematic review and meta-analysis.

OBJECTIVE: To determine the prevalence and associations between anxiety/depression, and gastrointestinal (GI) symptoms across gastroparesis and functional dyspepsia. METHODS: Twenty adult studies were identified through systematic searches of three databases (PubMed, CINAHL and PsycINFO) in September 2023. Meta-analysis was performed to estimate the pooled prevalence rates of anxiety and depression across gastroparesis and functional dyspepsia, and to determine whether the associations of anxiety/depression and gastrointestinal (GI) symptoms differ in gastroparesis versus functional dyspepsia. RESULTS: The overall pooled prevalence rate for anxiety was similar (χ2(1) = 2.45, p = .12) in gastroparesis (49%) and functional dyspepsia (29%). The overall pooled prevalence rate for depression in gastroparesis (39%), and functional dyspepsia (32%) was also similar (χ2(1) = 0.81, p = .37). No significant relationship between anxiety and GI symptoms (r = 0.11) or depression and GI symptoms (r = 0.16) was found in gastroparesis, whilst significant, though weak, positive relationships between anxiety and GI symptoms (r = 0.30) and depression and GI symptoms (r = 0.32) were found in functional dyspepsia. The association between GI symptoms and anxiety, but not depression, across gastroparesis and functional dyspepsia was found to be significant (χ2(1) = 5.22, p = .02). CONCLUSION: Contributing to ongoing debate as to whether gastroparesis and functional dyspepsia are interchangeable syndromes, this review found that anxiety and depression prevalence was similar in both conditions. Psychological assessment and the utilisation of effective and holistic care in both conditions is therefore warranted.

Efficacy and safety of Xiangsha liujunzi decoction for functional dyspepsia: a systematic review and meta-analysis.

Background: Functional dyspepsia is a highly prevalent digestive disorder. The limited effectiveness of current pharmaceutical interventions necessitates the exploration of alternative therapeutic options for functional dyspepsia. Xiangsha liujunzi decoction, a well-known traditional Chinese medicine formulation, has been widely employed in the treatment of functional dyspepsia in China. Nevertheless, the effectiveness of Xiangsha liujunzi decoction in the treatment of functional dyspepsia remains uncertain. Objective: To examine the effectiveness and safety of Xiangsha liujunzi decoction for treating functional dyspepsia. Methods: We retrieved seven databases containing randomized controlled trials on functional dyspepsia published up until 31 July 2023. The quality of these studies was evaluated using the Cochrane Risk of Bias assessment tool. The analysis of data was performed using the software RevMan 5.4. The total clinical effectiveness rate was evaluated as the primary outcome. In addition, gastric emptying rate, symptom score and safety evaluation were evaluated as the secondary outcomes. Results: The meta-analysis included 23 studies, involving 2,101 individuals. Xiangsha liujunzi decoction demonstrated a significantly higher clinical effectiveness rate compared to the control group (RR 1.27; 95% CI 1.21, 1.33; p < 0.00001). Moreover, it exhibited superior gastric emptying rate and symptom score improvement compared to the control group. Nevertheless, no remarkable differences were detected in safety between Xiangsha liujunzi decoction and the control group (RR 0.67; 95% CI 0.16, 2.76; p = 0.58). Conclusion: The findings of this study suggest that Xiangsha liujunzi decoction exhibits effectiveness and no significant adverse events observed. However, because of the low quality of the enrolled studies, more high-quality and strict design randomized controlled trials are required in the future.

Postprandial symptoms in disorders of gut-brain interaction and their potential as a treatment target.

Postprandial, or meal-related, symptoms, such as abdominal pain, early satiation, fullness or bloating, are often reported by patients with disorders of gut-brain interaction, including functional dyspepsia (FD) or irritable bowel syndrome (IBS). We propose that postprandial symptoms arise via a distinct pathophysiological process. A physiological or psychological insult, for example, acute enteric infection, leads to loss of tolerance to a previously tolerated oral food antigen. This enables interaction of both the microbiota and the food antigen itself with the immune system, causing a localised immunological response, with activation of eosinophils and mast cells, and release of inflammatory mediators, including histamine and cytokines. These have more widespread systemic effects, including triggering nociceptive nerves and altering mood. Dietary interventions, including a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols, elimination of potential food antigens or gluten, IgG food sensitivity diets or salicylate restriction may benefit some patients with IBS or FD. This could be because the restriction of these foods or dietary components modulates this pathophysiological process. Similarly, drugs including proton pump inhibitors, histamine-receptor antagonists, mast cell stabilisers or even tricyclic or tetracyclic antidepressants, which have anti-histaminergic actions, all of which are potential treatments for FD and IBS, act on one or more of these mechanisms. It seems unlikely that food antigens driving intestinal immune activation are the entire explanation for postprandial symptoms in FD and IBS. In others, fermentation of intestinal carbohydrates, with gas release altering reflex responses, adverse reactions to food chemicals, central mechanisms or nocebo effects may dominate. However, if the concept that postprandial symptoms arise from food antigens driving an immune response in the gastrointestinal tract in a subset of patients is correct, it is paradigm-shifting, because if the choice of treatment were based on one or more of these therapeutic targets, patient outcomes may be improved.

The Presence of Ganglionic Acetylcholine Receptor Antibodies in Sera from Patients with Functional Gastrointestinal Disorders: A Preliminary Study.

BACKGROUND: Functional gastrointestinal disorders (FGIDs), including functional dyspepsia (FD) and irritable bowel syndrome (IBS), are characterized by chronic and recurrent gastrointestinal symptoms. Clinically, FD and IBS often resemble gastrointestinal dysmotility caused by autoimmune autonomic neuropathy. We examined the seropositive frequency of autoantibodies against ganglionic nicotinic acetylcholine receptors (gnAChRs) in patients presenting with FGIDs. OBJECTIVE: To elucidate the seropositivity of gnAChR antibodies and the clinical features of seropositive FD and IBS. MATERIALS AND METHODS: We measured autoantibodies against the gnAChR α3 and ß4subunits using luciferase immunoprecipitation systems. Serum samples from patients with any autonomic symptoms were obtained from hospitals in Japan between January 2012 and August 2018 (1787 serum samples of 1381 patients). We selected FD and IBS patients and compared the clinical characteristics and prevalence of autonomic symptoms between those with seropositive and seronegative IBS and FD. RESULTS: Nine IBS and two FD cases (one comorbid case with IBS) were found. We found four patients (36.4%) in whom gnAChR antibodies were positive in these eleven patients. Sicca symptoms were observed in three of four cases (75%) of seropositive FGID compared with zero of seven cases (0%) of seronegative FGID. CONCLUSIONS: We found patients with gnAChR antibodies in FD and IBS patients. These data will be valuable for elucidating the pathophysiology of these FGIDs and developing new treatment strategies.

Symptoms from the Gastroparesis Cardinal Symptom Index and clinical factors associated with delayed gastric emptying in patients with suspected gastroparesis.

BACKGROUND: The association between upper gastrointestinal symptoms and delayed gastric emptying (GE) shows conflicting results. This study aimed to assess whether the symptoms of the Gastroparesis Cardinal Symptom Index (GCSI) and/or the scores were associated with the result of GE tests and whether they could predict delayed GE. METHODS: Patients referred for suspected gastroparesis (GP) were included in a prospective database. Demographical data, medical history, and symptoms of the GCSI score were collected for each patient. A GE scintigraphy was then performed with a 4-hour recording. Delayed GE was defined as a retention rate ≥ 10% at 4 h. RESULTS: Among 243 patients included in this study, 110 patients (45%) had delayed GE. The mean age (49.9 vs. 41.3 years; p < 0.001) and weight loss (9.4 kg vs. 5.6 kg; p = 0.025) were significantly higher in patients with delayed GE. Patients with diabetes or a history of surgery had a higher prevalence of delayed GE (60% and 78%, respectively) than patients without comorbidity (17%; p < 0.001). The GCSI score was higher in patients with delayed GE (3.06 vs. 2.80; p = 0.045), but no threshold was clinically relevant to discriminate between patients with normal and delayed GE. Only vomiting severity was significantly higher in patients with delayed GE (2.19 vs. 1.57; p = 0.01). CONCLUSION: GE testing should be considered when there are symptoms such as a higher weight loss, comorbidities (diabetes, and history of surgery associated with GP), and the presence of vomiting. Other symptoms and the GCSI score are not useful in predicting delayed GE.

Electroacupuncture improves low-grade duodenal inflammation in FD rats by reshaping intestinal flora through the NF-κB p65/NLRP3 pyroptosis pathway.

Electroacupuncture (EA) is an effective alternative for the treatment of functional dyspepsia (FD). It reduces low-grade duodenal inflammation and improves the symptoms of FD by downregulating the expression of NF-κB p65 and NLRP3, but its mechanism needs to be elucidated. To examine the regulatory effect of electroacupuncture (EA) on intestinal flora and NF-κB p65/NLRP3 pyroptosis pathway in FD rats. The FD rat model was established via multi-factor stress intervention for two weeks. The rats were randomly divided into the NC group, model group, NF-kB inhibitor group (NF-κB inhibitor BAY 11-7082 was administered), EA group, and EA + NF-kB inhibitor group. After 14 days of treatment, the rats were sacrificed, and the protein and mRNA levels of NF-κB p65, IκB, and NLRP3 in the duodenum were evaluated by Western blotting assays and real-time fluorescent quantitative PCR. The Illumina MiSeq sequencing platform was used to analyze the V4 region of the 16S rRNA gene of intestinal flora and predict functional genes. The concentration of short-chain fatty acids (SCFAs) in feces was assessed by metabolomics. EA can decrease low-grade duodenal inflammation and promote gastrointestinal motility in FD rats. This effect is mediated by inhibition of the NF-κB p65/NLRP3 pyroptosis pathway, an increase in the alpha and beta diversity of gut microbiota in the duodenum, an increase in the abundance of beneficial bacteria at the phylum and genus levels, and an increase in the content of SCFAs. The protective effect of EA against FD might involve multiple hierarchy and pathways. EA may remodel intestinal flora by inhibiting the NF-κB p65/NLRP3 pyroptosis pathway, thereby improving low-grade duodenal inflammation in FD rats.

Comparison of the effects of Amomum tsaoko and its adulterants on functional dyspepsia rats based on metabolomics analysis.

Amomum tsaoko (AT) is commonly used in clinical practice to treat abdominal distension and pain. It is also a seasoning for cooking, with the functions of appetizing, invigorating the spleen, and being digestive-promoting. Amomum tsaoko (AT) has three adulterants, Amomum paratsaoko (AP), Amomum koenigii (AK), and Alpinia katsumadai Hayata, because of the confusion in historical classics regarding recorded sources as well as the near geographic distribution and fruit morphological similarities. In this study, we established a functional dyspepsia (FD) rat model and then treated it with the corresponding medicinal solutions AT, AP, AK, and AKH. The gastric emptying rate, intestinal propulsion rate, serum biochemical indicators, histopathological changes, and fecal metabolism were measured. The efficacy and mechanism of AT, AP, AK, and AKH in the treatment of FD were compared. Fecal metabolomics revealed that 20 potential biomarkers were involved in seven significant metabolic pathways in FD rats. These pathways include ubiquinone and other terpenoid-quinone biosynthesis, glycerophospholipid metabolism, tyrosine metabolism, primary bile acid biosynthesis, purine metabolism, folate biosynthesis, and amino sugar and nucleotide sugar metabolism. AP regulates 6 metabolic pathways, 5 metabolic pathways affected by AT, 4 metabolic pathways affected by AK, and 2 metabolic pathways affected by AKH.The above results suggest that the different effects of AT, AP, AK, and AKH on FD rats may be due to their different regulatory effects on the metabolome.