Genome-wide cross-disease analyses highlight causality and shared biological pathways of type 2 diabetes with gastrointestinal disorders.

Studies suggest links between diabetes and gastrointestinal (GI) traits; however, their underlying biological mechanisms remain unclear. Here, we comprehensively assess the genetic relationship between type 2 diabetes (T2D) and GI disorders. Our study demonstrates a significant positive global genetic correlation of T2D with peptic ulcer disease (PUD), irritable bowel syndrome (IBS), gastritis-duodenitis, gastroesophageal reflux disease (GERD), and diverticular disease, but not inflammatory bowel disease (IBD). We identify several positive local genetic correlations (negative for T2D - IBD) contributing to T2D's relationship with GI disorders. Univariable and multivariable Mendelian randomisation analyses suggest causal effects of T2D on PUD and gastritis-duodenitis and bidirectionally with GERD. Gene-based analyses reveal a gene-level genetic overlap between T2D and GI disorders and identify several shared genes reaching genome-wide significance. Pathway-based study implicates leptin (T2D - IBD), thyroid, interferon, and notch signalling (T2D - IBS), abnormal circulating calcium (T2D - PUD), cardiovascular, viral, proinflammatory and (auto)immune-mediated mechanisms in T2D and GI disorders. These findings support a risk-increasing genetic overlap between T2D and GI disorders (except IBD), implicate shared biological pathways with putative causality for certain T2D - GI pairs, and identify targets for further investigation.

Molecular characterization and phylogenetic analysis of babA gene of Helicobacter pylori isolated from Indian patients with gastrointestinal diseases.

INTRODUCTION: Outer membrane protein (OMP) of Helicobacter pylori (H. pylori) i.e., blood group antigen binding adhesin (babA) is responsible for the attachment of H. pylori in the gastric epithelium. Its adherence is causative for gastric pathology such as gastritis, peptic ulcer disease (PUD), or digestive tract disorders like erosive reflux disease (ERD) and (NERD) non-erosive reflux disease and together called Gastroesophageal reflux disease (GERD). BabA manifests rapid and varied selection via substitution of amino acid in its Leb-carbohydrate binding domain (CBD) which enables better binding preferences for distinct human populations and ABO blood group phenotypes. The positive evolutionary selection of the pathogenic factor of this genetically diverse bacterium has enabled it to adapt to the host gastric environment. Analyzing the association of virulent genes (cagA, vacA) and babA will help us better understand bacteria's pathogenicity. METHOD: 109 H. pylori strains from patients with distinct gastrointestinal diseases were genotyped using Polymerase Chain Reaction(PCR) for cagA, vacA, and babA followed by Sanger sequencing and phylogenetic analysis. RESULT: In the babA + ve genotype, a statistically significant association with p = 0.04 and < 0.0001 is seen in gastritis and ERD respectively. A significant association of genotype vacAs1m2 (p = 0.0002) was seen in gastritis, vacAs1m1 (p = 0.02) in NERD, vacAs1m1 (p < 0.0001) and vacAs1m2 (p = 0.002) in ERD. This relationship helps to detect gastritis or ERD where BabA gene can be used as an independent marker for detecting their presence. CONCLUSION: The appearance of variants within distinct disease categories is due to local genetic variation.

Mutational spectrum of CFTR in cystic fibrosis patients with gastrointestinal and hepatobiliary manifestations.

BACKGROUND: Cystic fibrosis (CF) is a rare and debilitating autosomal recessive disorder. It hampers the normal function of various organs and causes severe damage to the lungs, and digestive system leading to recurring pneumonia. Cf also affects reproductive health eventually may cause infertility. The disease manifests due to genetic aberrations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This study aimed to screen for CFTR gene variants in Pakistani CF patients representing variable phenotypes. METHODS: Clinical exome and Sanger sequencing were performed after clinical characterization of 25 suspected cases of CF (CF1-CF25). ACMG guidelines were followed to interpret the clinical significance of the identified variants. RESULTS: Clinical investigations revealed common phenotypes such as pancreatic insufficiency, chest infections, chronic liver and lung diseases. Some patients also displayed symptoms like gastroesophageal reflux disease (GERD), neonatal cholestasis, acrodermatitis, diabetes mellitus, and abnormal malabsorptive stools. Genetic analysis of the 25 CF patients identified deleterious variants in the CFTR gene. Notably, 12% of patients showed compound heterozygous variants, while 88% had homozygous variants. The most prevalent variant was p. (Met1Thr or Met1?) at 24%, previously not reported in the Pakistani population. The second most common variant was p. (Phe508del) at 16%. Other variants, including p. (Leu218*), p. (Tyr569Asp), p. (Glu585Ter), and p. (Arg1162*) were also identified in the present study. Genetic analysis of one of the present patients showed a pathogenic variant in G6PD in addition to CFTR. CONCLUSION: The study reports novel and reported variants in the CFTR gene in CF patients in Pakistani population having distinct phenotypes. It also emphasizes screening suspected Pakistani CF patients for the p. (Met1Thr) variant because of its increased observance and prevalence in the study. Moreover, the findings also signify searching for additional pathogenic variants in the genome of CF patients, which may modify the phenotypes. The findings contribute valuable information for the diagnosis, genetic counseling, and potential therapeutic strategies for CF patients in Pakistan.

Sedentary lifestyle, physical activity, and gastrointestinal diseases: evidence from mendelian randomization analysis.

BACKGROUND: The causal associations of physical activity and sedentary behavior with the risk of gastrointestinal disease are unclear. We performed a Mendelian randomization analysis to examine these associations. METHODS: Genetic instruments associated with leisure screen time (LST, an indicator of a sedentary lifestyle) and moderate-to-vigorous intensity physical activity (MVPA) at the genome-wide significance (P < 5 × 10-8) level were selected from a genome-wide association study. Summary statistics for gastrointestinal diseases were obtained from the UK Biobank study, the FinnGen study, and large consortia. Multivariable MR analyses were conducted for genetically determined LST with adjustment for MVPA and vice versa. We also performed multivariable MR with adjustment for genetically proxied smoking, body mass index (BMI), waist-to-hip ratio, type 2 diabetes, and fasting insulin for both exposures. FINDINGS: Genetically proxied longer LST was associated with an increased risk of gastrointestinal reflux, gastric ulcer, duodenal ulcer, chronic gastritis, irritable bowel syndrome, diverticular disease, Crohn's disease, ulcerative colitis, non-alcoholic fatty liver disease, alcoholic liver disease, cholangitis, cholecystitis, cholelithiasis, acute pancreatitis, chronic pancreatitis, and acute appendicitis. Most associations remained after adjustment for genetic liability to MVPA. Genetic liability to MVPA was associated with decreased risk of gastroesophageal reflux, gastric ulcer, chronic gastritis, irritable bowel syndrome, cholecystitis, cholelithiasis, acute and chronic pancreatitis. The associations attenuated albeit directionally remained after adjusting for genetically predicted LST. Multivariable MR analysis found that BMI and type 2 diabetes mediated the associations of LST and MVPA with several gastrointestinal diseases. INTERPRETATION: The study suggests that a sedentary lifestyle may play a causal role in the development of many gastrointestinal diseases. FUNDING: Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001), Natural Science Foundation of Hunan Province (2021JJ30999), Swedish Heart-Lung Foundation (Hjärt-Lungfonden, 20210351), Swedish Research Council (Vetenskapsrådet, 2019-00977), Swedish Cancer Society (Cancerfonden), the Wellcome Trust (225790/7/22/Z), United Kingdom Research and Innovation Medical Research Council (MC_UU_00002/7) and National Institute for Health Research Cambridge Biomedical Research Centre (NHIR203312).

[HLA genotypes associated with gastrointestinal symptoms in patients with spondyloarthritis without inflammatory bowel disease]. / Genotipos HLA asociados a síntomas gastrointestinales en pacientes con espondiloartritis sin enfermedad inflamatoria intestinal.

OBJECTIVE: This study aimed to establish the association between HLA-A, B, DR genotypes and gastrointestinal variables in patients with SpA without inflammatory bowel disease (IBD). METHODS: Retrospective study of 91 patients with SpA and 401 healthy controls, with typing by Illumina Sequencing/PacBio and LIFECODES HLA-PCR/SSO multiplex sequencing technology. The presence of gastrointestinal symptoms was evaluated by administering a survey, and those who presented 2 or more symptoms were taken for clinical evaluation by rheumatology and gastroenterology, colonoscopy and histopathological study. (Ethics committee approval). RESULTS: The 59,3% of the patients were men, with a mean age of 43,9±11.4 years; 80,2% were classified as ankylosing spondylitis. 14, 28 and 19 genotypes for the HLA-A*, HLA-B* and HLA-DR* loci were identified in both groups, of which a relationship with gastrointestinal symptoms was identified: A*26, A*29 and B*27 were associated to abdominal pain, DRB1*11 and DRB1*16 with abdominal distention, A*30, B*38, DRB1*13 and DRB1*14 with weight loss, B*40 with diarrhea >4 weeks, and presence of mucus in the stools with A*02 and DRB1*11 (p<0.05). Furthermore, the presence of B*15 had a statistical relationship with intolerance to some food, highlighting the B*27 genotype in relation to grains and dairy products, A*23 with grains, vegetables and meats, and B*49 with vegetables and dairy (p<0.05). Regarding the endoscopic variables, macroscopic changes were found in the ileum mucosa related to A*02, B*48, DRB1*14 and the relationship between B*27 and ulcers at this level should be highlighted. Macroscopic changes in the sigmoid colon with B*48 and the rectum with A*30. In microscopic changes, inflammatory alterations of the ileum are mentioned with genotypes DRB1*07, DRB1*13 and DRB1*14, a genotype that is related to changes in the ileum both endoscopically and histologically (p<0.05). CONCLUSIONS: These findings indicate a potential genetic predisposition related to HLA genotypes that may increase the likelihood of food intolerance, gastrointestinal symptoms, and even visible and microscopic changes, specifically in the ileal tissue. The study highlights the presence of B*27 and other noteworthy HLA class I and class II genes (such as DRB1*14) in the diverse Colombian population.

OBJETIVO: Establecer la asociación entre genotipos HLA-A, B, DR y variables gastrointestinales en pacientes con EspA, sin enfermedad inflamatoria intestinal (EII). MÉTODOS: Estudio retrospectivo de 91 pacientes con EspA y 401 controles sanos, con tipificación por tecnología de secuenciación Illumina Sequencing/PacBio, y LIFECODES HLA-PCR/SSO multiplex. Se evaluó la presencia de síntomas gastrointestinales por aplicación de una encuesta, y, aquellos que presentaran dos o más síntomas, fueron llevados a valoración clínica por reumatología y gastroenterología, colonoscopia y estudio histopatológico. (Aprobación del Comité de Ética, HMC, 2022 - 2020). RESULTADOS: El 59,3% de los pacientes fueron hombres, con edad media de 43,9 ± 11,4 años. El 80,2% se clasificó como espondilitis anquilosante. Se identificaron en ambos grupos 14, 28 y 19 genotipos para los loci HLA-A*, HLA-B* y HLA-DR*, de los cuales se identificó relación con síntomas gastrointestinales: A*26, A*29 y B*27, con dolor abdominal; DRB1*11 y DRB1*16, con distensión abdominal; A*30, B*38, DRB1*13 y DRB1*14, con pérdida de peso; B*40, con diarrea >4 semanas y presencia de moco en las deposiciones con A*2 y DRB1*11 (p<0,05). Además, la presencia de B*15, tuvo relación estadística con intolerancia a algún tipo de alimento, a resaltar el genotipo B*27, en relación con granos y lácteos; A*23 con granos, verduras y carnes; y el B*49, con verduras y lácteos (p<0,05). Frente a las variables endoscópicas, se encontraron cambios macroscópicos en la mucosa de íleon relacionados con A*02, B*48, DRB1*14 y, a destacar, la relación B*27 con úlceras a este nivel. Cambios macroscópicos en colon sigmoides con B*48 y en recto con A*30. En cambios microscópicos, se mencionan alteraciones inflamatorias de íleon con genotipos DRB1*07, DRB1*13 y DRB1*14, genotipos que se relaciona a cambios en íleon tanto endoscópica e histológicamente (p<0,05). CONCLUSIONES: Estos resultados sugieren una posible susceptibilidad genética asociada al HLA, con genotipos que pueden predisponer a intolerancia alimentaria, síntomas gastrointestinales, e incluso, a cambios macroscópicos e histológicos, particularmente en tejido de íleon, entre los cuales está presente el B*27, pero resaltan otros interesantes en HLA clase I, como clase II (DRB1*14), en una población de alto mestizaje como la colombiana.

Association between gut microbiota and seven gastrointestinal diseases: A Mendelian randomized study.

BACKGROUND: Observational research has shed light on the ability of gut microbes to influence the onset and progression of gastrointestinal diseases. The causal relationships between specific gut microbiomes and various gastrointestinal conditions, however, remain unknown. METHODS: We investigated the relationship between gut microbiota and seven specific gastrointestinal disorders using a robust two-sample Mendelian randomization (MR) approach. The inverse variance-weighted (IVW) method was used as the primary analysis tool in our study. Furthermore, we conducted multiple sensitivity analyses to strengthen the robustness of our findings and ensure the reliability of the IVW method. RESULTS: Our research has discovered significant links between the composition of gut microbiota and a variety of gastrointestinal ailments. We found compelling links between 13 gut microbiota and fatty liver, four gut microbiota and cirrhosis, eight gut microbiota and hepatocellular carcinoma, four gut microbiota and cholelithiasis, 12 gut microbiota and acute pancreatitis, eight gut microbiota and chronic pancreatitis, and 11 gut microbiota and pancreatic cancer. These findings shed light on the intricate relationship between gut microbes and the emergence of these specific gastrointestinal conditions. CONCLUSIONS: The findings of this extensive study not only validate the potential role of specific gut microbiota in gastrointestinal diseases, but also fill a critical gap in previous research. The discovery of these specific gut microbiota is a significant step forward because they may serve as novel and promising biomarkers for both the prevention and treatment of gastrointestinal conditions.

Genetic liability for gastrointestinal inflammation disorders and association with gastrointestinal symptoms in children with and without autism.

Children with autism spectrum disorder (ASD) have a greater prevalence of gastrointestinal (GI) symptoms than children without ASD. We tested whether polygenic scores for each of three GI disorders (ulcerative colitis, inflammatory bowel disease, and Crohn's disease) were related to GI symptoms in children with and without ASD. Using genotyping data (564 ASD cases and 715 controls) and external genome-wide association study summary statistics, we computed GI polygenic scores for ulcerative colitis (UC-PGS), inflammatory bowel disease (IDB-PGS), and Crohn's disease (CD-PGS). Multivariable logistic regression models, adjusted for genetic ancestry, were used to estimate associations between each GI-PGS and (1) ASD case-control status, and (2) specific GI symptoms in neurotypical children and separately in ASD children. In children without ASD, polygenic scores for ulcerative colitis were significantly associated with experiencing any GI symptom (adjusted odds ratio (aOR) = 1.36, 95% confidence interval (CI) = 1.03-1.81, p = 0.03) and diarrhea specifically (aOR = 5.35, 95% CI = 1.77-26.20, p = 0.01). Among children without ASD, IBD-PGS, and Crohn's PGS were significantly associated with diarrhea (aOR = 3.55, 95% CI = 1.25-12.34, p = 0.02) and loose stools alternating with constipation (aOR = 2.57, 95% CI = 1.13-6.55, p = 0.03), respectively. However, the three PGS were not associated with GI symptoms in the ASD case group. Furthermore, polygenic scores for ulcerative colitis significantly interacted with ASD status on presentation of any GI symptom within a European ancestry subset (aOR = 0.42, 95% CI = 0.19-0.88, p = 0.02). Genetic risk factors for some GI symptoms differ between children with and without ASD. Furthermore, our finding that increased genetic risks for GI inflammatory disorders are associated with GI symptoms in children without ASD informs future work on the early detection of GI disorders.

Shared genetic influences between eating disorders and gastrointestinal disease in a large, population-based sample of adult women and men.

BACKGROUND: Some preliminary research suggests higher rates of gastrointestinal disease in individuals with eating disorders (EDs). However, research is limited, and it remains unknown what etiologic factors account for observed associations. This was the first study to examine how EDs and dimensional ED symptoms (e.g. body dissatisfaction, binge eating) are phenotypically and etiologically associated with gastrointestinal disease in a large, population-based twin sample. METHODS: Adult female (N = 2980) and male (N = 2903) twins from the Michigan State University Twin Registry reported whether they had a lifetime ED (anorexia nervosa, bulimia nervosa, or binge-eating disorder) and completed a measure of dimensional ED symptoms. We coded the presence/absence of lifetime gastrointestinal disease (e.g. inflammatory bowel disease) based on responses to questions regarding chronic illnesses and medications. We first examined whether twins with gastrointestinal disease had higher rates of EDs and ED symptoms, then used correlated factors twin models to investigate genetic and environmental contributions to the overlap between disorders. RESULTS: Twins with gastrointestinal disease had significantly greater dimensional ED symptoms (ß = 0.21, p < 0.001) and odds of a lifetime ED (OR 2.90, p = 0.001), regardless of sex. Shared genetic factors fully accounted for the overlap between disorders, with no significant sex differences in etiologic associations. CONCLUSIONS: Comorbidity between EDs and gastrointestinal disease may be explained by overlap in genetic influences, potentially including inflammatory genes implicated in both types of disorders. Screening for gastrointestinal disease in people with EDs, and EDs in those with gastrointestinal disease, is warranted.

Exploration of the causal effects of leukocyte telomere length and four gastrointestinal diseases: a two-sample bidirectional Mendelian randomization study.

BACKGROUND: To explore the underlying causality between leukocyte telomere length (LTL) and four gastrointestinal diseases, we designed a two-sample bidirectional Mendelian randomization study. METHODS: Two-sample Mendelian randomization (MR) was used to explore genetic causality between LTL and four gastrointestinal diseases, including irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), gastrointestinal ulcers disease (GUD), and nonalcoholic fatty liver disease (NAFLD). We utilized inverse-variance weighted (IVW) as the primary method for MR analysis. Supplementary analyses were conducted using methods such as MR-Egger regression, weighted-median, Maximum Likelihood (MaxLik), Robust adjusted profile score (MR-RAPS), Contamination mixture (ConMix), and MR-mix. Cochran's Q was calculated to check for heterogeneity. The MR-Egger regression and MR pleiotropy residual sum and outlier (MR-PRESSO) were detected for pleiotropy. RESULTS: The IVW analysis suggests that there may be a potential causal relationship between LTL and two diseases (odds ratio (OR): 1.062; 95% confidence interval (CI): 1.003, 1.124; p = 0.038 for IBS and OR: 0.889; 95% CI: 0.798, 0.990; p = 0.032 for GERD). However, other methods do not entirely align with the results of the IVW analysis. In the reverse MR analysis, we did not find statistically significant associations between LTL and these four diseases. CONCLUSION: The current evidence does not definitively rule out a causal relationship between LTL and these four gastrointestinal diseases but suggests a potential association between LTL and IBS, or LTL and GERD. Exploring the relationship between gastrointestinal diseases and LTL may offer new insights into the onset, progression, and treatment of these diseases.

Evaluating the molecular and genetic mechanisms underlying gut motility disorders.

INTRODUCTION: Gastrointestinal (GI) motility disorders comprise a wide range of different diseases affecting the structural or functional integrity of the GI neuromusculature. Their clinical presentation and burden of disease depends on the predominant location and extent of gut involvement as well as the component of the gut neuromusculature affected. AREAS COVERED: A comprehensive literature review was conducted using the PubMed and Medline databases to identify articles related to GI motility and functional disorders, published between 2016 and 2023. In this article, we highlight the current knowledge of molecular and genetic mechanisms underlying GI dysmotility, including disorders of gut-brain interaction, which involve both GI motor and sensory disturbance. EXPERT OPINION: Although the pathophysiology and molecular mechanisms underlying many such disorders remain unclear, recent advances in the assessment of intestinal tissue samples, genetic testing with the application of 'omics' technologies and the use of animal models will provide better insights into disease pathogenesis as well as opportunities to improve therapy.

Genetic and observational associations of lung function with gastrointestinal tract diseases: pleiotropic and mendelian randomization analysis.

BACKGROUND: The two-way communications along the gut-lung axis influence the immune function in both gut and lung. However, the shared genetic characteristics of lung function with gastrointestinal tract (GIT) diseases remain to be investigated. METHODS: We first investigated the genetic correlations between three lung function traits and four GIT diseases. Second, we illustrated the genetic overlap by genome-wide pleiotropic analysis (PLACO) and further pinpointed the relevant tissue and cell types by partitioning heritability. Furthermore, we proposed pleiotropic genes as potential drug targets by drug database mining. Finally, we evaluated the causal relationships by epidemiologic observational study and Mendelian randomization (MR) analysis. RESULTS: We found lung function and GIT diseases were genetically correlated. We identified 258 pleiotropic loci, which were enriched in gut- and lung-specific regions marked by H3K4me1. Among these, 16 pleiotropic genes were targets of drugs, such as tofacitinib and baricitinib targeting TYK2 for the treatment of ulcer colitis and COVID-19, respectively. We identified a missense variant in TYK2, exhibiting a shared causal effect on FEV1/FVC and inflammatory bowel disease (rs12720356, PPLACO=1.38 × 10- 8). These findings suggested TYK2 as a promising drug target. Although the epidemiologic observational study suggested the protective role of lung function in the development of GIT diseases, no causalities were found by MR analysis. CONCLUSIONS: Our study suggested the shared genetic characteristics between lung function and GIT diseases. The pleiotropic variants could exert their effects by modulating gene expression marked by histone modifications. Finally, we highlighted the potential of pleiotropic analyses in drug repurposing.

Assessing causality between osteoarthritis and gastrointestinal disorders: a Mendelian randomization study.

The association between osteoarthritis (OA) and gastrointestinal disorders was found in observational studies. However, the causality is still elusive. A bidirectional Mendelian randomization (MR) analysis using genome wide association studies data was conducted to assess the causal association between OA and gastrointestinal diseases [including peptic ulcer disease (PUD), gastroesophageal reflux disease (GORD), and inflammatory bowel disease (IBD)]. A two-step MR (TSMR) was conducted between OA, gastrointestinal diseases and drugs to explore the mediating effects of non-steroidal anti-inflammatory drugs (NSAIDs) and opioids use. We used multivariable MR (MVMR) analysis to further validate the impact of prescription history on diseases. Results had statistical significance at a Bonferroni corrected P-value below 0.008. We observed that genetically predicted OA had a significant positive association with GORD [odds ratio (OR) = 1.26, P = 5e-05], but not with PUD or IBD. Regarding the other direction, gastrointestinal disorders as exposure had a null association with OA. Using TSMR, OA patients tended to increase the use of NSAIDs (OR = 1.45, P = 0.001) and opioids (OR = 1.77, P = 2e-05), but only the use of opioids increased the risk of GORD (OR = 1.43, P = 5e-09). Further MVMR analysis showed that the adverse effect of OA on GORD was significantly reduced after adjusting for opioids use (OR = 1.20, P = 0.038). This study provides evidence for the causal association between OA and increased risk of GORD, which is partly attributed to opioids use in OA patients but not NSAIDs.

Evidence of shared genetic factors in the etiology of gastrointestinal disorders and endometriosis and clinical implications for disease management.

In clinical practice, the co-existence of endometriosis and gastrointestinal symptoms is often observed. Using large-scale datasets, we report a genetic correlation between endometriosis and irritable bowel syndrome (IBS), peptic ulcer disease (PUD), gastro-esophageal reflux disease (GORD), and a combined GORD/PUD medicated (GPM) phenotype. Mendelian randomization analyses support a causal relationship between genetic predisposition to endometriosis and IBS and GPM. Identification of shared risk loci highlights biological pathways that may contribute to the pathogenesis of both diseases, including estrogen regulation and inflammation, and potential therapeutic drug targets (CCKBR; PDE4B). Higher use of IBS, GORD, and PUD medications in women with endometriosis and higher use of hormone therapies in women with IBS, GORD, and PUD, support the co-occurrence of these conditions and highlight the potential for drug repositioning and drug contraindications. Our results provide evidence of shared disease etiology and have important clinical implications for diagnostic and treatment decisions for both diseases.

Genetic analysis confirms a link between gastrointestinal disorders and endometriosis.

Patients with endometriosis often report gastrointestinal symptoms in addition to those usually considered hallmarks of the disorder (pain and infertility). Yang et al.1 identify genetic risk factors that can contribute to a shared disease etiology, providing new opportunities for improvements in disease management.

Mechanosensing Piezo channels in gastrointestinal disorders.

All cells in the body are exposed to physical force in the form of tension, compression, gravity, shear stress, or pressure. Cells convert these mechanical cues into intracellular biochemical signals; this process is an inherent property of all cells and is essential for numerous cellular functions. A cell's ability to respond to force largely depends on the array of mechanical ion channels expressed on the cell surface. Altered mechanosensing impairs conscious senses, such as touch and hearing, and unconscious senses, like blood pressure regulation and gastrointestinal (GI) activity. The GI tract's ability to sense pressure changes and mechanical force is essential for regulating motility, but it also underlies pain originating in the GI tract. Recent identification of the mechanically activated ion channels Piezo1 and Piezo2 in the gut and the effects of abnormal ion channel regulation on cellular function indicate that these channels may play a pathogenic role in disease. Here, we discuss our current understanding of mechanically activated Piezo channels in the pathogenesis of pancreatic and GI diseases, including pancreatitis, diabetes mellitus, irritable bowel syndrome, GI tumors, and inflammatory bowel disease. We also describe how Piezo channels could be important targets for treating GI diseases.

Research progress on the molecular mechanism of electroacupuncture at "Zusanli" (ST36) for regulating gastrointestinal dysfunction. / 电针"足三里"è°ƒèŠ‚èƒƒè‚ åŠŸèƒ½å¼‚å¸¸çš„åˆ†å­æœºåˆ¶ç ”ç©¶è¿›å±•.

Gastrointestinal dysfunction is manifested as digestive symptoms. Clinically, Zusanli (ST36) is crucial in the acupoint prescriptions of acupuncture no matter which type of the disease is differentiated in traditional Chinese medicine, but the underlying mechanism remains to be explored. Aiming to summarize the current status of the researches in terms of ameliorating gastrointestinal mucosal damage and regulating gastrointestinal motility disorders, we systematically reviewed the basic researches on the intervention with electroacupuncture (EA) at "ST36" in treatment of the diseases related to gastrointestinal dysfunction in the past 5 years, after searching the articles from Chinese and English databases. The results suggest that EA at ST36 may regulate the local gastrointestinal inflammation, oxidative stress and immune microenvironment to relieve gastrointestinal mucosal damage and adjust gastrointestinal motility disorders by means of modulating the central and peripheral nerve signaling as well as the function of mast cells and Cajal interstitial cells.

Birth weight, childhood obesity, adulthood obesity and body composition, and gastrointestinal diseases: a Mendelian randomization study.

OBJECTIVE: This Mendelian randomization study aimed to investigate the associations of birth weight, childhood BMI, and adulthood BMI, waist-hip ratio, and body composition with the risk of 24 gastrointestinal diseases. METHODS: Independent genetic instruments associated with the exposures at the genome-wide significance level (p < 5 × 10-8 ) were selected from corresponding large-scale genome-wide association studies. Summary-level data for gastrointestinal diseases were obtained from the UK Biobank, the FinnGen study, and large consortia of European ancestry. RESULTS: Genetically predicted higher levels of birth weight were associated with a lower risk of gastroesophageal reflux. Genetically predicted higher childhood BMI was associated with an increased risk of duodenal ulcer, nonalcoholic fatty liver disease, and cholelithiasis. However, the associations did not persist after adjusting for genetically predicted adulthood BMI. Genetically predicted higher adulthood BMI and waist-hip ratio were associated with 19 and 17 gastrointestinal diseases, respectively. Genetically predicted greater visceral adiposity was associated with an increased risk of 17 gastrointestinal diseases. There were no strong associations among genetically predicted whole-body fat and fat-free mass indices with gastrointestinal diseases. CONCLUSIONS: This study suggests that greater adulthood adiposity, measured as either BMI, waist-hip ratio, or visceral adipose tissue, is causally associated with an increased risk of a broad range of gastrointestinal diseases in the European population.

Gastrointestinal Dysfunction in Genetically Defined Neurodevelopmental Disorders.

Gastrointestinal symptoms are common in most forms of neurodevelopment disorders (NDDs) such as in autism spectrum disorders (ASD). The current patient-reported outcome measures with validated questionnaires used in the general population of children without NDDS cannot be used in the autistic individuals. We explore here the multifactorial pathophysiology of ASD and the role of genetics and the environment in this disease spectrum and focus instead on possible diagnostics that could provide future objective insight into the connection of the gut-brain-microbiome in this disease entity. We provide our own data from both humans and a zebrafish model of ASD called Phelan-McDermid Syndrome. We hope that this review highlights the gaps in our current knowledge on many of these profound NDDs and that it provides a future framework upon which clinicians and researchers can build and network with other interested multidisciplinary specialties.

The Role of Ion Channels in Functional Gastrointestinal Disorders (FGID): Evidence of Channelopathies and Potential Avenues for Future Research and Therapeutic Targets.

Several gastrointestinal (GI) tract abnormalities, including visceral hypersensitivity, motility, and intestinal permeability alterations, have been implicated in functional GI disorders (FGIDs). Ion channels play a crucial role in all the functions mentioned above. Hormones and natural molecules modulate these channels and represent targets of drugs and bacterial toxins. Mutations and abnormal functional expression of ion channel subunits can lead to diseases called channelopathies. These channelopathies in gastroenterology are gaining a strong interest, and the evidence of co-relationships is increasing. In this review, we describe the correlation status between channelopathies and FGIDs. Different findings are available. Among others, mutations in the ABCC7/CFTR gene have been described as a cause of constipation and diarrhea. Mutations of the SCN5A gene are instead associated with irritable bowel syndrome. In contrast, mutations of the TRPV1 and TRPA genes of the transient receptor potential (TRP) superfamily manifest hypersensitivity and visceral pain in sensory nerves. Recently, mice and humans affected by Cantu syndrome (CS), which is associated with the mutations of the KCNJ8 and ABCC9 genes encoding for the Kir6.1 and SUR2 subunits, showed dysfunction of contractility throughout the intestine and death in the mice after the weaning on solid food. The discovery of a correlation between channelopathies and FIGD opens new avenues for discovering new direct drug targets for specific channelopathies, leading to significant implications for diagnosing and treating functional GI diseases.

Distinctive gastrointestinal motor dysfunction in patients with MNGIE.

BACKGROUND: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare mitochondrial disease caused by mutations in TYMP, encoding thymidine phosphorylase. Clinically it is characterized by severe gastrointestinal dysmotility associated with cachexia and a demyelinating sensorimotor polyneuropathy. Even though digestive manifestations are progressive and invariably lead to death, the features of gastrointestinal motor dysfunction have not been systematically evaluated. The objective of this study was to describe gastrointestinal motor dysfunction in MNGIE using state-of-the art techniques and to evaluate the relationship between motor abnormalities and symptoms. METHODS: Prospective study evaluating gastrointestinal motor function and digestive symptoms in all patients with MNGIE attended at a national referral center in Spain between January 2018 and July 2022. KEY RESULTS: In this period, five patients diagnosed of MNGIE (age range 16-46 years, four men) were evaluated. Esophageal motility by high-resolution manometry was abnormal in four patients (two hypoperistalsis, two aperistalsis). Gastric emptying by scintigraphy was mildly delayed in four and indicative of gastroparesis in one. In all patients, small bowel high-resolution manometry exhibited a common, distinctive dysmotility pattern, characterized by repetitive bursts of spasmodic contractions, without traces of normal fasting and postprandial motility patterns. Interestingly, objective motor dysfunctions were detected in the absence of severe digestive symptoms. CONCLUSIONS AND INFERENCES: MNGIE patients exhibit a characteristic motor dysfunction, particularly of the small bowel, even in patients with mild digestive symptoms and in the absence of morphological signs of intestinal failure. Since symptoms are not predictive of objective findings, early investigation is indicated.