American journal of physiology. Gastrointestinal and liver physiology最新文献

{"title":"Misfolding <i>CPA1</i> mutation accelerates precancerous pancreas lesions in <i>KC</i> mice.","authors":"Alexandra Demcsák, Miklós Sahin-Tóth","doi":"10.1152/ajpgi.00025.2025","DOIUrl":"10.1152/ajpgi.00025.2025","url":null,"abstract":"<p><p>Germline mutations in the <i>CPA1</i> gene encoding carboxypeptidase A1 were found in association with chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC). The mutations increase pancreatic disease risk, presumably, by causing proenzyme misfolding and endoplasmic reticulum stress. Previously, we showed that <i>CPA1 N256K</i> mice that carry the p.N256K misfolding human <i>CPA1</i> mutation in the mouse <i>Cpa1</i> gene develop spontaneous chronic pancreatitis. Here, our aim was to investigate whether <i>CPA1 N256K</i> mice have increased susceptibility to PDAC induced by a <i>Kras</i> mutation. We generated <i>Kras^LSL-G12D</i> × <i>p48-Cre</i> (<i>KC</i>) and <i>Kras^LSL-G12D</i> × <i>p48-Cre</i> × <i>CPA1 N256K</i> (<i>KC-CPA1</i>) mice and compared the development of pancreas pathology in the two strains at 1, 3, 6, and 12 mo of age. We observed progressive parenchymal remodeling in both strains, with more rapid changes in <i>KC-CPA1</i> mice. Thus, histological analysis revealed loss of normal pancreas parenchyma, extensive fibrosis, and aberrant ductal structures such as acinar-to-ductal metaplasia and precancerous pancreatic intraepithelial neoplasia. At 3 mo, these microscopic changes were significantly more abundant in <i>KC-CPA1</i> versus <i>KC</i> mice. Owing to the massive fibrosis, the pancreas weight of <i>KC</i> and <i>KC-CPA1</i> mice was significantly increased relative to C57BL/6N and <i>CPA1 N256K</i> controls, with the largest increase observed in 3-mo-old <i>KC-CPA1</i> animals. The observations indicate that a misfolding <i>Cpa1</i> mutation accelerated the development of precancerous lesions and fibro-inflammatory remodeling in the pancreas of <i>KC</i> mice, providing support for the notion that <i>CPA1</i> mutations might be risk factors for human PDAC.<b>NEW & NOTEWORTHY</b> Inborn mutations in the <i>CPA1</i> gene encoding carboxypeptidase A1 have been proposed to increase the risk of pancreatic ductal adenocarcinoma (PDAC) by causing enzyme misfolding and endoplasmic reticulum stress in the pancreas. Here, we demonstrated in a novel mouse model that a misfolding <i>Cpa1</i> mutation accelerated the development of precancerous lesions driven by mutant <i>Kras</i> in the pancreas. The observations offer experimental support for the notion that <i>CPA1</i> mutations are risk factors for human PDAC.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":"329 4","pages":"G546-G556"},"PeriodicalIF":3.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12829554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serotonin, a downstream effector of GLP-2, enhances lacteal contractility and lymph flow.","authors":"Lili Tian, Majid Mufaqam Syed-Abdul, Gary F Lewis","doi":"10.1152/ajpgi.00205.2025","DOIUrl":"10.1152/ajpgi.00205.2025","url":null,"abstract":"<p><p>Glucagon-like peptide-2 (GLP-2) is known to exert some of its biological effects through the release of neurotransmitters, and in view of the absolute requirement for the enteric nervous system (ENS) demonstrated in our recent GLP-2-induced lipid mobilization studies, we aimed to identify the neurotransmitter that mediates GLP-2's effect on intestinal lipid mobilization. We also examined the role of vascular endothelial growth factor receptor 3 (VEGFR3) as an intermediate in the signaling cascade. Using a rat lymph fistula model, 5 h after an intraduodenal (id) lipid bolus, the following intraperitoneal (ip) administrations were applied in two different sets of experiments: <i>Experiment 1: 1</i>) placebo, <i>2</i>) GLP-2, and <i>3</i>) GLP-2 + ketanserin (serotonin receptor antagonist). <i>Experiment 2: 1</i>) placebo, <i>2</i>) serotonin, <i>3</i>) serotonin + MAZ-51 (a VEGFR3 inhibitor), <i>4</i>) serotonin + SAR131675 (a second VEGFR3 inhibitor). Lymph flow and triglyceride (TG) output were assessed for 60 min (<i>experiment 1</i>) or 90 min (<i>experiment 2</i>) after administration. In another set of animals, GLP-2 or serotonin was administered intraperitoneally, and blood samples were collected to quantify plasma serotonin concentration. Intravital imaging of a prospero-related homeobox 1-enhanced green fluorescent protein rat model was used to assess lacteal contractility after placebo or serotonin administration. We demonstrated that single-dose GLP-2 administration acutely increased serotonin concentration in plasma, serotonin enhanced lymph flow, lymph TG output, and lacteal contractility. Antagonism of the serotonin receptor decreases GLP-2-enhanced mesenteric lymph flow and TG output, and inhibition of VEGFR3 abolishes serotonin-induced lymph flow and TG output<b>NEW & NOTEWORTHY</b> Our data suggests that the neurotransmitter serotonin mediates glucagon-like peptide-2 (GLP-2)'s effect on intestinal lipid mobilization by enhancing lymph flow and lacteal contractility, and vascular endothelial growth factor receptor 3 (VEGFR3) is one of the downstream targets of serotonin involved in this cascade.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G562-G570"},"PeriodicalIF":3.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liquid nutrient drink testing induces gastric myoelectrical abnormalities that correlate with gastroduodenal symptoms.","authors":"Hassan Shaaban, Chris Varghese, Gabriel Schamberg, India Wallace, Mikaela Law, Nooriyah Poonawala, William Xu, Christopher N Andrews, Armen Gharibans, Jan Tack, Gregory O'Grady, Stefan Calder","doi":"10.1152/ajpgi.00070.2025","DOIUrl":"https://doi.org/10.1152/ajpgi.00070.2025","url":null,"abstract":"<p><p>Chronic gastroduodenal symptoms experienced in functional dyspepsia, chronic nausea and vomiting syndromes, and gastroparesis affect over 10% of the global population and impose a significant healthcare burden. The relationship between aberrant gastric myoelectrical activity and symptom genesis remains incompletely defined. In this study, we evaluated the effects of gastric distension induced by a liquid nutrient drink test (LNDT) on gastric myoelectrical activity in healthy volunteers using noninvasive body surface gastric mapping (BSGM) with the Gastric Alimetry system (Auckland, New Zealand). Twenty healthy participants (10 females) underwent BSGM with 30-min fasting baseline, LNDT with Ensure administered at 30 mL/min until maximal toleration, and 4-h postprandial recording. Gastric Alimetry Rhythm Index (GA-RI), principal gastric frequency (PGF), and BMI-adjusted amplitude were analyzed across time and in relation to symptoms using mixed models. During LNDT, PGF decreased significantly (2.7 ± 0.2 vs. an overall average 3.0 ± 0.2 cycles/min, <i>P</i> < 0.001) and GA-RI declined (β = -0.11, 95% CI -0.21 to -0.002, <i>P</i> = 0.047) with a concurrent increase in nausea ratings. In the first postprandial hour, bloating, nausea, and overall symptom burden were elevated, with sustained reductions in GA-RI and PGF correlating with higher symptom scores. Spectral analyses revealed transient abnormalities temporally aligned with symptom genesis. These findings indicate that excessive gastric distension provokes aberrant gastric myoelectrical activity that is closely associated with foregut symptoms, supporting the role of these abnormalities in the pathophysiology of neurogastroduodenal disorders.<b>NEW & NOTEWORTHY</b> Body surface gastric mapping with liquid nutrient drink test found that excessive gastric distension provokes dysrhythmias that are closely associated with foregut symptoms, supporting the role of disrupted gastric myoelectrical function in the pathophysiology of neurogastroduodenal disorders.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":"329 3","pages":"G363-G370"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144939482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The synergistic interplay between vitamin A, dietary fiber, and the microbiota-gut-brain axis: a potential mechanism for preventing Alzheimer's disease.","authors":"Shadt Skawratananond, Grace E McCrea, Paul Lie, Matthew B Buxton, Sean P Daly, Nicholas A Vojtkofsky, Shane C Smith, Charlie Zhang, Matthew Hernandez, Ashly Hindle, Aric F Logsdon, J Josh Lawrence","doi":"10.1152/ajpgi.00097.2025","DOIUrl":"10.1152/ajpgi.00097.2025","url":null,"abstract":"<p><p>The human gastrointestinal tract harbors a vast and diverse microbial community, with the gut microbiome playing a fundamental role in numerous biological processes that influence overall health and disease progression. Emerging evidence has identified bacterial lipopolysaccharides in the hippocampus of patients with Alzheimer's disease (AD), highlighting the intricate relationship between the gastrointestinal tract, gut microbiome, and the central and enteric nervous systems-commonly referred to as the \"microbiota-gut-brain axis.\" In this review, we explore the mechanisms by which the microbiota-gut-brain axis contributes to AD pathogenesis. We propose that sufficient levels of all-trans retinoic acid (ATRA), the bioactive form of vitamin A, enhance intestinal barrier integrity by upregulating tight junction proteins and modulating immune function through the induction of regulatory T-cell differentiation, thereby mitigating inflammation. Furthermore, dietary fiber complements this process by promoting the production of short-chain fatty acids, such as butyrate, via bacterial fermentation. Butyrate, in turn, acts as a histone deacetylase inhibitor, upregulating ATRA bioavailability by elevating aldehyde dehydrogenase gene expression. Our mechanistic framework is supported by the endotoxin hypothesis of AD, which maintains that the movement of infectious pathogens across the blood-brain barrier causes a vicious cycle of inflammation, a key factor of AD pathogenesis, leading to amyloid-β deposition, microglial activation, and CYP26A1-mediated ATRA degradation. Finally, we discuss microbiome-based therapeutic strategies and dietary interventions, including prebiotic compounds, probiotic bacteria, fecal microbiota transplantation, the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet, and a combined approach featuring vitamins A/D and dietary fiber, as potential approaches to prevent progression to AD via the microbiota-gut-brain axis.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G484-G499"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12622890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel gene therapy for ARPKD based on CFTR.","authors":"Cristian Ciobanu, Patricia Outeda, William B Guggino, Liudmila Cebotaru","doi":"10.1152/ajpgi.00109.2025","DOIUrl":"10.1152/ajpgi.00109.2025","url":null,"abstract":"<p><p>Autosomal recessive polycystic kidney disease (ARPKD) is associated with cysts derived from abnormal bile ducts. We focused on targeting the cysts and show that a gene therapy for ARPKD that targets the abnormal bile ducts is feasible. We injected 1-mo-old, <i>Pkhd1</i>^{del3-4/del3-4} mice intraperitoneally with 2 × 10¹² particles/kg of adeno-associated virus (AAV1) containing either a GFP vector or a truncated cystic fibrosis transmembrane conductance regulator (CFTR) vector, Δ27-264-CFTR, or left them untreated. Two months after treatment, the cyst area and size in the liver were lower in the CFTR vector-treated mice than in mice receiving the GFP vector. We detected vector genomes and mRNA expression only in mice receiving the corresponding CFTR or GFP vector. We observed abundant GFP immunofluorescence in the cholangiocytes of the cysts and also saw expression of GFP and CFTR proteins above background levels in the corresponding treated mice. CFTR immunofluorescence was predominantly apically located in the ARPKD cholangiocytes, but after CFTR vector installation, it increased in the basolateral membrane. We stained mouse livers with <i>Maackia amurensis</i> lectin (MAL) or <i>Sambucus nigra</i> lectin (SNA), specific for α2,3- and α2,6-N-linked sialic acid, respectively, to detect the presence of sialic acid moieties contributing to AAV1 binding. Although immunofluorescent SNA was detected in the wild-type bile ducts, MAL 1 was not. MAL immunofluorescence was present in remarkably high levels on the apical surfaces of the cysts in cholangiocytes, offering a good target for AAV gene therapy. A gene therapy using an AAV1-based vector containing a truncated CFTR could be therapeutic in ARPKD.<b>NEW & NOTEWORTHY</b> Autosomal recessive polycystic kidney disease (ARPKD) causes severe disease in babies in the womb. Those who survive the neonatal period face chronic kidney and liver disease throughout their life. The overall goal of our study here is to develop a gene therapy to treat ARPKD.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G434-G442"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Budding baboon blues: the prenatal diet lands a lasting gut punch.","authors":"Anna Grigorian, Mengyun Wu, Jerrold R Turner","doi":"10.1152/ajpgi.00252.2025","DOIUrl":"10.1152/ajpgi.00252.2025","url":null,"abstract":"","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G510-G512"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13127741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144939552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum for Lastuvkova et al., 2025, volume 328, p. G558-G577.","authors":"","doi":"10.1152/ajpgi.00262.2024_COR","DOIUrl":"https://doi.org/10.1152/ajpgi.00262.2024_COR","url":null,"abstract":"","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":"329 3","pages":"G433"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144939521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic insights into intestinal stem cell disruption during infection.","authors":"Naomi Chege, Constance A M Finney","doi":"10.1152/ajpgi.00352.2024","DOIUrl":"10.1152/ajpgi.00352.2024","url":null,"abstract":"<p><p>The intestinal epithelium is in continual flux. It must balance maintaining a healthy microbiota with detecting and destroying intestinal pathogens. Intestinal stem cells (ISCs), which sit in the crypts below the intestinal villi, control this process. Depending on the molecular signals they receive, ISCs rapidly differentiate into the different intestinal epithelial cell subsets, making the intestine a remarkably adaptable organ. However, pathogens can hijack ISC functions to their advantage and establish infections. In this review, we explore the mechanisms used by pathogens to exploit ISCs.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G371-G389"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging advances in intestinal models for in vitro preclinical research.","authors":"Precious Adedayo Adesina, Masato Ooka, Charlotte TeKrony, Menghang Xia","doi":"10.1152/ajpgi.00087.2025","DOIUrl":"10.1152/ajpgi.00087.2025","url":null,"abstract":"<p><p>Traditional in vitro intestinal model systems frequently fail to accurately replicate human intestinal physiology for absorption, distribution, metabolism, excretion, and toxicity (ADMET) assessments. These limitations, coupled with the growing demand for faster drug discovery and high-throughput screening capabilities, have refined more physiologically relevant models. Recent advancements have led to the development of cell-based intestinal systems that better reflect in vivo conditions, ranging from monolayer and coculture models to complex three-dimensional (3-D) cell culture systems, microfluidic devices, and bioengineered models. This review provides a comprehensive overview of current progress, ongoing challenges, and future directions in developing and applying human in vitro intestinal models for chemical testing.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G403-G416"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12721397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hysteresis of the lower esophageal sphincter: relevance to the pathogenesis of esophageal achalasia and its phenotypes.","authors":"Anand S Jain, William Breaux, Joshua K Robertson, Se-Eun Kim, Billynda McAdoo, Steven Keilin, Felix Fernandez, Shanthi Srinivasan, Ravinder K Mittal","doi":"10.1152/ajpgi.00089.2025","DOIUrl":"10.1152/ajpgi.00089.2025","url":null,"abstract":"<p><p>Hysteresis is a change in strain for a given repeated stress; it is a material property of the viscoelastic tissues. We aimed to determine hysteresis of the esophagogastric junction (EGJ) in patients with esophageal achalasia and differences in EGJ hysteresis in different achalasia phenotypes. In a cross-sectional study design, we measured the change in EGJ distensibility index (DI) with repeated distensions (a marker of hysteresis) and the effects of atropine on the DI using functional lumen imaging probe in 40 patients with esophageal achalasia (types 1, 2, and 3). The DI increased significantly with second distension (hysteresis) as compared with first distension, but not with subsequent ones. Atropine, which ablates active smooth muscle contraction, had no effect on the DI value. Patients with type 1 esophageal achalasia and those with severe dilatation (stage III and IV disease) had a higher DI and lower hysteresis, as compared with esophageal achalasia subtypes 2 and 3. A low DI following atropine suggests that the passive elements (viscoelastic properties) of EGJ are an important cause of low DI in esophageal achalasia. Hysteresis of the EGJ, a material property of the viscoelastic tissue, is different in different achalasia subtypes.<b>NEW & NOTEWORTHY</b> Hysteresis, a key biomechanical property of the esophagogastric junction (EGJ), may play a crucial role in achalasia pathogenesis. Using functional lumen imaging probe (FLIP) topography, we demonstrate that EGJ distensibility increases with repeated distensions, with subtype-dependent variability. Our findings suggest that hysteresis is associated with achalasia progression and treatment outcomes, offering novel insights into esophageal biomechanics. These results may guide refinements in FLIP-based diagnostics and inform future therapeutic approaches targeting determinants of hysteresis.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G500-G509"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12413816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}