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

{"title":"Fecal microbial transplants as investigative tools in cancer.","authors":"Margaret S Bohm, Arvind V Ramesh, Joseph F Pierre, Katherine L Cook, E Angela Murphy, Liza Makowski","doi":"10.1152/ajpgi.00171.2024","DOIUrl":"10.1152/ajpgi.00171.2024","url":null,"abstract":"<p><p>The gut microbiome plays a critical role in the development, progression, and treatment of cancer. As interest in microbiome-immune-cancer interactions expands, the prevalence of fecal microbial transplant (FMT) models has increased proportionally. However, current literature does not provide adequate details or consistent approaches to allow for necessary rigor and experimental reproducibility. In this review, we evaluate key studies using FMT to investigate the relationship between the gut microbiome and various types of cancer. In addition, we will discuss the common pitfalls of these experiments and methods for improved standardization and validation as the field uses FMT with greater frequency. Finally, this review focuses on the impacts of the gut and extraintestinal microbes, prebiotics, probiotics, and postbiotics in cancer risk and response to therapy across a variety of tumor types.<b>NEW & NOTEWORTHY</b> The microbiome impacts the onset, progression, and therapy response of certain types of cancer. Fecal microbial transplants (FMTs) are an increasingly prevalent tool to test these mechanisms that require standardization by the field.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G711-G726"},"PeriodicalIF":3.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559651/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279173","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":"Decreased expression of DRA (<i>SLC26A3</i>) by a p38-driven IL-1α response contributes to diarrheal disease following in vivo challenge with <i>Brachyspira</i> spp.","authors":"Nitin Challa, Cole B Enns, Brandon A Keith, John C S Harding, Matthew E Loewen","doi":"10.1152/ajpgi.00049.2023","DOIUrl":"10.1152/ajpgi.00049.2023","url":null,"abstract":"<p><p>In this study, we uncovered the novel mechanism of IL-1α-mediated downregulated in adenoma (DRA) (<i>SLC26A3</i>) downregulation in the context of <i>Brachyspira</i> spp.<i>-</i>induced malabsorptive diarrhea. Experimentally infected pigs with <i>Brachyspira</i> spp. had significantly reduced DRA expression in the colon accompanied by IL-1α upregulation. This response was recapitulated in vitro by exposing Caco-2 cells to either <i>Brachyspira</i> lysate or IL-1α. Both p38 and MAPK-activated protein kinase 2 (MAPKAPK-2 also referred as MK-2) showed an increased phosphorylation after exposure to either. SB203580 application, a p38 inhibitor blocked the MK-2 phosphorylation and attenuated the DRA and IL-1α response to both lysate and IL-1α. Exposure to IL-1 receptor antagonist (IL-1RA) produced a similar response. In addition, exposure of cells to either of these blockers without IL-1α or lysate results in increased DRA and decreased IL-1α expression, revealing that DRA needs IL-1α signaling for basal physiological expression. Dual inhibition with both blockers completely inhibited the effect from IL-1α while significantly attenuating the response from <i>Brachyspira</i> lysate, suggesting a minor contribution from another pathway. Together this demonstrates that <i>Brachyspira</i> activates p38 MAPK signaling driving IL-1α expression, which activates IL-1R1 causing DRA downregulation while also driving upregulation of IL-1α through p38 in a positive feedback mechanism. In conclusion, we elucidated a major pathway involved in DRA downregulation and its role in <i>Brachyspira</i>-induced diarrhea. In addition, these observations will aid in our understanding of other inflammatory and infectious diarrhea conditions.<b>NEW & NOTEWORTHY</b> The diarrheal disease caused by the two infectious spirochete spp. <i>B. hyodysenteriae</i> and <i>B. hampsonii</i> reduced the expression of DRA (<i>SLC26A3</i>), a major Cl^-/HCO^-₃ exchanger involved in Cl^- absorption. This is attributed to the upregulation of IL-1α driven by p38 MAPK. This work also describes a potential new mechanism in inflammatory diseases while showing the importance of IL-1α in maintaining DRA levels.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G655-G672"},"PeriodicalIF":3.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892706","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":"Amniotic fluid modifies esophageal epithelium differentiation and inflammatory responses.","authors":"Mark Rochman, Andrea M Klinger, Julie M Caldwell, Yoel Sadovsky, Marc E Rothenberg","doi":"10.1152/ajpgi.00197.2024","DOIUrl":"10.1152/ajpgi.00197.2024","url":null,"abstract":"<p><p>The interplay between genetic and environmental factors during pregnancy can predispose to inflammatory diseases postnatally, including eosinophilic esophagitis (EoE), a chronic allergic disease triggered by food. Herein, we examined the effects of amniotic fluid (AF) on esophageal epithelial differentiation and responsiveness to proallergic stimuli. Multiplex analysis of AF revealed the expression of 66 cytokines, whereas five cytokines including IL-4 and thymic stromal lymphopoietin (TSLP) were not detected. Several proinflammatory cytokines including TNFα and IL-12 were highly expressed in the AF from women who underwent preterm birth, whereas EGF was the highest in term birth samples. Exposure of esophageal epithelial cells to AF resulted in transient phosphorylation of ERK1/2 and the transcription of early response genes, highlighting the direct impact of AF on esophageal epithelial cells. In a three-dimensional spheroid model, AF modified the esophageal epithelial differentiation program and enhanced the transcription of IL-13-target genes, including <i>CCL26</i> and <i>CAPN14</i>, which encodes for a major genetic susceptibility locus for eosinophilic esophagitis. Notably, <i>CAPN14</i> exhibited upregulation in spheroids exposed to preterm but not term AF following differentiation. Collectively, our findings call attention to the role of AF as a potential mediator of the intrauterine environment that influences subsequent esophageal disorders.<b>NEW & NOTEWORTHY</b> The interaction between amniotic fluid and the esophageal epithelium during pregnancy modifies esophageal epithelial differentiation and subsequent responsiveness to inflammatory stimuli, including interleukin 13 (IL-13). This interaction may predispose individuals to inflammatory conditions of the esophagus, such as eosinophilic esophagitis (EoE), in later stages of life.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G629-G639"},"PeriodicalIF":3.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559652/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142071830","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":"Feeding intolerance after pediatric cardiac surgery is associated with dysbiosis, barrier dysfunction, and reduced short-chain fatty acids.","authors":"Jacob Owens, Haowen Qiu, Cole Knoblich, Lisa Gerjevic, Jacques Izard, Linda Xu, Junghyae Lee, Sai Sundeep Kollala, Daryl J Murry, Jean Jack Riethoven, Jesse A Davidson, Amar B Singh, Ali Ibrahimiye, Laura Ortmann, Jeffrey D Salomon","doi":"10.1152/ajpgi.00151.2024","DOIUrl":"10.1152/ajpgi.00151.2024","url":null,"abstract":"<p><p>Congenital heart disease (CHD) is the most common birth defect, occurring in roughly 40,000 U.S. births annually. Malnutrition and feeding intolerance (FI) in CHD range from 30% to 42% and are associated with longer hospitalization and increased mortality. Cardiopulmonary bypass (CPB) required for surgical repair of CHD induces a systemic inflammatory response worsening intestinal dysbiosis and leading to intestinal epithelial barrier dysfunction (EBD), possibly contributing to postoperative FI. The objective of this study was to determine the relationship of postoperative FI with intestinal microbiome, short-chain fatty acids (SCFAs), and EBD in pediatric CHD after cardiac surgery. This was a prospective study of patients aged 0-15 years undergoing cardiac surgery with CPB. Samples were collected preoperatively and postoperatively to evaluate the gut microbiome, plasma EBD markers, short-chain fatty acids (SCFAs), and plasma cytokines. Clinical data were collected to calculate a FI score and evaluate patient status postoperatively. We enrolled 26 CPB patients and identified FI (<i>n</i> = 13). Patients with FI had unique microbial shifts with the reduced SCFA-producing organisms <i>Rothia</i>, <i>Clostridium innocuum</i>, and <i>Intestinimonas</i>. Patients who developed FI had associated elevations in the plasma EBD markers claudin-2 (<i>P</i> < 0.05), claudin-3 (<i>P</i> < 0.01), and fatty acid binding protein (<i>P</i> < 0.01). Patients with FI had reduced plasma and stool SCFAs. Mediation analysis showed the microbiome functional shift was associated with reductions in stool butyric and propionic acid in patients with FI. In conclusion, we provide novel evidence that intestinal dysbiosis, markers of EBD, and SCFA depletion are associated with FI. These data will help identify mechanisms and therapeutics to improve clinical outcomes following pediatric cardiac surgery.<b>NEW & NOTEWORTHY</b> Feeding intolerance contributes to postoperative morbidity following pediatric cardiac surgery. The intestinal microbiome and milieu play a vital role in gut function. Short-chain fatty acids are gut and cardioprotective metabolites produced by commensal bacteria and help maintain appropriate barrier function. Depletion of these metabolites and barrier dysfunction contribute to postoperative feeding intolerance following cardiac surgery. Identifying mechanistic targets to improve the intestinal milieu with the goal of improved nutrition and clinical outcomes is critical.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G685-G696"},"PeriodicalIF":3.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118824","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":"Somatostatin peptides prevent increased human colonic epithelial permeability induced by hypoxia.","authors":"Ibrahim Rajput, Vazhaikkurichi M Rajendran, Andrew J Nickerson, J Peter A Lodge, Geoffrey I Sandle","doi":"10.1152/ajpgi.00057.2024","DOIUrl":"10.1152/ajpgi.00057.2024","url":null,"abstract":"<p><p>Mesenteric ischemia increases gut permeability and bacterial translocation. In human colon, chemical hypoxia induced by 2,4-dinitrophenol (DNP) activates basolateral intermediate conductance K⁺ (IK) channels (designated KCa3.1 or KCNN4) and increases paracellular shunt conductance/permeability (<i>G</i>_S), but whether this leads to increased macromolecule permeability is unclear. Somatostatin (SOM) inhibits IK channels and prevents hypoxia-induced increases in <i>G</i>_S. Thus, we examined whether octreotide (OCT), a synthetic SOM analog, prevents hypoxia-induced increases <i>G</i>_S in human colon and hypoxia-induced increases in total epithelial conductance (<i>G</i>_T) and permeability to FITC-dextran 4000 (FITC) in rat colon. The effects of serosal SOM and OCT on increases in <i>G</i>_S induced by 100 µM DNP were compared in isolated human colon. The effects of OCT on DNP-induced increases in <i>G</i>_T and transepithelial FITC movement were evaluated in isolated rat distal colon. <i>G</i>_S in DNP-treated human colon was 52% greater than in controls (<i>P</i> = 0.003). <i>G</i>_S was similar when 2 µM SOM was added after or before DNP treatment, in both cases being less (<i>P</i> < 0.05) than with DNP alone. OCT (0.2 µM) was equally effective preventing hypoxia-induced increases in <i>G</i>_S, whether added after or before DNP treatment. In rat distal colon, DNP significantly increased <i>G</i>_T by 18% (<i>P</i> = 0.016) and mucosa-to-serosa FITC movement by 43% (<i>P</i> = 0.01), and 0.2 µM OCT pretreatment completely prevented these changes. We conclude that OCT prevents hypoxia-induced increases in paracellular/macromolecule permeability and speculate that it may limit ischemia-induced gut hyperpermeability during abdominal surgery, thereby reducing bacterial/bacterial toxin translocation and sepsis.<b>NEW & NOTEWORTHY</b> Somatostatin (SOM, 2 µM) and octreotide (OCT, 0.2 µM, a long-acting synthetic analog of SOM) were equally effective in preventing chemical hypoxia-induced increases in paracellular shunt permeability/conductance in isolated human colon. In rat distal colon, chemical hypoxia significantly increased total epithelial conductance and transepithelial movement of FITC-dextran 4000, changes completely prevented by 0.2 µM OCT. OCT may prevent or limit gut ischemia during abdominal surgery, thereby decreasing the risk of bacterial/bacterial toxin translocation and sepsis.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G701-G710"},"PeriodicalIF":3.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124581","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":"Regional and conditional variability of FXR: new lessons on ileal inflammation and gut barrier functions.","authors":"Susan A Joyce, Dervla O'Malley","doi":"10.1152/ajpgi.00226.2024","DOIUrl":"10.1152/ajpgi.00226.2024","url":null,"abstract":"","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G626-G628"},"PeriodicalIF":3.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142071831","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 keratin cytoskeleton emerges as a regulator of mitochondria in the colonic epithelium.","authors":"Michelle Dixit, Joseph Burclaff","doi":"10.1152/ajpgi.00228.2024","DOIUrl":"10.1152/ajpgi.00228.2024","url":null,"abstract":"","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G699-G700"},"PeriodicalIF":3.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141791701","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":"Choline-deficient, high-fat diet-induced MASH in Göttingen Minipigs: characterization and effects of a chow reversal period.","authors":"Henning Hvid, Sara T Hjuler, Pierre Bedossa, Dina G Tiniakos, Ioannis Kamzolas, Lea M Harder, Yaxin Xue, James W Perfield, Rikke K Kirk, Markus Latta, Lars F Mikkelsen, Henrik D Pedersen","doi":"10.1152/ajpgi.00120.2024","DOIUrl":"10.1152/ajpgi.00120.2024","url":null,"abstract":"<p><p>The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) is increasing, and translational animal models are needed to develop novel treatments for this disease. The physiology and metabolism of pigs have a relatively high resemblance to humans, and the present study aimed to characterize choline-deficient and high-fat diet (CDAHFD)-fed Göttingen Minipigs as a novel animal model of MASLD/MASH. Göttingen Minipigs were fed CDAHFD for up to 5 mo, and the phenotype was investigated by the analysis of plasma parameters and repeated collection of liver biopsies. Furthermore, changes in hepatic gene expression during the experiment were explored by RNA sequencing. For a subset of the minipigs, the diet was changed from CDAHFD back to chow to investigate whether the liver pathology was reversible. Göttingen Minipigs on CDAHFD gained body weight, and plasma levels of cholesterol, AST, ALT, ALP, and GGT were increased. CDAHFD-fed minipigs developed hepatic steatosis, inflammation, and fibrosis, which in 5 of 16 animals progressed to cirrhosis. During an 11-wk chow reversal period, steatosis regressed, while fibrosis persisted. Regarding inflammation, the findings were less clear, depending on the type of readout. MASH Human Proximity Scoring (combined evaluation of transcriptional, phenotypic, and histopathological parameters) showed that CDAHFD-fed Göttingen Minipigs resemble human MASLD/MASH better than most rodent models. In conclusion, CDAHFD-fed minipigs develop a MASH-like phenotype, which, in several aspects, resembles the changes observed in human patients with MASLD/MASH. Furthermore, repeated collection of liver biopsies allows detailed characterization of histopathological changes over time in individual animals.<b>NEW & NOTEWORTHY</b> The physiology and metabolism of pigs have a relatively high resemblance to humans. This study characterizes a new animal model of MASLD/MASH using CDAHFD-fed Göttingen Minipigs. Göttingen Minipigs fed CDAHFD gained weight and developed hepatic steatosis, inflammation, fibrosis, and cirrhosis. After an 11-wk chow-reversal period, hepatic steatosis and some inflammatory parameters reversed. Combined evaluation of phenotypic, transcriptional, and histological parameters revealed the minipig model showed a higher resemblance to human disease than many rodent models.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G571-G585"},"PeriodicalIF":3.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747164","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":"Elongation factor 1A1 inhibition elicits changes in lipid droplet size, the bulk transcriptome, and cell type-associated gene expression in MASLD mouse liver.","authors":"Rachel B Wilson, Yun Jin Chen, Richard Zhang, Siddhant Maini, Tallulah S Andrews, Rennian Wang, Nica M Borradaile","doi":"10.1152/ajpgi.00276.2023","DOIUrl":"10.1152/ajpgi.00276.2023","url":null,"abstract":"<p><p>Eukaryotic elongation factor 1A1 (EEF1A1), originally identified for its role in protein synthesis, has additional functions in diverse cellular processes. Of note, we previously discovered a role for EEF1A1 in hepatocyte lipotoxicity. We also demonstrated that a 2-wk intervention with the EEF1A1 inhibitor didemnin B (DB) (50 µg/kg) decreased liver steatosis in a mouse model of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) [129S6/SvEvTac mice fed Western diet (42% fat) for 26 wk]. Here, we further characterized the hepatic changes occurring in these mice by assessing lipid droplet (LD) size, bulk differential expression, and cell type-associated alterations in gene expression. Consistent with the previously demonstrated decrease in hepatic steatosis, we observed decreased median LD size in response to DB. Bulk RNA sequencing (RNA-Seq) followed by gene set enrichment analysis revealed alterations in pathways related to energy metabolism and proteostasis in DB-treated mouse livers. Deconvolution of bulk data identified decreased cell type association scores for cholangiocytes, mononuclear phagocytes, and mesenchymal cells in response to DB. Overrepresentation analyses of bulk data using cell type marker gene sets further identified hepatocytes and cholangiocytes as the primary contributors to bulk differential expression in response to DB. Thus, we show that chemical inhibition of EEF1A1 decreases hepatic LD size and decreases gene expression signatures associated with several liver cell types implicated in MASLD progression. Furthermore, changes in hepatic gene expression were primarily attributable to hepatocytes and cholangiocytes. This work demonstrates that EEF1A1 inhibition may be a viable strategy to target aspects of liver biology implicated in MASLD progression.<b>NEW & NOTEWORTHY</b> Chemical inhibition of EEF1A1 decreases hepatic lipid droplet size and decreases gene expression signatures associated with liver cell types that contribute to MASLD progression. Furthermore, changes in hepatic gene expression are primarily attributable to hepatocytes and cholangiocytes. This work highlights the therapeutic potential of targeting EEF1A1 in the setting of MASLD, and the utility of RNA-Seq deconvolution to reveal valuable information about tissue cell type composition and cell type-associated gene expression from bulk RNA-Seq data.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G608-G622"},"PeriodicalIF":3.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970442","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":"Acquired dysfunction of CFTR underlies cystic fibrosis-like disease of the canine gallbladder.","authors":"Jody L Gookin, Jenny Holmes, Lane L Clarke, Stephen H Stauffer, Bryanna Meredith, Michael W Vandewege, Nicole Torres-Machado, Steven G Friedenberg, Gabriela S Seiler, Kyle G Mathews, Kathryn Meurs","doi":"10.1152/ajpgi.00145.2024","DOIUrl":"10.1152/ajpgi.00145.2024","url":null,"abstract":"<p><p>Mucocele formation in dogs is a unique and enigmatic muco-obstructive disease of the gallbladder caused by the amassment of abnormal mucus that bears striking pathological similarity to cystic fibrosis. We investigated the role of cystic fibrosis transmembrane conductance regulatory protein (CFTR) in the pathogenesis of this disease. The location and frequency of disease-associated variants in the coding region of CFTR were compared using whole genome sequence data from 2,642 dogs representing breeds at low-risk, high-risk, or with confirmed disease. Expression, localization, and ion transport activity of CFTR were quantified in control and mucocele gallbladders by NanoString, Western blotting, immunofluorescence imaging, and studies in Ussing chambers. Our results establish a significant loss of CFTR-dependent anion secretion by mucocele gallbladder mucosa. A significantly lower quantity of CFTR protein was demonstrated relative to E-cadherin in mucocele compared with control gallbladder mucosa. Immunofluorescence identified CFTR along the apical membrane of epithelial cells in control gallbladders but not in mucocele gallbladder epithelium. Decreases in mRNA copy number for <i>CFTR</i> were accompanied by decreases in mRNA for the Cl^-/[Formula: see text] exchanger <i>SLC26A3</i>, K⁺ channels (<i>KCNQ1</i>, <i>KCNN4</i>), and vasoactive intestinal polypeptide receptor (<i>VIPR1</i>), which suggest a driving force for change in secretory function of gallbladder epithelial cells in the pathogenesis of mucocele formation. There were no significant differences in CFTR gene variant frequency, type, or predicted impact comparing low-risk, high-risk, and definitively diagnosed groups of dogs. This study describes a unique, naturally occurring muco-obstructive disease of the canine gallbladder, with uncanny similarity to cystic fibrosis, and driven by the underlying failure of CFTR function.<b>NEW & NOTEWORTHY</b> Cystic fibrosis transmembrane conductance regulatory protein (CFTR) genomic variants and expression of mRNA, protein, and electrogenic anion secretory activity of CFTR were characterized in dog gallbladder. Acquired inhibition of CFTR expression by gallbladder epithelium was identified as underpinning a naturally occurring muco-obstructive disease of the dog gallbladder that bears striking pathological similarity to animal models of cystic fibrosis.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G513-G530"},"PeriodicalIF":3.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747163","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}