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

{"title":"Gut neuropeptide involvement in Parkinson's disease.","authors":"Hayley N Templeton, Stuart A Tobet, Luke A Schwerdtfeger","doi":"10.1152/ajpgi.00383.2024","DOIUrl":"10.1152/ajpgi.00383.2024","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a neurodegenerative disorder affecting over 10 million people. A key pathological feature of PD is the accumulation of misfolded α-synuclein (aSyn) protein in the substantia nigra pars compacta. Aggregation of aSyn can form Lewy bodies that contribute to dopaminergic neuron degeneration and motor symptoms, such as tremor, rigidity, and bradykinesia. Beyond the central nervous system, aSyn aggregates have been detected in the gastrointestinal (GI) tract, suggesting a link between peripheral aSyn and nonmotor PD symptoms. GI symptoms, often preceding motor symptoms by up to 20 years, highlight the bidirectional communication between the central nervous system and the enteric nervous system (gut-brain axis) in PD. Although microbiome alterations and intestinal inflammation have been associated with PD, functional impacts on gut-brain signaling or aSyn aggregation remain unclear. Intestinal neuropeptides are key modulators of gut-brain communication, alter immune response to pathogens and environmental toxins, and may contribute to the function of the luminal gut barrier. Dysregulation of gut neuropeptide signaling, including vasoactive intestinal peptide, neuropeptide Y, calcitonin gene-related peptide, ghrelin, cholecystokinin, glucagon-like peptide 1, and substance P, have been associated with pathologic effects of PD in animal models. Despite their potential role in pathogenesis and disease modulation, gut neuropeptide roles in PD are underexplored. This article reviews current knowledge surrounding microbial metabolite and immune influences on gut neuropeptide signaling, aSyn aggregation in the enteric nervous system, and downstream neuroimmune pathway alterations within the context of PD and its mouse models.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G716-G733"},"PeriodicalIF":3.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952218","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":"Spontaneous ileitis and postsurgical murine models of enteric hyperoxaluria.","authors":"Karim Jaber, Nadim Zaidan, Melody Ho, Xiaozhong Xiong, Rashmi Mishra, Ambika Nair, Arnav Mishra, Yi Chu, Mohamad Mokadem, Lama Nazzal","doi":"10.1152/ajpgi.00043.2025","DOIUrl":"10.1152/ajpgi.00043.2025","url":null,"abstract":"<p><p>Enteric hyperoxaluria, a risk factor for kidney stone disease, often arises from malabsorptive bariatric surgeries or inflammatory bowel diseases. Current murine models for studying this condition are limited, necessitating new approaches. This study aims to establish two novel and distinct mouse models to investigate enteric hyperoxaluria: one simulating Roux-en-Y gastric bypass surgery and the other Crohn's ileitis. In the first model, diet-induced obese C57BL/6J male mice underwent either sham or bypass surgery, followed by 3 wk on a high-fat, oxalate-enriched diet. In the second model, SAMP1/YitFc and AKR mice were gradually introduced to high-fat diets, later supplemented with oxalate while reducing fat content. Samples of urine, blood, and feces were collected to assess oxalate, creatinine, and fecal lipid profiles. Results showed hyperoxaluria and increased stool fat content, indicating fat malabsorption, in both SAMP1 and bypass mice compared with controls. Kidney injury was also observed. These findings confirm the successful establishment of enteric hyperoxaluria in both models, highlighting the role of dietary oxalate, intestinal inflammation, and fat malabsorption in disease progression. These models provide valuable tools for exploring cellular and molecular mechanisms in enteric hyperoxaluria and may inform future therapeutic strategies.<b>NEW & NOTEWORTHY</b> This study is among the first to establish an enteric hyperoxaluria (EH) phenotype in two different and novel mouse models secondary to Roux-en-Y gastric bypass and ileitis. It also elucidates key factors affecting EH using the SAMP1 mice, revealing the significant roles of GI tract inflammation, fat malabsorption, and dietary fat in developing hyperoxaluria.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G760-G773"},"PeriodicalIF":3.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143960988","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":"Host-microbial interactions in the esophagus.","authors":"Nonyelum Ebigbo, Rhonda F Souza","doi":"10.1152/ajpgi.00079.2025","DOIUrl":"10.1152/ajpgi.00079.2025","url":null,"abstract":"<p><p>Host-microbial interactions within the gastrointestinal tract are increasingly recognized as contributors to health and disease, yet our understanding of these interactions in the esophagus remains limited. Dysbiosis of the esophageal microbiome has been linked to esophageal disorders, but the precise mechanisms underlying microbial contributions to esophageal pathophysiology remain speculative. This review explores the mechanisms by which the esophageal microbiome modulates mucosal immunity, epithelial barrier integrity, and inflammatory responses. We highlight key host receptors that mediate these interactions and microbial metabolites that influence the local immune environment and epithelial function. By synthesizing current knowledge on how the microbiome impacts esophageal health, we identify significant knowledge gaps and propose areas for future research.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G848-G860"},"PeriodicalIF":3.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958094","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":"Liver bypass in the development of pathogen-associated pulmonary vascular disease: contribution of mesocaval and portosystemic shunts.","authors":"Claudia Lucia Martins Silva, Prasanth N Puthanveetil, Suellen Darc Oliveira","doi":"10.1152/ajpgi.00409.2024","DOIUrl":"10.1152/ajpgi.00409.2024","url":null,"abstract":"<p><p>Portosystemic and mesocaval shunts are aberrant vascular connections that bypass hepatic detoxification process, directly linking the portal to the systemic circulation. These shunts, whether congenital or acquired, might play a pivotal role in the pathogenesis of systemic inflammatory diseases, such as schistosomiasis-associated pulmonary hypertension (Sch-PH) by facilitating the dissemination of pathogen-derived eggs and antigens from the gut and mesentery into the lungs. Beyond the translocation of <i>Schistosoma mansoni</i> eggs, emerging evidence implicates that gut-lung microbiome dysbiosis contributes to the development of pulmonary hypertension (PH) in the preclinical animal model of Sch-PH. Sch-PH emerges as a chronic complication of schistosomiasis and evolves silently, progressively increasing the mean pulmonary arterial pressure and vascular resistance, leading to right heart hypertrophy, failure, and significant morbidity and mortality. Chronic schistosomiasis is often linked to the development of portal hypertension, which significantly contributes to the formation of the porto/mesocaval shunt as a compensatory response that can have far-reaching implications on pulmonary vascular physiology. In addition, portal hypertension compromises the integrity of the intestinal barrier, exacerbating peritoneal and mesenteric inflammation, potentially facilitating microbial and metabolite entrance into the systemic circulation. This article briefly discusses the mechanisms by which porto/mesocaval shunts contribute to PH, especially Group I PH, focusing on the interplay between portosystemic shunting, microbial translocation, and systemic dissemination of proinflammatory metabolites.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G791-G800"},"PeriodicalIF":3.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12199453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963530","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":"Dietary 3-aminobenzoic acid enhances intestinal barrier integrity and attenuates experimental colitis.","authors":"Miho Tanaka, Takahiko Toyonaga, Fumiyuki Nakagawa, Takeo Iwamoto, Yudai Hasegawa, Akira Komatsu, Natsuki Sumiyoshi, Naoki Shibuya, Ayaka Minemura, Tadashi Ariyoshi, Asami Matsumoto, Kentaro Oka, Masayuki Shimoda, Masayuki Saruta","doi":"10.1152/ajpgi.00406.2024","DOIUrl":"10.1152/ajpgi.00406.2024","url":null,"abstract":"<p><p>Disruption of intestinal epithelial integrity and increased permeability is central to the pathogenesis of ulcerative colitis (UC). In this study, we identified 3-aminobenzoic acid (3-ABA), a dietary component abundant in azuki beans, soybeans, and chickpeas as a regulator of epithelial permeability and inflammation in the colon. Screening 119 gut microbial metabolites revealed the ability of 4-ABA, a structural isomer of 3-ABA, to enhance barrier function in Caco2 cells. Further analysis of structural isomers identified 3-ABA as the most effective, significantly increasing transepithelial electrical resistance and reducing epithelial permeability. Using liquid chromatography-mass spectrometry, 3-ABA was detected in dietary beans and human fecal samples. Fecal 3-ABA levels were significantly lower in patients with UC compared with healthy individuals. Metagenomic and functional prediction analyses revealed dysbiosis in patients with UC, characterized by an enrichment of bacterial genes involved in ABA degradation. Gene expression analysis of 3-ABA-stimulated Caco2 cells demonstrated upregulation of tight junction molecules, such as CLDN1 and TJP1, enhancing epithelial barrier integrity. In a dextran sodium sulfate-induced colitis mouse model, rectal 3-ABA administration ameliorated colitis by enhancing epithelial barrier function and reducing inflammation. These findings highlight 3-ABA's potential as a dietary therapeutic agent for UC, offering a novel strategy to enhance intestinal integrity and mitigate inflammation.<b>NEW & NOTEWORTHY</b> Increased intestinal epithelial permeability is central to the pathogenesis of ulcerative colitis (UC). 3-Aminobenzoic acid (3-ABA), a dietary component abundant in beans, decreased epithelial permeability and attenuated colonic inflammation in a mouse experimental colitis model. Reduced fecal 3-ABA levels in patients with UC were associated with dysbiosis-driven accelerated degradation. These findings highlight the therapeutic potential of 3-ABA in UC by targeting colonic epithelium.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G801-G810"},"PeriodicalIF":3.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955911","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":"ASBT governs neonatal bile acid homeostasis early in life despite its strong ileal repression.","authors":"Joyce Morales Aparicio, Zhengzheng Hu, Amy M Peiper, Lufuno Phophi, Haley M Wilt, Meera S Nair, Harrison Winton, Katherine Blessing, Gabriela R Gonzalez, Stephanie M Karst","doi":"10.1152/ajpgi.00117.2025","DOIUrl":"https://doi.org/10.1152/ajpgi.00117.2025","url":null,"abstract":"<p><p>Neonatal bile acid metabolism is distinct from that of adults due to developmental regulation of key transporters and enzymes. The apical sodium-dependent bile acid transporter (ASBT) is transiently repressed in the intestine after birth, yet its role in neonatal bile acid homeostasis remains unclear. Here, we demonstrate that ASBT plays a crucial role in limiting fecal bile acid loss and suppressing hepatic bile acid synthesis in neonates. ASBT-deficient pups exhibited a marked decrease in serum bile acids and concomitant increase in fecal bile acids, accompanied by upregulated hepatic bile acid synthesis genes, including CYP7A1, CYP7B1, and CYP27A1. We also illuminated a tissue-specific distinction in neonatal negative feedback regulation of bile acid synthesis, with intact hepatic regulation but impaired intestinal regulation. Our study identifies ASBT as a key regulator of neonatal bile acid homeostasis despite its strong repression early in life, highlighting its role in bile acid retention and synthesis regulation.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085689","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":"Dynamic functional luminal imaging probe analysis of the anal sphincter opening function during straining in healthy volunteers.","authors":"Charlotte Desprez, Anne-Marie Leroi, Guillaume Gourcerol, Ali Zifan, Thomas Duflot","doi":"10.1152/ajpgi.00369.2024","DOIUrl":"10.1152/ajpgi.00369.2024","url":null,"abstract":"<p><p>The objective of the present study was to introduce a novel method of assessing anal canal opening in healthy volunteers (HV) using the EndoFLIP system. By analyzing dynamic loops during push maneuvers, the study aimed to identify the most reliable markers of anal canal opening function during this maneuver. Forty HV women were recruited and underwent anal canal assessments with the EndoFLIP system, both at rest and during push maneuvers. Cross-sectional area (CSA)-pressure loops were constructed for each HV at distension volumes of 40 mL and 50 mL. Key parameters (pressure and CSA) derived from these loops were identified as potential markers of anal function to reduce dimensionality. Anal opening function during push maneuver was quantified in both percentage (relative variation) and absolute (absolute variation) values for pressure and CSA. The direction of the CSA-pressure loops during the push maneuver at 40 mL and 50 mL of distension was upward and to the right, indicating an increase in both pressure and CSA during straining. None of the demographic data were significant predictors of any characteristics of the CSA-pressure loops at 40 mL and 50 mL of distension. The mean relative variation in pressure and CSA at 50 mL of distension and, to a lesser extent, the maximal relative variation pressure and CSA, were identified as markers with the lowest variability. This pilot study points to potential markers for assessing anal opening function during push maneuvers. Further confirmatory studies are necessary to establish the clinical utility of these markers.<b>NEW & NOTEWORTHY</b> In the present study, we generated a bioinformatics pipeline for analyzing anal EndoFLIP data in healthy volunteers using automated data reprocessing to identify potential markers of anal opening function during the push maneuver. Mean relative variations in pressure and CSA at 50 mL of distension were identified as the most indicative parameters. Given that this was a pilot study, our findings warrant further confirmatory research to establish the clinical relevance of these markers.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G513-G521"},"PeriodicalIF":3.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802218","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":"Oryzanol ameliorates MCD-induced metabolic dysfunction-associated steatohepatitis in mice via gut microbiota reprogramming and TLR4/NF-κB signaling suppression.","authors":"Naqash Alam, Xinhua Ding, Yu Fu, Linying Jia, Sadiq Ali, Enqi Liu","doi":"10.1152/ajpgi.00190.2024","DOIUrl":"https://doi.org/10.1152/ajpgi.00190.2024","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatohepatitis (MASH) has emerged as a major global health concern that affects about a quarter of the global population. Recently, host-gut microbiota metabolic interactions have emerged as key mechanistic pathways in MASH development. Oryzanol (ORY), a rice bran bioactive compound, exhibits antioxidant, anti-inflammatory, hypolipidemic, and hypoglycemic properties. Here, we investigated the potential of ORY in alleviating MASH and its association with gut microbiota and MASH progression. Male C57BL/6J mice were fed normal chow diet or methionine-choline-deficient diet and received ORY supplementation at 300 mg/kg/day via gavage for 4 wk. Liver injury, inflammation, lipid accumulation, and TLR4/NF-κB signaling protein levels were assessed. In addition, changes in gut microbiota diversity and abundance across groups were evaluated using 16S rDNA sequencing. Our results demonstrated that ORY significantly reduced lipid accumulation and liver enzymes, ameliorated liver and ileum damage, and restored intestinal barrier function in MASH mice. Furthermore, ORY decreased plasma lipopolysaccharide levels, and inflammatory cytokines and downregulated TLR4, MyD88, and NF-κB protein levels in the liver. ORY enhanced tight junction protein level (ZO-1, occludin) in the gut. Microbial analysis revealed that ORY positively impacted Firmicutes and Bacteroidetes abundance, promoted beneficial bacteria like <i>Lactobacillus</i> and <i>Lachnospiraceae_NK4A136_group</i>, and inhibited harmful bacteria such as <i>Mucispirillum</i>, <i>Bacteroides</i>, and <i>Colidextribacter</i>. Notably, ORY increased <i>Akkermansia</i> abundance, potentially modulating metabolic and inflammatory pathways. ORY exerted restorative and reversible effects on the pathophysiological damage within the gut-liver axis in MASH mice. The therapeutic mechanism may be related to the modulation of the gut microbiota and TLR4/NF-κB signaling pathway.<b>NEW & NOTEWORTHY</b> This study demonstrates that oryzanol (ORY), a bioactive rice bran compound, alleviates metabolic dysfunction-associated steatohepatitis (MASH) in mice by reducing lipid accumulation and inflammation. ORY beneficial effects are associated to the modulation of gut microbiota, enhancing gut barrier integrity, and lowering endotoxemia and TLR4/NF-κB signaling pathway. These findings suggest ORY potential in MASH prevention and treatment, highlighting its influence on gut-liver axis dynamics.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":"328 5","pages":"G578-G593"},"PeriodicalIF":3.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961267","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 spatiotemporal development of mesenteric lymphatic changes in the <i>TNF</i>^ΔARE/+ mouse model of terminal ileitis.","authors":"Keith Keane, Matthew Stephens, Simon Roizes, Jingna Xue, Shan Liao, Pierre-Yves von der Weid","doi":"10.1152/ajpgi.00334.2024","DOIUrl":"10.1152/ajpgi.00334.2024","url":null,"abstract":"<p><p>Crohn's disease (CD) is a chronic inflammatory bowel disease, which also encompasses significant alterations of the mesenteric lymphatic system. Whether these changes are a mere consequence of or directly contribute to the inflammation is unknown. Here, we characterized the spatial and temporal development of these events in the <i>TNF</i>^ΔARE/+ mouse, which develops CD-like ileitis and significant mesenteric lymphatic alterations. At 8, 12, 20, and 28 wk of age, specific pathogen-free (SPF), germ-free (GF) <i>TNF</i>^ΔARE/+ and wild-type (WT) mice were assessed for ileitis via myeloperoxidase (MPO) activity while mesenteric lymphatic alterations were assessed by confocal immunofluorescence imaging. Lymphatic alterations in the SPF <i>TNF</i>^ΔARE/+ occurred in a stepwise manner between 8 and 28 wk of age beginning with the development of mesenteric lymphadenopathy at 8 wk despite no significant ileitis. By 12-wk ileal MPO significantly elevates concomitantly with lymphangiectasia of the mesenteric collecting lymphatic vessels (CLVs) and clustering of CD45⁺ immune cells around them. At 20 wk, significant lymphangiogenesis of the initials (initial lymphatic vessel) and tertiary lymphoid organs aligned along lymphatic collectors (CA-TLOs) had developed. At 28 wk, lymphangiectasia, lymphangiogenesis, and CA-TLOs increased. However, 28-wk-old GF <i>TNF</i>^ΔARE/+, while displaying no ileitis, presented with mesenteric lymphadenopathy, lymphangiectasia, and lymphangiogenesis but no immune cell clustering nor CA-TLOs. The <i>TNF</i>^ΔARE/+ mice develop terminal ileitis and lymphatic alterations in a stepwise manner beginning with mesenteric lymph node lymphadenopathy and ileal inflammation, followed by CLV dilation and lymphangiogenesis. These lymphatic alterations are exacerbated by the gut microbiome, with immune cell clustering and tertiary lymphoid organ formation being entirely dependent of its presence.<b>NEW & NOTEWORTHY</b> The mesenteric lymphatic system displays striking morphological alterations in Crohn's disease. To assess the importance of these changes in the perpetuation of the disease, we established the timeframe of their occurrence with respect to the development of ileitis in a mouse model of Crohn's disease and in the same model derived germ-free where intestinal inflammation does not occur. Although immune-related alterations seem to depend on microbiome, changes specifically affecting lymphatic vessels persist in its absence.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G624-G643"},"PeriodicalIF":3.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584378","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":"Hypobaric hypoxia exposure impairs colonic goblet cell subpopulation via the HIF-1α signaling pathway.","authors":"Shaojie Zhang, Xiufang Jiang, Wangjingyi Zhang, Fansen Meng, Jiayue Gao, Xiang Cheng, Yazhuo Hu, Jing Liu, Tong Zhao, Lingling Zhu, Gangshi Wang","doi":"10.1152/ajpgi.00372.2024","DOIUrl":"10.1152/ajpgi.00372.2024","url":null,"abstract":"<p><p>Exposure to hypobaric hypoxia during rapid ascent to high altitudes significantly impacts intestinal barrier function. Goblet cells, as one of the primary cell types in the intestinal mucosa, play a crucial role in maintaining this barrier. However, the effects of hypobaric hypoxia on goblet cell function and the underlying molecular mechanisms remain unclear. In this study, we established a mouse model of hypobaric hypoxia exposure (simulating an altitude of 6,000 m) and studied its effects on colonic goblet cells by transcriptomic analysis. In addition, the hypoxia-treated (1% O₂) goblet cell line Ls174t was used to investigate potential mechanisms underlying hypoxia-induced changes in goblet cells. In the present study, we discovered that hypobaric hypoxia exposure not only reduced the number of colonic goblet cells in mice by 27.6% but also impaired their mucus secretion. Transcriptome sequencing analysis of sorted goblet cells from the mice colon revealed significant changes in gene expression profiles, particularly in the expression of canonical goblet cell markers such as calcium-activated chloride channel regulator 1 (<i>Clca1</i>) and Fcγ-binding protein (<i>Fcgbp</i>). We confirmed the effects of hypobaric hypoxia/hypoxia exposure on CLCA1 and FCGBP expression at both mRNA and protein levels in mouse colonic tissues and in Ls174t cells. The expression of these canonical goblet cell marker genes was dependent upon hypoxia-inducible factor-1α (HIF-1α) activity; their expression decreased upon hypoxia-induced activation of HIF-1α and increased when HIF-1α was knocked down using siRNA. Thus, hypobaric hypoxia exposure regulates the distribution and function of colonic goblet cell subsets through the HIF-1α signaling pathway.<b>NEW & NOTEWORTHY</b> We investigated the role of hypoxia-inducible factor-1α (HIF-1α) in colonic goblet cell injury under hypobaric hypoxia exposure. Our results indicate that the elevation of HIF-1α caused by hypobaric hypoxia exposure can significantly reduce canonical goblet cells and disrupt intestinal mucosal barrier function. It provides a potential intervention strategy for restoring goblet cell function under hypobaric hypoxic conditions.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G465-G478"},"PeriodicalIF":3.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707861","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}