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

{"title":"FAM134B controls collagen I dynamics in hepatic stellate cell-driven fibrosis.","authors":"Jagannath Misra, Zachary Hanquier, Reese Baxter, Nipuni Barupala, Alexander Jackson, Jessica L Maiers","doi":"10.1152/ajpgi.00170.2025","DOIUrl":"10.1152/ajpgi.00170.2025","url":null,"abstract":"<p><p>Liver fibrosis is driven by the accumulation of scar tissue in response to injury. Activated hepatic stellate cells (HSCs) secrete fibrogenic proteins that deposit into the extracellular matrix, leading to fibrosis. Increased production of fibrogenic proteins by HSCs leads to endoplasmic reticulum (ER) stress, triggering the unfolded protein response (UPR). The UPR is important in regulating HSC activation and fibrogenesis, but mechanisms driving this regulation are unclear. A key process regulated by the UPR is degradation of misfolded proteins through various pathways, including ER-to-lysosome-associated degradation (ERLAD). ERLAD targets proteins for lysosomal degradation and can involve autophagosomes engulfing portions of the ER, termed ER-phagy. ER-phagy is implicated in degradation of misfolded fibrillar collagen, but its role in fibrogenesis is unknown. We show that collagen I levels are posttranslationally regulated by autophagy, and this correlates with ER-phagy receptor expression. Furthermore, activation of HSCs induces ER-phagy flux and expression of ER-phagy receptors, including FAM134B, in a process dependent on UPR transducer ATF6α. Loss of FAM134B decreases intracellular collagen I without affecting COL1A1 mRNA. Moreover, FAM134B deletion blocks transforming growth factor β-induced collagen I deposition despite increased secretion. Together, we show that ER-phagy receptor FAM134B is pivotal for collagen I deposition during fibrogenesis.<b>NEW & NOTEWORTHY</b> We show for the first time that TGFβ-mediated activation of HSCs induces selective autophagy of the endoplasmic reticulum (ER-phagy), through upregulation of ER-phagy receptors and ER-phagic flux. We further show that the unfolded protein response is critical for this effect. Finally, we identify the ER-phagy receptor FAM134B as a critical regulator of collagen I dynamics and fibrogenesis, with loss of FAM134B dysregulating collagen I secretion and deposition.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G123-G136"},"PeriodicalIF":3.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12818557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145686780","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":"HNF4A intestinal ablation positively influences the fate of ileal goblet cells during <i>Salmonella typhimurium</i> infection.","authors":"Dianne Pupo Gómez, Vilcy Reyes Nicolás, Gisela Cofino Marrero, Ariane Cristina De Castro, Christine Jones, Linnette Maria Leon Chirino, Nathalie Perreault, Alfredo Menendez, Francois Boudreau","doi":"10.1152/ajpgi.00224.2025","DOIUrl":"10.1152/ajpgi.00224.2025","url":null,"abstract":"<p><p>Hepatocyte nuclear factor 4 A (HNF4A) is a transcription factor that regulates a diverse range of intestinal epithelial genes involved in tissue renewal, differentiation, and metabolism, among other functions. The HNF4A locus is associated with inflammatory bowel disease (IBD) susceptibility, and its deletion in the mouse intestine causes long-term chronic inflammation of the colon. However, it remains unclear whether HNF4A is part of the regulatory mechanisms involved in the inflammatory processes of the small intestine. Using a tamoxifen-inducible mouse intestinal knockout of <i>Hnf4a</i>, we observed a spontaneous increase in mucosal barrier permeability in the absence of HNF4A. However, when these mice were infected with the invasive-deficient <i>Salmonella typhimurium</i> SB103, this increase in permeability did not result in an increase in liver and spleen bacterial colonization compared with undeleted mice. Interestingly, ileal secretory cell lineage differentiation was favored when HNF4A was depleted during the early stages of infection. This resulted in increased production of ileal goblet cells and the expression of <i>Muc2</i>, as well as the expression of specific antimicrobial peptides such as <i>Reg3g and Rtnlb</i>. We conclude that epithelial HNF4A is sensitive to <i>Salmonella</i> in the ileum and that its reduction in expression during the early phase of infection may contribute to rapidly reinforcing the chemical barrier response to elicit mucosal threat from pathogens.<b>NEW & NOTEWORTHY</b> HNF4A is associated with inflammatory bowel disease susceptibility and protects against chronic colon inflammation. Whether HNF4A acts similarly in the small intestine remains speculative. Although its deletion led to an increase in paracellular permeability, exposure to an attenuated <i>Salmonella typhimurium</i> strain did not cause systemic infection. Ileal goblet cell lineage commitment was stimulated with increased expression of antimicrobial peptide genes. HNF4A reduction of expression may contribute to early mucosal protection against luminal pathogen burdens.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G154-G169"},"PeriodicalIF":3.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145832845","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":"Antibiotics alter duodenal immune populations upon gluten exposure in mice: implications for non-coeliac gluten sensitivity.","authors":"Jennifer C Pryor, Emily C Hoedt, Wai Sinn Soh, Sophie Fowler, Shandelle Caban, Kyra Minahan, Simonne Sherwin, Cheenie Nieva, Huw McCarthy, Jay Horvat, Kateleen E Hedley, Kerith Duncanson, Grace L Burns, Nicholas J Talley, Simon Keely","doi":"10.1152/ajpgi.00159.2025","DOIUrl":"10.1152/ajpgi.00159.2025","url":null,"abstract":"<p><p>A growing proportion of the non-celiac population experiences adverse symptoms to gluten. The pathogenesis of non-celiac gluten sensitivity (NCGS) is unclear, but elevated duodenal eosinophils and altered mucosa-associated microbiota (MAM) populations have been reported. Given the microbiome's role in gluten digestion and its susceptibility to antibiotics, we hypothesized that altering the microbiome with antibiotics would modify immune responses to gluten in mice. BALB/C mice consuming gluten-free chow received amoxicillin/clavulanate (5 mg/kg) or PBS-vehicle daily for 5 days. Mice were then treated with a 3-mg wheat-gluten suspension, or vehicle, on <i>days 4</i> and <i>5</i> before euthanasia on <i>day 7</i>. Duodenal immune cells were analyzed by histology and flow cytometry, whereas the duodenal MAM and fecal microbiome were characterized via 16S rRNA and shotgun metagenomic sequencing, respectively. Antibiotic treatment followed by gluten reintroduction significantly reduced <i>Staphylococcus</i> in the duodenal MAM, enriched <i>Bacteroides</i> in feces, and resulted in altered microbial carbohydrate and lipid metabolism, compared with vehicle controls. Treatment with antibiotics and gluten also increased duodenal eosinophils, which positively correlated with the genus <i>Blautia.</i> Flow cytometry revealed that sequential antibiotic and gluten treatment resulted in a greater proportion of active eosinophils and epithelial γδ T-cells, compared with vehicle control mice. This study demonstrated that modulating the microbiome with antibiotics was sufficient to alter the immune response to gluten in mice, suggesting that the microbiome may determine the capacity for gluten to induce immune responses. These findings contribute valuable insights into possible microbial mechanisms underlying NCGS, such as altered gluten metabolism or production of immunomodulatory metabolites.<b>NEW & NOTEWORTHY</b> A mouse model examined how microbial modulation affects immune responses to gluten. Antibiotic treatment followed by gluten reintroduction reduced duodenal <i>Staphylococcus</i> and altered microbial carbohydrate and lipid metabolism pathways in the fecal microbiome. Antibiotics and gluten treatment resulted in increased abundance and activation of duodenal eosinophils and elevated γδ T-cells in the duodenal epithelium. These findings highlight the role the microbiome plays in gluten-induced immune responses, providing insights into mechanisms behind non-celiac gluten sensitivity.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G137-G153"},"PeriodicalIF":3.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145740559","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":"Low-dose galactose rebalances HBP-mTORC1-SREBP-1c signaling to suppress hepatic lipogenesis and protect against early-stage alcohol-related liver disease.","authors":"Yanhui Li, Rui Guo, Yanyu Qian, Izabela Hawro, Jose Cordoba-Chacon, Yuwei Jiang, Zhenyuan Song","doi":"10.1152/ajpgi.00379.2025","DOIUrl":"10.1152/ajpgi.00379.2025","url":null,"abstract":"<p><p>Overactivation of hepatic de novo lipogenesis (DNL) contributes to fatty liver disease. Although glucose and fructose strongly promote DNL, diary-rich galactose is only weakly lipogenic. However, whether and how it regulates hepatic DNL remains unclear. In this study, we investigated whether low-dose galactose supplementation attenuates glucose- or fructose-induced DNL activation and protects against fatty liver diseases driven by DNL overactivation, such as alcohol-associated liver disease (ALD). In this study, we used integrated hepatocyte and mouse models to assess hepatic DNL and related signaling under high-glucose or high-fructose conditions, with or without low-dose galactose. Pharmacological and genetic interventions targeting the Leloir and hexosamine biosynthetic pathways (HBP) defined underlying mechanisms. For in vivo validation, male C57BL/6 mice were fed an isocaloric control or ethanol-containing diet for 4 wk. We found that glucose engages the HBP-mTORC1-SREBP-1c axis to stimulate hepatic DNL, whereas fructose acts predominantly through carbohydrate-responsive element-binding protein (ChREBP). Low-dose galactose selectively suppressed glucose-induced hepatic fat accumulation, concomitant with the inhibition of the HBP-mTORC1-SERBP-1c pathway. These effects required an intact Leloir pathway for galactose metabolism and were not observed with fructose. In alcohol-fed mice, hepatic HBP-mTORC1-SREBP-1c signaling was markedly upregulated, contributing to steatosis and liver injury. Replacing even a small fraction of dietary glucose with galactose normalized these alterations, attenuating hepatic lipid accumulation and injury without altering systemic glucose levels. In conclusion, glucose-induced hepatic lipogenesis involves the HBP-mTORC1-SREBP-1c pathway, which is also activated during chronic alcohol exposure. Low-dose galactose, obtainable from dairy sources, attenuates this pathway, thereby limiting excessive lipogenesis and protecting against early-stage ALD.<b>NEW & NOTEWORTHY</b> This study demonstrates that low-dose galactose, a dairy-derived monosaccharide, regulates hepatic de novo lipogenesis (DNL) by selectively inhibiting glucose-induced DNL activation. Mechanistically, low-dose galactose suppresses hexosamine biosynthetic pathway (HBP) flux, protein O-GlcNAcylation, and mTORC1 signaling, thereby inhibiting SREBP-1c activation in a Leloir pathway-dependent manner. Notably, galactose supplementation prevented early-stage alcohol-related liver disease by attenuating hepatic HBP-O-GlcNAcylation-SREBP-1c signaling.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G170-G188"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12977332/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958315","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":"Inflammatory pain alters colorectal motility via spinal oxytocinergic pathways.","authors":"Tomoya Sawamura, Ayuna Mori, Natsufu Yuki, Kazuya Takashima, Yuuki Horii, Mitsuhiro Yoshimura, Yoichi Ueta, Takahiko Shiina, Yasutake Shimizu","doi":"10.1152/ajpgi.00427.2025","DOIUrl":"10.1152/ajpgi.00427.2025","url":null,"abstract":"<p><p>Gastrointestinal motility is regulated primarily by the enteric and the central nervous systems. Our previous studies revealed that central circuits regulating colorectal motility partially overlap with those involved in pain modulation, suggesting functional interactions between the nociceptive modulatory pathway and the autonomic regulatory pathway of colorectal motility. Here, we examined whether peripheral inflammatory pain alters the neural components of the descending pathway regulating colorectal motility. Complete Freund's adjuvant (CFA) was administered unilaterally into the hind paw of rats to induce inflammation. Colorectal motility was assessed in vivo under anesthesia with α-chloralose and ketamine. In sham-treated rats, intraluminal administration of capsaicin, a noxious stimulus to the colorectal lumen, enhanced colorectal motility. In contrast, the capsaicin-induced colorectal motility response was suppressed in rats 3 days after CFA treatment. This suppression was rescued by the intrathecal administration of a GABA_A receptor antagonist or an oxytocin (OXT) receptor antagonist. Furthermore, spinal OXT administration and chemogenetic activation of OXT neurons in naïve rats elicited a marked inhibition of capsaicin-induced motility responses of the colorectum. Notably, the inhibitory effect of activated OXT neurons was abolished by the intrathecal administration of a GABA_A receptor antagonist. These results indicate that the descending OXT pathway becomes operative in response to persistent pain caused by peripheral inflammation and that the inhibitory effect on colorectal motility may involve local GABAergic transmission within the spinal cord. These changes may reduce parasympathetic outflow to the colorectum and contribute to defecation disorders involving central neural mechanisms.<b>NEW & NOTEWORTHY</b> This study focused on the remodeling of the neural pathways regulating colorectal motility and examined whether peripheral inflammation outside the gastrointestinal tract affects this process. In rats administered a complete Freund's adjuvant into their hind paw, colorectal motility responses induced by intracolonic administration of capsaicin were suppressed. This suppression involved oxytocinergic and GABAergic transmission in the spinal cord. These results demonstrate that inflammatory pain in the hind paw induces remodeling of the neural pathways regulating colorectal motility.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G214-G224"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987969","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":"Pathologically relevant trypsinogen activation in pancreatitis.","authors":"Andrea Geisz-Fremy","doi":"10.1152/ajpgi.00152.2025","DOIUrl":"10.1152/ajpgi.00152.2025","url":null,"abstract":"<p><p>Pancreatitis is an inflammatory disorder of the pancreas that occurs in acute, recurrent acute, and chronic forms, often leading to severe complications and long-term functional impairment. The disease develops through multiple pathological mechanisms, including the premature activation of the digestive proenzyme trypsinogen within the pancreas. Conversion of trypsinogen to its active form trypsin may be catalyzed by the lysosomal protease cathepsin B or may occur through autoactivation, a self-amplifying reaction in which trypsin activates trypsinogen. Accumulating evidence from genetic, biochemical, and animal model studies on trypsinogen mutations associated with human pancreatitis strongly supports autoactivation as a key driver of disease pathogenesis, whereas cathepsin B-mediated activation may play a context-dependent, lesser role. This review explores the biochemical pathways of intrapancreatic trypsinogen activation and discusses their respective contributions to the multifactorial pathogenesis of pancreatitis.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G87-G97"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13098729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145779848","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":"Microbial dysbiosis alters serotonin signaling in a postinflammatory murine model of visceral pain.","authors":"Timothy D Roth, Lillian Russo-Savage, Yasaman Bahojb Habibyan, Catherine M Keenan, Laurie E Wallace, Yasmin Nasser, Gary M Mawe, Brigitte Lavoie, Keith A Sharkey","doi":"10.1152/ajpgi.00240.2025","DOIUrl":"10.1152/ajpgi.00240.2025","url":null,"abstract":"<p><p>Serotonin (5-HT) is a multifunctional signaling molecule in the gastrointestinal (GI) tract. 5-HT synthesis is regulated by the gut microbiota. Microbial dysbiosis has been implicated in visceral pain and persistent alterations in gut function that occur following inflammation. Here, we tested the hypothesis that alterations in gut microbiota in a postinflammatory model of visceral pain contribute to dysregulated 5-HT signaling. We used mice treated with dextran sodium sulfate (DSS) 42 days earlier (postcolitis) or untreated mice as donors for fecal microbiota transplants (FMTs) into germ-free mice to explore changes in enterochromaffin (EC) cell populations, expression of 5-HT synthesis, transport, and degradation genes, levels of 5-HT and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and 5-HT release. Significant differences were observed in EC cells, <i>Tph1</i>, <i>Slc6a4</i>, and <i>Maoa</i> gene expression, 5-HT and 5-HIAA levels, and 5-HT release between germ-free mice and mice receiving an FMT from either control or postcolitis donor mice. We observed no differences in the total number of EC cells, <i>Tph1</i>, or <i>Slc6a4</i> gene expression of mice after FMT from postcolitis or control mice. However, there was a significant increase in <i>Maoa</i> gene expression in the terminal ileum, an increased 5-HIAA/5-HT ratio in the proximal colon, and reduced 5-HT release to mechanical and chemical stimulation in the proximal and distal colon after FMT from postcolitis mice. Collectively, these findings provide additional evidence that the gut microbiota regulates 5-HT signaling. Moreover, they reveal functional changes in EC cell sensitivity in the presence of an altered microbiota after recovery from inflammation. <b>NEW & NOTEWORTHY</b> The gut microbiota regulates serotonin biosynthesis in enterochromaffin cells. Here, we show that a dysbiotic gut microbiota that occurs after recovery from inflammation alters serotonin signaling and produces functional changes in enterochromaffin cell sensitivity.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G29-G44"},"PeriodicalIF":3.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12797318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145666723","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":"Neutrophil-T cell cross talk in noninfectious liver diseases.","authors":"Barbora Gromova, Viera Kupcova, Marie Serena Longhi, Roman Gardlik","doi":"10.1152/ajpgi.00192.2025","DOIUrl":"10.1152/ajpgi.00192.2025","url":null,"abstract":"<p><p>Sterile inflammation, resulting from hepatocyte death and subsequent release of damage-associated molecular patterns (DAMPs), significantly contributes to liver disease pathogenesis. Neutrophils, as primary responders to liver injury, undergo NETosis-an immune response generating neutrophil extracellular traps (NETs), further amplifying inflammatory damage. Extracellular DNA (ecDNA), a major constituent of NETs and released cell fragments, potentiates inflammation through pattern recognition receptor activation. Mitochondrial DNA, released during hepatocyte damage, especially provokes robust immune responses due to its bacterial DNA-like structure and unmethylated CpG motifs. Concurrently, purinergic signaling-particularly via ATP release and its conversion into adenosine by ectonucleotidases CD39 and CD73-critically modulates immune homeostasis and inflammatory responses. Dysregulated expression of CD39/CD73, driven by altered aryl hydrocarbon receptor (AhR) signaling, exacerbates inflammatory states through disturbed regulatory T (Treg) and T helper (Th) 17 cell balance. Recent insights highlight that neutrophils and NETs not only drive innate inflammatory responses but significantly influence adaptive immunity by modulating T cell differentiation. NET components, such as cathelicidin and histones, actively promote Th17 differentiation while simultaneously impairing Treg functions, thereby sustaining inflammatory conditions. In addition, T cells reciprocally influence neutrophil activation and recruitment, predominantly through interleukin-17A (IL-17A) production. Detailed mechanisms underlying neutrophil-T cell cross talk in autoimmune hepatitis, acute liver failure, ischemia/reperfusion injury, alcoholic liver disease, and metabolic dysfunction-associated steatotic liver disease underscore potential therapeutic targets. Future strategies targeting NET formation, ecDNA clearance via DNase therapy, purinergic receptor modulation, and restoring AhR signaling hold promise for effectively attenuating sterile inflammation and immune dysregulation in liver diseases.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G10-G28"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12912180/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145646975","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":"Impaired intestinal cell proliferation parallels increased senescence after burn injury in aged mice.","authors":"Travis M Walrath, Mara R Evans, Kenneth Meza Monge, Kevin M Najarro, David J Orlicky, Juan-Pablo Idrovo, Rachel H McMahan, Elizabeth J Kovacs","doi":"10.1152/ajpgi.00176.2025","DOIUrl":"10.1152/ajpgi.00176.2025","url":null,"abstract":"<p><p>The global population is aging, with one in six people projected to be 65 yr or older by 2050. Since people aged 65 and older experience higher rates of morbidity and mortality after burn injury, there is an increased need to develop effective burn treatments in this age group. Heightened morbidity and risk of mortality may stem from increased gut leakiness and death of intestinal epithelial cells of aged individuals. Herein, we used our clinically relevant model of scald burn injury in young and aged mice to ascertain whether the colon, isolated colonic epithelium, and organoids grown from the colon have deficiencies in cell growth, senescence, and apoptosis pathways. Aged, burn-injured mice displayed increased senescence marker <i>cdkn2a</i> in the colon and isolated epithelium, and displayed a reduction in proliferation marker <i>cdk4</i> in the colon when compared with young mice. Changes in senescence and proliferation coincided with a reduction in stem cell marker <i>lgr5</i> in the colon and colonic epithelium, suggesting a burn-related reduction in the stemness of the epithelial crypt. Although we failed to see histological changes in the colonic epithelium, we observed an increase in proapoptotic cleaved caspase 3 and 9 within the colons of aged, burn-injured mice. Finally, there was a decrease in the expression of antimicrobial peptide <i>ang4</i>, and not <i>camp</i> in the colons of aged, burn-injured mice. Taken together, these data suggest that in the colon, disruption of proliferation and apoptosis in aged burn-injured mice occurs primarily in the nonepithelial compartment.<b>NEW & NOTEWORTHY</b> Aged mice have more senescent cells in their colons and burn injury in aged mice leads to suppression of proliferation markers in the colon, but not in epithelial cells or cultured organoids. Colonic expression of stem cell marker <i>lgr5</i> is reduced in colon from aged, burn-injured mice, and a proapoptotic caspase cascade was seen in this cohort. Finally, antimicrobial peptide <i>ang4</i> expression is decreased in colons from both aged and aged, burn-injured mice.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G1-G9"},"PeriodicalIF":3.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12797342/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145626967","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":"Association between gastric rhythm and gastroesophageal reflux defined by simultaneous body surface gastric mapping and 24-h pH testing.","authors":"William Xu, Sam Simmonds, Daphne Foong, Sameer Bhat, Chris Varghese, Christopher N Andrews, Gabriel Schamberg, Armen Gharibans, Thomas L Abell, David Rowbotham, Vincent Ho, Stefan Calder, Gregory O'Grady","doi":"10.1152/ajpgi.00255.2025","DOIUrl":"10.1152/ajpgi.00255.2025","url":null,"abstract":"<p><p>Gastroesophageal reflux disease (GERD) is common and often medically refractory. Abnormal gastric myoelectrical function may contribute to pathogenesis. This prospective observational study with matched controls assessed if myoelectrical abnormalities measured using body surface gastric mapping were correlated with reflux measured by 24-h pH testing and symptom severity. Gastric Alimetry was performed simultaneously on patients undergoing 24-h pH testing for investigation of reflux symptoms, with a standardized 4.5-h test and validated symptom logging. Data were segmented into 15-min epochs. Forty subjects were recruited (mean age 46.5 yr, 60% female): 20 undergoing pH testing (12 with GERD and 8 symptomatic patients without) and 20 controls. Patients with GERD displayed lower gastric rhythm stability measured by the Gastric Alimetry Rhythm Index (GA-RI) when compared with controls (<i>P</i> = 0.011), but not with patients without GERD (<i>P</i> = 0.605). Lower gastric rhythm stability measured by GA-RI was associated with increased esophageal acid exposure (DeMeester score; <i>r</i> = -0.46, <i>P</i> = 0.042). Periods of decreased gastric rhythm stability measured by GA-RI were not temporally correlated with reflux (<i>r</i> = 0.08, <i>P</i> = 0.182) or heartburn severity (<i>r</i> = 0.04, <i>P</i> = 0.309) but were correlated with nausea (<i>r</i> = -0.22, <i>P</i> < 0.001) and excessive fullness (<i>r</i> = -0.28, <i>P</i> < 0.001). We demonstrated that gastric rhythm instability is associated with increased symptom severity and overall acid exposure in patients with GERD. Although there was no temporal link between rhythm instability and heartburn, rhythm instability was temporally associated with increased nausea and fullness. GA-RI therefore offers an emerging biomarker of concurrent gastric neuromuscular dysfunction in patients with GERD.<b>NEW & NOTEWORTHY</b> Gastroesophageal reflux disease (GERD) is common and often medically refractory. We assessed whether gastric myoelectrical function contributes to pathogenesis by simultaneously measuring myoelectrical activity with Gastric Alimetry and reflux events on 24-h pH testing in patients. We demonstrated that gastric rhythm instability is associated with increased symptom severity and acid exposure in patients with GERD. Although there was no temporal link between rhythm instability and heartburn found, rhythm instability was temporally associated with dyspepsia.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G62-G71"},"PeriodicalIF":3.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145666731","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}