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

{"title":"The neogenin-hemojuvelin axis in murine liver is crucial for hepcidin expression.","authors":"Caroline A Enns, Shall Jue, Bethel Demissu, An-Sheng Zhang","doi":"10.1152/ajpgi.00167.2026","DOIUrl":"10.1152/ajpgi.00167.2026","url":null,"abstract":"<p><p>Neogenin (NEO1) is a ubiquitously expressed, multifunctional receptor that binds hemojuvelin (HJV); both proteins are essential components within hepatocytes for maintaining systemic iron homeostasis. Previous research established that the targeted ablation of hepatic <i>Neo1</i> or <i>Hjv</i> in mice markedly reduces expression of the central iron-regulatory hormone, hepcidin. Reduction in hepcidin results in unrestricted iron absorption that leads to severe systemic iron overload. Hepatic hepcidin expression is primarily induced via the bone morphogenetic protein (BMP) signaling pathway, which requires a complex of plasma membrane proteins, including HJV acting as a BMP coreceptor. However, the precise mechanism by which NEO1 and HJV are orchestrated to robustly activate this pathway remains poorly understood. In this study, we systemically investigated the mechanisms by which hepatic Neo1 coordinates with Hjv to facilitate hepcidin induction using various knockout mouse models. Our data indicate that although Hjv is a more potent inducer of hepcidin than hepatic Neo1, the simultaneous ablation of both <i>Neo1</i> and <i>Hjv</i> greatly reduces hepcidin expression. These results suggest that these two proteins form a crucial functional axis for controlling hepcidin levels. Further analysis revealed that ∼84% of hepcidin expression relies on the synergistic association of Neo1 with Hjv. In comparison, Hjv retains a significantly compromised (∼12%) ability to induce hepcidin independently of Neo1, whereas Neo1 possesses only a residual (∼3%) independent induction capacity. Collectively, these data support a model in which hepatic Neo1 acts primarily as a molecular scaffold to facilitate assembly of the hepcidin-inducing signaling complex through Hjv.<b>NEW & NOTEWORTHY</b> Hepcidin expression in hepatocytes relies on a multiprotein plasma membrane complex. This study establishes a critical functional axis between neogenin and hemojuvelin within this complex, revealing how their coordination is essential for systemic iron homeostasis. Our findings provide a new mechanistic framework for understanding the assembly of the hepcidin-signaling complex.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":"331 5","pages":"G489-G503"},"PeriodicalIF":3.0,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149178856","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":"Longitudinal Shifts in Gut Microbiota After Cholecystectomy: A Point of No Return in Losing Lactobacillus Spp.","authors":"Yu-Tse Chiu, Fu-Jen Lee, Chen-Ya Kuo, Po-Chih Yang, Jia-Uei Wong, Kai-Shun Liang, Ching-Hung Tseng, Jaw-Town Lin, Chun-Ying Wu, Chi-Yang Chang","doi":"10.1152/ajpgi.90057.2026","DOIUrl":"https://doi.org/10.1152/ajpgi.90057.2026","url":null,"abstract":"<p><p>Cholecystectomy alters bile acid dynamics and may influence gut microbiota composition. However, longitudinal data with preoperative baseline assessment remain limited, and existing evidence is largely based on cross-sectional studies with inconsistent findings. In this prospective cohort study, we aimed to characterize longitudinal changes in gut microbiota following cholecystectomy and explore their clinical relevance. Patients planning to undergo laparoscopic cholecystectomy were recruited and followed for 12 months. Stool samples were collected at baseline and at 1, 3, 6, and 12 months postoperatively. Microbiota composition was analyzed using 16S rRNA gene sequencing. Microbial diversity and differential abundance were evaluated using complementary statistical approaches, including longitudinal analyses accounting for repeated measurements. Clinical outcomes, including stool form and defecation frequency, were recorded. Twenty participants completed follow-up. Overall microbial diversity and community structure showed only modest changes over time. In contrast, differential abundance analyses consistently demonstrated an early postoperative reduction in the genus <i>Lactobacillus</i>, which remained relatively stable thereafter. Functional prediction suggested modest alterations in metabolic pathways without major disruption of global microbial function. No participants developed clinically significant post-cholecystectomy diarrhea. In conclusion, gut microbiota after cholecystectomy exhibited relatively modest overall changes but selective taxonomic alterations, particularly a persistent reduction in <i>Lactobacillus</i>. These findings suggest targeted microbial restructuring rather than global dysbiosis and may help explain the low incidence of post-cholecystectomy diarrhea.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126530","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":"Sex- and hepatocyte PPARγ-dependent effects of an obesogenic dietary approach to induce MASH with fibrosis in mice.","authors":"Marta Sierra-Cruz, Izabela Hawro, Samuel M Lee, Jose Muratalla, Jose Cordoba-Chacon","doi":"10.1152/ajpgi.00117.2026","DOIUrl":"10.1152/ajpgi.00117.2026","url":null,"abstract":"<p><p>Mouse models of metabolic dysfunction-associated steatotic liver disease (MASLD) are valuable tools for identifying novel molecular mechanisms that drive progression from MASLD to metabolic dysfunction-associated steatohepatitis (MASH). However, developing a robust MASLD/MASH mouse model with obesity and peripheral metabolic dysfunction remains a challenge. In this study, we have fed two different MASH-inducing diets to male mice with pre-existing high-fat (HF) diet-induced obesity. While a HF diet with 40% Kcal from fat (mostly corn-oil shortening), 2% cholesterol, and 22% fructose reduced adiposity in mice with pre-existing obesity, a high-fat diet with 60% Kcal from fat (mostly lard), 2% cholesterol and supplemented with 10% fructose in the drinking water (HFC+Fr diet) promoted body weight and fat mass gain. Of note, 24 weeks of the HFC+Fr diet induced obesity, metabolic dysfunction, liver steatosis, and increased the expression of hepatic peroxisome proliferator-activated receptor  (<i>Pparg</i>, PPARG) in both male and female mice. However, HFC+Fr diet promoted MASH with fibrosis only in male mice, which was reduced by the knockout of <i>Pparg</i> in hepatocytes (<i>Pparg</i>^ΔHep). In addition, the expression of key hepatic genes involved in methionine metabolism was downregulated by the HFC+Fr diet in control male mice, whereas <i>Pparg</i>^ΔHep upregulated their expression. Overall, the HFC+Fr diet is obesogenic and promotes MASLD in both male and female mice. However, the HFC+Fr diet promotes MASH in a sex- and hepatocyte PPARG-specific manner, which may be associated with downregulation of genes involved in hepatic methionine metabolism.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149102721","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":"Colonic metabolomic and transcriptomic alterations in a mouse model of metabolic syndrome.","authors":"Jaclyn A Rivas, David P Scieszka, Eduardo Peralta-Herrera, Crystal Madera Enriquez, Seth D Merkley, Audrey L Nava, Rama R Gullapalli, Yan Guo, Eliseo F Castillo","doi":"10.1152/ajpgi.00121.2026","DOIUrl":"10.1152/ajpgi.00121.2026","url":null,"abstract":"<p><p>Metabolic syndrome (MetS), characterized by abdominal obesity, insulin resistance, dyslipidemia, and hypertension, affects a substantial proportion of the global population and increases the risk for cardiovascular disease, diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). Despite its prevalence, there are currently no effective pharmacological therapies targeting MetS, highlighting the need to identify novel etiological mechanisms, particularly within the gastrointestinal (GI) tract. Using a mouse model of MetS and healthy lean controls, we assessed the colonic microenvironment through metabolomic, transcriptomic, and microbiome analyses. Colonic organoids were cultured to further explore epithelial alterations. Additionally, human MetS fecal metabolomics data were cross compared with the mouse model to validate translational relevance. MetS mice exhibited upregulation of colonic anabolic pathways, including glycolysis, the pentose phosphate pathway, and the tryptophan/kynurenine pathway, without evidence of intestinal inflammation. Microbiome analysis revealed an increased abundance of the genus <i>Lactobacillus</i> in MS NASH mice. Colonic organoids from MetS mice showed altered goblet cell differentiation. Comparative analysis with human MetS fecal metabolomics demonstrated similar dysregulated pathways, underscoring the translational relevance of these findings. Our study reveals significant metabolic and microbial alterations in the colon of MS NASH mice, implicating a dysfunctional GI tract as a potential etiological factor in MetS. These findings highlight specific metabolic pathways and microbial signatures that could serve as future therapeutic targets for MetS.<b>NEW & NOTEWORTHY</b> This study identifies the colon as a metabolically active tissue affected in metabolic syndrome. Despite the absence of intestinal inflammation, MS NASH mice displayed altered colonic metabolism and microbiota composition, with conserved metabolite changes matching those seen in humans with metabolic syndrome. These findings highlight colonic metabolic dysfunction as a potential driver of gut dysbiosis and disease progression in metabolic syndrome and metabolic dysfunction-associated steatotic liver disease (MASLD).</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G462-G473"},"PeriodicalIF":3.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13592510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148682808","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":"Reversal of injury-induced fibrosis and anal sphincter muscle dysfunction by sFRP2 in rabbits.","authors":"Jagadeesh Thippeswamy, Merlin Mamachan, Hillary Zhou, Manesh Kumar Panner Selvam, Mahadevan Rajasekaran, Ravinder K Mittal","doi":"10.1152/ajpgi.00157.2026","DOIUrl":"10.1152/ajpgi.00157.2026","url":null,"abstract":"<p><p>Anal sphincter injury is a major cause of anal incontinence (AI), and current treatments rarely restore anal sphincter muscle function. Secreted frizzled-related protein 2 (sFRP2) may promote muscle regeneration and reduce fibrosis, but its ability to reverse the established external anal sphincter (EAS) fibrosis and restore function is not known. This study examined whether sFRP2 promotes functional and structural recovery in a rabbit model of established EAS muscle fibrosis. Adult female rabbits underwent EAS myotomy and, 6 wk later, received local injections of sFRP2 or saline. Anal canal pressure was recorded before injury, immediately after myotomy, 6 wk postinjury, and every 2 wk for 6 wk following treatment with sFRP2. Myotomy significantly reduced anal canal pressure and induced fibrosis in the EAS muscle at 6 wk. sFRP2 treatment restored anal canal pressure to near preinjury levels within 2 wk after sFRP2 injection, which remained elevated 6 wk posttreatment, whereas saline-treated rabbits maintained low pressure. In the sFRP2 compared with saline-treated animals, (<i>1</i>) histological analysis demonstrated significant increase in EAS muscle percent, (<i>2</i>) hydroxyproline assay showed reduced collagen content, (<i>3</i>) Western blot analysis revealed increased expression of embryonic myosin heavy chain (eMyHC), myogenin, and active JNK, along with reduced vimentin, transforming growth factor (TGF)-β1, and nuclear active β-catenin, whereas collagen 1A1 (Col1A1) and pSmad2/3 showed a downward trend, and (<i>4</i>) proteomic analysis showed reduced fibrogenesis and TGF-β signaling, with activation of planar cell polarity (PCP)-JNK, and striated muscle contraction pathways. These findings suggest that sFRP2 restores EAS muscle function and promotes muscle regeneration, thus representing a potential novel therapy for the injury-induced anal sphincter dysfunction.<b>NEW & NOTEWORTHY</b> This study demonstrates for the first time that local administration of sFRP2 into fully established external anal sphincter (EAS) fibrosis reverses fibrosis and restores anal canal pressure in a rabbit model. Through coordinated modulation of Wnt/β-catenin, TGF-β, and PCP-JNK signaling pathways, sFRP2 promotes true muscle regeneration. These findings identify sFRP2 as a promising novel therapy for injury-induced anal sphincter dysfunction.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G474-G488"},"PeriodicalIF":3.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149023581","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":"Soluble adenylyl cyclase regulates tight junctions of human intestinal epithelial cells via claudin-4.","authors":"Hang Lam Li, Kam Ho-Mok, Arthur Verhoeven, Ronald Oude Elferink","doi":"10.1152/ajpgi.00316.2025","DOIUrl":"10.1152/ajpgi.00316.2025","url":null,"abstract":"<p><p>Although cAMP is a major intracellular messenger, studies on modulating effects of cAMP on tight junctions in epithelial cells are very limited. In this study, we characterized a bidirectional and prominent regulation of the tight junction by soluble adenylyl cyclase (sAC) in human intestinal epithelial (Caco2Bbe1) cells. Pharmacological inhibition and knockdown of sAC substantially increased TEER, whereas overexpression of sAC reciprocally decreased TEER. Mechanistically, EPAC1 was the sole cAMP effector responsible for the regulation of TEER by sAC. Pharmacological inhibition or knockdown of sAC and inhibition of EPAC1 resulted in increased protein expression of claudin-4, and again, with a reciprocal decrease of claudin-4 protein expression upon sAC overexpression. These interventions did not affect paracellular lucifer yellow permeability. sAC inhibition also induced phosphorylated extracellular signal-regulated kinase (p-ERK) protein expression. Although the ERK inhibitor, SCH772984, decreased TEER, ERK did not seem to be involved in the regulation of claudin-4 expression via sAC. Concluding from these data, sAC activity exerts a prominent bidirectional control over the ionic permeability of tight junctions in Caco2Bbe1 monolayers by regulating claudin-4 protein expression via EPAC1. This suggests a pivotal role of sAC in modulation of tight junctions in human intestinal epithelial cells, and proposes a molecular mechanism by which cAMP modulate tight junctions.<b>NEW & NOTEWORTHY</b> It is established that cAMP modulates tight junctions, but little is known about the mechanism behind. Here, for the first time, soluble adenylyl cyclase (sAC) was found to exert exclusive control over the ionic paracellular permeability in Caco2Bbe1 monolayers, while sparing the paracellular permeability of larger molecules. EPAC1 and claudin-4 were shown to be involved in the mechanism. Our data also suggest that other adenylyl cyclases are of minor importance in regulating ionic paracellular permeability.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G448-G461"},"PeriodicalIF":3.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886000","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":"Ethanol reshapes FFC-driven steatohepatitis through time-dependent fibrosis and lipid-droplet remodeling.","authors":"Jasmin Weninger, Amani Lee, George W Marek, Naomi Lange, Amy S Mauer, Gyanendra Puri, Vijay H Shah, Harmeet Malhi","doi":"10.1152/ajpgi.00223.2026","DOIUrl":"10.1152/ajpgi.00223.2026","url":null,"abstract":"<p><p>Metabolic dysfunction and alcohol exposure drive steatotic liver disease, yet how ethanol intersects with metabolic steatohepatitis remains incompletely defined. Our iterative model examined how ethanol ingestion alters high-fat, -fructose, and -cholesterol (FFC)-driven liver injury, identifying metabolic dysfunction and alcohol-associated liver disease (MetALD)-relevant features. A pilot study in male and female C57BL/6J mice compared chow diet (CD), FFC, CD + ethanol (E), and FFC + E on high-glucose/fructose (sugar) water (SW) at 6, 16, and 24 wk. A redesigned study lowered glucose/fructose exposure, modified ethanol acclimation, and tested five male cohorts: CD, CD + SW, FFC + SW, CD + SW + E, FFC + SW + E, at 16 and 24 wk. In the pilot study, FFC-dominant hepatomegaly, aminotransferase elevation, steatosis, chemokine induction, and fibrosis, without additive ethanol effects, were observed. In the redesigned model, FFC drove weight gain, hepatomegaly, steatosis, aminotransferase elevation, and chemokine (C-C motif) ligand 2 (<i>Ccl2</i>)<i>/</i>tissue inhibitor of metalloproteinase 1 (<i>Timp1</i>)-associated fibroinflammatory remodeling. However, ethanol selectively modified collagen-positive fibrotic remodeling and lipid-droplet architecture. At 16 wk, FFC + SW + E increased collagen area compared with FFC + SW despite lower body/liver mass and no additive aminotransferase response. Boron-dipyrromethene (BODIPY) morphometry showed enlarged lipid droplets in both FFC groups, but FFC/ethanol demonstrated reduced lipid-droplet area. In contrast, hepatic triglycerides increased with FFC but did not differ between FFC + SW and FFC + SW + E, supporting altered lipid-storage architecture rather than lipid accumulation or steatosis. chemokine (C-X-C motif) ligand 1 (<i>Cxcl1</i>) was induced by ethanol in CD mice but not uniformly upregulated on FFC. By 24 wk, fibrosis, alpha-smooth muscle actin staining, quantitative PCR (qPCR) markers, and NanoString immune profiles converged between FFC groups. Thus, chronic ethanol in a MetALD mouse model selectively modifies collagen-positive fibrotic remodeling, lipid storage, and inflammatory features of FFC-driven liver injury.<b>NEW & NOTEWORTHY</b> This study presents a refined murine MetALD model designed to distinguish ethanol-modified features from FFC-driven metabolic steatohepatitis. Chronic ethanol did not uniformly worsen liver injury. Instead, it selectively modified disease trajectory through greater early collagen-positive fibrotic remodeling, altering lipid-droplet architecture, and context-dependent inflammatory chemokine signaling. By 24 wk, FFC and FFC/ethanol injury programs converged, supporting MetALD as a timing- and pathway-dependent modification of metabolic steatohepatitis.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G399-G413"},"PeriodicalIF":3.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13597029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787197","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":"Three-dimensional architecture of the liver: structural organization, methodological advances, and functional implications.","authors":"Roy Siegelmann, Jagoda Litowczenko, Gilad Gomé, Tolga Durak, Ron Weiss","doi":"10.1152/ajpgi.00133.2026","DOIUrl":"10.1152/ajpgi.00133.2026","url":null,"abstract":"<p><p>Though comprising only 2%-3% of body weight, the liver performs more than 500 distinct biochemical tasks, despite a parenchyma built almost entirely of hepatocytes-a single cell type that alone metabolizes carbohydrates, lipids, and proteins, synthesizes plasma proteins, produces bile, and detoxifies xenobiotics. How one cell type achieves this breadth turns out to depend on three-dimensional architecture and the zonal gradients it creates. Anatomists have offered many frameworks for this organization: the classical hexagonal lobule, the portal lobule, the metabolic acinus, and the modular polyhedral architecture recovered by serial reconstruction of human tissue. Position within the lobule dictates function: roughly half the hepatocyte transcriptome is zonated along the portal-to-central axis, organized by a Wnt gradient from central-vein endothelium, and the zonation is so strong that drug toxicities, steatosis, and fibrosis each strike preferentially in different zones. This review surveys the methods used to study liver architecture across scales-vascular corrosion casting, serial sectioning, micro-computed tomography, tissue clearing, light-sheet microscopy, and single-cell and spatial transcriptomics-and their findings, together with the computational models that attempt to integrate these scales and predict tissue-level behavior. A remarkable feature of the liver is its capacity to regenerate: lost mass and much of its architecture can be restored. Regeneration in the adult liver recapitulates much of development, raising the prospect that bioengineered and synthetic-biology approaches may eventually rescue failing human tissue. The tools to pursue this are increasingly available, though substantial gaps remain before such approaches reach the clinic.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G414-G447"},"PeriodicalIF":3.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148756890","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":"Butyrate Triggers Neuronal Signaling via Release of Colonic Serotonin in a Microfluidic Model of Gut-Brain Axis.","authors":"Awurama Ofori-Kwafo, Hemaa Sree Kumar, Emily B Otmanowski, Earshed Al Mamun, Ajla Habibic-Beskovic, Qiuhong Li, Jasenka Zubcevic, Yuan Tang","doi":"10.1152/ajpgi.00014.2026","DOIUrl":"https://doi.org/10.1152/ajpgi.00014.2026","url":null,"abstract":"<p><p>Host-microbiota interactions play a central role in regulating gastrointestinal and cardiometabolic physiology, yet the mechanistic pathways linking microbial metabolites to sensory neuronal activation remain poorly defined. In particular, the rapid signaling events through which short-chain fatty acids such as butyrate influence epithelial and neuronal function in the colon have not been fully resolved due to limitations of existing models. Here, we developed and validated a compartmentalized microfluidic tri-channel model that spatially organizes primary colonic epithelial cells, sensory neurons, and microbial inputs to enable real-time, directional analysis of microbial-epithelial-neuronal communication to mimic the in vivo environment of the gastrointestinal tract. Using computational modeling and real-time imaging, we demonstrate a timeline in which butyrate elicits dose-dependent calcium (Ca²⁺) influx in the sensory neurons, mediated through a multi-step signaling cascade: butyrate stimulation of colonic epithelial cells, via epithelial GPR41 and GPR43 receptors, triggering a rapid serotonin (5-HT) release that subsequently engages 5-HT3a receptors on sensory neurons to induce Ca²⁺ influx, indicative of neuronal activation. Pharmacological inhibition of epithelial GPR41 and GPR43 receptors, or neuronal 5-HT3a receptors abolished these responses, demonstrating the requirement for both (epithelial and neuronal) components in the signaling pathway. Epithelial cells were essential intermediaries, as neurons cultured without them failed to respond to butyrate. Moreover, we establish the feasibility of a live microbiota-epithelial-neuronal tri‑culture model that can be used for future mechanistic dissection of microbiota-gut-brain signaling.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149103208","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":"Endoscopic gastric pacing: A minimally invasive approach for slow wave entrainment in rhythmic and dysrhythmic states.","authors":"Nipuni D Nagahawatte, Sophie Rose, Linley Nisbet, Thomas L Abell, John A Windsor, Leo K Cheng","doi":"10.1152/ajpgi.90031.2026","DOIUrl":"https://doi.org/10.1152/ajpgi.90031.2026","url":null,"abstract":"<p><p><b>Background:</b> Disordered gastric electrical rhythms contribute to debilitating motility disorders and existing therapies remain largely symptomatic without restoring coordinated activity. Electrical pacing has shown promise but currently relies on surgical techniques, limiting clinical adoption. This study evaluated endoscopic mucosal pacing as a minimally invasive alternative for modulating gastric electrical activity. <b>Methods:</b> In pigs (n=11), intraluminal gastric pacing was delivered via a catheter-based mucosal electrode. Feasibility and efficacy were assessed under distinct electrophysiological states induced by propofol (rhythmic) and isoflurane (dysrhythmic) anesthesia. High-resolution serosal mapping quantified spatiotemporal responses. Pacing parameters, including pulse-amplitude (2-8 mA), pulse-width (100-400 ms), and electrode configuration (unipolar vs bipolar), were systematically varied to determine conditions for reliable entrainment. <b>Results:</b> Mucosal pacing successfully entrained gastric electrical activity under both rhythmic and dysrhythmic conditions. Entrainment outcomes were comparable between unipolar and bipolar configurations. Dysrhythmic states required substantially greater pacing input to achieve entrainment (75% success at 25,600 mA²ms (pulse-amplitude: 8mA, pulse-width: 400 ms)) than rhythmic states (86% at 6,400 mA²ms (pulse-amplitude: 4mA, pulse-width: 400 ms)). Overall, entrainment success was significantly greater under propofol than isoflurane (common odds ratio 3.6; P=0.007). <b>Conclusions:</b> Endoscopic mucosal pacing enables minimally invasive modulation of gastric electrical activity, with state-dependent pacing requirements informing personalized bioelectronic therapies and establishing a translational pathway for ingestible treatment platforms.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073210","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}