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

{"title":"Role of interstitial cells of Cajal in regulating tone and responses to enteric motor neurons in the murine pyloric sphincter.","authors":"Ji Yeon Lee, Sang Don Koh, Sal A Baker, Kenton M Sanders","doi":"10.1152/ajpgi.00350.2025","DOIUrl":"10.1152/ajpgi.00350.2025","url":null,"abstract":"<p><p>Gastric slow waves fail to propagate through the pyloric sphincter (PS), thus isolating the specialized motility patterns of the stomach and small intestine. We investigated the role of interstitial cells of Cajal (ICC) in PS of mice. Ca²⁺ waves in ICC, events responsible for electrical slow waves, propagated along the gastric wall but failed to propagate into the PS. ICC in PS fired localized Ca²⁺ transients and displayed low expression of voltage-dependent Ca²⁺ conductances. These are properties of intramuscular ICC (ICC-IM) that cannot regenerate and propagate slow waves. A T-type Ca²⁺ channel antagonist had no effect on Ca²⁺ transients, but these events were blocked by thapsigargin and cyclopiazonic acid, suggesting that they result from Ca²⁺ release. PS ICC expressed ANO1, a Ca²⁺-activated Cl^- conductance. Ca²⁺ released from stores activates ANO1 channels, thus exerting a depolarizing influence on PS. Ani9, a selective antagonist of ANO1 channels, hyperpolarized cells and reduced contractile tone. Electrical field stimulation (EFS) of intrinsic neurons yielded inhibitory junction potentials (IJPs), and cessation of EFS resulted in poststimulus depolarization and contraction. <i>N</i>^ω-nitro-l-arginine (L-NNA) abolished relaxation responses to EFS and switched responses to contractions. Application of atropine or Ani9 (in the presence of L-NNA) abolished contraction during EFS. Our results describe new and fundamental functions of ICC-IM in the PS. The inability of these cells to propagate slow waves provides the insulator function of PS muscles and localized Ca²⁺ transients, and activation of ANO1 regulates PS tone and mediates inputs from enteric neurons.<b>NEW & NOTEWORTHY</b> The pyloric sphincter is an electrical insulator between the stomach and small intestine, isolating and maintaining the unique motility patterns of these organs. Using Ca²⁺ imaging techniques, this study demonstrates why slow waves do not propagate between organs and how interstitial cells of Cajal serve to regulate pyloric tone and responses to enteric motor neurons.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G330-G340"},"PeriodicalIF":3.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028164","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":"Highly Ca²⁺-permeable transient receptor potential vanilloid 6 contributes to the protection against colitis by regulating epithelial barrier function.","authors":"Yuki Murayama, Hiroyuki Yasuda, Michiko Saito, Shusaku Hayashi, Kenjiro Matsumoto, Shinichi Kato","doi":"10.1152/ajpgi.00318.2025","DOIUrl":"10.1152/ajpgi.00318.2025","url":null,"abstract":"<p><p>Transient receptor potential vanilloid 6 (TRPV6) is a highly Ca²⁺-permeable cation channel predominantly expressed in the intestinal epithelium. It plays a crucial role in maintaining systemic calcium homeostasis by regulating Ca²⁺ absorption in the intestine. However, its local physiological and pathophysiological roles in the intestine remain unexplored. The exact cause of inflammatory bowel disease is not fully understood; however, disruption of the intestinal epithelial barrier is a key pathogenic mechanism. In this study, we aimed to elucidate the role of TRPV6 in the pathogenesis of colitis. Experimental colitis was induced in TRPV6-deficient [knockout (KO)] and wild-type (WT) mice by administering 2% dextran sulfate sodium (DSS) solution in drinking water for 7 days. DSS treatment resulted in weight loss, diarrhea/bloody stool, histological colonic injury, and colon shortening. The systemic symptoms and colonic injury were significantly worse in TRPV6KO mice than in WT mice. DSS treatment increased tumor necrosis factor-α, interleukin-1β, interleukin-6 mRNA expressions, and myeloperoxidase activity, and these responses were significantly enhanced in TRPV6KO mice compared with WT mice. Under normal (no DSS-treated) conditions, TRPV6KO mice exhibited increased intestinal permeability compared with WT mice. No difference was observed in the number of goblet cells between WT and TRPV6KO mice; however, the expression of intercellular junction proteins, including E-cadherin, claudin-3, and occludin, was significantly suppressed in TRPV6KO mice compared with WT mice. These findings suggest that TRPV6 protects against DSS-induced colitis, potentially by regulating epithelial barrier function through intracellular junction protein expressions.<b>NEW & NOTEWORTHY</b> This study is the first to reveal the local role of TRPV6 in the intestine. TRPV6KO exacerbated dextran sulfate sodium-induced colitis and increased intestinal permeability compared with wild-type mice. Furthermore, intercellular junction protein expression was lower in TRPV6KO mice. TRPV6 protects against colitis by maintaining epithelial barrier function by regulating intercellular junction protein expression. Thus, TRPV6 may be a novel therapeutic candidate for treating inflammatory bowel disease.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G302-G313"},"PeriodicalIF":3.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146123394","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-specific differences in liver DNA methylation patterns and epigenetic aging in mice.","authors":"Shant Apelian, Ramanaiah Mamillapalli, Abdullah Ucar, Nimisha Gawde, Hugh S Taylor","doi":"10.1152/ajpgi.00322.2025","DOIUrl":"10.1152/ajpgi.00322.2025","url":null,"abstract":"<p><p>Biological sex has been shown to influence aging outcomes, contributing to distinct trajectories in disease susceptibility and lifespan. DNA methylation patterns provide a quantitative measure of biological aging. This study investigated whether aged male and female mice display distinct liver DNA methylation patterns and differences in epigenetic aging. Liver samples were collected from 17 aged c57BL/6 mice (6 males, 11 females). Genomic DNA was extracted and bisulfite-converted before targeted enrichment of 2,045 murine age-associated CpG loci. Biological age (DNAge) was estimated using a previously developed DNA methylation-based predictor generated through elastic net regression. The difference (ΔDNAge) between DNAge and chronological age was computed. Sex-specific differences were assessed by comparing site-specific methylation ratios, ΔDNAge values, and through principal component analysis (PCA) and multiple linear regression. Twelve CpG sites across six genes (<i>Fam84b</i>, <i>Zswim6</i>, <i>Hsf4</i>, <i>Mn1</i>, <i>Qprt</i>, and <i>Rapgefl1</i>) showed significant sex-associated differences in methylation. <i>Fam84b</i> demonstrated the largest and most consistent sex-associated effect, with all three associated CpG sites showing higher methylation in males (regression coefficients: -0.204, -0.281, and -0.294). <i>Zswim6</i> exhibited consistent lower methylation ratios in females, whereas the other genes showed higher methylation in females. There were no sex differences in biological age or ΔDNAge (<i>P</i> = 0.596). Although the epigenetic clock did not reveal differences between sexes in aging, aged mice did exhibit sex-specific liver methylation patterns different from those reported in younger mice, suggesting that sex-dependent epigenetic changes may emerge later in life and may reflect sexual dimorphism in liver function with age.<b>NEW & NOTEWORTHY</b> Males and females are known to age differently and develop certain diseases at different rates. Here, we examined the livers of aged male and female mice to see if they show different DNA methylation patterns. We found that aged male and female mice had distinct DNA methylation patterns at specific genes. Interestingly, most of these methylation differences were not present in younger mice, suggesting that sex differences in the genome may change with age.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G361-G367"},"PeriodicalIF":3.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146200128","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":"Inhibitory effects of somatostatin on glucagon-like peptide-1-mediated acceleration of peristalsis in the rat proximal colon.","authors":"Hiroyuki Nakamori, Fuko Hosoi, Hikaru Hashitani","doi":"10.1152/ajpgi.00189.2025","DOIUrl":"10.1152/ajpgi.00189.2025","url":null,"abstract":"<p><p>Colonic motility is controlled by the enteric nervous system that is modulated not only by autonomic neurotransmitters but also by substances released from enteroendocrine cells. Glucagon-like peptide-1 (GLP-1) secreted from L cells accelerates peristalsis of the proximal colon, whereas somatostatin released from D cells inhibits GLP-1 secretion via the activation of somatostatin receptor subtype 5 (SST₅). Here, effects of somatostatin on GLP-1-mediated acceleration of colonic peristalsis were investigated. Cannulated segments of rat proximal colon were serosally perfused with oxygenated physiological salt solution and luminally perfused with degassed solution. Colonic wall motion was imaged and converted into spatiotemporal maps. Distributions of somatostatin and SST₅ receptors were assessed via immunohistochemistry. Intraluminal administration of somatostatin alone did not affect oro-aboral propagating peristaltic contractions, but prevented luminal-applied GLP-1 (30 nM)-induced acceleration of peristaltic waves. Somatostatin also prevented the prokinetic action of endogenous GLP-1 that was released upon the stimulation by luminal-applied short-chain fatty acids (SCFA, 3 mM) or lipopolysaccharide. In colonic segments that had been pretreated with selective SST₅ receptor antagonist 1, a lower concentration of GLP-1 (10 nM) or SCFA (300 µM) became capable of accelerating peristaltic waves. GLP-1-positive epithelial cells coexpressed SST₅ receptors, whereas GLP-1 receptor-positive epithelial cells and afferent neurons contained somatostatin. Thus, L cell-derived GLP-1 that accelerates colonic peristalsis may simultaneously stimulate D cells and afferents to release somatostatin that serves as a break on prokinetic actions of GLP-1 by activating SST₅ receptors on L cells. This interplay between GLP-1 and somatostatin would prevent excessive colonic motility.<b>NEW & NOTEWORTHY</b> Somatostatin inhibited the prokinetic action of glucagon-like peptide-1 (GLP-1), short-chain fatty acids, and lipopolysaccharide. The inhibitory effect of somatostatin was mediated by the activation of somatostatin receptor subtype 5 that was expressed on L cells. Sources of somatostatin were D cells and intrinsic primary afferent neurons, both of which expressed GLP-1 receptors. Thus, colonic peristalsis may well be regulated by the functional interaction between excitatory GLP-1 and inhibitory somatostatin.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G256-G269"},"PeriodicalIF":3.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146058551","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":"New approach methodologies in Crohn's disease link molecular disease subtypes to clinical outcomes.","authors":"Harrison M Penrose, Saptarshi Sinha, Courtney Tindle, Kameron Zablan, Helen N Le, Jennifer Neill, Pradipta Ghosh, Brigid S Boland","doi":"10.1152/ajpgi.00393.2025","DOIUrl":"10.1152/ajpgi.00393.2025","url":null,"abstract":"<p><p>Current clinical decision-making is hindered by the absence of predictive preclinical models that faithfully bridge molecular diversity to patient outcomes. Here, we apply the principle of abstraction-deriving essential features from human tissues to build next-generation new approach methodologies (NAMs) that transform patient-derived organoids (PDOs) into predictive vehicles for Crohn's disease (CD). From our living biobank of adult stem cell-derived colonic PDOs, we previously defined two molecular CD subtypes: immune-deficient infectious CD (IDICD) and stress and senescence-induced fibrostenotic CD (S2FCD), each defined by unique genomic, transcriptomic, and functional profiles with matched therapeutic vulnerabilities. In this study, we prospectively anchored PDO-derived molecular phenotypes to real-world clinical outcomes, revealing that S2FCD maps to baseline and progressive colonic disease activity, whereas IDICD tracks with prior ileocecal surgery, penetrating disease behavior, as well as baseline and progressive ileal disease activity. By abstracting NAMs from human tissues and cycling insights between small-\"n\" organoids and Phase 3-sized datasets, this framework recasts PDOs as dynamic, predictive platforms that capture the past, present, and future of disease behavior. Beyond oncology, this work establishes PDOs as vehicles for prospective clinical trial-like studies in inflammatory diseases and highlights colonic immune dysfunction as a potential driver of ileal CD.<b>NEW & NOTEWORTHY</b> In this prospective study, Penrose et al. evaluate a living biobank of genotyped and phenotyped patient-derived organoids (PDOs) as predictive tools in Crohn's disease, demonstrating their ability to faithfully capture past, present, and future disease behavior. By positioning PDOs as new approach methodologies (NAMs), this work extends PDO-informed precision medicine beyond oncology and into complex inflammatory disorders, translating molecular diversity into actionable clinical insights.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G322-G329"},"PeriodicalIF":3.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13008478/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146148891","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":"Expression of Concern for Garneau et al., volume 293, 2007, p. G758-G772.","authors":"","doi":"10.1152/ajpgi.00050.2007_EOC","DOIUrl":"10.1152/ajpgi.00050.2007_EOC","url":null,"abstract":"","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":"330 3","pages":"G314"},"PeriodicalIF":3.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147343519","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":"WNT3a induces external anal sphincter fibrosis and dysfunction in rabbits.","authors":"Jagadeesh Thippeswamy, Merlin Mamachan, Jennifer Shin, Sushma Halekote Rudramurthy, Manesh Kumar Panner Selvam, Mahadevan Rajasekaran, Ravinder K Mittal","doi":"10.1152/ajpgi.00349.2025","DOIUrl":"10.1152/ajpgi.00349.2025","url":null,"abstract":"<p><p>Injury and aging of the external anal sphincter (EAS) muscle lead to fibrosis and muscle dysfunction, major contributors to fecal incontinence. Activation of the WNT/β-catenin signaling pathway has been linked to fibrosis in various tissues, including skeletal muscle. This study examined whether the WNT agonist Wnt3a induces fibrosis and dysfunction in the EAS muscle. Adult female New Zealand White rabbits received four local injections of Wnt3a or saline into the EAS muscle. Anal canal pressure was measured by manometry every 2 wk for 8 wk, followed by histological, immunofluorescent, immunohistochemistry (IHC), Western blot, and proteomic analyses of the EAS muscle. Rabbits treated with Wnt3a exhibited a significant reduction in anal canal pressure 8 wk postinjection (<i>P</i> ≤ 0.05) compared with controls. Histologic evaluation revealed increased connective tissue (<i>P</i> = 0.06), significant collagen deposition, and decreased muscle area and fiber thickness (<i>P</i> ≤ 0.05). Western blot analysis showed elevated levels of β-catenin, nuclear active β-catenin (PY489), Smad1/2/3, signal transducer and activator of transcription 3 (Stat3), transforming growth factor-β (TGF-β), and vimentin (<i>P</i> ≤ 0.05), with p-Stat3, p-Smad3, and collagen-4 trending upward. Immunofluorescence and IHC confirmed increased β-catenin, collagen-4, and TGF-β levels, and proteomic data indicated altered pathways related to muscle contraction, fibrosis, and atrophy. These findings demonstrate that direct administration of a WNT agonist promotes EAS fibrosis and dysfunction, mirroring changes associated with aging and injury. Local application of WNT antagonists may represent a therapeutic strategy to prevent anal sphincter dysfunction following injury.<b>NEW & NOTEWORTHY</b> In the current study, for the first time we investigated the effects of a local injection of Wnt3a-an agonist of the WNT signaling pathway-on EAS function, muscle replacement by fibrosis, and the activation of downstream WNT signaling pathways. Wnt3a injection resulted in impaired EAS function and replacement of muscle with fibrosis. Notably, the downstream signaling remained active even 8 wk after the Wnt3a injection.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G349-G360"},"PeriodicalIF":3.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13023414/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146163734","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":"Esophageal symptom burden remains high and associates with failed swallows after 5 years in patients with ineffective esophageal motility.","authors":"Andree H Koop, Induja R Nimma, Kevin Avaiya, Manar Al Jawish, Einar V Acuna, Brian E Lacy","doi":"10.1152/ajpgi.00287.2025","DOIUrl":"10.1152/ajpgi.00287.2025","url":null,"abstract":"<p><p>Ineffective esophageal motility (IEM) is a motor disorder of the esophagus diagnosed by high-resolution esophageal manometry (HRM) and associated with symptoms of gastroesophageal reflux disease (GERD) and dysphagia; however, the long-term significance is unclear. The goal of this study was to assess esophageal symptoms in patients with IEM diagnosed 5 or more years earlier. Adult patients diagnosed with IEM ≥5 years earlier by HRM were included and sent validated esophageal symptom questionnaires including the Gastroesophageal Reflux Disease Questionnaire (GerdQ), Gastroesophageal Reflux Disease Health-related Quality of Life (GERD-HRQL) Questionnaire, and the Brief Esophageal Dysphagia Questionnaire (BEDQ). Symptom scores were assessed by esophageal motor function including the number of intact, failed, and ineffective swallows. Statistical analysis was performed using Fisher's exact test, Mann-Whitney <i>U</i> test, and Spearman correlation coefficients. Forty-seven patients were included, and 26 (55.3%) were positive for GERD by the GerdQ score, 21 (44.7%) by GERD-HQRL, and 35 (74.5%) for dysphagia by BEDQ score. Presence of ≥7 swallows with failed peristalsis was associated with a greater GerdQ score (9 vs. 7, <i>P</i> = 0.029) and dissatisfaction with current symptoms; ≥8 failed swallows was associated with worse dysphagia by the BEDQ score (21.5 vs. 12, <i>P</i> = 0.037). Number of failed swallows correlated with GerdQ (ρ = 0.46, <i>P</i> = 0.0011) and GERD-HRQL scores (ρ = 0.43, <i>P</i> = 0.0025). In this cross-sectional survey study of patients with IEM diagnosed five or more years earlier, at least 45% reported GERD symptoms, 75% dysphagia symptoms; the number of swallows with failed peristalsis was associated with worse GERD and dysphagia symptoms.<b>NEW & NOTEWORTHY</b> Patients with ineffective esophageal motility continue to experience significant symptoms years after diagnosis. In this survey of 47 patients diagnosed ≥5 years earlier, 45% reported GERD symptoms and 75% reported dysphagia. Greater numbers of failed swallows correlated with worse GERD and dysphagia scores, highlighting the long-term clinical impact of IEM and its association with esophageal symptom burden.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G315-G321"},"PeriodicalIF":3.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146091770","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":"Bolus pressure and bolus mismatch in patients with dysphagia and preserved esophageal peristalsis.","authors":"Myeongsook Seo, Segyeong Joo, Ravinder K Mittal","doi":"10.1152/ajpgi.00388.2025","DOIUrl":"10.1152/ajpgi.00388.2025","url":null,"abstract":"<p><p>Dysphagia is common in patients with preserved contraction phase of esophageal peristalsis, such as those diagnosed with functional dysphagia (FD) or esophagogastric junction outflow obstruction (EGJOO); it amounts to ≥50% patients undergoing high-resolution manometry impedance (HRMZ) study. We aimed to characterize the distension phase of esophageal peristalsis (bolus domain) and identify abnormalities that may contribute to dysphagia in these patients. HRMZ recordings from 35 healthy controls, 35 patients with FD, and 35 patients with EGJOO were analyzed. Distension-contraction plots were used to assess the luminal cross-sectional area, bolus pressure, and regions without bolus (\"no-bolus areas\") within the bolus domain of peristalsis. The proportion of no-bolus area was compared among groups, and receiver operating characteristic (ROC) analysis evaluated diagnostic performance. Esophageal wall compliance during the distension phase was also determined. Both FD and EGJOO groups exhibited a significantly greater proportion of no-bolus area within the bolus domain compared with controls, particularly in the distal esophagus (<i>P</i> < 0.001). Pressure peaks frequently occurred in the absence of bolus, indicating pseudo-bolus pressures. Ultrasound imaging revealed transient luminal collapse against the manometry catheter in the \"pseudo-bolus\" zone. Esophageal wall compliance was reduced in both patient groups. ROC analysis demonstrated that the percentage of no-bolus area discriminated patients from controls with high accuracy (area under the curve 0.83 for FD, 0.88 for EGJOO). We propose that impaired esophageal distensibility and transient luminal collapse within the bolus domain cause functional obstruction and possibly dysphagia.<b>NEW & NOTEWORTHY</b> This study introduces a novel impedance-based method to analyze the bolus domain of esophageal peristalsis, emphasizing bolus pressure and bolus mismatch. Patients with functional dysphagia and EGJOO demonstrated impaired esophageal distension, reduced wall compliance, and frequent pseudo-bolus pressures from transient luminal collapse during peristalsis. These findings suggest that dysphagia may result from dynamic obstruction due to esophageal collapse during peristalsis rather than fixed outflow obstruction, highlighting bolus domain mechanics as a complementary diagnostic tool.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G293-G301"},"PeriodicalIF":3.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146091838","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":"Late-in-life treadmill training mitigates gut microbiome imbalances and cardiovascular disease risk in mice.","authors":"Jae Min Cho, Seul-Ki Park, Adhini Kuppuswamy Satheesh Babu, Sohom Mookherjee, Michele Hansen, Chrissa Petersen, Ying Zhong, Thunder Jalili, Michael S Robeson, Umesh D Wankhade, Pon Velayutham Anandh Babu, J David Symons","doi":"10.1152/ajpgi.00354.2025","DOIUrl":"10.1152/ajpgi.00354.2025","url":null,"abstract":"<p><p>Primary aging associates with an imbalanced gut microbiome and cardiovascular disease (CVD) risk in mice and humans. Strong evidence from clinical and preclinical studies supports that habitual physical exercise improves cardiovascular function and intestinal health in adults. Here we tested the hypothesis that exercise training, even when initiated late-in-life, reestablishes a beneficial and cooperative intestinal microbiome to an extent that associates with reduced risk for CVD. At 21 mo of age, male C57BL/6 mice started a progressive resistance treadmill training program 6 days per week (Old + ETR) for 12 wk. Twenty-one-month-old (Old) and 4-mo-old (Adult) male mice remained sedentary. First, reductions in exercise capacity and soleus muscle citrate synthase activity displayed by Old vs. Adult mice were restored in Old + ETR animals. Next, systolic function [fractional shortening (FS)], diastolic function (E/A ratio), and overall left-ventricular function [myocardial performance index (MPI)] otherwise depressed in Old vs. Adult mice were normalized in Old + ETR animals. Third, elevated trimethylamine (TMA) and TMA <i>N</i>-oxide (TMAO), and heightened inflammatory markers [e.g., interferon (IFN)-γ and keratinocyte-derived chemokine (KC)], observed in Old vs. Adult mice were lowered in Old + ETR animals. Importantly, the abundance of beneficial microbial features, including <i>Bacteroides</i>, Muribaculaceae, <i>Parabacteroides</i>, and the <i>Rikenellaceae RC9</i> gut group, otherwise depressed by aging, was normalized in Old + ETR mice. Finally, the <i>Rikenellaceae RC9</i> gut group was positively correlated with FS, and Parabacteroides was negatively correlated with IFN-γ. These findings support that late-in-life exercise training beneficially remodels the gut microbiome to an extent that associates with reduced CVD risk in male mice.<b>NEW & NOTEWORTHY</b> It is unknown whether exercise training, if started late-in-life, reestablishes a beneficial and cooperative intestinal microbiome. Here we demonstrate that a 12-wk treadmill running program in older mice rejuvenates the gut microbiome and attenuates markers of cardiovascular disease (CVD) risk. Notably, specific microbial taxa correlate with activity-induced improvements in overall myocardial performance and inflammation, highlighting the importance of gut health on CVD and illustrating the restorative benefits that can be attained from a low-cost lifestyle intervention.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G280-G292"},"PeriodicalIF":3.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111724","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}