搜索结果：American journal of physiology. Gastrointestinal and liver physiology

Breast cancer is a leading cause of mortality and morbidity among females worldwide. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, we provided an updated comprehensive assessment of the epidemiological trends, disease burden, and risk factors associated with breast cancer globally, regionally, and nationally from 1990 to 2023. Breast cancer incidence, mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) were estimated by age and sex for 204 countries and territories from 1990 to 2023. Mortality estimates were generated using GBD Cause of Death Ensemble models, leveraging data from population-based cancer registration systems, vital registration systems, and verbal autopsies. Mortality-to-incidence ratios were calculated to derive both mortality and incidence estimates. Prevalence was calculated by combining incidence and modelled survival estimates. YLLs were established by multiplying age-specific deaths with the GBD standard life expectancy at the age of death. YLDs were estimated by applying disability weights to prevalence estimates. The sum of YLLs and YLDs equalled the number of DALYs. Breast cancer burden attributable to seven risk factors was examined through the comparative risk assessment framework. The GBD forecasting framework was used to forecast breast cancer incidence and mortality from 2024 to 2050. Age-standardised rates were calculated for each metric using the GBD 2023 world standard population. In 2023, there were an estimated 2·30 million (95% uncertainty interval [UI] 2·01 to 2·61) breast cancer incident cases, 764 000 deaths (672 000 to 854 000), and 24·1 million (21·3 to 27·5) DALYs among females globally. In the World Bank low-income group, where a low age-standardised incidence rate (ASIR) was estimated (44·2 per 100 000 person-years [31·2 to 58·4]), the age-standardised mortality rate (ASMR) was the highest (24·1 per 100 000 [16·8 to 31·9]). The highest ASIR was in the high-income group (75·7 per 100 000 [67·1 to 84·0]), and the lowest ASMR was in the upper-middle-income group (11·2 per 100 000 [10·2 to 12·3]). Between 1990 and 2023, the ASIR in the low-income group increased by 147·2% (38·1 to 271·7), compared with a 1·2% (-11·5 to 17·2) change in the high-income group. The ASMR decreased in the high-income group, changing by -29·9% (-33·6 to -25·9), but increased by 99·3% (12·5 to 202·9) in the low-income group. The increase in age-standardised DALY rates followed that of ASMRs. Risk factors such as dietary risks, tobacco use, and high fasting plasma glucose contributed to 28·3% (16·6 to 38·9) of breast cancer DALYs in 2023. The risk factors with a decrease in attributable DALYs between 1990 and 2023 were high alcohol use and tobacco. By 2050, the global incident cases of breast cancer among females were forecast to reach 3·56 million (2·29 to 4·83), with 1·37 million (0·841 to 2·02) deaths. The stable incidence and declining mortality rates of female breast cancer in high-income nations reflect success in screening, diagnosis, and treatment. In contrast, the concurrent rise in incidence and mortality in other regions signals health system deficits. Without effective interventions, many countries will fall short of the WHO Global Breast Cancer Initiative's ambitious target of achieving an annual reduction of 2·5% in age-standardised mortality rates by 2040. The mounting breast cancer burden, disproportionately affecting some of the world's most vulnerable populations, will further exacerbate health inequalities across the globe without decisive immediate action. Gates Foundation, St Jude Children's Research Hospital.

Epigenetic regulations link environmental factors to the development of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). We determined the role of hepatocyte histone deacetylase 4 (HDAC4) in the pathogenesis of MASLD. Male and female hepatocyte-specific Hdac4 knockout (Hdac4HKO) mice and control Hdac4 floxed (Hdac4fl/fl) mice were fed a high-fat, high-sucrose, high-cholesterol diet for 16 wk to induce obesity and MASLD. The loss of hepatic Hdac4 increased serum alanine transaminase activity and exacerbated hepatic steatosis with higher liver weights and triglyceride levels than Hdac4fl/fl mice in males. Hepatic expression of lipogenic genes was significantly higher in male and female Hdac4HKO mice than in controls. Moreover, primary hepatocytes and the liver of Hdac4HKO mice exhibited perturbed insulin signaling, characterized by reduced phosphorylated AKT2. Interestingly, hepatocyte Hdac4 loss increased inflammatory and fibrogenic genes in gonadal white adipose tissue (gWAT). Serum cytokine array and proteomic analysis demonstrated alterations in several serum factors, which may contribute to crosstalk between the liver and WAT in Hdac4HKO, leading to obesity-induced metabolic dysfunction in gWAT. In conclusion, hepatocyte Hdac4 loss exacerbates hepatic steatosis, accompanied by disturbed insulin signaling and WAT inflammation and fibrosis in obese mice, underscoring its crucial role in liver-WAT crosstalk.NEW & NOTEWORTHY We examined the role of hepatocyte histone deacetylase 4 (HDAC4) in the development of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) using Hdac4-deficient mice with hepatocyte-specific deletion. We found that deleting Hdac4 in hepatocytes worsens hepatic steatosis and disrupts insulin signaling in the liver. In addition, this deletion caused inflammation and fibrosis in the white adipose tissue of obese mice, highlighting the role of HDAC4 in the liver-adipose axis.

Supplemental oxygen is widely used to treat hypoxemia, but prolonged exposure induces oxidative stress. We investigated whether hyperoxia-induced reactive oxygen species contribute to fatty liver injury and delineated the underlying mechanism. To enhance translational relevance, mice were housed under normoxic (21% O2) or hyperoxic (30% O2) conditions for 10 days. We also used H2O2-treated HepG2 cells and human liver organoids. Western blotting, real-time PCR, and immunostaining were performed to assess molecular changes. Hyperoxia increased systemic oxidative stress, inflammatory markers, liver weights, and hepatic triglyceride (TG) accumulation. These changes were accompanied by repression of fatty acid β-oxidation (FAO) and mitochondrial biogenesis genes and activation of lipogenesis. Hyperoxia also increased glycolysis, as shown by increased glucose transporter 2 (GLUT2) and glucokinase (Gck) expression, and activated protein kinase B (AKT) signaling without altering hypoxia-inducible factor-2α (HIF-2α) expression. Consistently, H2O2-treated HepG2 cells and human liver organoids exhibited similar alterations, including TG accumulation, upregulation of glycolytic and lipogenic markers, downregulation of FAO genes, and increased fibrosis marker and inflammation. Notably, siHIF-2α failed to attenuate TG accumulation, confirming an HIF-2α-independent mechanism. Finally, inhibition of AKT signaling attenuated TG accumulation and fibrosis in vitro by preventing glycolysis (via downregulation of GCK) and de novo lipid synthesis, whereas improving mitochondrial function; however, GLUT2 expression remained unaffected. In summary, hyperoxia-induced oxidative stress promotes hepatic TG accumulation and fibrosis by impairing mitochondrial function and enhancing glycolysis and lipogenesis in an AKT-dependent, HIF-2α-independent manner. These findings highlight risks of oxygen therapy on hepatic metabolism and identify AKT signaling as a therapeutic target to mitigate hyperoxia-induced fatty liver injury.NEW & NOTEWORTHY Hyperoxia-induced oxidative stress caused hepatic triglyceride accumulation and fibrosis through mitochondrial dysfunction, suppressed FAO, and enhanced glycolysis and lipogenesis. These effects were AKT-dependent but HIF-2α-independent, highlighting AKT signaling as a potential therapeutic target to mitigate oxygen-related fatty liver injury.

The migrating motor complex (MMC) is a key feature of fasting gastrointestinal (GI) motility, but its disruption in neuropathic conditions remains poorly characterized. Wireless motility capsules (WMCs) offer a noninvasive means of collecting motility data, facilitating study of larger cohorts. We aimed to develop WMC-derived metrics to identify neuropathic dysmotility and its associations with autonomic nervous system (ANS) function. We analyzed WMC data from 98 controls and 71 people living with human immunodeficiency virus (HIV; PWH) in whom autonomic neuropathy (AN) and delayed small bowel transit time (dSBTT) are common. We studied nine contractility metrics, including established and novel metrics targeting rhythmic bursts of sustained contractile activity. Autonomic function, summarized as Modified Composite Autonomic Severity Score (MCASS), was used to draw associations with contractility measures. All contractility metrics were higher in PWH compared with controls (P ≤ 0.01 for all). Among PWH, those with AN showed the highest contractility, whereas those with dSBTT had the lowest. In controls, rhythmic bursts were more clustered, especially in the later portions of the small bowel recording, and had less variability in contraction amplitude and timing, potentially indicating greater organization. Overall, worse autonomic function was associated with higher contractility. WMC-derived metrics effectively capture fasting small bowel motility and may distinguish neuropathic patterns, which appear to progress from increased, disorganized contractility to decreased contractility as dSBTT develops. Future studies should validate these findings in other WMCs and populations to clarify their potential in advancing understanding of the pathophysiology of gut-brain-axis disorders.NEW & NOTEWORTHY This study introduces novel WMC-derived contractility indices to quantify gastrointestinal motility, enabling noninvasive characterization of neuropathic dysmotility. In PWH, hypercontractility and disorganized rhythmic bursts were observed despite autonomic neuropathy and delayed transit, suggesting a spectrum in which inefficient high-amplitude contractions initially may preserve transit before progressive delay ensues. Leveraging raw pressure data from WMC technology, these indices are linkable to extrinsic autonomic biomarkers and may advance understanding of gut-brain axis disorder pathophysiology.

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. Nω-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.NEW & NOTEWORTHY 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.

Information on childhood cancer burden is crucial for effective cancer policy planning. Unfortunately, observed paediatric cancer data are not available in every country, and previous global burden estimates have not discretely reported several common cancers of childhood. We aimed to inform efforts to address childhood cancer burden globally by analysing results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, which now include nine additional cancer causes compared with previous GBD analyses. GBD 2023 data sources for cancer estimation included population-based cancer registries, vital registration systems, and verbal autopsies. For childhood cancers (defined as those occurring at ages 0-19 years), mortality was estimated using cancer-specific ensemble models and incidence was estimated using mortality estimates and modelled mortality-to-incidence ratios (MIRs). Years of life lost (YLLs) were estimated by multiplying age-specific cancer deaths by the standard life expectancy at the age of death. Prevalence was estimated using survival estimates modelled from MIRs and multiplied by sequelae-specific disability weights to estimate years lived with disability (YLDs). Disability-adjusted life-years (DALYs) were estimated as the sum of YLLs and YLDs. Estimates are presented globally and by geographical and resource groupings, and all estimates are presented with 95% uncertainty intervals (UIs). Globally, in 2023, there were an estimated 377 000 incident childhood cancer cases (95% UI 288 000-489 000), 144 000 deaths (131 000-162 000), and 11·7 million (10·7-13·2) DALYs due to childhood cancer. Deaths due to childhood cancer decreased by 27·0% (15·5-36·1) globally, from 197 000 (173 000-218 000) in 1990, but increased in the WHO African region by 55·6% (25·5-92·4), from 31 500 (24 900-38 500) to 49 000 (42 600-58 200) between 1990 and 2023. In 2023, age-standardised YLLs due to childhood cancer were inversely correlated with country-level Socio-demographic Index. Childhood cancer was the eighth-leading cause of childhood deaths and the ninth-leading cause of DALYs among all cancers in 2023. The percentage of DALYs due to uncategorised childhood cancers was reduced from 26·5% (26·5-26·5) in GBD 2017 to 10·5% (8·1-13·1) with the addition of the nine new cancer causes. Target cancers for the WHO Global Initiative for Childhood Cancer (GICC) comprised 47·3% (42·2-52·0) of global childhood cancer deaths in 2023. Global childhood cancer burden remains a substantial contributor to global childhood disease and cancer burden and is disproportionately weighted towards resource-limited settings. The estimation of additional cancer types relevant in childhood provides a step towards alignment with WHO GICC targets. Efforts to decrease global childhood cancer burden should focus on addressing the inequities in burden worldwide and support comprehensive improvements along the childhood cancer diagnosis and care continuum. St Jude Children's Research Hospital, Gates Foundation, and St Baldrick's Foundation.

Visceral hypersensitivity is a pivotal mechanism in pain associated with irritable bowel syndrome (IBS). Calcitonin gene-related peptide (CGRP) is expressed by visceral afferents. The aim of this study was to evaluate the efficacy of rimegepant, a CGRP antagonist, on abdominal pain, rectal compliance and sensation, gut transit, and safety in participants with nonconstipation IBS with pain. We conducted a pilot, randomized, double-blind, placebo-controlled, parallel-group design trial (NCT06221111) of oral rimegepant 75 mg every other day (as approved for migraine prophylaxis) in adults with nonconstipation IBS pain. The trial consisted of three periods: 2-wk run-in, 4-wk treatment, and 4-wk post-treatment with diary recording of daily abdominal pain (primary endpoint) and bowel movements (BMs). Rectal compliance and sensation were measured using barostat distensions and gastrointestinal and colonic transit by scintigraphy. Statistical analysis compared rimegepant with placebo using analysis of covariance with sex, level of anxiety, and baseline measurements as covariates. Twenty-four participants were randomized to rimegepant (n = 12) or placebo (n = 12); baseline demographics, rectal sensation, and compliance were similar between the groups. Rimegepant did not significantly reduce abdominal pain, daily BM frequency, or BM consistency relative to baseline. Compared with placebo, rimegepant significantly reduced sensations of gas, urgency, and pain during 24 mmHg, and gas and urgency sensations during 36 mmHg rectal distension (all P ≤ 0.05 unadjusted). Rimegepant decreased rectal compliance. No significant effects were noted during washout. There were no serious adverse events or adverse events of ≥ Grade 3 severity. Rimegepant's effects on rectal sensation suggest further studies in nonconstipation IBS pain are warranted. Clinical Trial Registry Number: NCT06221111.NEW & NOTEWORTHY This pilot, randomized, double-blind trial in a relatively small sample of patients with IBS-related pain shows rimegepant significantly reduced sensations of gas, urgency, and pain during rectal distention and decreased rectal compliance. Decrease in compliance implies that changes in physical properties or distensibility of rectum did not contribute to alterations in rectal sensation. Same dose of rimegepant did not significantly impact daily abdominal pain, BM frequency, or colonic transit. There were no serious adverse events.

Severe acute pancreatitis (SAP) often leads to incomplete tissue repair and prolonged exocrine dysfunction. Acinar-to-ductal metaplasia (ADM) is a critical regenerative process postinjury, but persistent ADM impedes functional recovery. Axl and Mertk belong to the TAM family of receptor tyrosine kinases, which are expressed primarily in macrophages to mediate efferocytosis and promote pro-resolving macrophage polarization, and have been implicated in tissue repair. However, their roles in resolving ADM and restoring exocrine function remain unclear. We utilized cerulein-induced SAP models in mice with either global or cell-specific deletion of Axl and Mertk. Pancreatic repair was assessed by histology, transcriptomics, and functional assays. Coculture of primary acinar cells with bone marrow-derived macrophages. The expression of AXL and MERTK in the pancreas was upregulated on Day 4 during pancreatic repair after SAP. Global deletion of Axl and Mertk similarly delayed tissue repair, resulting in persistent ADM, impaired acinar redifferentiation, and defective restoration of exocrine function. Transcriptomics revealed aberrant activation of developmental signaling pathways, including Hedgehog, Wnt, and Notch, and sustained suppression of acinar digestive enzyme genes. In vitro coculture experiments showed that M2 macrophages lacking Axl and Mertk promoted persistent ADM, in contrast to M1 macrophages. AXL and MERTK in macrophages are crucial regulators of pancreatic regeneration after SAP, facilitating ADM resolution and exocrine recovery through interactions between acinar cells and M2 macrophages. These findings highlight that macrophage AXL and MERTK could act as a potential therapeutic target for enhancing long-term restoration of pancreatic function following SAP.NEW & NOTEWORTHY Deleting Axl and Mertk in myeloid cells disrupts the healing process, resulting in persistent ductal structures and failure to recover exocrine function. This repair failure is linked to the abnormal persistence of developmental signaling pathways and is mediated by interactions between acinar cells and macrophages, emphasizing the importance of AXL and MERTK in macrophages in pancreatic functional recovery.

Gastric reflux induces esophageal mucosal inflammation, partially mediated by the activation of hypoxia inducible factor 2α (HIF-2α). Pepsin, present in the refluxate, amplifies this inflammatory process and exacerbates tissue injury. Therefore, pepsin inhibition represents a promising strategy to reduce inflammation and preserve esophageal mucosal integrity. In this study, we evaluated the effects of darunavir, a protease inhibitor presently used to treat human immunodeficiency virus infection, in a gastroesophageal reflux disease (GERD) model in Swiss mice. Animals were anesthetized (ketamine and xylazine) and subjected to partial pyloric ligation and total ligation of the gastric fundus. Four experimental groups were established: sham (control), sham + darunavir, GERD, and GERD + darunavir. After 3 days, animals were euthanized, and the esophagus was collected to measure wet weight (edema), myeloperoxidase (MPO) activity, and keratinocyte-derived cytokines (KC). Western blot was performed for HIF-2α and tight junction proteins zonula occludens-1 (ZO-1) and occludin (OCLD). Histology with analysis of dilation of the intercellular space (DIS). Esophageal barrier function was assessed by transepithelial electrical resistance and fluorescein as an index of paracellular permeability. Darunavir's antipeptic activity was also demonstrated in vitro. GERD-induced inflammation, with significant increases in edema, MPO, KC, DIS, histological changes and HIF-2α, and disrupted barrier function, reducing ZO-1 and OCLD levels. All these alterations were significantly reversed in darunavir-treated animals. These findings demonstrate that darunavir, a clinically available drug with antipepsin properties, inhibits GERD-induced inflammation and HIF-2α activation, preserving tight junction proteins and mucosal integrity. Thus, darunavir could be repurposed as a novel therapeutic option for GERD.NEW & NOTEWORTHY The gastroesophageal reflux of pepsin contributes importantly to esophageal damage in patients with GERD. We have found that darunavir, a drug presently used to treat HIV, inhibits pepsin activity and, in an animal model of GERD, darunavir reduces esophageal inflammation and HIF-2α levels while preserving levels of tight junction proteins and esophageal mucosal integrity. These findings suggest that darunavir might have a role as a novel treatment for GERD.

Glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as promising therapeutic candidates for metabolic dysfunction-associated steatohepatitis (MASH). Importantly, semaglutide was recently approved as the first GLP-1-based treatment for people with MASH with moderate-to-severe fibrosis. Translational models that recapitulate human MASH are critical for guiding early-stage drug discovery, enabling rigorous efficacy evaluation, and facilitating the progression of drug candidates into clinical development. In this study, we investigated the efficacy of semaglutide across an extensive series of experiments in the liver biopsy-confirmed GAN diet-induced obese MASH (GAN DIO-MASH) mouse model, benchmarking outcomes against those from pivotal clinical trials of semaglutide in MASH. Treatment outcomes in the GAN DIO-MASH mouse closely mirrored clinical findings, particularly for hepatic steatosis and inflammation endpoints. Longer semaglutide treatment durations (≥16 wk) led to pronounced and consistent improvements in quantitative fibrosis histology across studies. In comparison, the response rate for fibrosis stage improvement with semaglutide was modest and largely independent of treatment duration. Notably, pooling data from long-term intervention studies revealed more favorable effects on fibrosis stage. Importantly, the GAN DIO-MASH mouse recapitulated many human MASH-associated changes in circulating proteins and semaglutide-responsive biomarkers. Collectively, these results support the therapeutic effects of semaglutide in MASH and underscore the reproducibility and clinical translatability of multiple disease-relevant features of the GAN DIO-MASH mouse model, highlighting its applicability as a robust platform for preclinical drug development.NEW & NOTEWORTHY Translational preclinical models that faithfully recapitulate human MASH are essential for guiding early-stage drug discovery by enabling rigorous efficacy assessment. In this study, we demonstrate that the biopsy-confirmed GAN DIO-MASH mouse model replicates semaglutide treatment responses across metabolic, biochemical, and histological endpoints, as well as key biomarker signatures observed in pivotal clinical trials in people with MASH. These findings strongly support the model's clinical translatability to facilitate efficient progression of therapeutic candidates into clinical development.

Fibroblast-like cells (FLCs) exist in the smooth muscle layers of visceral organs, yet in many instances their functional role(s) have not been identified. FLCs express platelet-derived growth factor receptor (PDGFR) α and are a novel class of excitable cells recently described in visceral organs. Crenolanib is a benzamidine quinolone derivative originally developed as an inhibitor of PDGFR to treat certain solid tumors with PDGFRα overexpression mutations. In the present study, we used crenolanib to disrupt PDGFRα expression and signaling in the gastrointestinal (GI) tracts of BALB/c mice. Intraperitoneal injections of crenolanib (100 µg/g body wt) or DMSO control vehicle were given to littermates from postpartum P1 through P15. Crenolanib-injected mice were smaller in size and weight. The gastrointestinal tracts were also shorter and appeared partially distended. qPCR revealed downregulation of key gene transcripts involved in PDGFRα cell signaling including Pdgfra, Kcnn3, and P2ry1. Confocal immunofluorescence demonstrated significant decreases in PDGFRα and SK3 protein expression. c-Kit expression was slightly inhibited, but gastric, intestinal, and colonic pacemaker activity was not affected by crenolanib. Purinergic inhibitory postjunctional motor responses were greatly attenuated in the GI tracts of crenolanib-treated animals compared with vehicle-treated controls in response to electric field-evoked nerve stimulation. These data provide evidence for a functional role of PDGFRα+ cells in inhibitory neuroeffector motor responses throughout the gastrointestinal tract.NEW & NOTEWORTHY The physiological roles of newly described PDGFRα+ interstitial cells in neurotransmission within the gastrointestinal (GI) tract have predominantly come from studies on isolated cells. Here we used an inhibitor of PDGFRα, crenolanib, to examine the effects of PDGFRα+ cells in enteric inhibitory neurotransmission. Crenolanib caused loss of PDGFRα+ cells and neurally evoked fast inhibitory junction potentials associated with purine neurotransmission, providing evidence for the function of PDGFRα+ cells within intact tissues of the GI tract.

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 (P ≤ 0.05) compared with controls. Histologic evaluation revealed increased connective tissue (P = 0.06), significant collagen deposition, and decreased muscle area and fiber thickness (P ≤ 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 (P ≤ 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.NEW & NOTEWORTHY 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.

The intestinal epithelium is a key component of the intestinal barrier, which is the largest and most complex barrier of the human body, regulating nutrient absorption while restricting the entry of harmful antigens. Breakdown of this barrier facilitates microbial and dietary antigenic translocation, triggering local immune system activation and inflammation. Although barrier alteration alone may not be sufficient to initiate disease, accumulating evidence highlights its critical role in the pathogenesis and progression of a wide range of gastrointestinal and systemic disorders. Early identification of intestinal epithelium and barrier alterations could enable timely therapeutic approaches. This systematic review provides an overview of current in vivo (both noninvasive and invasive) and ex vivo/in vitro approaches used to assess intestinal epithelial barrier alterations. Noninvasive in vivo approaches rely mainly on urinary detection of orally ingested probes, but their clinical utility is limited by lack of standardization and specificity. Circulating and fecal constitutive markers derived from the intestinal barrier, which reflect epithelial alterations, together with indicators of microbial translocation, provide complementary insights but remain insufficiently validated. Advanced invasive endoscopic modalities such as confocal laser endomicroscopy enable near-histological, real-time visualization but are costly and largely used as research tools in specialist centers. In vitro, transepithelial electrical resistance assessment remains the reference standard, though novel technologies (including impedance spectroscopy and organic electrochemical transistors) offer enhanced sensitivity and resolution. Despite progress, major gaps remain, including the absence of a standardized definition of epithelial barrier breakdown, the lack of a practical diagnostic tool, methodological heterogeneity, unvalidated thresholds, and limited prospective validation.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the intestines accompanied by profound extraintestinal manifestations. Although IBD shows a clear clinical association with cardiovascular derangements, whether and how chronic colitis impairs heart function remains unclear. To address this gap, we investigated the impact of chronic colitis on cardiac performance and the cardiac transcriptome using two mouse models: dextran sodium sulfate (DSS)-treated and Il10-/- mice. Heart function was assessed by echocardiography and molecular characterization was performed using RNA-sequencing (RNA-Seq), reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR), and Western blot. Both models exhibited significant functional cardiac impairment, characterized by reduced ejection fraction and fractional shortening along with histologically evident increase in collagen deposition, inflammation, and myofibril reorganization. Molecular analyses revealed a profibrotic cardiac environment. RNA sequencing unveiled a shared upregulation of eicosanoid-associated and inflammatory genes (Cyp2e1, Map3k6, Pck1, and Cfd) across both models, alongside model-specific alterations in pathways governing cAMP and cGMP signaling, arachidonic and linoleic acid metabolism, and immune cell responses. DSS colitis caused differential regulation of 232 cardiac genes, whereas Il10-/- colitis yielded 105 dysregulated genes. Notably, reconstitution of a healthy balance of gut microbiota by therapeutic fecal microbiota transplantation (FMT), validated using quantitative polymerase chain reaction (qPCR), successfully rescued heart function and mitigated fibrosis in both models. However, Il10-/- mice demonstrated relatively less cardiac recovery following FMT, highlighting interleukin-10 (IL-10)'s cardioprotective and anti-inflammatory contribution. Collectively, these findings provide evidence that chronic colitis impairs heart function, offer novel insights into colitis-induced cardiac remodeling, and suggest that FMT mitigates cardiac dysfunction by correcting gut dysbiosis, attenuating systemic inflammation, and reestablishing homeostasis along the gut-heart axis.NEW & NOTEWORTHY Inflammatory bowel disease (IBD) extends beyond the gut, as chronic inflammation and microbiota dysbiosis contribute to serious extraintestinal complications. This study demonstrates that chronic colitis induces cardiac remodeling and dysfunction in two mouse models, marked by reduced cardiac performance, fibrosis, and upregulated fibrotic and inflammatory genes. Importantly, fecal microbiota transplantation (FMT) alleviated cardiac injury, highlighting its therapeutic potential. These findings reveal FMT as a promising therapy against chronic inflammation contributing to cardiovascular complications in IBD.

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 (Fam84b, Zswim6, Hsf4, Mn1, Qprt, and Rapgefl1) showed significant sex-associated differences in methylation. Fam84b 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). Zswim6 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 (P = 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.NEW & NOTEWORTHY 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.

Serine/threonine phosphatase 1 (PP1) and phosphatase 2A (PP2A) play important roles in mediating cellular signaling in different tissues to different stimuli, including in protein synthesis, growth, cell cycle regulation, and secretion. However, their roles in various pancreatic exocrine functions, such as pancreatic acinar fluid/electrolyte secretion, is still unclear. Therefore, in the present study, we examined the ability of vasoactive intestinal peptide (VIP) and secretin, which stimulate cAMP generation in pancreatic acini, to activate serine/threonine phosphatase 1 (PP1) and phosphatase 2A (PP2A), the signaling cascades involved, and their possible role in activating sodium-potassium adenosine triphosphatase (Na+-K+-ATPase). Our results demonstrate that VIP and secretin activate PP1 and PP2A. However, they differ in their signaling cascades. Both VIP and secretin stimulate PP1 through cAMP-stimulated activation of protein kinase A (PKA) and exchange protein directly activated by cAMP (EPAC). However, VIP stimulates PP2A through the activation of cAMP-mediated EPAC, whereas secretin does it through activation of PKA. Despite these differences, in cAMP effect on activation, both VIP and secretin activate PP2A through a p21-activated kinase 4 (PAK4)-mediated mechanism, without involvement of PAK2. Furthermore, PP1 and PP2A activation is needed for Na+-K+-ATPase activation, which mediates pancreatic acinar fluid and electrolyte secretion. These results support the conclusion that PP1 and PP2A play an important role in pancreatic acinar fluid and electrolyte secretion, mediated by a PAK4-dependent mechanism, which when combined with their recently described roles in pancreatic enzyme secretion, pancreatitis, and pancreatic acinar growth and cancer, demonstrate the important roles they play in both physiological and pathological responses in the exocrine pancreas, similar to their previously established roles in the endocrine pancreas.NEW & NOTEWORTHY The roles of the serine/threonine phosphatase 1/2A in mediating fluid/electrolyte secretion by pancreatic acinar cells remains unclear. This study demonstrates that PP1/PP2A are activated vasoactive intestinal peptide (VIP)/secretin in pancreatic acini. VIP/secretin both activate PP1/PP2A but differed for their ability to activate exchange protein directly activated by cAMP (EPAC) and protein kinase A (PKA). VIP/secretin require PAK4, not PAK2, activation to stimulate PP2A, not PP1; however, PP1/PP2A activation stimulate sodium-potassium adenosine triphosphatase (Na+-K+-ATPase) activity. This study shows that PP1/PP2A play important roles in VIP-secretin-stimulated pancreatic acinar fluid/electrolyte secretion.

Alcohol-induced liver fibrosis is a devastating manifestation of alcohol-related liver disease (ALD). However, conventional mouse models fail to recapitulate this fibrotic phenotype, limiting their translational relevance. Mice develop and retain robust brown adipose tissue (BAT) for thermoregulation, which confers protection against hepatic steatosis. Here, we identify BAT as a key protective tissue against alcohol-induced liver fibrosis in mice. BAT was inactivated in mice via denervation or surgically ablated, followed by 8 wk of chronic plus binge alcohol exposure. Both BAT denervation and ablation markedly exacerbated hepatic steatosis, injury, and inflammation compared with sham controls. Remarkably, BAT inactivation or ablation induced robust hepatic stellate cell (HSC) activation and liver fibrosis in both sexes, as evidenced by increased α-smooth muscle actin expression, enhanced Sirius red and Masson's trichrome staining, and elevated hydroxyproline content. These fibrotic changes were absent in sham-operated controls. Mechanistically, BAT-conditioned medium-containing BAT-secreted batokines-induced lipid accumulation, oxidative stress, and cell injury in hepatocyte cultures. Furthermore, batokines directly targeted cultured macrophages and HSCs and suppressed their activities. Collectively, these results unveil a hepatoprotective role of BAT and batokines in ALD progression and establish a physiologically and translationally relevant mouse model of ALD by combining BAT inactivation with chronic plus binge alcohol exposure.NEW & NOTEWORTHY Brown adipose tissue confers resistance to alcohol-related liver disease through secreting batokines. Inactivation of brown fat exacerbates alcohol-induced liver steatosis, inflammation, and fibrosis.

Probiotics have been proven to be effective in inducing and maintaining remission of inflammatory bowel disease (IBD). However, their precise mechanisms remain unclear. Interactions between the gut microbiota and enteric glial cells (EGCs) have gained increasing attention. We aimed to investigate whether and how Bifidobacterium longum (B.l), as a typical probiotic, exerts anti-inflammatory effects by acting on EGCs. Herein, we demonstrate that EGCs possess bacterial phagocytosis and antigen-presenting functions, and their costimulatory molecule expression is differentially regulated by bacteria. Specifically, B.l significantly upregulates EGC expression of programmed death-ligand 1 (PD-L1), while enterohemorrhagic Escherichia coli (EHEC) markedly increases CD86 expression. B.l ameliorates dextran sulfate sodium (DSS)-induced experimental colitis by activating the p38 MAPK signaling pathway, upregulating PD-L1 expression in EGCs, and inducing the conversion of CD4+ cells into regulatory T (Treg) cells through the PD-L1/PD-1 pathway. This process promotes Treg cell expansion, inhibits pathogenic T-helper type 17 (Th17) cells, increasing IL-10 production, and reduces TNF-α and IL-1β production. Notably, ablation of EGCs significantly diminishes the efficacy of B.l in alleviating experimental colitis. In conclusion, our findings suggest that B.l induces the conversion of CD4+ cells into Treg cells by acting on EGCs and alleviating intestinal inflammation. These findings support the notion that EGCs are not only neural cells but also potential immune cells, which exert immune regulatory functions depending on the type of bacteria and which signaling molecules are being expressed. This study provides new data for elucidating the mechanisms of probiotics in the treatment of IBD.NEW & NOTEWORTHY The interactions between gut microbiota and enteric glial cells (EGCs) are increasingly recognized. This study reveals that EGCs possess bacterial phagocytosis and antigen-presentation functions, which are modulated differently by various bacteria. Specifically, Bifidobacterium longum (B.l) relieves DSS-induced colitis by enhancing PD-L1 expression on EGCs and promoting Treg cell differentiation through EGC-mediated immune regulation. Understanding the dual role of EGCs as both neural and immune cells expands our comprehension of gut microbiota-neural-immune interaction in intestinal health.

Fibroblast growth factor 15 (FGF15) plays a crucial role in the negative feedback loop of bile acid (BA) production by reducing mRNA levels of hepatic Cyp7a1, a rate-limiting enzyme of BA synthesis. Here, we investigated the postprandial regulation of Fgf15 mRNA levels in the ileum to unveil the physiological regulation of FGF15 production by feeding in mice. The postprandial Fgf15 mRNA level reached the minimum level in the distal ileum following starvation for 20 h and subsequent feeding for 3 h. In mice lacking tauro-β-muricholic acid, which is an endogenous antagonist for the farnesoid-X-receptor (FXR), the Fgf15 mRNA level in the distal ileum was still 3 h-postprandially reduced. We further explored the postprandial regulation of Fgf15 transcription in various sites of the ileum and found that the 3 h-postprandial Fgf15 levels were reduced in the distal ileum while elevated in the proximal ileum. Furthermore, the 3 h-postprandial plasma FGF15 level was reduced despite the elevated Fgf15 mRNA level in the proximal ileum. In mice lacking Fxr in the intestine, the relative amount of 3 h-postprandial Fgf15 mRNA level was still reduced in the distal ileum, whereas the 3 h-postprandial elevation was blunt in the proximal ileum. Oral administration of soybean oil, fatty acids, and PPARγ agonist pioglitazone reduced Fgf15 expression in the distal ileum, indicating that PPARγ signaling is involved in the negative regulation of Fgf15 mRNA level. Collectively, our data show the complicated regulation of plasma FGF15 concentration by bidirectional change in Fgf15 mRNA levels by food intake in different sites of the ileum.NEW & NOTEWORTHY It is considered that feeding stimulates the release of bile acids, which ultimately bind to FXR to increase the Fgf15 transcription in the ileum. However, we found that Fgf15 mRNA levels were postprandially reduced, particularly in the distal ileum, and this reduction was mediated through fatty acid-PPARγ signaling. In the proximal ileum, however, we observed that Fgf15 mRNA levels were postprandially elevated through bile acid-FXR signaling, which was consistent with the current idea.