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.

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.

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.

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.

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-CT, 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.

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.

The gastric mucus layer protects the epithelium from gastric acid and ingested pathogens. However, studies of human gastric mucus have been limited due to poor accessibility of native human mucus and the abundance of contaminants in these samples. Here, we explored the potential of human gastric organoids as models for mucus production. Immunofluorescence staining confirmed that the organoids produced mucus containing MUC5AC and MUC6. The luminal mucus had viscoelastic properties similar to those of native human gastric mucus, as determined by particle tracking microrheology. To collect organoid-produced gastric mucus, termed bioengineered gastric mucus (BGM), organoids were cultured as monolayers at the air-liquid interface (ALI), and apically secreted mucus was harvested and analyzed by MUC5AC ELISA, proteomics, cryo-field emission scanning electron microscopy (CryoFE-SE), and rheometry. BGM contained high-molecular weight molecules also found in native gastric mucus. Proteomic analysis confirmed that BGM contained MUC5AC, MUC6, MUC1, and other stomach-specific molecules such as pepsin C, trefoil factor 2, and gastrokine. CryoFE-SE showed that both BGM and native mucus had a porous structure and a characteristic honeycomb scaffold. However, the viscosity of the BGM was generally lower than that of native human gastric mucus, and BGM failed to exhibit gelation at low pH. Collectively, these findings demonstrate the potential as well as some limitations of BGM as an accessible model system for human gastric mucus.NEW & NOTEWORTHY We demonstrate the structural and functional similarities of organoid-derived gastric mucus and native mucus collected from human patients. The bioengineered gastric mucus mimics its native counterpart in its proteomic profile and physical architecture. This work highlights the translational potential of organoid-derived mucus for functional investigations of the human gastric mucus layer.

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.

Postinfectious irritable bowel syndrome (PI-IBS) is defined by persistent gastrointestinal symptoms that follow recovery from an episode of infectious enteritis, which worsen after experiencing psychological stress. Mucosal neurite outgrowth stimulated by neurotrophins and serotonin/5-hydroxytryptamine receptor subtype 7 (5-HT7) activation is linked to visceral hypersensitivity. Rifaximin (RFX) is a poorly absorbed antibiotic that improves IBS symptoms; however, the exact mechanisms remain unclear. The aims are to evaluate changes in microbiota and neuroplasticity in PI-IBS mice after RFX treatment and the analgesic effects of combined treatment with a novel 5-HT7 antagonist, CYY1005 (CYY). A mouse model with dual triggers of Giardia postinfection and water avoidance stress exhibited intestinal hyperalgesia, as measured by visceromotor responses (VMRs). Higher Shannon diversity and increased relative abundances of Lachnospiraceae, Dehalobacteriaceae, and Ruminococcus gnavus were observed in the microbiota of PI-IBS mice, which were restored to baseline after RFX treatment. Reduced VMRs were associated with attenuated mucosal neurite outgrowth and brain-derived neurotrophic factor (BDNF) expression after RFX treatment. BDNF/high affinity tropomyosin receptor kinase B activation induced mTOR-dependent nerve fiber elongation and upregulated tryptophan hydroxylase 2 and 5-HT7 expression via Rac1/ROCK pathway in SH-SY5Y neuron cultures. Combined treatment with RFX and CYY reduced VMRs to levels comparable with those of the control groups. Finally, bacteria-free colonic mouse supernatants induced neurite elongation in SH-SY5Y cells, which was inhibited by neutralizing anti-BDNF antibodies. In conclusion, microbiota restoration by RFX treatment attenuated BDNF-induced neurite outgrowth and alleviated visceral hypersensitivity in mice. Analgesic combinations of RFX and a 5-HT7 receptor antagonist reduced intestinal nociception to baseline levels.NEW & NOTEWORTHY A mouse model of postinfectious IBS was developed using dual triggers of Giardia postinfection and water avoidance stress to mimic diverse risk factors. Rifaximin treatment reduced intestinal hyperalgesia and was associated with decreased mucosal neurite outgrowth and brain-derived neurotrophic factor (BDNF) expression. BDNF activation induced nerve fiber elongation and upregulated 5-HT7 expression via separate signaling pathways. Analgesic combinations of RFX and a 5-HT7 receptor antagonist reduced intestinal nociception to baseline.

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.

Although recognized as a key regulator of gastrointestinal tissues, Wnt signaling pathway function in the stomach is poorly understood. This study aimed to define Wnt functions and identify Wnt-regulated genes in the stomach. Reporter mouse analysis localized Wnt signaling to the base and proliferative region in both the corpus and the antrum. Canonical Wnt inhibition in vivo using Sox2-CreERT2; Ctnnb1fl/fl mice reduced epithelial cell proliferation with loss of gastric stem cells. Wnt-regulated genes and potential effector pathways were studied by bulk RNA sequencing (RNA-Seq) analysis of corpus and antral organoids 24 h after Wnt inhibition in vitro. Cell signature analysis revealed that gastric organoids adopt a surface cell transcriptional profile following Wnt inhibition instead of a basal cell profile. Furthermore, retinoid metabolism terms were differentially expressed after Wnt inhibition, with decreased expression of retinoic acid target genes. Inhibition of retinoic acid signaling in corpus and antral organoids showed a marked increase in surface cell marker expression, consistent with the effects of Wnt inhibition. In the mouse, immunostaining showed differential localization of retinoid metabolic components in luminal pit cells (ALDH3A1) and basal chief/deep mucous cells (STRA6), with expression changes after β-catenin deletion in Sox2-CreERT2; Ctnnb1fl/fl mice, consistent with the Wnt-regulated cell fate changes observed in organoids. Together, these studies showed that Wnt signaling is required for gastric stem cell survival and promotes differentiation of cell types at the gland base. We identified retinoid metabolism as a candidate Wnt-regulated pathway, with cell-specific expression of key components, and regulation of surface cell marker expression by retinoic acid signaling.NEW & NOTEWORTHY Using mouse genetic and organoid models, we show that canonical Wnt signaling promotes gastric epithelial cell proliferation and regulates differentiation along the base-lumen gland axis in the stomach. Transcription profiling of Wnt-inhibited gastric organoids identified retinoic acid signaling as a potential Wnt-regulated effector pathway in the stomach. Accordingly, manipulation of retinoic acid signaling in organoids altered differentiated marker expression consistent with Wnt inhibition, supporting the presence of a Wnt-retinoic acid signaling axis in the stomach.

Clinical studies suggested that antibiotics (ABx) administration might increase esophagogastric junction adenocarcinoma risk, but the underlying mechanisms remain unclear. We previously demonstrated that the administration of a high-fat diet (HFD) and acid bile salts (ABS) to K19-Wnt1/C2mE mice might promote the metabolic-driven tumor growth at the squamocolumnar junction (SCJ) cooperatively with gut dysbiosis. To clarify whether ABx-induced dysbiosis promotes tumorigenesis, we evaluated the effects of HFD + ABS ± ABx treatment on tumor immune evasion in mice. In HFD + ABS + ABx-treated mice, SCJ tumor growth with increased tumor cell proliferation and infiltration of inflammatory cells positive for CD8, programmed cell death protein 1, and programmed cell death-ligand 1 (PD-L1) was observed, along with apoptosis suppression. Protein expressions of interferon-gamma (IFNγ) and phosphorylated signal transducer and activator of transcription (p-STAT) 3 were upregulated in the tumors of the HFD + ABS + ABx group, whose p-STAT1 expression was equivalent to that of the control group. The mice exhibited insulin resistance and metabolic endotoxemia, and metagenomic analysis of their ileal excrement revealed dysbiosis with a decrease in butyrate-producing bacteria and bacterial butanoate metabolism activity. Moreover, IFNγ stimulation of human-derived NUGC-4 cells increased the protein expression of PD-L1, p-STAT1, and p-STAT3, all of which decreased in response to STAT inhibitors. Transfection with small interfering RNA targeting STAT1 or STAT3 did not attenuate PD-L1 induction, which was inhibited by the combined knockdown. Therefore, oral HFD + ABS + ABx administration to K19-Wnt1/C2mE mice may promote SCJ tumors through tumor immune evasion via IFNγ-STAT1/STAT3-PD-L1 signaling, along with metabolic endotoxemia.NEW & NOTEWORTHY Coadministration of antibiotics with a high-fat diet and acid bile salts exacerbated dysbiosis, insulin resistance, and systemic inflammation, thereby promoting tumor progression via tumor immune evasion at the squamocolumnar junction (SCJ) in K19-Wnt1/C2mE mice. In the tumor, interferon-gamma-induced programmed death-ligand 1 through the activation of signal transducer and activator of transcription 1 (STAT1) and STAT3. Understanding the link between dysbiosis and tumor immunity might aid in the development of new immunotherapies for SCJ tumors.

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.

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.

Liver fibrosis remains a major unmet medical need, and quantitative evaluation of antifibrotic candidates requires ex vivo models that preserve tissue function while supporting higher-throughput pharmacological testing. Precision-cut liver slices (PCLSs) maintain native multicellular architecture but are limited by suboptimal oxygenation and insufficient throughput, particularly in fibrotic tissue. Therefore, we aimed to establish a high-oxygen culture system using commercially available gas-permeable plates to enable quantitative antifibrotic testing in rat PCLSs. Normal and choline-deficient high-fat diet-induced fibrotic PCLSs were cultured under 20% or 80% O2 in gas-permeable (G-Rex; NOK, InnoCell) or conventional nongas-permeable formats. High-oxygen gas-permeable conditions improved viability, assessed by cumulative lactate dehydrogenase release, and enhanced hepatic function, including albumin secretion and glycogen preservation. Under optimized conditions, transforming growth factor-β1 and platelet-derived growth factor-BB markedly induced Col1a1 and Acta2 expression and increased collagen type I production. Fibrotic PCLSs maintained activated stellate cell features and sustained collagen secretion for 96 h. This platform enabled quantitative pharmacological profiling: the activin receptor-like kinase 5 (ALK5) inhibitor SB-525334 consistently suppressed fibrogenic gene expression and collagen production, whereas the multikinase inhibitor nintedanib showed weaker inhibition. Miniaturization to gas-permeable 96-well plates preserved functional and pharmacological performance, increasing experimental yield per liver. Overall, this accessible, high-oxygen PCLS system overcomes oxygenation limitations and enables reliable, medium-throughput antifibrotic testing in a physiologically intact ex vivo fibrosis model.NEW & NOTEWORTHY Precision-cut liver slices preserve native hepatic architecture but are difficult to maintain and miniaturize for quantitative drug testing, particularly in fibrotic tissue. High-oxygen culture using readily available gas-permeable plates improves viability and hepatocyte function while sustaining fibrogenic readouts, enabling concentration-response antifibrotic testing in 96-well formats. This medium-throughput workflow increases data yield per liver and provides a practical, consistent platform for antifibrotic evaluation.

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.

Myosin 5b (MYO5B) is a motor protein that plays an essential role in trafficking proteins to the apical membrane. Recent studies have demonstrated that MYO5B traffics ion transporters, like NHE3, DRA, and SGLT1, water channels, like AQP7, and efflux transporters, like P-glycoprotein. However, the role of MYO5B in trafficking glycoproteins involved in mucosal defense remains unclear. Here, we investigate whether MYO5B is required for the apical localization of mucin 13 (MUC13) and deleted in malignant brain tumors 1 (DMBT1), two glycoproteins critical for epithelial protection and wound healing. To address the requirement of MYO5B in glycoprotein trafficking, we immunostained the small intestine and colon of neonatal germline and adult inducible intestine-specific MYO5B knockout (KO) mice and examined MUC13 and DMBT1 localization. Organoids derived from germline and inducible KO mice were analyzed to confirm findings in an epithelial-only system. In addition, staining was performed on human organoids expressing MYO5B-tail green fluorescent protein (GFP). MYO5B loss in vivo resulted in the intracellular accumulation of MUC13 and DMBT1, reducing their colocalization with the apical marker γ-actin in both models. MUC13 colocalized with the lysosomal marker lysosomal-associated membrane protein 1 (LAMP1) in adult mice after MYO5B loss, indicating that a portion of cytoplasmic MUC13 undergoes lysosomal degradation. Mislocalization of MUC13 was observed in vitro in intestinal MYO5B-deficient organoids. MYO5B-tail GFP was associated with MUC13 in human intestinal organoids. MYO5B is required for the apical delivery of MUC13 and DMBT1 in the intestinal epithelium. Disrupting this pathway may contribute to mucosal dysfunction in MYO5B-related diseases, highlighting potential therapeutic targets for restoring epithelial barrier integrity.NEW & NOTEWORTHY This work identifies MYO5B as an important regulator of the apical localization of the mucosal defense glycoprotein MUC13. Our findings suggest a link between epithelial trafficking machinery and glycocalyx organization, demonstrating that MYO5B deficiency is associated with altered localization of these proteins and increased lysosomal accumulation of MUC13. These observations provide additional insight into epithelial dysfunction in MYO5B-associated enteropathies and may have broader relevance to inflammatory bowel disease.

Functionally defective genetic variants of the calcium channel transient receptor potential vanilloid type 6 (TRPV6) have been shown to markedly increase the risk for chronic pancreatitis in humans. Genetic inactivation of Trpv6 in mice worsened the severity of pancreatitis induced by secretagogue hyperstimulation. The aims of the present study were to reexamine the role of loss-of-function TRPV6 gene variants in an adult Hungarian cohort with nonalcoholic chronic pancreatitis and to characterize cerulein-induced pancreatitis in a novel Trpv6-deleted mouse strain. We found that 2.1% of chronic pancreatitis patients carried defective TRPV6 variants, whereas no such variants were identified in control subjects. Homozygous deletion of Trpv6 in C57BL/6N mice (Trpv6-KO) caused no spontaneous pancreatitis but slightly increased the severity of cerulein-induced acute pancreatitis and delayed recovery after an acute episode in a subset of mice. Cerulein-induced intrapancreatic trypsin and chymotrypsin activity was unchanged in Trpv6-KO mice relative to C57BL/6N controls. Crossing homozygous Trpv6-KO mice with heterozygous Spink1-KO mice did not result in spontaneous pancreatitis. Our results confirmed the association of defective TRPV6 variants with human chronic pancreatitis in a nonalcoholic cohort. Furthermore, we found that TRPV6 played a relatively minor role in cerulein-induced murine pancreatitis, highlighting the need for better animal models for studying human TRPV6 variants.NEW & NOTEWORTHY Prior studies indicated that defective variants of transient receptor potential vanilloid type 6 (TRPV6) encoding a constitutive calcium channel increased the risk of chronic pancreatitis in humans, and genetic inactivation of Trpv6 aggravated the severity of experimental pancreatitis in mice. We reexamined these findings by conducting a genetic case-control study and characterizing novel Trpv6-deleted mice. We confirmed the association of defective TRPV6 variants with human chronic pancreatitis but found that Trpv6 deficiency had limited impact on secretagogue-induced pancreatitis in mice.