消化内科领域文献阅读汇编

Interleukin-10 (IL-10) is an essential regulator of intestinal immune homeostasis. Neutralising autoantibodies against IL-10 (anti-IL-10) have been identified in children and also adult patients with IBD. Positivity for anti-IL-10 autoantibodies was associated with carriage of HLA-DRB1*01:03 allele. To determine the prevalence of anti-IL-10 in paediatric IBD and assess the associated clinical phenotype. We conducted a cross-sectional multicentre study across paediatric IBD cohorts from four countries. Anti-IL-10 antibodies were investigated in serum and plasma from paediatric patients with IBD (mean age of IBD onset 11.2±3.8 years). IL-10-neutralisation capacity was confirmed by functional IL-10 reporter assay, competitive ELISA and cytokine release assay. Clinical data were analysed to evaluate disease phenotype and treatment outcomes, with comparison with matched controls. HLA-DRB1*01:03 analysis was performed. Anti-IL-10 positivity was identified in 26/1045 paediatric patients with IBD (2.5%) (Crohn's disease n=6, UC n=19, IBD unclassified n=1; IBD diagnosis age of 13±3 years). Anti-IL-10 autoantibodies were of the IgG class and amplified pro-inflammatory cytokine responses in vitro. Anti-IL-10-positive patients exhibited more severe disease compared with matched controls, including an increased prevalence of difficult-to-treat disease (23% vs 6%, p=0.03), higher rate of acute severe UC (26% vs 6%; p=0.038) and higher rates of colectomy (27% vs 6%, p=0.01). Eighty percent (16/20) of anti-IL-10-positive patients with available HLA data carried the HLA-DRB1*01:03 allele, compared with 1.5% in the anti-IL-10-negative group. Anti-IL-10 autoantibodies are present in a subgroup of paediatric patients with IBD and are associated with difficult-to-treat disease.

Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, represents a chronic, immune-mediated pathology in which genetic susceptibility, environmental exposures, and microbial perturbations converge to destabilize intestinal homeostasis. Despite a steady global rise in incidence affecting more than 10 million people worldwide, current single-pathway biologic and small-molecule therapies still leave 30-40% of patients without durable remission, with progression to stricturing, fistulizing, or transmural complications. Yet the mechanistic integration of innate and adaptive immune networks, epithelial barrier dysfunction, and microbiota‑driven inflammation remains fragmented. This review summarizes recent advances in understanding the pathophysiological mechanisms driving IBD, focusing on innate and adaptive immune networks. Current therapies, including cytokine or integrin-targeting biologics and small-molecule inhibitors like Janus Kinase (JAK) antagonists, are critically evaluated in light of their restricted pathway coverage. In response to these challenges, emerging strategies are examined targeting nonimmune pathways, including microRNA‑124-mediated gene regulation, fecal microbiota transplantation, and mesenchymal stromal cell therapies that combine immunomodulation with tissue repair. The development of effective IBD therapies is likely to benefit from combining complementary treatment strategies, guided by molecular and cellular profiling. This review underscores a paradigm shift from monotherapies to integrated, multitarget approaches as the new frontier in IBD management.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder characterized by epithelial barrier disruption, persistent mucosal inflammation, and progressive intestinal fibrosis, for which effective therapeutic options remain limited. Thymosin β4 (Tβ4) is a highly conserved endogenous peptide with established roles in tissue repair and immune regulation, but its contribution to IBD pathogenesis has not been fully elucidated. Here, we found that TMSB4X, the gene encoding Tβ4, was downregulated in colonic tissues of IBD patients. To investigate its functional significance, we generated Tmsb4x-deficient mice and demonstrated that loss of endogenous Tβ4 markedly increased susceptibility to dextran sulfate sodium (DSS)-induced colitis. Conversely, oral administration of recombinant human Tβ4 (rhTβ4) significantly improved survival, alleviated body weight loss, reduced epithelial injury, and suppressed inflammatory cytokine production in both prophylactic and therapeutic colitis models. Furthermore, rhTβ4 attenuated intestinal fibrosis, as evidenced by reduced expression of fibrosis-associated markers and decreased collagen I deposition. Transcriptomic analysis revealed that rhTβ4 partially restored DSS-induced gene dysregulation and suppressed mineralocorticoid receptor (MR, NR3C2) signaling, a pathway further supported by reporter assays and downstream target gene analyses. Collectively, these findings identify Tβ4 as an endogenous protective factor against intestinal inflammation and fibrosis and suggest that pharmacological restoration of Tβ4 activity may represent a promising therapeutic strategy for IBD through modulation of mineralocorticoid receptor signaling.

Aging is a complex, irreversible physiological process characterized by gradual deterioration of tissue structure and function, accompanied by impaired regenerative capacity, dysregulated immune homeostasis, and increased susceptibility to chronic age-related diseases (e.g., neurodegenerative disorders, metabolic syndromes, age-related skin lesions, and inflammatory bowel disease). In recent years, plant-derived extracellular vesicles (PDEVs), the lipid bilayer membrane vesicles released by plant cells, have emerged as innovative candidates for anti-aging therapy because of their inherent biocompatibility, safety, and sustainable sourcing advantages. These nanoscale particles contain proteins, lipids, and nucleic acids. Emerging evidence from in vitro and rodent in vivo models has indicated that PDEVs can effectively delay age-related phenotypes and alleviate pathological changes through multiple mechanisms, such as scavenging reactive oxygen species to mitigate oxidative damage, regulating the immune microenvironment to suppress chronic inflammation, modulating gut microbiota composition to restore intestinal homeostasis, and promoting tissue regeneration (a core application in regenerative medicine) by activating stem cell function and repairing damaged tissues. Additionally, PDEVs offer unique potential as natural or engineered cargo-carriers for drug loading and delivery. This review outlines the biogenesis, composition, isolation, characterization, and storage strategies for PDEVs. Furthermore, we systematically summarize advances in the biological functions of PDEVs and their therapeutic applications in various age-related diseases. Finally, we discuss current challenges and future prospects for PDEVs in clinical translation. We hope this work provides valuable insights for advanced research and potential applications of PDEVs in the management of aging and age-related diseases.

Serologic immunity to hepatitis A virus (HAV) and hepatitis B virus (HBV) protects against acute infection and severe outcomes among high-risk groups; however, contemporary data on population-level immunity remain limited, especially in high-risk populations. To estimate the prevalence and factors associated with serologic immunity in the overall population and across high-risk subgroups, including those with chronic liver disease (CLD), chronic kidney disease, diabetes, and immunosuppression and pregnant people. This cross-sectional study used data from the National Health and Nutrition Examination Survey from January 2017 to August 2023 and included adults aged 20 years or older with available HAV and HBV serologic test results. Data were analyzed from January 3 to May 10, 2026. The primary outcomes were the prevalence of serologic immunity to HAV, defined by hepatitis A antibody positivity, and HBV, defined by hepatitis B surface antibody positivity, with vaccine-derived immunity specifically identified by surface antibody positivity in the absence of hepatitis B core antibodies. Data were weighted to generate nationally representative estimates of the US adult population. Multivariable survey-weighted logistic regression models were used to identify independent factors associated with viral hepatitis immunity. Among 13 514 individuals, representing an estimated 226.1 million US adults (mean [SE] age, 48.65 [0.40] years; 51.76% female), 39.5% (95% CI, 37.7%-41.3%) demonstrated serologic immunity to hepatitis A, corresponding to approximately 89.4 million individuals. For HBV, 27.1% (95% CI, 25.8%-28.4%) demonstrated serologic immunity, corresponding to approximately 61.3 million individuals, while vaccine-derived immunity was present in 25.2% (95% CI, 23.9%-26.5%). In adjusted models, HAV immunity was associated with younger age (eg, 20-29 vs ≥65 years: adjusted odds ratio [AOR], 0.51; 95% CI, 0.44-0.60); lower educational attainment (eg,

中文摘要：针对甲型肝炎病毒（HAV）和乙型肝炎病毒（HBV）的血清免疫可保护高危人群免受急性感染和严重后果，但关于人群水平免疫力的当代数据仍然有限，尤其是在高危人群中。本研究旨在估计总体人群及高危亚组（包括慢性肝病（CLD）、慢性肾脏病、糖尿病、免疫抑制者和孕妇）中血清免疫力的患病率及其相关因素。这项横断面研究使用了2017年1月至2023年8月美国国家健康与营养调查的数据，纳入了20岁及以上且具有HAV和HBV血清学检测结果的成人。数据分析时间为2026年1月3日至5月10日。主要结局是HAV血清免疫（定义为甲肝抗体阳性）和HBV血清免疫（定义为乙肝表面抗体阳性）的患病率，其中疫苗来源的免疫力特指在乙肝核心抗体阴性的情况下表面抗体阳性。数据经加权处理以生成美国成人人群的全国代表性估计值。采用多变量调查加权逻辑回归模型识别与病毒性肝炎免疫力相关的独立因素。在13514名个体（代表约2.261亿美国成人，平均[SE]年龄48.65[0.40]岁，51.76%为女性）中，39.5%（95% CI，37.7%-41.3%）具有甲肝血清免疫，对应约8940万人。对于乙肝，27.1%（95% CI，25.8%-28.4%）具有血清免疫，对应约6130万人，而疫苗来源的免疫力存在于25.2%（95% CI，23.9%-26.5%）的人群中。在校正模型中，HAV免疫力与较年轻年龄（例如，20-29岁对比≥65岁：校正比值比[AOR]，0.51；95% CI，0.44-0.60）、较低教育程度（例如，低于9年级对比大学及以上：AOR，0.32；95% CI，0.24-0.42）、非西班牙裔黑人（AOR，1.67；95% CI，1.34-2.09）、墨西哥裔美国人（AOR，4.22；95% CI，3.42-5.21）、其他西班牙裔（AOR，2.01；95% CI，1.60-2.54）、非西班牙裔亚裔（AOR，3.03；95% CI，2.45-3.76）及多种族或其他（AOR，1.36；95% CI，1.04-1.79）种族/民族、美国以外出生（AOR，4.54；95% CI，3.74-5.52）以及知晓肝病（OR，1.65；95% CI，1.29-2.09）相关。肥胖与较低的HAV免疫力几率相关（AOR，0.83；95% CI，0.72-0.96）。疫苗来源的HBV免疫力与较年轻年龄（例如，20-29岁对比≥65岁：AOR，0.18；95% CI，0.15-0.23）、女性（AOR，1.36；95% CI，1.18-1.56）、非西班牙裔亚裔（AOR，1.47；95% CI，1.17-1.86）和非西班牙裔黑人（AOR，1.15；95% CI，1.00-1.32）种族/民族以及较高教育程度（例如，低于9年级对比大学及以上：AOR，3.29；95% CI，2.35-4.61）相关。在高危亚组中，HAV免疫力范围为代谢功能障碍相关酒精性肝病患者的26.7%（95% CI，18.9%-34.4%）至慢性HBV感染者的63.7%（95% CI，50.0%-77.4%），而HBV疫苗来源的免疫力范围为慢性肾脏病患者的14.0%（95% CI，11.3%-16.6%）至孕妇的38.6%（95% CI，28.0%-49.1%）。这项横断面研究发现，人群水平的HAV和HBV血清免疫不理想，且高危临床亚组中仍有大量易感者。这些发现凸显了病毒性肝炎保护方面的持续差距，并支持针对HAV和HBV的靶向、系统性疫苗接种策略，尤其是在高危人群中。

Gut microbiome dysbiosis causes various intestinal diseases. However, an undefined composition and potential biosafety risks limit the applicability of traditional fecal microbiota transplantation (FMT). Synthetic microbial communities (SynComs), which are compositionally defined and rationally designed emerging live biotherapeutics, offer a novel alternative to FMT. This review establishes strict boundaries between SynComs and traditional donor-derived preparations, comparatively evaluating "top-down" and "bottom-up" construction strategies. We explored the mechanisms underlying the SynComs-mediated synergistic restoration of intestinal homeostasis via direct targeted antagonism and modulation of the host immune network. Moreover, we systematically evaluated the current research landscape of SynComs in Clostridioides difficile infection, inflammatory bowel disease, and colorectal cancer. This review examines fundamental challenges, including host colonization resistance, chemistry, manufacturing, and control barriers, biosafety risks, and microbiokinetic regulatory frameworks, thereby addressing the translational gap. Our analysis of current literature provides a theoretical basis for the clinical translation of SynComs as emerging live biotherapeutics.

Background Hypoxia from sedation-induced upper airway obstruction remains a major risk during endoscopy in obese patients. Nasal cannulae provide oxygenation but do not address obstruction. The Capnography Monitoring Bite Block Oxygenation endoscopy oropharyngeal airway (COMBO device) was feasible in a pilot study, but its efficacy compared with standard care remains unclear. This multicenter RCT evaluated whether the COMBO device reduces hypoxia vs. standard nasal cannula in obese patients undergoing endoscopy. In this multicenter RCT at three Chinese hospitals, adults with a BMI ≥28 kg/m² undergoing sedated endoscopy were randomized 1:1 to the COMBO device or standard nasal cannula. All patients received oxygen (6 L/min) and EtCO₂ monitoring. The primary outcome was hypoxia (SpO₂ 75% to < 90% for < 60 s). 591 patients were analyzed. The incidence of hypoxia was lower in the COMBO group than in the standard nasal cannula group (6.38% [19/298] vs. 21.50% [63/293]; absolute difference, -15.13%, 95% CI -20.59 to -9.66; P < 0.001), and the incidence of subclinical respiratory depression was also lower in the COMBO group than in the control group (15.10% [45/298] vs. 27.65% [81/293]; absolute difference -12.54%, 95% CI -19.08 to -6.01; P < 0.001). Severe hypoxia did not differ significantly (0% vs. 0.34% [1/293]; P = 0.997). Other sedation-related adverse events were comparable. The COMBO device was associated with significantly less hypoxia during sedated endoscopy in obese patients, without increasing adverse events. By maintaining airway patency and enabling monitoring, it may provide a safe and effective strategy for high-risk patients.

Fiber supplementation is widely used and recommended for irritable bowel syndrome (IBS), however there is no recent evidence synthesis. We aimed to investigate the efficacy of fiber supplements in IBS through a systematic review and meta-analysis of randomized controlled trials. We searched MEDLINE, Embase, Web of Science, and Cochrane Central Register of Controlled Trials (inception to 9 April 2026). Trials recruiting adults with IBS that investigated fiber supplements compared with a suitable placebo control were included. Dichotomous clinical response data were summarized with a risk ratio and 95% confidence intervals. The review was registered prospectively on PROSPERO (CRD42024600758). The search identified 4008 records, and 30 RCTs were eligible including 1904 people with IBS. The most common fiber types were wheat bran (n=7), psyllium (n=6), inulin-type fructans (n=5), and β-galacto-oligosaccharides (B-GOS) (n=2) and two RCTs used fiber co-administration. Sixteen RCTs (n=1293) reported clinical response, with 52% responding to fiber vs 44% to control (RR 1.21 [CI 1.03 to 1.41]; P=0.02; I2=38%), with benefit specifically for psyllium (RR 1.53 [95% CI 1.06 to 2.19]). Nine RCTs (n=497) reported overall GI symptoms (integrative scores), showing no significant effect (SMD -0.25 [95% CI -0.67 to 0.17]; P=0.25; I2 =78%), except for B-GOS, which improved symptoms. Subgroup analysis for IBS subtype was not possible for most outcomes. Fiber supplementation, and specifically psyllium, leads to clinical response in IBS. Future RCTs should report outcomes for individual IBS subtypes or only recruit specific IBS-subtypes to better enable identification of distinct patterns of response.

Aberrant activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been increasingly recognized as a key driver of autoimmune and inflammatory diseases. In recent years, accumulating evidence has highlighted the close association between cGAS-STING signaling and the pathogenesis of these disorders, suggesting that pharmacological targeting of this pathway may represent a promising therapeutic strategy. This review provides a comprehensive overview of the molecular mechanisms underlying cGAS-STING hyperactivation and its pathological roles across diverse diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), non-alcoholic steatohepatitis (NASH), STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutières syndrome (AGS), COPA syndrome, Niemann-Pick disease type C (NPC), neurodegenerative diseases and cancer. We critically evaluate current and emerging pharmacological strategies targeting the cGAS-STING pathway, encompassing direct cGAS and STING inhibitors, protein degradation technologies, epigenetic modulation, regulation of biomolecular phase separation, and artificial intelligence (AI)-enabled drug discovery approaches. By integrating disease-specific pathogenic mechanisms with therapeutic opportunities, this review highlights key challenges and future directions in the development of cGAS-STING-targeted therapies. Collectively, these insights provide a translational perspective for precision targeting of pathological cGAS-STING activation.

Toll-like receptors (TLRs) are considered general sensors of bacterial encounters. Here, we examined whether other pattern recognition receptors are commonly activated during bacterial infection. TLR-independent interferon (IFN) responses were induced in macrophages in response to diverse bacterial encounters. Of the cytoplasmic receptor families examined, the cyclic dinucleotide (CDN) sensor STING was required for IFN responses to evolutionarily diverse bacteria. Various bacterial CDNs were present in murine tissues; these activated stimulator of interferon genes (STING) after bacteriolysis in phagolysosomes in a manner requiring two CDN transporters. Importantly, bacterial CDNs were increased in colonic biopsies from patients with inflammatory bowel disease. Systemic delivery of dead, CDN-laden bacteria promoted anti-tumor immunity in mice. Detection of diverse CDNs, including pyrimidine-based CDNs, was an evolutionarily conserved feature of STING, with distinct binding modes for purine- and pyrimidine-based CDNs. Thus, a phagocytosis-CDN-STING connection places cytoplasmic sensing as a common outcome of host-bacteria interactions that set the immune tone of a tissue, with implications for host defense.

Orally administered small-molecule programmed death ligand 1 (PD-L1) inhibitors may have the potential to improve patient outcomes in the treatment of a range of cancers compared with their antibody-based counterparts. A small molecule might achieve better tumor tissue penetration, and oral administration could significantly improve convenience and access for patients. Three phase 1 open-label, non-randomized, dose escalation, and expansion studies evaluated the safety, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of three agents in patients with advanced solid tumors: INCB086550 (NCT03762447), INCB099280 (NCT04242199), and INCB099318 (NCT04272034). Overall, 138, 182, and 104 patients received INCB086550, INCB099280, and INCB099318, respectively. Most had previously received ≥2 lines of cancer therapy for advanced or metastatic disease; 9.6%-16.5% had received prior immunotherapy. All three agents were rapidly absorbed and showed stable dose-dependent PK. With INCB086550, 88 patients (63.8%) had ≥1 treatment-related treatment-emergent adverse event (TEAE), and 19 (13.8%) had ≥1 treatment-related grade ≥3 TEAE. In total, 14 patients (10.1%) had a nervous system-associated TEAE for which an immune-mediated etiology could not be ruled out; events were predominantly peripheral sensory and motor neuropathies. With INCB099280 and INCB099318, 144 (79.1%) and 69 (66.3%) of patients had ≥1 treatment-related TEAE, and 25 (13.7%) and 12 (11.5%) had ≥1 treatment-related grade ≥3 TEAE, respectively. The most frequent immune-related adverse events were skin reactions (INCB099280 and INCB099318) and hepatitis (INCB099280). No dose-limiting toxicities (DLTs) occurred during dose escalation with INCB086550 or INCB099318; two DLTs occurred in two patients with INCB099280 (grade 2 vomiting with 600 mg once daily and grade 2 maculopapular rash with 800 mg two times per day). Overall objective response rates for INCB086550, INCB099280, and INCB099318 were 10.9% (95% CI 6.2% to 17.3%; n=15), 8.8% (95% CI 5.1% to 13.9%; n=16), and 8.7% (95% CI 4.0% to 15.8%; n=9), respectively. Target engagement and PD activity were demonstrated, including PD-L1 binding, and increases in cytokine and chemokine production, as well as T-cell activation and proliferation. Both INCB099280 and INCB099318 had an acceptable safety profile, with preliminary evidence of antitumor activity. The risk of immune-mediated neuropathy led to discontinuation of the clinical program for INCB086550.

Liver sinusoidal endothelial cells (LSECs) form a specialized discontinuous microvascular interface between sinusoidal blood and the hepatic parenchyma. Functioning as a central regulator of hepatic homeostasis, LSECs integrate metabolic, inflammatory, and hemodynamic signals to maintain sinusoidal permeability, immune tolerance, vascular tone, and lipid exchange. During acute injury or sustained hepatic stress, LSECs may lose their differentiated sinusoidal phenotype and acquire features of capillarization, including fenestrae loss, subendothelial matrix accumulation, impaired scavenging activity, and attenuation of KLF2-eNOS-NO signaling. Capillarized LSECs are not merely a byproduct of hepatic damage; instead, they may function as early endothelial sentinels and important contributors to the amplification of parenchymal injury, inflammation, fibrogenesis, and tumor immune evasion. This review summarizes the physiological functions of LSECs and examines mechanisms through which LSEC dysfunction contributes to acute liver injury, metabolic dysfunction-associated steatotic liver disease, viral hepatitis, cirrhosis, and hepatocellular carcinoma. By comparing conserved mechanisms with disease-specific spatial and molecular triggers, this review highlights how LSEC phenotypic switching disrupts the angiocrine-immune-fibrotic axis and contributes to disease progression. Recent advances in single-cell and spatial omics, LSEC subpopulation heterogeneity, and capillarization-aware therapeutic delivery are further discussed. Finally, therapeutic reprogramming of dysfunctional LSECs toward a quiescent, fenestrated, and tolerogenic phenotype is proposed as a strategy to restore sinusoidal homeostasis and improve treatment of liver diseases.

Oral drug delivery relies on precise, site-specific release within the gastrointestinal (GI) tract, commonly achieved using stimuli-responsive polymer (SRP) coatings that regulate dissolution under varying physiological conditions to maximize therapeutic efficacy. Continuous advancements in polymer chemistry and composite formulations have enabled increasingly sophisticated control over drug release profiles. However, a critical challenge remains in accurately assessing how these materials degrade, dissolve, and perform under true in vivo GI conditions. While numerous in vitro models have been developed to approximate physiological environments, they often fail to capture the complexity of GI dynamics, including variations in pH, fluid composition, motility, and transit behavior. As a result, there is a significant need for technologies capable of directly monitoring the real-time behavior of these materials during in vivo transit to better understand their performance and guide formulation design. To address this unmet need, we present a miniaturized ingestible sensing capsule designed for in situ, formulation-centric evaluation of polymer dissolution dynamics within the GI tract. The platform integrates impedance-based sensing to monitor changes in the physical and structural integrity of SRP coatings and polymeric pharmaceutical formulations during dissolution, alongside potentiometric pH sensing for anatomical localization within the GI environment. This dual-sensing approach enables simultaneous tracking of material degradation and spatial positioning, providing direct insight into where and how dissolution occurs in vivo. Systematic in vitro characterization using simulated and extracted GI fluids across physiologically relevant conditions demonstrated an approximately 100-fold reduction in impedance upon dissolution of the polymeric coating, reflecting sensitivity to structural breakdown and fluid ingress. The integrated pH sensor exhibited a linear response across the physiologically relevant range of pH 2 to 8, enabling reliable identification of GI segments. A power-optimized hardware-software co-design enabled periodic sensing and wireless data transmission at intervals between 250 ms and 1 s, achieving an average power consumption as low as 90.7 μW. This low-power operation supports extended device functionality over time scales exceeding typical GI transit durations, while maintaining stable performance and minimizing battery-related risks. As a proof of concept, the system was evaluated using widely used pH-responsive SRP coatings, including Eudragit® EPO (gastric-targeted dissolution) and Eudragit® L100 (intestinal-targeted dissolution). Device performance was validated through both in vitro studies and in vivo evaluation in a porcine model under endoscopy-guided placement, demonstrating accurate tracking of coating dissolution kinetics with spatial correlation to GI segments. Drug release profiles were independently confirmed using spectrometric quantification of identically coated commercial pharmaceutical tablets, establishing consistency between electrical sensing outputs and pharmacological release behavior. Overall, this ingestible platform enables quantitative, spatially resolved, in vivo assessment of polymer-based drug delivery systems, providing a powerful tool for researchers and pharmaceutical developers to directly evaluate formulation performance under realistic physiological conditions. The technology is envisioned to support the design, optimization, and clinical translation of advanced oral drug delivery systems by enabling improved understanding of material behavior, release kinetics, and patient-specific variability in the GI tract.