消化内科领域文献阅读汇编

Pouchitis, de-novo small intestinal inflammation is the most common complication developing in patients with ulcerative colitis after total large bowel resection and ileal pouch-anal anastomosis (IPAA) reconstruction. While the first line treatment is antibiotics, the microbial properties underlying flare, remission, and relapse remain vague. We aimed to investigate how antibiotic treatment drives microbial shifts that underlie remission and contribute to relapse. Patients after IPAA were prospectively recruited during clinical flare (active pouchitis defined by the pouchitis disease activity index) and received a two-week course of metronidazole with either ciprofloxacin or doxycycline. Longitudinal follow up was conducted during a year. Clinical data were recorded, and fecal samples were obtained during consequent flares, recovery, and relapses. Microbial gene repertoire, strains, and resistance to antibiotics were determined. Metagenomic sequencing was integrated with whole-genome sequencing of Escherichia coli isolates, providing strain-specific virulence and antibiotic resistance profiles. Patients (n=21) recruited provided 130 samples over one-year follow-up. Both antibiotic regimens induced rapid but transient clinical improvement, reflected by a decrease in fecal calprotectin (728 to 265 μg/g, p<.05), and a marked reduction in bacterial exotoxin genes (p<.05), yet both parameters rebounded by 6 weeks post-treatment. Antibiotic resistance gene abundance significantly increased during treatment (p<.05), without expansion of resistance gene diversity, indicating that pre-existing resistant strains increased. Antibiotic-induced remission in pouchitis likely results from a temporary suppression of exotoxin-producing bacteria, enabling resistant, low-virulence strains to transiently dominate; The fact that harmful strains quickly rebound after treatment cessation highlights the need for targeted approaches to achieve sustained microbial control.

Interleukin (IL)-17 inhibitors have emerged as effective therapies for moderate to severe hidradenitis suppurativa (HS), but concerns remain regarding their potential association with inflammatory bowel disease (IBD). It is known that there is an increased risk of IBD in HS populations, but it remains unclear whether IL-17 inhibition increases the IBD risk or unmasks underlying disease. To evaluate the incidence of IBD in patients with HS treated with IL-17 inhibitors and to compare IBD event rates between treatment and placebo groups. PubMed, Embase, and the Cochrane CENTRAL were searched from inception through November 2025. Randomized clinical trials (RCTs), nonrandomized studies, and case reports reporting IBD outcomes in patients with HS treated with IL-17 inhibitors were included. Of 1467 records identified, 24 studies met inclusion criteria (10 RCTs, 11 nonrandomized studies, and 3 case reports). Extracted variables included study design, IL-17 inhibitor, study duration, dosing regimen, sample size, patient age, sex, baseline personal or family history of IBD, new-onset IBD, relapse of preexisting IBD, IBD subtype and clinical features, and time to IBD onset. Incidence of IBD event, defined as new-onset or worsening Crohn disease or ulcerative colitis during IL-17 inhibitor treatment in a patient with HS. For RCTs, pooled risk differences were calculated using a common effects Mantel-Haenszel model. For nonrandomized studies, a single group meta-analysis of proportions was performed to estimate pooled IBD incidence. Case reports were synthesized qualitatively. Across 10 RCTs, new-onset IBD occurred in 6 of 2572 patients treated with IL-17 inhibitors (0.23%) and in 0 of 1066 patients treated with placebo through week 16. There was no significant difference between groups (risk difference, 0.002; 95% CI, -0.003 to 0.007). In nonrandomized studies, 7 new-onset IBD events occurred among 469 patients (crude incidence, 1.49%), with a pooled incidence of 3.90% (95% CI, 2.30%-6.50%). Across randomized trials, long-term extension studies, and nonrandomized studies, 17 new-onset cases and 4 IBD flares were reported. In this systematic review and meta-analysis, IBD events were rare. No significant increase in IBD risk was observed with IL-17 inhibitors, although low event rates and inconsistent reporting limited interpretation.

Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract with high risk of surgery. Despite advances in medical treatment, of those patients who undergo ileocolonic resections, up to 70% of patients experience postoperative recurrence (POR) within 1 year of surgery. This underscores the need for a better understanding of the pathogenesis of POR. We hypothesise that the transient 'disease-free' state following surgical resection biologically mirrors the earliest preclinical stages of new-onset CD and that shared biomarkers across preclinical and postoperative settings reflect common pathogenic pathways. Identifying these shared signatures may offer a unique opportunity to elucidate mechanisms underlying both disease initiation and recurrence and to inform strategies aimed at prevention of new onset CD as well as POR. In this review, we synthesise insights from recent biomarker and multiomics studies spanning preclinical and postoperative CD cohorts. We highlight predictive biomarkers shared across CD onset and POR, including genetic variants, immune mediators such as CXCL9 and interleukin 6, microbial signatures involving Faecalibacterium and Ruminococcus and markers of gut barrier dysfunction and systemic inflammation. We also discuss emerging omics approaches including glycomics, urine metabolomics and high-dimensional immunophenotyping that may further refine risk stratification, capture pathogenic heterogeneity and provide mechanistic insight into host-microbe-immune interactions. Finally, we outline potential intervention strategies targeting these shared pathways and propose that the postoperative setting could be a pragmatic human model to test biomarker-guided preventive approaches applicable across the CD spectrum.

Enteric hyperoxaluria (EH) results from increased oxalate bioavailability in the gastrointestinal (GI) tract, often affecting patients with inflammatory bowel disease (IBD). We investigated the pathophysiology of EH in an ileitis mouse model, hypothesizing that fat malabsorption, increased gut permeability, and microbial shifts collectively contribute to the hyperoxaluric phenotype in the setting of GI tract inflammation. SAMP1/YitFc (SAMP1) mice and their parental AKR controls were fed one of three diets varying in fat content (10%, 45%, or 60% kcal), each supplemented with 1% oxalate, for 6 weeks. Plasma (P), urine (U), oxalate (Ox), and creatinine (Cr) levels were measured, while stool lipid species were analyzed using mass spectrometry. Intestinal permeability was assessed using sucralose and 13C2 oxalate gastric gavage in SAMP1 and AKR mice. Histology, qPCR, and Western blotting were performed on kidney, liver, and GI tissues. Microbial DNA was analyzed at the community, genus, and functional levels. Changes in bacterial metabolic pathways were investigated in the mice fed the highest fat content. The oxalobiome of SAMP1 and AKR mice was characterized using our bioinformatics pipeline. On high-fat diets, SAMP1 mice had higher UOx, POx, and PCr levels than AKR mice. Increased levels of diacylglycerols and free fatty acids in SAMP1 stool samples suggested fat malabsorption. A decrease in ZO1 and occludin intestinal expression, coupled with significantly increased urinary sucralose and oxalate levels, indicated increased intestinal permeability. Microbiome analysis revealed the enrichment of Lactobacilli and Bacteroides in SAMP1 mice, with bacterial pathways favoring lipid synthesis and glyoxylate metabolism. Ileal SLC26A6 protein expression was significantly reduced in SAMP1 mice. SAMP1 mice also developed progressive kidney injury with interstitial inflammation. These findings highlight fat malabsorption as a central pathophysiologic disturbance in EH that reduces luminal calcium availability for oxalate binding, is associated with enhanced intestinal permeability, and accompanies microbiome and enzymatic pathway alterations.

The extent of production and use of plastics leads to release of nanoplastics (NPL) into the environment, where they undergo weathering that could alter their toxicological properties. NPL enter the human food chain via contaminated food, and food packaging, and within the body they are known to pass through epithelial barriers. In parallel to the increasing exposure to plastics, the incidence of non-communicable diseases, including intestinal diseases, is rising worldwide. This study focuses on how oral exposure of gestating and lactating female mice to 50 nm polystyrene beads, pristine (PS50) or weathered (PS50w) affects intestinal function in offspring. Two aspects of intestinal function were studied: oral tolerance and the onset of intestinal disorders. Gestating mice received 1.25 mg of PS50 or PS50w by oral gavage administered daily from gestational day 15. Exposure was continued during lactation until pups were weaned (Postnatal Day, PND21). To study oral tolerance, offspring were exposed to ovalbumin (OVA) both orally and systemically. To study intestinal disorders, colitis was induced by exposure to Dextran Sulfate Sodium (DSS) from PND63. Perinatal exposure to PS50 or PS50w had no impact on mortality of gestating or lactating dams or sex ratio in litters, but did lead to increased body weight at PND63 in offspring. No impact on tolerance to OVA was observed. However, macroscopic scores for DSS-induced colitis in adult offspring were significantly worsened in both sexes. In this context, in male offspring, PS50w was more deleterious than PS50. Early-life exposure to PS50 or PS50w has long-lasting consequences on gut physiology, and effects show sexual dimorphism. The results presented raise questions on the kinetics of later-life effects linked to perinatal PS50 and PS50w exposure, and introduce the notion of imprinting.

Microbial dysbiosis and disrupted mucosal immune homeostasis are integrally involved in the pathogenesis of inflammatory bowel diseases (IBDs). Live biotherapeutic products (LBPs) offer a potential therapeutic strategy to restore beneficial microbes and mitigate disease. We investigated the therapeutic efficacy of 2 LBPs, human Clostridia consortia 17-mix and 11-mix, by treating established colitis in murine models. Both LBPs exhibited therapeutic effects in T cell-mediated chronic colitis models induced by human microbiota and in pathobiont-driven gnotobiotic colitis models established with combinations of IBD-relevant human-derived strains. Metagenomic and metabolomic analyses elucidated mechanisms that go beyond established functions driven by short-chain fatty acids (SCFAs) and interleukin (IL)-10-producing regulatory T cells. Notably, LBPs exerted therapeutic effects by directly inhibiting resident pathobionts and through IL-10-independent activation of host anti-inflammatory aryl hydrocarbon receptor (AhR) pathways by bacterial tryptophan metabolites. These results elucidate SCFA- and IL-10-independent protective mechanisms exerted by defined resident bacterial strains that are depleted in IBD dysbiosis.

Inflammasomes ignite innate immune defense in response to infectious pathogens and noninfectious dangers, primarily through sensors composed of nucleotide-binding domain (NBD), leucine-rich repeat (LRR)-containing (NLR) family proteins. NLRP6 is an inflammasome sensor that plays critical roles in regulating intestinal inflammation, and its overactivation is linked to autoinflammatory diseases such as inflammatory bowel disease. However, how NLRP6 is maintained in an inhibited structure is unknown. Here we report two cryogenic-electron microscopy structures of human NLRP6 monomer in the adenosine-5'-triphosphate (ATP)/NBD-bound (twisted conformation) and unbound (extended conformation) states. The ATP-binding event connects and compacts the NACHT subdomains and the LRR domain, thus maintaining NLRP6 in an inhibitory conformation. NBD interacts directly with helical domain 1, winged-helix domain and helical domain 2, further contributing to the autoinhibition. Disruption of ATP binding and NBD interactions unleashes the NLRP6 inflammasome activation in the cellular study. The structural comparison between twisted and extended conformations reveals that the rearrangement of an NLRP6-specific acidic loop modulates NLRP6 activity. Although ATP-binding of NLRP6 and MCC950 (a potent NLRP3 inhibitor)-binding of NLRP3 share a similar interaction location in the structures, MCC950 does not inhibit NLRP6 in cells. Together, our data reveal the ATP-mediated cooperative inhibition mechanism of NLRP6 and provide insight into the therapeutic intervention of NLRP6-related autoinflammatory disorders.

Among the tens of thousands of annotated long noncoding RNAs (lncRNAs) in the human genome, only a small fraction have been functionally characterized. Here, we show that a well-established inflammatory bowel disease (IBD) risk locus encoded a conserved lncRNA, lnc15 (2310015A10Rik/ENSMUSG00000097729), whose structure was destabilized by risk-associated variants, leading to its degradation. Deletion of lnc15 in mice resulted in molecular features of inflammation under steady-state conditions and conferred heightened susceptibility to experimental colitis. Lnc15 was abundantly expressed in T cells, with highest expression in regulatory T (Treg) cells. Mechanistically, lnc15 suppressed the transcription factor T-BET by recruiting the CCR4-NOT RNA degradation complex to Tbx21 mRNA. Our study identifies that lnc15 simultaneously enhances Treg cell suppressive function and impairs conventional T cell pathogenicity in the context of intestinal inflammation. Collectively, these findings identify lnc15 as a functional lncRNA that links noncoding genetic variation to immune regulation and prevention of mucosal inflammation. VIDEO ABSTRACT.

The commensal yeast Candida albicans is a major inducer of human mucosal Th17 cells. How C. albicans drives Th17 cell responses at homeostasis, and whether such responses contribute to inflammatory diseases, remains poorly understood. Here, we showed that C. albicans-reactive Th17 cells targeted a limited set of proteins enriched in fungal extracellular vesicles. At homeostasis, these cells predominantly resided in the oral mucosa. However, T cell receptor profiling revealed shared clonotypes across oral and gut tissues, with C. albicans being a major driver of this repertoire overlap. In patients with Crohn's disease, C. albicans-specific Th17 cells with features of oral priming were enriched in intestinal tissues, where they retained their focused antigen specificity but acquired pathogenic Th17 cell traits. Together, our results reveal a stable, antigen-restricted C. albicans Th17 subset that is shared across mucosal sites and undergoes functional adaptation in the inflamed intestine. These cells represent a potential target for immune modulation in Crohn's disease.

Faecal microbiota transplantation (FMT) shows variable efficacy in inflammatory bowel disease (IBD), and current donor selection strategies rely primarily on microbiome characteristics, while host immune responses to donor microbiota remain largely unexplored. Here, we investigated whether recipient-specific immune responses to donor microbiota could be leveraged to develop a personalised donor-recipient matching strategy for FMT in IBD. We developed a proof-of-concept (POC) assay, termed Gut Microbiota-Leukocyte Reaction (GMLR), to assess immune compatibility between donor microbiota and recipients with IBD. Lamina propria mononuclear cells isolated from intestinal biopsies were exposed ex vivo to microbiota from healthy donors, and cytokines relevant to IBD pathophysiology were measured. Donor microbiota clustered into distinct groups associated with differential immune signatures, including significant IL-22 induction (p = 0.033), whereas IL-17 showed a non-significant trend toward reduction (p = 0.054) that was not consistently observed across immune cell subsets. However, immune responses were highly individualised across recipients, with substantial inter-patient variability. Based on these responses, we developed an algorithm to generate donor-recipient compatibility scores, providing a framework to prioritise potential donor-recipient pairs. Our findings suggest that donor-recipient immune compatibility is highly personalised and may represent a key determinant of FMT efficacy, challenging the "super-donor" paradigm. This ex vivo proof-of-concept platform may help prioritise donor-recipient pairs and should be prospectively validated against clinical FMT outcomes. This work was supported by the Italian Ministry of Health, Associazione Italiana per la Ricerca sul Cancro (AIRC), the European Union-NextGeneration EU (HEAL ITALIA project), and the Italian Ministry of Education and Research (MUR).

CD8+ T cell dysfunction is a major obstacle to hepatitis B virus (HBV) clearance and antitumor immunity. Here, using a humanized mouse model, we identify a T cell receptor targeting a clinically relevant HBV epitope and reveal ANKRD11 as a key epigenetic regulator of CD8+ T cell dysfunction in chronic infection and tumors. Ankrd11 knockout in CD8+ T cells enhances HBV-specific T cell proliferation and effector differentiation, especially under immunosuppressive conditions, via AP-1 family gene upregulation. Loss of Ankrd11 both drives the conversion of progenitor exhausted T cells into terminally exhausted T cells, and reprograms PD-1-TOX- tolerant cells into functional effectors, improving antiviral and antitumor responses. Ankrd11-deficient T cells show increased granzyme and superior effector function, enhancing viral control and tumor regression. These findings position ANKRD11 as a promising immunotherapy target for chronic HBV infection and cancer.

Hepatitis E virus (HEV) causes approximately 19.47 million symptomatic cases annually and is an emerging cause of chronic hepatitis in immunocompromised individuals. No definite evidence demonstrates that laboratory mice are susceptible to all known HEV genotypes. The factors that define the host species range of HEV remain unclear. Given the numerous genetic variants and toolkits available for mice, which permit deep mechanistic studies, we aimed to develop an inbred mouse model of HEV infection. AG129 and C57BL/6J mice were infected with HEV. Key infection parameters included HEV RNA detection by RT-PCR and RNAscope, liver function tests, histopathological examination. Single-cell RNA sequencing was employed alongside transcriptomic analysis to delineate infection dynamics and investigate virus-host interactions. We show that an emerging human-pathogenic rat-derived HEV-C1 strain can breach the species barrier and robustly infect AG129 mice. Using single-cell sequencing and RNAscope, we demonstrate viral tropism for liver macrophages and hepatocytes, providing a previously unknown single-cell atlas of intrahepatic HEV-C1 infection. We subsequently adapted this HEV-C1 isolate by serial passaging in AG129 mice. After 13 passages, the resulting mouse-adapted strain acquired the ability to infect immunocompetent C57BL/6J mice. Both the immunocompromised and immunocompetent mouse models supported efficient HEV replication and enabled antiviral and vaccine testing. CD4 depletion experiments suggest that impairment of CD4+ T cell responses may contribute to the establishment of persistent infection. We developed two mouse models using AG129 and C57BL/6J mice, both of which support efficient HEV-C1 replication. This work establishes the first immunocompetent mouse model for HEV infection. These mouse models offer a robust platform for studying HEV immunopathogenesis, evaluating antivirals and vaccines, and investigating mechanisms of cross-species transmission. PX496820, PX572923 RNA-Seq data: https://ngdc.cncb.ac.cn/gsa/ IMPACT AND IMPLICATIONS: HEV research is hampered by the lack of suitable small-animal models, and our study fills this gap by establishing two mouse models, particularly the immunocompetent C57BL/6J mouse model, which should support the use of versatile genetic and immunological tools for deep mechanistic studies in the future. This study also provides a single-cell atlas of HEV infection dynamics, revealing intrahepatic viral tropism. We identified CD4+ T cell depletion as a pivotal driver of chronic infection. These mouse models offer a robust platform for studying HEV immunopathogenesis, evaluating antivirals and vaccines, and investigating mechanisms of cross-species transmission.

PEGylated interferon-α (PEGIFNα) shows promise in treating chronic hepatitis B (CHB), yet patient response remains suboptimal. While suppressing hepatitis B virus (HBV) antigens by RNA interference (RNAi) could enhance PEGIFNα efficacy in CHB patients, the underlying immunological mechanisms remain obscure. Using our newly established extracellular humanized IFNAR (IFNAR-hEC) mouse model of chronic HBV infection, we evaluated the efficacy of a GalNac-conjugated siRNA (GalNac-siHBV) alone or in combination with PEGIFNα. Phenotypic and functional characteristics of immune cells were assessed by flow cytometry, ELISpot, and single-cell RNA sequencing (scRNA-seq). High circulating HBsAg reduced antiviral effects and immune responsiveness of PEGIFNα. Combined PEGIFNα and RNAi therapy synergistically and durably suppressed HBsAg (~4log10 IU/mL, vs PBS) and achieved HBsAg seroconversion in ~30% of mice, outperforming either monotherapy. Mechanistically, PEGIFNα enhanced global T and B cell function, whereas combined therapy further amplified HBV-specific T and B cell responses. scRNA-seq analysis indicated that combined therapy attenuated inhibitory B cell-B cell interactions, strengthened MHC-I-mediated T cell crosstalk, and enhanced MHC-II signaling networks across B cells and hepatocytes/Cd8+ T cells, collectively improving the lymphocyte functionality and facilitating HBsAg seroconversion. Reinforcing MHC-I/II signaling with agonistic antibodies (α4-1BB, αCD40) or IL-2-Fc further potentiated antiviral immune responses of combinational regimen. Combined RNAi and PEGIFNα therapy exerts synergistic antiviral effects by relieving HBV antigen-induced immune tolerance and orchestrating a functional T cell-B cell crosstalk network centered on MHC-I/II signaling. Enhancing antigen presentation pathways represents a promising adjunctive strategy to improve functional cure rate of CHB.

The recently published Rome V adult diagnostic criteria facilitated an updated epidemiological survey of disorders of gut-brain interaction (DGBI). We aimed to describe the global epidemiology of DGBI using the Rome V criteria and compare it with the Rome IV Rome Foundation Global Epidemiology Study. A population-based Internet survey of 28,771 adults was conducted in 15 countries using the Rome V diagnostic questionnaire. DGBI prevalence was determined and compared with the Rome IV data. Multivariable logistic regression models were used to examine associations of demographic factors to Rome V DGBI status in the global population and to assess potentially associated clinical factors. The surveys yielded similar results. The prevalence of at least one DGBI using the Rome V criteria was 40.9%, compared with 40.5% for Rome IV. In both, the prevalence was higher among females and decreased with increasing age. In the Rome V sample (25 DGBI), the most prevalent oesophageal disorder was functional dysphagia at 4.1%, the most prevalent gastroduodenal disorder was functional dyspepsia at 8.1%, unclassified bowel disorder was the most prevalent bowel disorder (9.6%), followed by chronic constipation (8.9%) and IBS (8.5%) and proctalgia fugax was the most prevalent anorectal disorder (7.3%). The prevalence rates for two new DGBI were 5.1% for abdominal migraine and 1.4% for inability to belch syndrome. The Rome V global prevalence of DGBI is consistent with Rome IV. This bolsters confidence in the validity of prevalence rates for DGBI and reaffirms their high global burden.

Global prevalence estimates of paediatric disorders of gut-brain interaction (DGBI) are largely unknown and published studies are hindered by heterogeneous methodology. To determine the multinational prevalence and burden of paediatric DGBI as defined by Rome V. Caregivers of 8000 children aged 0-17 years from China, Italy, Mexico and the USA completed an online Rome V survey assessing gastrointestinal symptoms, illness burden and comorbid health conditions. Prevalence was calculated by DGBI category, country, sex and age. Paediatric DGBI were highly prevalent, affecting 28.0% (95% CI 27.0% to 29.0%) of children. Upper DGBI were present in 8.7% (95% CI 8.2% to 9.5%) and lower DGBI in 23.7% (95% CI 22.8% to 24.7%). The most common lower DGBI were defecation and anorectal disorders (20.2%) followed by abdominal pain disorders (4.4%) and discomfort disorders (1.8%). The most common upper DGBI were gastroduodenal disorders (6.6%), followed by functional feeding disorders (3.4%) and oesophageal disorders (0.6%). Significant geographic differences were observed with the highest prevalence in Mexico and the lowest in China. There was a female predominance in gastroduodenal and discomfort disorders. Overall prevalence declined with age, from approximately 41% in children aged 0-3 years to 22% in adolescents. DGBI were associated with significant anxiety, depression, functional disability and healthcare utilisation, as well as parental time spent in care and coordination particularly when upper and lower DGBI overlapped. This global Rome V study demonstrates the high multi-national prevalence, burden and heterogeneity of paediatric DGBI, supporting improved recognition, classification, research and clinical care.

Peg-interferon (peg-IFN) plays an increasingly important role in HBV cure strategies, either in combination with novel antivirals, as a lead-in or as consolidation treatment. We aimed to provide estimates of hepatitis B surface antigen (HBsAg) decline and clearance that can be achieved with peg-IFN addition to nucleos(t)ide analogue (NA) therapy. This is a post hoc meta-analysis of individual participant data from eight clinical trials involving chronic hepatitis B patients on NA therapy who received peg-IFN add-on. The primary endpoint was HBsAg loss at end of follow-up (EOF, 6-12 months after end of peg-IFN). Secondary analyses focused on HBsAg decline. 581 patients were included. At the start of peg-IFN therapy (SOT), 44% were hepatitis B envelope antigen (HBeAg) positive, mean HBsAg level was 3.03 log10 IU/mL (HBsAg<100: 12%; 100-1000: 28%; ≥1000: 60%), and planned duration of peg-IFN was 48 weeks in 496 patients (85%).At EOF, 50 (8.6%) patients achieved HBsAg loss (HBsAg<100/100-1000/≥1000: 37.7/9.8/2.3%, p<0.001) Findings were consistent across ethnicities (Caucasian: 30.0/8.7/3.6%; Asian: 39.3/9.2/2.2%). In patients with SOT HBsAg≥1000 IU/mL, levels <1000 and <100 were achieved in 29.7% and 8.9% at 24 weeks and in 47.5% and 16.3% at 48 weeks of peg-IFN therapy, respectively. Peg-IFN add-on results in HBsAg loss in 18% of patients with SOT HBsAg<1000 IU/mL, and in 38% if SOT HBsAg<100 IU/mL. Among patients with higher HBsAg levels, peg-IFN could be used to reduce HBsAg to below thresholds associated with response to novel compounds.

Plasmablast-derived HBV surface antigen (HBsAg)-specific monoclonal antibody (mAb) and structural basis for binding to native HBsAg are poorly known. We aimed to identify plasmablast-derived HBsAg-specific mAbs, evaluate their antiviral activities and resolve their structure for binding to native HBsAg. A previously vaccinated volunteer was enrolled in this study, who was boosted with a dose of recombinant hepatitis B vaccine and donated the blood sample. Activated plasmablasts were sorted from fresh peripheral blood mononuclear cells and mAbs were expressed. Their gene features, cross-genotypic binding activities and antiviral functions in vitro and in vivo were comprehensively analysed. The cryo-electron microscopy (cryo-EM) was used to determine the structure of representative mAb bound to the native HBsAg. In this study, we cloned a series of HBsAg-specific mAbs directly from clonally expanded plasmablasts from a vaccinated individual. Most of the mAbs displayed cross-reactivities of binding to different genotype HBsAg proteins and antiviral functions such as neutralisation and antibody-dependent cellular phagocytosis. These human anti-HBsAg mAbs, especially SY-4-class and SY-23-class, could be good candidates for antibody drugs. The cryo-EM structure of SY-23 bound to the dimeric HBsAg was determined, revealing its binding mechanism and unprecedented structural detail of the major antigenic loop (AGL) of HBsAg. Overall, our work has uncovered the diverse gene features and varied anti-HBV activities of plasmablast-derived mAbs, providing a series of antibody drug candidates and the long-sought-after atomic model of AGL has paved the way for a wholistic characterisation of the AGL's dynamic conformation during HBV infection and immune response.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a prevalent condition affecting 25-30% of the global population and is closely linked to obesity, type 2 diabetes, and other cardiometabolic risk factors. Although liver biopsy remains the gold standard for diagnosis, its invasive nature has prompted a shift toward non-invasive biomarkers for disease assessment, staging, and monitoring. Multiple non-invasive biomarkers have been studied or are currently under investigation to assess both fibrosis and steatosis among patients with MASLD. This review aims to summarize the current literature on emerging and established biomarkers for MASLD, focusing on their roles in detecting inflammation, fibrosis, metabolic dysfunction, and steatosis, including imaging-based surrogate endpoints and composite biomarker panels.

Refractory ascites (RA) is a severe complication that impedes long-term survival after pediatric liver transplantation (LT), but its etiology remains complex and heterogeneous. To systematically evaluate the prognostic impact, clinical risk factors, and immunological features of RA, we retrospectively analyzed 1455 pediatric recipients who received LT in Renji Hospital between October 2016 and December 2021. RA was associated with increased mortality and graft loss after pediatric LT. Univariate analysis identified 13 clinical factors associated with RA, whereas a preliminary multivariable model showed only moderate discrimination, suggesting substantial heterogeneity among RA patients. Based on unsupervised clustering of clinical parameters, RA individuals were classified into two subgroups. Type I ascites was mainly associated with low graft-to-recipient weight ratio, decreased preoperative white blood cell count, and platelet count, indicating the involvement of persistent portal hypertension. In contrast, type II ascites was characterized by ABO incompatibility, elevated early postoperative soluble IL-2 receptor, and increased risk of T-cell-mediated rejection, suggesting excessive alloimmune activation. These findings indicate that RA after pediatric LT comprises distinct clinical entities with different pathogenic implications. Prudent graft selection and close monitoring of immune status may help prevent RA and improve post-transplant outcomes.

Cholangiopathies comprise a heterogeneous group of chronic liver diseases characterised by progressive bile duct injury, ductular reaction and fibrotic remodelling. Despite distinct aetiologies, these disorders share common cellular stressors that ultimately converge on cholangiocyte dysfunction and loss. In this context, programmed cell death has emerged as a central mechanism linking epithelial stress, immune activation and the development of biliary fibrosis. A range of regulated cell death pathways, including apoptosis, necroptosis, pyroptosis, ferroptosis and autophagy-dependent cell death, can be triggered in cholangiocytes in a disease-dependent and context-dependent manner. Growing evidence suggests that these pathways rarely act in isolation. Instead, they intersect through shared molecular nodes, forming integrated cell death programmes such as PANoptosis. Importantly, it is becoming clear that not only overt cell death but also sublethal activation of death-related signalling can perpetuate cholangiocyte dysfunction and fuel chronic disease progression. Current therapeutic strategies, such as ursodeoxycholic acid and peroxisome proliferator-activated receptor agonists, mainly aim to modify bile composition and improve biochemical parameters. However, they do not directly target the molecular networks governing cholangiocyte death, which may partly explain their limited impact on fibrosis and long-term outcomes. In this review, we synthesise current knowledge on regulated cell death mechanisms in cholangiopathies, highlight key conceptual and technical challenges that complicate their interpretation and therapeutic targeting, and discuss how sublethal death signalling may connect with senescence to sustain cholangiopathy progression and shape therapeutic perspectives.

Supragastric belching (SGB) can trigger reflux episodes, but the contribution of SGB to pathological reflux burden is incompletely understood. To characterise and identify clinical predictors for excessive SGB-related gastro-oesophageal reflux disease (GERD) phenotype. This was a multicentre cross-sectional study of patients with acid exposure time (AET) >6% on pH-impedance monitoring off therapy across 11 international tertiary centres. SGB episodes were manually identified. Excessive SGB was defined by ≥13 episodes/24 hours. SGB-related AET was determined by duration of pH <4 following an SGB episode. Univariate and multivariable analyses assessed relationships between excessive SGB and conclusive GERD. Of 580 patients (age 56.1±0.6 year, 62% women) from four world regions (Europe/North America/Latin America/Asia), 107 (18.5%) had excessive SGB (p=0.97 across regions). Excessive SGB-related GERD phenotype had lower total AET (p=0.01) with 24.6±2.2% total AET attributable to SGB, higher total reflux episodes (TRE, p=0.0006) and higher number of SGB-related symptom episodes (p<0.0001). On logistic regression, higher TRE (OR 1.01, 95% CI 1.004 to 1.014, p=0.0004) independently predicted excessive SGB, while predominant perceptive symptoms (heartburn/chest pain, OR 0.36, 95% CI 0.155 to 0.854, p=0.002) and higher distal AET (OR 0.96, 95% CI 0.920 to 0.998, p=0.042) were negative predictors. On receiver-operating characteristics curve analysis, >115 TRE and >56 proximal reflux episodes achieved >90% specificity for excessive SGB. Excessive SGB is found in up to 20% of patients with conclusive GERD, with 25% of AET attributable to SGB. Higher TRE (>115 TRE, >56 proximal episodes) and more SGB-associated symptoms are predictors of excessive SGB-related GERD phenotype.

Alcohol-associated liver disease (ALD) is a major cause of morbidity, yet therapies for severe inflammation remain limited. We examined whether circulating and hepatic immunoglobulin A (IgA) and hepatic myeloid-cell IgA binding are associated with interleukin-1 beta (IL-1β)-linked inflammation and hepatocyte injury in ALD. This single-centre cross-sectional study enrolled consecutive adults with ALD (n=276), chronic hepatitis B (CHB; n=177) and healthy controls (n=20). A clinically indicated liver-biopsy subcohort underwent flow cytometry, immunohistochemistry and real-time quantitative PCR. Mice received 16-day chronic-plus-binge ethanol feeding±fingolimod (FTY720; 1 mg/kg/day). CD14+ monocytes were stimulated on plate-bound secretory IgA (sIgA)±lipopolysaccharide (LPS) and conditioned media were applied to Huh7 cells. Serum IgA was higher in ALD (median 323-412 mg/dL) than in healthy/CHB (194/211 mg/dL; p<0.001) and correlated with hepatic IgA+area (ρ=0.680, p<0.001). Serum IgA correlated with CD68-normalised IL1B transcripts (ρ=0.383, p=0.008), while hepatic CD14+ cells from ALD samples showed greater IgA binding than those from CHB samples (p<0.05). In mice, serum IgA correlated with IgA-bound macrophage frequency (n=16, ρ=0.844, p<0.001). FTY720 reduced serum IgA (p<0.01), IgA-bound macrophages (p<0.001) and Cd68-normalised Il1b transcripts (p<0.01), and attenuated ethanol-induced liver injury (alanine aminotransferase/aspartate aminotransferase; p<0.05). Spatial transcriptomics suggested attenuation in monocyte-derived macrophage-enriched regions and IL-1-linked programmes with FTY720. sIgA+LPS monocyte supernatants contained higher tumour necrosis factor-α/IL-1β than LPS alone (Δ+280/+798 pg/mL, p<0.01) and increased Huh7-cell apoptosis (Δ+2.96% p; p<0.01). IgA binding to hepatic myeloid cells is associated with interleukin (IL)-1-linked inflammation in ALD, and in ethanol-fed mice pharmacologic modulation of immune-cell trafficking was accompanied by reduced IgA-bound hepatic myeloid cells and attenuated IL-1-related inflammation.