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Cholestatic liver diseases (CLD) are characterized by impaired normal bile flow, culminating in excessive accumulation of toxic bile acids. The majority of patients with CLD ultimately progress to liver cirrhosis and hepatic failure, necessitating liver transplantation due to the lack of effective treatment. Recent investigations have underscored the pivotal role of the gut microbiota-bile acid axis in the progression of hepatic fibrosis via various pathways. The obstruction of bile drainage can induce gut microbiota dysbiosis and disrupt the intestinal mucosal barrier, leading to bacteria translocation. The microbial translocation activates the immune response and promotes liver fibrosis progression. The identification of therapeutic targets for modulating the gut microbiota-bile acid axis represents a promising strategy to ameliorate or perhaps reverse liver fibrosis in CLD. This review focuses on the mechanisms in the gut microbiota-bile acids axis in CLD and highlights potential therapeutic targets, aiming to lay a foundation for innovative treatment approaches.

Since Vogt[1] recognized and classified the types of anomalies in 1929, many other classification systems have been proposed, including the Ladd, Gross, Swenson, and Kluth classification systems. [...]the illustration of the anatomical pattern of different types of EA/TEF was modified by close comparison with the original images from 434 patients with EA/TEF. According to our study, whether the proximal esophageal pouch is dilated may provide physicians with valuable insight into the diagnosis. [...]an accurate depiction of the gap length reveals why gastrotomy is preferred over primary anastomosis in type A and B patients. Because the distal esophageal remnant barely extends beyond the hiatus of the diaphragm, the gap between the pouches is too wide to be covered by one-stage reconstruction.

Background/Purpose This study aimed to evaluate discrepancies in prognosis after the Kasai portoenterostomy (KPE) procedure between neonatal and non-neonatal periods among patients undergoing the KPE procedure less than 60 days after birth (≤ 60 days). Methods All type III BA patients who performed KPE less than 60 days from June 2020 to May 2024 in the Department of Neonatal Surgery of Beijing Children’s Hospital were retrospectively reviewed. They were divided into two groups according to the age at Kasai: the early KPE group (EK group, or neonatal group ≤ 30 days after birth) and the late KPE group (LK group, or non-neonatal group 31–60 days after birth), to evaluate the effect of surgical age on the postoperative efficacy following Kasai. Results 61 BA patients were included in our study. The median age at KPE in the EK group was 14.0 [10.0, 20.0] days and 47.0 [36.8, 51.1] days in the LK group. Regarding postoperative complications, Patients in the EK group tended to have a higher incidence of postoperative intestinal obstruction (10.5% vs. 0.0%, p  = 0.033) compared to those in the LK group. However, the postoperative long-term prognosis of KPE in the EK group seemed much better than in the LK group. Compared to the LK group, a significantly greater proportion of patients in the EK group achieved successful jaundice clearance (84.2% vs. 40.5%, p  = 0.002) and successful bile acids clearance (63.2% vs. 19.0%, p  = 0.001). Additionally, the one-year NLS in the EK group was also higher than the LK group despite without statistically significant difference (88.2% vs. 61.5%, p  = 0.046). Kaplan-Meier curve also showed a significant difference between the two groups ( p  = 0.049, HR = 3.91, 95%Cl 1.46–10.46). Further, we evaluate the changes in biochemical indexes and liver hardness indicators over time in BA patients who had achieved one-year NLS. We found that compared to BA patients in the LK group, those in the EK group exhibited faster jaundice clearance and bile acids clearance, and more normalized biochemical indicators and liver hardness one year after Kasai. Conclusion Performing KPE procedure in the neonatal period was associated with a better long-term prognosis despite of potential increased risk of postoperative adhesive ileus.

Rare autosomal-recessive variants in tetratricopeptide repeat domain 7A ( TTC7A ) gene have been shown to cause intestinal and immune disorders of variable severity. Missense mutations in TTC7A gene, usually retaining most of the functional motifs, is associated with relative milder clinical presentations. In this study, we reported a patient who was suffering from severe multiple intestinal atresia (MIA) with combined immunodeficiency (CID) that led to the pyloric diaphragm, ileum atresia, colon stenosis, and multiple episodes of sepsis. In spite of several surgeries and supportive treatment, the patient died of severe sepsis and multiple organ failure at age of 3 months. The whole exome sequencing (WES) of peripheral blood samples identified a novel homozygous TTC7A missense mutation (c. 206T>C, p. L69P), inherited from his parents with consanguineous marriage. In silico analysis revealed that a hydrogen bond present between Gly65 and Leu69 in the wild-type TTC7A was disrupted by the Leu69Pro mutation. Moreover, this homozygous missense mutation led to a reduced TTC7A expression in lymphocytes and intestinal tissues, accompanied by impeded lymphocyte development. Further studies demonstrated that the PI4K-FAM126A-EFR3A pathway was impaired in colon tissues. Our data strongly support the linkage of severe MIA-CID with the missense mutation in TTC7A gene. More knowledge of the TTC7A protein functions will have important therapeutic implications for patients with MIA-CID.

BackgroundBiliary atresia (BA) is a severe neonatal hepatobiliary disease that leads to progressive liver fibrosis and liver failure. Hepatic stellate cells (HSCs) have been identified as the main contributors to liver fibrogenesis, with their activation playing a crucial role in fibrosis development. Yiqihuoxue prescription (YQHX), a traditional herbal formula, has demonstrated effective anti-fibrotic properties in multiple hepatic diseases. This study aims to investigate the function and underlying mechanisms of YQHX in HSCs activation and liver fibrogenesis in BA.MethodsWe conducted a series of experiments using rhesus-rotavirus (RRV)-induced BA mice model and cultured HSCs. Neonatal mice were intraperitoneally injected with RRV within 12 hours of birth. Starting from day five, YQHX group received YQHX by oral gavage daily for 9 days. Pups were sacrificed on day 14 for tissue collection and analysis, and serum was collected to measure liver function. H&E and Masson’s trichrome staining were performed for the examination of histological changes. A fibrosis model was established by inducing HSCs activation with tgfβ, and the effects of YQHX on cellular ferroptosis and fibrosis were investigated. UPLC-HRMS was utilized to identify the chemical components in YQHX, and molecular docking analysis was performed between them and NCOA4.ResultsWe found that YQHX ameliorates hepatic injury and fibrosis in the RRV-induced BA mice model (IDDF2024-ABS-0308 Figure 1). In vitro experiments demonstrate that YQHX inhibits HSCs activation by suppressing their proliferation/migration and promoting apoptosis (IDDF2024-ABS-0308 Figure 2), which also occurs in the tgfβ-induced HSCs activation model (IDDF2024-ABS-0308 Figure 3, IDDF2024-ABS-0308 Figure 4). Mechanistically, we found that seven of the top ten compounds in YQHX exhibited molecular docking with NCOA4, a major regulator of ferritinophagy, thereby reducing the release of ferrous iron. We observed a decrease in NCOA4 expression with increasing YQHX concentration.YQHX enhanced the inhibition of activated HSCs after the knockdown of NCOA4 with lentivirus. Consequently, YQHX improved cellular iron overload and oxidative stress by inhibiting the expression of NCOA4, thereby suppressing the activation of HSCs (IDDF2024-ABS-0308 Figure 5).Abstract IDDF2024-ABS-0308 Figure 1Abstract IDDF2024-ABS-0308 Figure 2Abstract IDDF2024-ABS-0308 Figure 3Abstract IDDF2024-ABS-0308 Figure 4Abstract IDDF2024-ABS-0308 Figure 5ConclusionsYQHX can ameliorate hepatic fibrosis by targeting NCOA4 to induce the ferritinophagy of activated HSCs, providing a promising therapeutic strategy for hepatic fibrosis in BA.

BackgroundBiliary atresia (BA) is a severe liver disease in neonates, which is caused by obliteration of the intra- and the extrahepatic biliary duct leading to cholestasis, and progressive liver injury and fibrosis. Epithelial-mesenchymal transformation (EMT) of bile duct epithelial cells is considered to be a key mechanism in the pathogenesis of liver fibrosis. The present study aimed to explore the role and underlying mechanism of ferroptosis in EMT and liver fibrosis.MethodsThirty-four cases of BA liver tissue and twenty-two cases of adjacent normal liver tissue from hepatoblastoma were subjected to RNA-sequencing and proteomic analysis to verify the expression differences of EMT and fibrosis between BA and non-BA liver tissues, as well as the correlation between the expression level of the differential gene SFXN3 in BA and clinical pathological characteristics. A mouse liver model of biliary atresia induced by rotavirus in rhesus monkeys was constructed to verify the expression differences of EMT and fibrosis-related genes. A fibrosis model was constructed by inducing cholangiocytes with TGF-β, and the effects of SFXN3 knockdown and overexpression on cellular ferroptosis, EMT, and fibrosis were studied.ResultsWe found that EMT-related molecules were significantly upregulated in BA patients. In addition, RT-PCR and Western blot experiments on liver of BA mice also revealed significant activation of fibrosis and EMT-related molecules In terms of mechanism, we found that SFXN3 was significantly upregulated in the fibrotic liver of patients (IDDF2024-ABS-0285 Figure 1). And it is positively correlated with the degree of fibrosis, EMT and clinical assay index. We discovered through colocalization that SFXN3 is localized to the biliary epithelial cells (IDDF2024-ABS-0285 Figure 2). Mechanically, we found that nuclear receptor coactivator NCOA4, a master regulator of ferritin phagocytosis, significantly activates and degrades ferritin during EMT, thereby releasing large amounts of ferrous, further leading to SFXN3-dependent mitochondrial iron overload. Conversely, knockdown of NCOA4 or SFXN3 with small interfering RNAs could effectively ameliorate ferroptotic cell death, cellular or mitochondrial iron overload and lipid peroxides accumulation (IDDF2024-ABS-0285 Figure 3).AbstractIDDF2024-ABS-0285 Figure 1Abstract IDDF2024-ABS-0285 Figure 2Abstract IDDF2024-ABS-0285 Figure 3ConclusionsOverall, our findings underscore that ferritinophagy activation and SFXN3-dependent mitochondrial iron overload play critical roles in ferroptosis and EMT in biliary atresia.

BackgroundBiliary atresia (BA) is the most common serious neonatal biliary disease, characterized by progressive biliary inflammation and fibrosis. We aim to comprehensively and systematically investigate the complex pathological process of BA from multiple molecular dimensions, combining transcriptomics, proteomics, metabolomics, and single-cell RNA sequencing.MethodsTranscriptomic, proteomic, and metabolomic techniques were utilized for detecting and integrating the molecular characteristics of BA liver tissues. By combining single-cell RNA sequencing data, we were able to pinpoint the immune cells regulated by the abnormal metabolite in BA. In vitro experiments were detected to reveal the role and mechanism of the abnormal metabolite signaling pathway in the progression of BA. In vivo, the effect of inhibiting abnormal signaling pathway on alleviating bile duct injury and fibrosis was verified in the rotavirus type A (RRV) induced mouse model.ResultsWe found the aberrant regulation and activation of the sphingolipid metabolism pathway was observed in BA by transcriptomic, proteomic, and metabolomic data analysis. By integrating BA single-cell RNA sequencing data, we found that Sphingosine-1-Phosphate Receptor 4 (S1PR4), a receptor of Sphingosine-1-Phosphate signaling, was primarily expressed in CX3CR1+CD8+ effector T (Teff) cells. In vitro experiments demonstrated that S1P promoted the migration of CX3CR1+CD8+Teff cells, and S1P/S1PR4 signaling facilitated the differentiation of CX3CR1+CD8+Teff cells into CD8+ tissue-resident memory T (TRM) cells. Co-culture of CD8+TRM cells could induce apoptosis of cholangiocytes. In the RRV mouse model, S1PR4 inhibitor could alleviate liver inflammation and fibrosis by inhibiting the accumulation of CD8+TRM cells (IDDF2024-ABS-0207 Figure 1. S1P S1PR4 promotes the differentiation of CD8 TRM cells aggravating bile duct injury in biliary atresia).Abstract IDDF2024-ABS-0207 Figure 1S1P S1PR4 promotes the differentiation of CD8 TRM cells aggravating bile duct injury in biliary atresiaConclusionsThis study used multi-omics data integration to reveal aberrant regulation of the sphingolipid metabolism pathway in BA. The activated S1P/S1PR4 signaling pathway in BA liver recruited CX3CR1+CD8+Teff cells to accumulate around the cholangiocytes. S1P/S1PR4 signaling promoted the differentiation of CX3CR1+CD8+Teff cells into CD8+TRM cells, subsequently triggering apoptosis and injury of cholangiocytes, thus exacerbating the progression of BA. Targeting S1P/S1PR4 signaling activation is a promising therapeutic strategy for BA treatment.

The terrestrial methane budget varies between different vegetation types and soil conditions and is highly uncertain for alpine grasslands. This work used eddy covariance techniques to continuously measure CH4 flux (NEEm) over a semiarid alpine meadow on the northeastern Qinghai-Tibetan Plateau from January 2017 to August 2019. The diel NEEm averaged 0.14 ± 0.98 nmol CH4 m−2 s−1 (mean ± S.D.), with a rough pattern of daytime release and nocturnal uptake. The 8-day NEEm exhibited a similar sinusoid variation, with a peak of 6.8 mg CH4 m−2 d−1 at the end of April and a minimum of −1.5 mg CH4 m−2 d−1 at the end of August. The maximum release probably coincided with the thawing of frozen soil in the root zone, and the peak uptake may be related to high soil temperature. Monthly CH4 uptake was highest from June to September and consumed 51.7 mg CH4 m−2 from the atmosphere. CH4 production in the other months totaled 647.6 mg CH4 m−2. The semiarid alpine meadow thus acted as a weak net CH4 source, releasing ca 0.6 g CH4 m−2 year−1 to the atmosphere. The boosted regression trees analysis shows that the sensible heat flux (H) is positively related to half-hour NEEm and accounted for 34% of its variability. The piecewise structural equation models reveal that the magnitude of the effects from soil temperature and vapor pressure deficit on 8-day and monthly NEEm were almost equal, but acted in opposite directions. Vegetation growth and soil moisture exerted little direct influence on NEEm variability at half-hour, 8-day, or monthly scales. Our results show that CH4 emissions of the nongrowing season dominate the annual methane budget for this alpine meadow area. Methane consumption during the growing season was significantly constrained by low soil temperature and high soil water content. These findings imply that semiarid alpine meadows may consume more methane during the growing season if soil temperatures increase and soil moisture levels decrease as projected by future warming scenarios, thus constituting a climate change negative feedback.Graphic abstract

Camellia oleifera Abel is a highly valued woody edible oil tree, which is endemic to China. It has great economic value because C. oleifera seed oil contains a high proportion of polyunsaturated fatty acids. C. oleifera anthracnose caused by Colletotrichum fructicola , poses a serious threat to C. oleifera growth and yield and causes the benefit of the C. oleifera industry to suffer directly. The WRKY transcription factor family members have been widely characterized as vital regulators in plant response to pathogen infection. Until now, the number, type and biological function of C. oleifera WRKY genes are remains unknown. Here, we identified 90 C . oleifera WRKY members, which were distributed across 15 chromosomes. C. oleifera WRKY gene expansion was mainly attributed to segmental duplication. We performed transcriptomic analyses to verify the expression patterns of CoWRKYs between anthracnose-resistant and -susceptible cultivars of C. oleifera . These results demonstrated that multiple candidate CoWRKY s can be induced by anthracnose and provide useful clues for their functional studies. CoWRKY78 , an anthracnose-induced WRKY gene, was isolated from C. oleifera . It was significantly down-regulated in anthracnose-resistant cultivars. Overexpression of CoWRKY78 in tobacco markedly reduced resistance to anthracnose than WT plants, as evidenced by more cell death, higher malonaldehyde content and reactive oxygen species (ROS), but lower activities of superoxide dismutase (SOD), peroxidase (POD), as well as phenylalanine ammonia-lyase (PAL). Furthermore, the expression of multiple stress-related genes, which are associated with ROS-homeostasis ( NtSOD and NtPOD ), pathogen challenge ( NtPAL ), and pathogen defense ( NtPR1 , NtNPR1 , and NtPDF1.2 ) were altered in the CoWRKY78 -overexpressing plants. These findings increase our understanding of the CoWRKY genes and lay the foundation for the exploration of anthracnose resistance mechanisms and expedite the breeding of anthracnose-resistant C. oleifera cultivars.