EBioMedicine最新文献

Background: Sudden Infant Death Syndrome (SIDS) is a leading cause of postneonatal mortality. The absence of specific biomarkers of SIDS diagnosis and risk leaves a significant gap in understanding SIDS pathophysiology. Metabolomics offers an avenue to better understand SIDS biology and identifying potential biomarkers.

Methods: Using Metabolon Inc., global discovery panel, we analysed 828 metabolites from post-mortem serum samples of infants from the Chicago Infant Mortality Study (CIMS) and the NIH NeuroBioBank (NBB). In total, 300 infants (195 SIDS; 105 non-SIDS) across multiple race/ethnicities (70% Black, 13% White, and 16% Hispanic) were included. Metabolite associations with SIDS were performed using Welch's t-tests, linear and logistic regression, and network-cluster analyses.

Findings: We identified thirty-five significant metabolite predictors of SIDS after adjustment for age, sex, race and ethnicity, and post-mortem interval, including ornithine (OR 21.98; p-value 6.44e-7), 5-hydroxylysine (OR 19.48; p-value 6.78e-7), 1-stearoyl-2-linoleoyl-GPC (18:0/18:2) (OR 16.80; p-value 3.4e-7), ribitol (OR 8.19; p-value 4.2e-8), and arabitol/xylitol. Using Weighted Gene Co-expression Network Analysis (WGCNA), ten metabolite clusters were identified. Four exhibited significant associations with SIDS. The two most correlated clusters were enriched for metabolites in the tyrosine metabolism pathway and lipid (sphingomyelins) pathways.

Interpretation: We identified metabolite biomarkers within key biological pathways and processes (e.g., nitrogen metabolism, lipid and fatty acid metabolism, stress response, nerve cell communication, hormone regulation, oxidative stress) with potential implications in SIDS pathology. Further research is needed to validate these biomarkers in additional SIDS cohorts.

Funding: The Chicago Infant Mortality Study was funded by Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute on Deafness and Other Communication Disorders under contract number NO1-HD-3-3188, the Centers for Disease Control and Prevention and the Association of Teachers of Preventive Medicine under cooperative agreement number U50/CCU300860-06, and the Playmates in Heaven Foundation. The current analyses were funded by Eunice Kennedy Shriver National Institute of Child Health and Human Development under 5R01HD101518-04.

The cyclic-GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway has emerged as a promising therapeutic target for colitis and colon cancers. Notably, inhibiting STING may mitigate the progression of colitis, whereas activating STING can enhance anti-tumor immune responses against colon cancer. This duality suggests that the development of STING agonists and inhibitors possesses significant clinical translational potential. In this review, we provide a comprehensive overview of STING inhibitors/agonists that have been systematically evaluated in the contexts of colitis and colon cancer and their specific molecular mechanisms. Other well-characterized STING inhibitors/agonists may also hold considerable promise for the treatment of these conditions, although efficacy validation remain necessary. Additionally, we delve into the latest advances concerning STING oligomerization, degradation and phase separation-dependent self-regulation, proposing potential druggable targets that could inspire the development of novel STING agonists or inhibitors. In Summary, targeting STING appears to be a promising strategy for the treatment of colitis and colon cancer.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) and its more severe form steatohepatitis (MASH) contribute to rising morbidity and mortality rates. The storage of fat in humans is closely associated with these diseases' progression. Thus, adipose tissue metabolic homeostasis could be key in both the onset and progression of MASH.

Methods: We conducted a case-control observational research using a systems biology-based approach to analyse liver, abdominal subcutaneous adipose tissue (SAT), omental visceral adipose tissue (VAT), and blood of n = 100 patients undergoing bariatric surgery (NCT05554224). MASH was diagnosed through histologic assessment. Whole-slide image analysis, lipidomics, proteomics, and transcriptomics were performed on tissue samples. Lipidomics and proteomics profiles were determined on plasma samples.

Findings: Liver transcriptomics, proteomics, and lipidomics revealed interconnected pathways associated with inflammation, mitochondrial dysfunction, and lipotoxicity in MASH. Paired adipose tissue biopsies had larger adipocyte areas in both fat depots in MASH. Enrichment analyses of proteomics and lipidomics data confirmed the association of liver lesions with mitochondrial dysfunction in VAT. Plasma lipidomics identified candidates with high diagnostic accuracy (AUC = 0.919, 95% CI 0.840-0.979) for screening MASH.

Interpretation: Mitochondrial dysfunction is also present in VAT in patients with obesity-associated MASH. This may cause a disruption in the metabolic equilibrium of lipid processing and storage, which impacts the liver and accelerates detrimental adaptative responses.

Funding: The project leading to these results has received funding from 'la Caixa' Foundation (HR21-00430), and from the Instituto de Salud Carlos III (ISCIII) (PI21/00510) and co-funded by the European Union.

Background: While metagenomic next-generation sequencing (mNGS) has been acknowledged as a valuable diagnostic tool for infections, its clinical validity and impact on patient management when using fresh tissue samples remains uncertain.

Methods: We conducted a retrospective cross-sectional study involving patients who underwent tissue mNGS at a tertiary hospital in China from February 2021 to February 2024, aiming to assess its ability to detect plausible pathogens and its clinical validity and impact.

Findings: A total of 520 mNGS results from 508 patients were analysed, detecting plausible pathogens in 302 (58.1%) tests, including 260 single-pathogen and 42 (13.9%) multi-pathogen results. Rare pathogens, such as Balamuthia mandrillaris, Bartonella henselae, and Sporothrix globosa, were identified. Of the multi-pathogen results, 22 were with predominance of anaerobes. mNGS showed higher positivity in cases with high initial suspicion of infection than those used for ruling out infection (PR 1.961, 95% CI: 1.604-2.394) and in patients living with HIV (PR 1.312, 95% CI: 1.047-1.643) or solid organ transplant recipients (PR 1.346, 95% CI: 1.103-1.643) compared to immunocompetent individuals. Sensitivity and specificity for diagnosing confirmed/probable infections were 85.0% (95% CI: 76.7%-93.3%) and 93.7% (95% CI: 86.8%-100.0%), respectively. mNGS influenced clinical management in 258 (49.6%) cases by identifying new infections and in 112 (21.5%) by excluding infections. It prompted initiation (20.2%), modification (23.1%), or discontinuation (6.3%) of antimicrobial therapy.

Interpretation: mNGS demonstrates high diagnostic accuracy for tissue infections. Its impact on clinical management highlights the need to integrate it into current diagnostic practices.

Funding: National Natural Science Foundation of China (No. 82472371), "Leading Geese" Research and Development Plan of Zhejiang Province (No. 2024C03218), and Pudong New Area Joint Project (PW2021D-09).

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) is associated with impaired regenerative capacity and poor postoperative prognosis following hepatectomy. Previous research has highlighted the importance of the gut-liver axis in the physiological and pathological processes of the liver. However, the contribution of gut bacteria to the regeneration of livers with MAFLD and its metabolic regulatory mechanisms remain elusive.

Methods: Partial hepatectomy (PHx) was performed on C57Bl/6J mice fed with high-fat diet (HFD) for 12 weeks. Pathological examination, immunohistochemistry, and qRT-PCR analysis were performed to assess the severity of steatosis and proliferative potential. The gut microbiome was examined by 16S rRNA gene sequencing and shotgun metagenomics, whereas liver metabolomics was analysed via untargeted and targeted metabolomics using liquid chromatography-tandem mass spectrometry (LC-MS).

Findings: HFD-induced hepatic steatosis in mice led to impaired liver regeneration following PHx. The gut microbiota and liver metabolites were altered along with the liver regeneration process. Longitudinal time-series analysis revealed dynamic alterations in these data, whereas correlation analysis screened out bacterial candidates that potentially influence liver regeneration in MAFLD by modulating metabolic pathways. Among these bacteria, the dominant bacterium Akkermansia was selected for subsequent investigation. MAFLD mice gavaged with Akkermansia muciniphila (A. muciniphila) exhibited reduced liver lipid accumulation and accelerated liver regeneration, possibly through the regulation of the tricarboxylic acid (TCA) cycle.

Interpretation: These data demonstrated the interplay between the gut microbiome, liver metabolomics, and liver regeneration in mice with MAFLD. A. muciniphila has the potential to serve as a clinical intervention agent to accelerate postoperative recovery in MAFLD.

Funding: This work was supported by the Research Project of Jinan Microecological Biomedicine Shandong Laboratory [JNL-2022008B]; the Zhejiang Provincial Natural Science Foundation of China [LZ21H180001]; the Fundamental Research Funds for the Central Universities [No. 2022ZFJH003].

Background: Low-income and Middle-income Countries (LMIC) are continually working to ensure everyone can access life-saving vaccines. Recognising the considerable impact of Information and Communication Technology (ICT) in healthcare, we performed a systematic review and meta-analysis to summarise ICT effectiveness in improving vaccine delivery in LMICs.

Methods: A systematic search from January 2010 to August 2023 in MEDLINE, EMBASE, Cochrane Library, BMJ Health & Care Informatics, and grey literature was performed. This search focused on randomised controlled trials (RCTs), non-RCTs, observational, and mixed-methods studies in English, examining ICT's effects on childhood immunisation in LMICs. Risk of bias in RCTs and non-RCTs was assessed using the Joanna Briggs Institute tool, and mixed-methods studies were evaluated with the Mixed Methods Appraisal Tool. A meta-analysis summarised ICT's impact on third pentavalent dose coverage and full immunisation by age one. The study is registered with PROSPERO (CRD42023446062).

Findings: Of 6535 screened studies, 27 involving 354,979 children were included. All apart from one study demonstrated a positive impact on immunisation coverage and timeliness, completeness and accuracy of records, number of adverse events reporting, vaccine stockouts, and cold chain expansion. The meta-analysis demonstrated that reminders effectively improved coverage rate of the third dose of the pentavalent vaccine (OR 2.32, 95% CI 1.34-4.03) and the full immunisation at one year of age (OR 2.61, 95% CI 1.2-5.67) with significant degrees of heterogeneity, respectively I² 82% and I² 89%. Main concerns for bias in RCTs included unblinded outcome assessors and intervention providers. Interpreting quasi-experimental studies was more challenging due to the higher risk of baseline differences between study arms, statistical methods, and dropouts. Mixed-methods studies often lacked clarity in integrating qualitative and quantitative data.

Interpretation: This systematic review confirms the benefits of ICT in immunisation programmes by enhancing various stages of vaccine delivery. Specifically, reminders have been shown to enhance childhood immunisation coverage rates.

Funding: Deutsche Gesellschaft für Internationale Zusammenarbeit (German Corporation for International Cooperation, GIZ) as part of the Digital Innovation in Pandemic Control (DIPC) Initiative, financed by the Bundesministerium für Wirtschaftliche Zusammenarbeit (Federal Ministry for Economic Cooperation and Development, BMZ).

Background: Gut commensal microbiota has been identified as a potential environmental risk factor for multiple sclerosis (MS), and numerous studies have linked the commensal microorganism with the onset of MS. However, little is known about the mechanisms underlying the gut microbiome and host-immune system interaction.

Methods: We employed bioinformatics methodologies to identify human microbial-derived peptides by analyzing their similarity to the MHC II-TCR binding patterns of self-antigens. Subsequently, we conducted a range of in vitro and in vivo assays to assess the encephalitogenic potential of these microbial-derived peptides.

Findings: We analyzed 304,246 human microbiome genomes and 103 metagenomes collected from the MS cohort and identified 731 nonredundant analogs of myelin oligodendrocyte glycoprotein peptide 35-55 (MOG_35-55). Of note, half of these analogs could bind to MHC II and interact with TCR through structural modeling of the interaction using fine-tuned AlphaFold. Among the 8 selected peptides, the peptide (P3) shows the ability to activate MOG_35-55-specific CD4⁺ T cells in vitro. Furthermore, P3 shows encephalitogenic capacity and has the potential to induce EAE in some animals. Notably, mice immunized with a combination of P3 and MOG_35-55 develop severe EAE. Additionally, dendritic cells could process and present P3 to MOG_35-55-specific CD4⁺ T cells and activate these cells.

Interpretation: Our data suggests the potential involvement of a MOG_35-55-mimic peptide derived from the gut microbiota as a molecular trigger of EAE pathogenesis. Our findings offer direct evidence of how microbes can initiate the development of EAE, suggesting a potential explanation for the correlation between certain gut microorganisms and MS prevalence.

Funding: National Natural Science Foundation of China (82371350 to GY).