EBioMedicine最新文献

Background: Disruptions in early-life gut microbiota and metabolites associated with maternal Western-style diet (WD) during critical windows of development are linked to metabolic and inflammatory diseases in offspring, including metabolic dysfunction-associated steatotic liver disease (MASLD) in later life. These disturbances can alter microbial metabolite production, such as tryptophan derivatives, which are crucial for immune and metabolic regulation. However, the specific effects of maternal supplementation with tryptophan metabolites on offspring gut microbiome maturation and MASLD risk remain unexplored.

Methods: WD-fed mouse dams were supplemented with microbial metabolites indole (Ind) or indole-3-acetic acid (I3A) during gestation and lactation; male offspring were weaned to chow diet for 9 weeks, followed by a 4-week WD challenge. Fecal microbiota transfer (FMT) was performed from offspring to naïve recipients, followed by a 4-week WD challenge. Human LX-2 stellate cells were used to study mechanisms for indole and very long-chain (VLC) ceramide effects on TGF-β-induced fibrosis.

Findings: Maternal supplementation with Ind or I3A had long-term protective effects in adult WD-challenged offspring against excess weight gain, steatosis, stellate cell activation, and fibrosis. Perinatal exposure to Ind or I3A activated offspring aryl hydrocarbon receptor (AHR) signalling in gut and liver, which trans-repressed known and new target genes, including ceramidases Asah2 and Acer3, leading to increased VLC ceramides. FMT from offspring with perinatal exposure to Ind protected recipients from WD-induced fibrogenesis and increased beneficial VLC ceramides in recipient livers. In vitro, LX-2 stellate cells cultured with Ind or VLC ceramides demonstrated an anti-fibrotic effect, which was abolished by AHR inhibition.

Interpretation: Maternal indole supplementation, through sustained activation of AHR in offspring gut and liver and an increase in hepatic VLC ceramides, prevents diet-induced MASLD and fibrosis in offspring, offering a novel therapeutic pathway for prevention of paediatric MASLD.

Funding: See Acknowledgements.

Vulnerable plaques, also known as high-risk plaques, are the main cause of acute cardiovascular events. Advances in nanotechnology have made it possible to monitor and stabilise these plaques. This review outlines the pathophysiological basis of vulnerable atherosclerotic plaques and explores the emerging role of nanoplatforms in their diagnosis and treatment. By integrating recent research advances, we highlight key strategies for plaque stabilisation from a clinical perspective and present a comprehensive framework to connect mechanistic insights with translational applications. In addition, we consider the major unresolved challenges in the field and suggest possible future directions. This review aims to facilitate the clinical translation of nanotechnology-based approaches and help bridge the gap between preclinical research and real-world clinical practice.

Background: Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disease, with highly diverse survival time. However, genetic and epigenetic factors influencing ALS survival across diverse populations remain unclear.

Methods: We performed whole-genome sequencing (WGS) and DNA methylome array in blood DNA of patients with ALS. For survival analysis, we used Cox proportional hazards model for genetic variants, DNA methylation (DNAm) of CpG sites or CpG-SNPs in Chinese and Canadian cohorts, followed by meta-analysis. We performed pathway enrichment analysis for candidate genes inferred from DNAm events associated with survival. In paired genome and methylome data, we analysed the effect of the candidate CpG-SNP genotypes on DNAm status.

Findings: Genome-wide cross-population meta-analysis of common variants in 511 patients with ALS showed a suggestive association of CAV1/CAV2 rs117002347 genotypes with survival. Epigenome-wide cross-population meta-analysis in 459 patients revealed that ALS survival was significantly linked to DNAm of 88 CpGs on 40 genes, and highlighted the AMPK and cytoskeleton pathways. Epigenome-wide cross-population meta-analysis of CpG-SNPs in 459 patients identified 8 loci on 4 genes, including BAG6 (cg27014438/rs28732154), which was further validated in another 204 patients with ALS. Moreover, analysis of paired genome/epigenome data (n = 454) indicated that BAG6 rs28732154 genotypes may modulate cg27014438 methylation, which is also a cis-eQTM of BAG6 expression in blood.

Interpretation: Our study identified BAG6 cg27014438 methylation as a potential epigenetic modifier of ALS survival. BAG6 cg27014438 methylation is modulated by rs28732154 genotypes, and linked to BAG6 expression. Our findings extended our understanding of epigenetic modifiers in ALS survival.

Funding: This work was supported by the National Natural Science Foundation of China (82071430, 82371878) (MZ), Shanghai Municipal Natural Science Foundation General Program (22ZR1466400) (MZ), the Fundamental Research Funds for the Central Universities (MZ), the G. Harry Sheppard Memorial Research Fund, and Canadian Consortium on Neurodegeneration in Aging (ER).

Background: Current treatment regimens for nontuberculous mycobacteria (NTM) infections, especially Mycobacterium abscessus, have suboptimal clinical outcomes, demanding novel therapeutic options. The aminoglycoside apramycin (APR) has been suggested as a therapeutic alternative to amikacin (AMK). Here, we report experimental data as part of an ongoing preclinical assessment of APR.

Methods: Antimicrobial activity against 828 isolates comprising the clinically most relevant NTM species were determined by broth microdilution. Bactericidal activity and killing kinetics of APR were determined across a variety of assay conditions against rough and smooth M. abscessus isolates in vitro and in vivo.

Findings: Both the MIC₉₀ and tentative epidemiological cutoff (TECOFF) of APR was 4 μg/mL for 358 M. abscessus isolates and thus eight-fold lower than the 32 μg/mL determined for AMK. For 25 Mycobacterium chelonae isolates, the MIC₉₀ and TECOFF of APR was 4 μg/mL and thus four-fold lower than the 16 μg/mL determined for AMK. For 360 Mycobacterium avium complex (MAC) isolates the MIC₉₀ was 32 μg/mL and the TECOFF was 64 μg/mL for both APR and AMK. The MICs of APR and AMK were largely indifferent to mucin, DNA, sputum or standard of care antimicrobials except bedaquiline, which appeared to exert an additive effect. 16 μg/mL of APR resulted in a multi-log CFU reduction of M. abscessus within 12 h, in contrast to AMK, which was bacteriostatic for at least 24 h up to a concentration of 256 μg/mL. This difference in bacterial killing was consistent across pH 6.0-7.4 in 7H9 and CAMHB culture medium, respectively. APR resulted in multi-log CFU reduction in surrogate caseum and, unlike AMK, demonstrated intracellular killing of M. abscessus and M. avium in macrophages. Concentrations of 16 μg/mL of APR or ≥128 μg/mL of AMK suppressed the dose-dependent M. abscessus frequency of spontaneous resistance to near below the detection limit. In a cystic fibrosis surrogate CFTR^-/- mouse infection model, APR demonstrated dose dependent CFU reduction of pulmonary M. abscessus 4530, by up to 2 logs at 64 mg/kg.

Interpretation: For M. abscessus and M. chelonae, the APR MIC₉₀ was four-to eight-fold lower than that of AMK, and demonstrated enhanced bacterial killing. Collectively, our findings suggest APR has potent activity against NTM and warrants consideration for further clinical development.

Funding: This study was supported by the Cystic Fibrosis Foundation (CFF) Therapeutic Development Award JUVABIS22W0 and CFF grant HOBBIE19I0.

Background: Brain age estimated from structural magnetic resonance images is commonly used as a biomarker of biological ageing and brain health. Ideally, as a clinically useful biomarker, brain age should indicate the current state of health and be predictive of future disease onset and detrimental changes in brain biology.

Methods: In this preregistered study, we evaluated and compared the clinical utility, i.e., diagnostic and prognostic performance, of six publicly available brain age prediction packages using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI).

Findings: Baseline brain age differed significantly between groups consisting of individuals with normal cognitive function, mild cognitive impairment, and Alzheimer's disease for all packages, but with comparable performance to estimates of grey matter volume. Further, brain age estimates were not centred around zero for participants with normal cognition and showed considerable variation between packages. Finally, brain age was only weakly correlated with disease onset, memory decline, and grey matter atrophy within four years from baseline in individuals without neurodegenerative disease.

Interpretation: The systematic discrepancy between chronological age and brain age among healthy subjects, combined with the weak associations between brain age and longitudinal changes in memory performance or grey matter volume, suggests that the current brain age estimates have limited clinical utility as a biomarker for biological ageing.

Funding: This work was supported by a Longevity Impetus Grant from the Norn Group, the Karolinska Institutet Loo och Hans Ostermans Stiftelse, Gun och Bertil Stohnes Stiftelse, Stiftelsen Gamla Tjänarinnor, Stiftelsen Söderström - Königska and Åhlén-stiftelsen (243016). PPS was supported by a grant from the Swedish Brain Foundation (PD2024-0444) and the Åke Wibergs Stiftelse (M24-0117).

Background: Human cytomegalovirus (HCMV) is one of the pathogens with the most significant impact on the immune system's composition, including the expansion of virus-specific CD8 T cells. Nevertheless, it remains unclear why individuals with expanded CD8 T cells recognising the pp65-HLA-A^∗02:01-restricted viral epitope NLVPMVATV (NLV-T cells) exhibit weakened immune control of HCMV reactivation.

Methods: Here, we characterised NLV-T cells from 116 healthy HCMV-positive donors, dividing them into two groups: those with low and those with high NLV-T cell frequencies (LF and HF, respectively). We phenotyped the cells using multi-colour spectral flow cytometry and single-cell RNA sequencing coupled with TCR profiling and examined their killing properties against peptide-loaded and virus-infected target cells.

Findings: Our comprehensive multimodal analysis revealed that NLV-T cells from HF donors exhibited a phenotype of advanced differentiation, marked by high levels of granzyme B and perforin expression, and efficiently eliminated peptide-loaded targets and HCMV-infected cells as long as cell surface HLA expression was unaffected. However, NLV-T cells from LF donors, possessing a less differentiated granzyme K-intermediate phenotype, demonstrated enhanced cytokine secretion and the ability to eliminate HCMV-infected cells, even in the presence of virus-induced HLA class-I downregulation.

Interpretation: Overall, these findings suggest that HCMV exploits CD8 T cell differentiation to evade immune protection. These data are crucial for understanding the previously observed decline in HCMV reactivation control in individuals with NLV-T cell accumulation. Moreover, our findings have clinical implications and could guide future research on adoptive T-cell therapy, and the potential use of HCMV as a vaccine vector.

Funding: Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)-Projects number 390874280 and FO334/7-2.

Background: Two crucial needs persist in delivering effective critical care: reliable differentiation of infectious vs non-infectious systemic inflammation and detection of impending sepsis before the occurrence of organ dysfunction. This prospective cohort study evaluates the clinical utility of the polymorphonuclear neutrophil (PMN) biomarker CD177/CD10 ratio to differentiate and monitor infections.

Methods: A total of 219 healthy volunteers and 145 patients were assigned to four clinically defined groups: healthy controls (HC), non-infectious inflammation (NI), non-septic infection (NS-I), and sepsis (S). Serial flow cytometric analysis of CD177 and CD10 expression in PMNs was conducted with longitudinal monitoring. Diagnostic efficacy was standardised against conventional biomarkers and organ dysfunction indices. A dynamic CD177/CD10 ratio-based subtyping system (rising/declining/stable pattern) was established for prognostic stratification.

Findings: The CD177/CD10 ratio exhibited superior diagnostic performance in infection identification. At a cut-off point (CFP) of 6.07, the area under the curve (AUC) value of the ratio to differentiate NS-I from S was 0.92, exceeding those of CRP (0.85) and PCT (0.85). Notably, this biomarker effectively differentiated NI (CFP = 0.67, AUC = 0.79) from NS-I (CFP = 0.98, AUC = 0.71). The dynamic CD177/CD10 ratio-based subtyping system showed robust prognostic efficacy: patients with the rising subtype exhibited a 7-day mortality rate of 62.5%, while those with decreasing and stable subtypes demonstrated survival rates of 85% and 92.59%, respectively.

Interpretation: The CD177/CD10 ratio can facilitate infection-specific differentiation and real-time therapeutic monitoring by quantifying the dynamic equilibrium between the extent of neutrophil activation and maturation. However, the CD177/CD10 ratio still requires validation through a multi-centre trial to confirm the generalisability of the established diagnostic and prognostic thresholds.

Funding: National Natural Science Foundation of China (No. U21A20370), Natural Science Foundation of Jiangsu Province (BK20240382), Science and Technology Innovation Project of Suzhou (SYW2024116).