The FASEB Journal最新文献

Unexplained Infertility (UI) is a complex condition of elusive etiology, where the interplay between immune dysregulation and metabolic disturbances remains poorly understood. We hypothesized that gut microbiota-derived metabolites act as central modulators of the systemic immune and metabolic balance in UI patients. We employed an integrated multiomics approach, combining metabolomics, gut microbiome analysis, and immune profiling, in a cross sectional discovery cohort (47 UI patients and 53 healthy controls), and validated key findings in an independent cohort (37 UI patients and 39 healthy controls). Our findings demonstrated that UI patients exhibited a proinflammatory Th1-dominant immune profile, marked by elevated proinflammatory cytokines and reduced anti-inflammatory IL-10. This immune imbalance was accompanied by a deficiency in protective gut-derived secondary metabolites, notably secondary bile acids and phenylpropanoic acid. Furthermore, gut microbiota analysis revealed significant dysbiosis (increased pathogenic taxa and decreased beneficial microbes) and a functional deficiency in the aromatic amino acid metabolism gene cluster, explaining the observed metabolite scarcity. Mechanistically, in vitro assays and network pharmacology indicated that these metabolites directly modulate the Th1/Th2 immune balance by regulating a core host network centered on TNF, PPARG, and PTGS2. In summary, our data reveal the role of a novel gut microbiota-metabolite-immune axis in UI pathophysiology, where a deficiency in protective gut-derived secondary metabolites contributes directly to systemic immune dysregulation and a proinflammatory state. These metabolites serve as potential candidates for future evaluation and represent promising therapeutic targets for interventions to restore immune homeostasis in UI patients.

The gut microbiome is widely viewed as an important regulator of host metabolism and immunity. Loss of microbial diversity can lead to gut dysbiosis, which has been linked to cardiometabolic and inflammatory disorders. Iron is an important micronutrient for both host and microbes, but its excess is toxic. To investigate the impact of dietary iron on the intestinal microbiome and host metabolism, wild type mice on standard chow were switched at baseline to a high-iron diet, containing 2% carbonyl iron for 3 weeks. Other groups of mice were switched to the high-iron diet only during the final 3 or 7 days of the 3-week period; control animals remained on standard chow. Fecal samples were collected at baseline (t = 0) and at the endpoint (t = 1) for microbiome analysis, while liver and skeletal muscle samples were analyzed for Akt phosphorylation as a marker of insulin sensitivity. Feeding with high carbonyl iron significantly altered the intestinal microbiome and increased overall alpha and beta diversity in a time-dependent manner. Differential abundance and network analyses revealed extensive taxonomic and structural reorganization, with notable increases in Akkermansiaceae, Rikenellaceae, Bilophila, Ruminiclostridium, and Lactobacillus, and decreases in Bifidobacteriaceae and Clostridiaceae_1. Iron overload was accompanied by reduced Akt phosphorylation, evident in the liver but not skeletal muscles at the 3-week endpoint. Together, these results demonstrate that feeding of mice with a high carbonyl iron diet reshapes gut microbial composition, increases diversity, and reorganizes microbial community networks. However, iron overload mitigates insulin responsiveness in the liver.

Duchenne muscular dystrophy (DMD) is a genetic muscular disease characterized by progressive muscle degeneration. p16 is expressed in skeletal muscles and induces cellular senescence in a rat model of DMD, whereas its ablation enhances muscle regeneration. However, the mechanism underlying this phenomenon remains unclear. This study aimed to elucidate the mechanism for p16-induced DMD exacerbation. RNA-seq analysis revealed p16-dependent upregulation of cytokine gene expression in DMD rat skeletal muscles, which also altered the systemic blood cytokine profile. Furthermore, the effect of an altered humoral environment on muscle regeneration was assessed using the transplanted extensor digitorum longus muscle. Regeneration of grafted muscles from wild-type rats was suppressed in DMD rats but was significantly improved by p16 ablation. Notably, p16 was expressed in the myofibers of DMD rats, and enzymatically isolated myofibers from DMD rats also showed p16-dependent cytokine expression. Thus, cytokines secreted by senescent-like myofibers mediate the anti-regenerative niche in DMD rats, uncovering a novel mechanism for disease progression and potential therapeutic targets.

Phospholipids are important components of the bilayer of biological membranes. Alterations of phospholipids are associated with metabolic disorders, including insulin resistance. However, how impaired insulin signaling impacts phospholipids has not been well established. Disruption of hepatic insulin signaling is achieved by insulin receptor substrate 1 (IRS1) and IRS2 double deletion (DKO) in the liver. Further deletion of TGF-β1 or Foxo1 in the liver of DKO mice was used to examine the role of TGF-β1 or Foxo1 in contributing to the alterations of phospholipid metabolism in DKO mice. Disruption of hepatic insulin signaling led to the dysregulation of phospholipids, including phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylserine (PS), sphingomyelin (SM), cardiolipin (CL), and lysophospholipids in the liver. Mechanistically, disruption of hepatic insulin signaling dysregulated the expression of genes related to phospholipid metabolism. Interestingly, further deletion of Tgfb1 in the liver of DKO mice (TKObeta1) attenuated the alterations of phospholipids and rescued the abnormal expression of genes related to phospholipid metabolism. Moreover, deletion of transcription factor Foxo1, a key mediator of insulin signaling, achieved similar beneficial effects as Tgfb1 deletion in DKO mice. Our study suggests that insulin signaling plays a crucial role in maintaining phospholipids balance in the liver via TGF-β1 or Foxo1. Targeting TGF-β1 or Foxo1 could be promising strategies to combat phospholipids alterations and related metabolic dysfunctions.

After fertilization in mammals, there is an epigenetic asymmetry reflected by differences in DNA demethylation and histone modifications between female and male pronuclei (FPN and MPN, respectively). Based on its expression level and amount, we investigated the role of maternal O-GlcNAc transferase (OGT), a key enzyme mediating O-GlcNAcylation, in regulating this asymmetry. By using a specific small-molecule inhibitor and small interfering RNA (siRNA)-mediated knockdown of OGT during oocyte maturation in mice, we evaluated the downstream effects on epigenetic modifications and early developmental capability. OGT inhibition significantly reduced fertilization rates and led to developmental arrest at the zygote or 2-cell stage, whereas the siRNA-mediated decrease of Ogt mRNA had less or no significant effect on preimplantation development. Immunostaining analyses revealed that OGT inhibition reduced 5-hydroxymethylcytosine levels in MPN, attributed to a reduction in Tet methylcytosine dioxygenase 3. In contrast, FPN showed delayed epigenetic changes, with the loss of 5-methylcytosine protection mediated by H3K9me2. Moreover, OGT inhibition increased histone methylation levels in MPN and disrupted epigenetic and size asymmetry between FPN and MPN. These alterations suggest that maternal OGT regulates multiple layers of epigenetic reprogramming in early zygotes. Taken together, these findings suggest that maternal OGT is essential for maintaining epigenetic asymmetry between parental pronuclei, primarily by modulating DNA demethylation and histone methylation in MPN.

Postmenopausal osteoporosis (PMOP) is increasingly recognized as an aging-associated, multisystem vulnerability state in which estrogen withdrawal amplifies immune and metabolic drift across bone marrow, muscle, adipose tissue, the gut, vasculature, and neural circuits. We synthesize evidence that key control nodes including RANKL–RANK–OPG imbalance, Th17/Treg disequilibrium, loss of regulatory B cell IL-10 restraint, inflammatory myeloid polarization, and expansion of bone marrow adipose tissue encode persistent osteoclastogenic tone and impaired formation. We map how microbiota-derived metabolites and barrier dysfunction tune osteoimmunity, and how exercise-responsive myokines and metabolites can counteract drift. Extracellular vesicles emerge as bidirectional couriers that propagate senescence and inflammation or support repair, but clinical translation requires ISEV-aligned methodological rigor and robust manufacturing, biodistribution, and safety frameworks. Building on these inter-organ axes, we propose a phenotype-aware “network reset” roadmap that integrates antifracture therapy with functional restoration, falls prevention, cardiometabolic risk control, and inflammatory monitoring, prioritizing composite endpoints and real-world implementation infrastructure. This systems framing shifts PMOP management from bone-only correction toward coordinated restoration of whole-body resilience.

Type 2 Diabetes (T2D), often preceded by reversible prediabetes, poses a major health challenge. Targeting early glucose dysregulation is a promising preventive strategy. Amino acids and their derivatives are emerging as key regulators of glucose homeostasis. Here, we investigate the role of O-acetyl-serine (OAS), a serine-derived metabolite produced by plants and microbes, including those of the gut microbiota, in glycaemia regulation. We developed a targeted method to quantify OAS in plasma and tissues, showing that it enters circulation and transiently accumulates in the pancreas. In vivo, OAS specifically and dose-dependently improves postprandial glycaemia in lean mice. Mechanistically, OAS acts as a glucose-dependent insulin secretagogue: a single oral dose increased pancreatic OAS levels by ~100-fold and amplified glucose-stimulated insulin secretion by 3.7-fold, without affecting basal insulin levels. In vitro, OAS enhanced insulin secretion in both INS-1 cells and rat islets, confirming a direct effect on pancreatic β-cells. OAS also increased GLP-1, but not GIP, levels at baseline and after glucose challenge. However, in vivo treatment with the GLP-1 receptor antagonist exendin (9–39) revealed that GLP-1 signaling only partially mediates OAS's effects, consistent with OAS direct action on insulin secretion. Finally, OAS restored glucose tolerance in a prediabetic mouse model induced by high-fat diet, without altering insulin sensitivity. This improvement was associated with increased postprandial insulin and GLP-1 levels. Together, these findings identify OAS as a glucose-dependent insulin secretagogue with therapeutic potential to enhance insulin secretion and prevent progression from prediabetes to T2D.