Nutritional disorders and muscle wasting associated with liver disease are key determinants of poor prognosis in patients with chronic liver disease. The formation of these conditions involves multiple factors, including impaired energy metabolism, enhanced protein degradation, and gut microbiota imbalance. In recent years, with the deepening of microbiome research, the concept of the “gut-liver-muscle axis” has gradually emerged to explain the more systematic interaction between gut microbiota, liver metabolism, and skeletal muscle homeostasis. Gut dysbiosis can promote liver inflammation and metabolic disorders through various pathways, further weakening muscle energy utilization and protein synthesis, ultimately leading to malnutrition and sarcopenia. This review systematically explores the crucial role of gut microbiota in liver disease-related malnutrition and muscle wasting, elucidates its potential mechanisms in influencing host metabolism and nutritional status through the “gut-liver-muscle axis,” and discusses the prospects of microbiome interventions in improving nutritional outcomes in liver disease.

Infection is a leading cause of high mortality in patients with chronic kidney disease (CKD), in which T cell dysfunction is considered as a typical feature in CKD patients. Although platelets are active participants in immune response, their role in regulating T cell function in CKD patients remains unclear. In this study, we demonstrate that CD8 + T cell senescence may be a major contributor to the immunosuppressed state of end-stage renal disease (ESRD) patients, and that platelets derived from ESRD patients can induce premature CD8 + T cell senescence, potentially through mediating mitochondrial dysfunction. Further investigations reveal that platelet-derived microparticles (PMPs) from ESRD patients promote CD8 + T cell senescence via transferring miR-550a-5p, thereby decreasing PMPCB expression and inducing NDUFS8 cleavage failure. Finally, inhibition of miR-550a-5p and pretreatment with Nicotinamide Mononucleotide is capable of preventing platelet-induced CD8 + T cell senescence in ESRD patients. Collectively, these findings suggest that the ectopic transient expression of platelet-derived miR-550a-5p in CD8 + T cells promotes cellular senescence by regulating the PMPCB-NDUFS8 axis, which can be exploited to treat the ESRD-associated immunosenescence.

BackgroundIdentifying sarcopenia in resource-limited settings presents a significant challenge. The objective of this study was to validate the clinical usefulness of the Artificial Intelligence to Identify Sarcopenia (AITIS) model, a test-free artificial intelligence model we previously proposed for identifying sarcopenia, in patients with chronic kidney disease (CKD).MethodsThis observational cross-sectional study enrolled 236 patients with stage IV–V CKD. Sarcopenia was diagnosed using the Asian Working Group for Sarcopenia 2019 criteria, which are based on handgrip strength, physical performance, and appendicular skeletal muscle mass measured by bioelectrical impedance analysis. Patient data, including age, sex, height, weight, and 20 functional measures, were used as predictors. The AITIS model was applied to predict sarcopenia, and its performance, explainability, and clinical usefulness were comprehensively analyzed.ResultsThe study included 129 men and 107 women (median age = 54.5 years). Sarcopenia was diagnosed in 62 patients (26.3%). The three most common functional limitations reported were jogging 1 km (n = 77, 32.6%), climbing stairs (n = 56, 23.7%), and walking 1 km (n = 13, 5.5%). In contrast, no difficulty was reported in getting in and out of bed, using the toilet, or controlling urination and defecation. The AITIS model demonstrated favorable performance in predicting sarcopenia within the study population [AUC (95% CI) = 0.792 (0.729–0.856), area under the precision-recall curve = 0.610, kappa = 0.398, accuracy (95% CI) = 0.758 (0.699–0.812), sensitivity = 0.597, specificity = 0.816]. Calibration curve analysis revealed good agreement between model predictions and the ground truth. Model performance improved in patients with less physical activity (AUC = 0.843, 95% CI = 0.764–0.922) and in those with stage IV CKD (AUC = 0.824, 95% CI = 0.739–0.909). The SHAP summary plot indicated that age, walking 1 km, and lifting 5 kg were the top three contributors to the model’s predictive ability. Decision curve analysis supported the model’s clinical usefulness.ConclusionThe AITIS model demonstrates strong generalizability and performance in predicting sarcopenia in patients with stage IV–V CKD. These findings may enhance clinical decision-making and facilitate the development of novel strategies for managing sarcopenia in CKD patients.

KEY POINTS:Platelet-activating factor receptor contributed to renal tubular epithelial cells G2/M arrest through suppressing mouse double minute 2-mediated p53 ubiquitin degradation in AKI-to-CKD transition. Phosphatidylethanolamine (18:0/18:1) served as a novel endogenous ligand of platelet-activating factor receptor, inducing the downstream signaling. WAY-639497, a small-molecule platelet-activating factor receptor antagonist identified by virtual screening, mitigated renal tubular epithelial cells G2/M arrest and AKI-to-CKD transition. BACKGROUND:AKI represents a critical clinical complication with a high propensity of progression to CKD, yet effective therapies remain limited. G protein-coupled receptors mediate diverse pathophysiological processes and are promising therapeutic targets. Here, we investigated the role of platelet-activating factor receptor (PTAFR), a lipophilic G protein-coupled receptor, in AKI-to-CKD transition. METHODS:A mouse model of ischemia-reperfusion injury (IRI)-induced AKI was built by bilateral renal artery clamping. The phenotypic role of PTAFR in renal tubular epithelial cells (RTECs) after AKI was investigated in tubule-specific PTAFR-deficiency mice. The functional and molecular mechanisms were determined by transcriptomic profiling, flow cytometry, coimmunoprecipitation, Western blotting, and immunofluorescence. Lipidomic analysis and biological experiments were used to identify the endogenous ligand of PTAFR. The translational potential of PTAFR was evaluated by structure-based high-throughput virtual screening of a small-molecule inhibitor in vivo and in vitro assays. RESULTS:The expression of PTAFR was upregulated in RTECs after AKI in vivo and in vitro . Tubule-specific depletion of PTAFR alleviated IRI-induced RTEC injury and kidney fibrosis after AKI. Mechanistically, PTAFR promoted RTECs G2/M arrest by suppressing mouse double minute 2-mediated p53 ubiquitin degradation. Phosphatidylethanolamine (18:0/18:1) was identified as a novel PTAFR endogenous ligand inducing RTECs G2/M arrest. Urinary phosphatidylethanolamine (18:0/18:1) was correlated with kidney dysfunction and was able to effectively distinguish patients with AKI from healthy controls. High-throughput virtual screening identified WAY-639497, a small-molecule PTAFR antagonist, that was able to mitigate IRI-induced RTEC injury and kidney fibrosis after AKI. CONCLUSIONS:PTAFR promoted tubular epithelial cell G2/M arrest by inhibiting mouse double minute 2-mediated p53 ubiquitin degradation and further contributed AKI-to-CKD transition.

3,5,6,7,8,3',4'-Heptamethoxyflavone (HMF), a natural component derived from Citrus plants, shows potential for the treatment of metabolic diseases. However, its therapeutic role in diabetic kidney disease (DKD) remains unclear. In this study, we intragastrically administered HMF (50 mg kg-1 d-1) to db/db mice for 12 weeks, followed by pharmacodynamic analysis. We then used network pharmacology to predict therapeutic targets by retrieving HMF drug targets from Swiss TargetPrediction, PharmMapper, and TCMSP, and DKD-related targets from GeneCards, OMIM, and DisGeNET. Overlapping targets were subjected to STRING-based PPI network construction, Cytoscape visualization, and CytoNCA-based core target screening. GO and KEGG enrichment analyses were performed via DAVID, and molecular docking was conducted using AutoDock Vina to validate the binding affinity between HMF and key targets. Finally, RT-qPCR and Western blotting were employed in HG-induced HK-2 cells and db/db mice to verify the effects of HMF on target proteins and related pathways. In vivo studies validated the therapeutic efficacy of HMF in DKD, demonstrating reduced hyperlipidemia, improved renal function, and attenuated renal pathology. Network pharmacology predicted 17 key genes underlying the mechanism of action of HMF. Enrichment analyses suggested the PI3K-AKT signaling pathway was involved in its therapeutic effects, while molecular docking predicted high-affinity binding of HMF to EGFR, CASP3, ESR1, MMP9, HSP90AB1, and AKT1. Furthermore, experimental findings demonstrate that HMF upregulates the key target ESR1 and downregulates PI3K, AKT1, and MMP9, whereas no significant changes are observed in CASP3 and HSP90AB1. These results demonstrate that HMF protects against DKD by regulating the ESR1/PI3K/AKT pathway, supporting its therapeutic potential.

Ionizing radiation-induced intestinal injury (IRIII) reduces survival in nuclear accident victims and compromises the efficacy of abdominal radiotherapy, and current treatment options remain limited. Human defensin 5 (HD5)-derived fragments are endogenous regulators of the gut microbiota, which affects host responses to radiation. However, whether these fragments influence intestinal radiosensitivity or can serve as lead compounds for IRIII therapeutics remains unclear. In this study, we investigated the role of HD5-derived fragments in IRIII and developed AT9(C/G), a potent radioprotective oligopeptide based on the lead fragment AT9. Fecal metagenomic and metabolomic analyses revealed that the oral administration of AT9(C/G) enriches Bifidobacterium pseudolongum and increases lithocholic acid (LCA) levels in the intestine. Both murine and clinical studies demonstrated a negative correlation between IRIII severity and fecal LCA levels. The radioprotective effect of LCA was further validated in both mouse models and human small intestinal organoids. Mechanistically, LCA suppresses ferroptosis in irradiated cells by remodeling lipid metabolism. Specifically, LCA activates Takeda G protein-coupled receptor 5 (TGR5), leading to the upregulation of sterol regulatory element-binding protein 1 (SREBP1), which transcriptionally modulates stearoyl-CoA desaturase 1 (SCD1) to catalyze monounsaturated fatty acid production. Pharmacological inhibition of SCD1 or genetic ablation of G-protein coupled bile acid receptor 1 (Gpbar1, encodes TGR5) attenuates the protective effects of AT9(C/G) in mice. This study establishes that an oligopeptide can modulate gut microbiota-derived LCA to confer intestinal radioprotection, presenting a promising preventive strategy against IRIII.

Background:Digital interventions can support sodium restriction in chronic kidney disease; yet, implementation and engagement barriers remain poorly understood. Objective:This mixed methods study evaluated a nurse-led digital program for sodium restriction, focusing on 3 key aspects: implementation, engagement, and patient experience. Methods:This study was initially designed as a randomized controlled trial but was revised to a mixed methods implementation study due to high rates of missing primary outcome data. Quantitative measures included 24-hour urinary sodium excretion (the primary outcome of the original randomized controlled trial), knowledge tests, blood pressure measurements, and quality-of-life assessments. Concurrently, we conducted in-depth qualitative interviews with a purposive sample of participants. Quantitative and qualitative data were collected in parallel, analyzed separately, and then integrated to provide a comprehensive understanding of participants' experiences with the intervention. Results:Among 99 enrolled patients (46 in the enhanced digital intervention group and 53 in the minimal digital control group), the program led to a significant improvement in sodium-related knowledge as a secondary exploratory outcome (P=.005). However, the 24-hour urine collection completion rate was only 24.2% (n=24), precluding reliable conclusions regarding the primary outcome. Qualitative findings revealed a "measurement paradox," in which the gold-standard assessment itself posed a major barrier to adherence. Integrated data illustrated a patient journey marked by early enthusiasm, followed by declining engagement due to digital fatigue, family resistance, and poor fit with daily life. This misalignment created a disconnect between acquired knowledge and measurable behavior change. Conclusions:A nurse-led digital intervention was associated with modest improvements in sodium knowledge in chronic kidney disease. However, success requires reducing the monitoring burden and improving real-world fit. The "measurement paradox" highlights the need for patient-centered outcome measures. We propose a "stage-matched intervention" framework to guide adaptive digital tools. Future research should prioritize multicenter pragmatic trials to bridge the knowledge-action gap.

Background: Digital therapeutics hold promise for improving self-management in chronic kidney disease (CKD), particularly for sodium restriction. However, the implementation of such interventions in real-world settings and the barriers to sustained engagement remain poorly understood. Objective: To conduct a convergent mixed-methods evaluation of a digital sodium restriction program for CKD patients, focusing on implementation processes, patient engagement trajectories, and the alignment between intervention design and lived experience. Methods: We conducted a prospective, single-center, convergent mixed-methods study. Quantitative measures included 24-hour urinary sodium excretion, knowledge tests, blood pressure and quality of life. Concurrently, we performed in-depth qualitative interviews with a purposive sample of participants. Quantitative and qualitative data were collected in parallel, analyzed separately, and then integrated to provide a comprehensive understanding of the patient experience. Results: Among 99 enrolled patients( (46 in the intervention group, 53 in the control group), the program led to a significant improvement in sodium-related knowledge (P=0.005). However, completion rates for the 24-hour urine collections were critically low (24%), precluding definitive conclusions about the primary behavioral outcome. Qualitative findings revealed a "measurement paradox," where the gold-standard assessment itself posed a major adherence barrier. Integration of data streams uncovered a patient journey characterized by an initial empowerment phase, often followed by a decline in engagement driven by digital fatigue, social pressures, and a misalignment between the intervention's demands and patients' daily lives. This misalignment created a disconnect between acquired knowledge and measurable behavior change. Conclusion: This study demonstrates that while knowledge-based gains are achievable, the success of digital dietary interventions is critically dependent on overcoming implementation barriers related to burdensome monitoring and contextual fit. We propose a "stage-matched intervention" framework as a roadmap for designing adaptive, person-centered digital tools that resonate with patients' lived experiences. Future research should prioritize pragmatic, multi-center trials embedded in routine care to validate these findings and bridge the persistent gap between knowledge and action in CKD management.

X-chromosomal genetic variants have been understudied in end-stage renal disease (ESRD), which holds the promise to provide valuable insights into sexually dimorphic traits and diseases. Here we performed an X chromosome-wide association study (XWAS) in a Chinese cohort (N = 2750), comprising 1489 cases with ESRD and 1261 controls, to identify locus associated with ESRD risk. One locus showing a consistent effect direction across sex but primarily supported by the male cohort was identified in COL4A5 (P = 2.43 × 10−6) in the metaanalysis combining summary statistics from the sex-stratified XWAS. COL4A5 codes for the alpha chain of type IV collagen, which is essential for the integrity of the glomerular basement membrane and normal glomerular function. Two male-specific loci, MIR3202-2 (P = 6.85 × 10−5) and SYTL4 (P = 1.71 × 10−5), were identified in the sex-stratified XWAS in males, and expression of SYTL4, TSPAN6, NOX1, CSTF2, and PCDH19 was found to be influenced by the ESRD loci near SYTL4 based on expression quantitative trait loci (eQTL) results from the Genotype-Tissue Expression (GTEx) project. In summary, our findings revealed three X-chromosome loci linked to ESRD risk, which provided foundational knowledge for genetic risk prediction and advanced our understanding of the molecular underpinnings of ESRD.

Vulnerable atherosclerotic plaques represent a critical pathological basis of acute cardiocerebrovascular events. Previous studies indicate that atherosclerotic plaques are more vulnerable under chronic kidney disease (CKD) milieus. Emerging evidence highlights that vascular smooth muscle cells (VSMCs) play a pivotal role in maintaining plaque stability, but the underlying mechanisms remain incompletely elucidated. Here, single-cell sequencing and functional enrichment analysis of arterial tissues from patients with CKD are performed, identifying lipid metabolism disorders in VSMCs. Further utilizing spatial and targeted lipidomics, apolipoprotein-E-deficient (ApoE−/−) mouse with CKD (CKD/ApoE−/− mouse) and bioinformatics analysis, we investigate the lipidomic profile of VSMCs and find that VSMCs in CKD-associated vulnerable plaques exhibit significant accumulation of polyunsaturated fatty acids (PUFAs), which induces VSMC ferroptosis and exacerbates plaque vulnerability. Mechanistically, the deficiency of ECH1 leads to the accumulation of PUFA in VSMCs, thereby inducing ferroptosis in fibrous cap VSMCs and fibrous cap thinning. Meanwhile, low expression of mRNA binding protein human antigen R (HuR) resulting from CKD milieus mediates the lack of ECH1 in VSMCs. In contrast, VSMC-specific overexpression of ECH1, inhibition of PUFA release using giripladib or suppression of PUFA lipid peroxidation with PRGL493 significantly alleviate VSMC ferroptosis and CKD-associated plaque vulnerability. These findings reveal that ECH1-deficiency-driven PUFA accumulation is responsible for VSMC ferroptosis and atherosclerotic plaque vulnerability. Targeted regulation of ECH1-mediated PUFA metabolism may be a promising preventive and therapeutic strategy for CKD-associated plaque vulnerability.

Acute kidney injury (AKI) is a prevalent and severe clinical condition. The most common etiology of AKI is renal ischemia/reperfusion injury (IRI), which is closely linked to dysregulation of lipid homeostasis and abnormal accumulation of lipid droplets (LDs) in renal tubular epithelial cells (RTECs) following ischemic insult. Cassiaside C is a naturally occurring naphthoquinone compound isolated from the seeds of Cassia obtusifolia, a traditional Chinese medicinal herb. While Cassia seeds have demonstrated pharmacological activity against various inflammatory conditions, the role of Cassiaside C in regulating lipid homeostasis and promoting lipid droplet degradation in RTECs during AKI remains unclear. This study aims to investigate the protective effects of Cassiaside C against renal ischemia-reperfusion injury and to elucidate the underlying molecular mechanisms. The therapeutic potential of Cassiaside C was evaluated by treatment in the hypoxia/reoxygenation (H/R) model of the HK-2 cell line and the renal ischemia-reperfusion (IR) model in mice. Our results show that Cassiaside C significantly attenuated lipid deposition in renal tubular epithelial cells during IRI-AKI, concomitantly reduced the expression of renal injury biomarkers, and improved overall renal function. Mechanistically, molecular docking and Western blot analyses indicated that Cassiaside C may directly bind to adipose triglyceride lipase (ATGL) and inhibit ATGL degradation, thereby enhancing lipid degradation. These findings suggest that Cassiaside C is a promising candidate for the treatment of IRI and may represent a novel therapeutic strategy targeting lipid metabolic dysfunction in AKI.

ABSTRACT:Polyploidization resulting from massive DNA synthesis is crucial for megakaryocyte (MK) maturation; however, the regulatory mechanisms of cell fitness on this special cellular process remain poorly understood. Here, we reveal that glutamine synthetase (GLUL) facilitates thrombocytopoiesis by restricting ammonia accumulation during polyploidization. GLUL is found to be distinctly expressed in platelet-producing MKs and increasingly elevated with the progression of polyploidization, whereas GLUL deficiency impairs MK maturation and platelet production. Mechanistically, GLUL detoxifies ammonia derived from adenosine deaminase acting on RNA 1-mediated double-stranded RNA editing in MKs undergoing polyploidization. Ammonia accumulation is observed in MKs defective in GLUL, leading to lysosomal and mitochondrial damage and even cell death. Fulvotomentoside A is identified as a potential GLUL agonist with the capacity to promote thrombocytopoiesis in mice after radiation and chemotherapy injury. Our findings uncover the biological significance of GLUL in MK maturation and provide a new avenue for regulating thrombocytopoiesis.

BACKGROUND:Proteinuria and hematuria are both significant predictors of impaired kidney function in IgA nephropathy (IgAN). We evaluated the efficacy and safety of ambrisentan, a selective endothelin A receptor antagonist, as adjunctive therapy in a real-world cohort of high-risk IgAN patients. METHODS:In this retrospective, single-center study, we analyzed 169 patients with biopsy-proven IgAN who received adjunctive ambrisentan for ≥6 months. A propensity score-matched historical control group (138 pairs) was generated from patients receiving standard care prior to the ambrisentan era. Laboratory test results were gathered at baseline, and at 3 and 6 months. A generalized estimating equation model was employed to adjust for potential confounders. RESULTS:In the full ambrisentan cohort (n = 169), median urinary protein-to-creatinine ratio (UPCR) decreased significantly by 58.4% (95% confidence interval [CI], 49.8-62.3) at 6 months, with 75.7% of patients achieving a ≥30% reduction. Hematuria was also significantly reduced (P < .001), and kidney function remained stable. Compared to the matched controls, the ambrisentan group (n = 138 after propensity score-matching) demonstrated a greater median relative reduction in UPCR (-59.7% vs. -53.7%; P = .015). However, a decrease in hemoglobin levels was observed, with an increased incidence of anemia. The proteinuria-lowering effect was enhanced in patients concurrently receiving angiotensin converting enzyme inhibitors (ACEi)/ angiotensin receptor blockers (ARBs) or finerenone. CONCLUSIONS:In this analysis incorporating a matched historical control, adjunctive ambrisentan significantly reduced proteinuria and hematuria in patients with IgAN without affecting kidney function. The proteinuria-lowering effect was more pronounced when ambrisentan was added to an ACEi/ARB or finerenone. Notably, a significant decline in hemoglobin levels was observed, indicating a need for monitoring. These results warrant further prospective trials to confirm the long-term renal benefits and safety of ambrisentan in IgAN.

End-stage renal disease (ESRD) remains to be a major clinical challenge with persistently high morbidity and mortality, and its molecular mechanisms, particularly those shared among diverse primary kidney diseases during the progression to ESRD, have not been studied. Here we conducted a large-scale two-stage epigenome-wide association study of ESRD in two independent cohorts consisting of 704 controls and 1031 ESRD cases resulting from multiple kidney diseases. We identified 52 ESRD-associated differentially methylated CpG loci (DMLs) that showed consistent association effect between the two cohorts and across diverse kidney diseases. These 52 DMLs implicated 144 candidate genes that showed enrichment in calprotectin complex, RAGE receptor binding and herpes simplex virus 1 infection. Of the 52 DMLs, 5 DMLs were found to be associated with common complications of ESRD, and another 7 DMLs were also found to be associated with renal function decline in early-stage chronic kidney disease, demonstrating their potential as prognostic biomarkers for ESRD risk and related clinical complications. By identifying prognostic biomarkers and revealing the important roles of inflammation and immune dysregulation and renal fibrosis in renal progression to ESRD across diverse primary kidney diseases, our study has contributed greatly to improve clinical management and advance the development of novel therapies for ESRD.

Renal aging involves structural and functional kidney decline (reduced size/nephrons, glomerulosclerosis, tubular atrophy, functional loss) and is an independent risk factor for kidney and systemic degenerative diseases. On 16 May 2025, the Aging Biomarker Consortium convened an expert consensus meeting in Shanghai, proposing a multidimensional biomarker framework: functional (estimated glomerular filtration rate, renal blood flow), structural (renal volume loss), and humoral (Klotho, N-terminal Pro-B-type natriuretic peptide, senescence-associated secretory phenotype factors). The consensus also supports machine-learning models for biological age assessment and calls for multi-center cohorts and translational collaboration to improve elderly kidney health.

Introduction: Although recent research suggests that alterations in gut microbiota play a critical role in the pathophysiology of kidney diseases, the causal relationship between specific intestinal flora and the risk of kidney diseases remains unclear. Here, we investigated the causal relationship between gut microbiota and different kidney diseases through Mendelian randomization analysis. Methods: Gut microbiota and three types of kidney diseases, including diabetic nephropathy, IgA nephropathy, and membranous nephropathy, were identified from large-scale genome-wide association studies summary data. Inverse variance weighted method was employed to estimate causal relationships. Cochran’s Q test was utilized to uncover any heterogeneity. The Mendelian randomization Egger intercept test was employed to detect horizontal pleiotropy, and the leave-one-out method was used for testing the stability. In addition, the reverse, multivariable, and two step Mendelian randomization analysis was conducted to assess the causation possibilities. Furthermore, the associations between three types of kidney diseases and immune infiltration were determined. Results: We identified 1,531 single nucleotide polymorphisms. There were 6 positive and 9 negative causal effects between gut microbiota and three types of kidney diseases. Specifically, Dialister was a protective factor for diabetic nephropathy while LachnospiraceaeUCG008 was a risk factor. Clostridiuminnocuum was a protective factor for IgA nephropathy, while ChristensenellaceaeR.7, Clostridiumsensustricto1, LachnospiraceaeUCG004, LachnospiraceaeUCG010, Oscillospira, RuminococcaceaeUCG010, and Terrisporobacter were risk factors for IgA nephropathy. Butyricicoccus, Catenibacterium, Flavonifractor, and Lachnospira were associated with an increased risk of membranous nephropathy, while RuminococcaceaeUCG011 was associated with a decreased risk of membranous nephropathy. Sensitivity analysis indicated the results were robust. No significant pleiotropy or heterogeneity was identified. Notably, the reverse Mendelian randomization analysis did not reveal any causal relationship. After adjusting for environmental confounders, including CO, PM 2.5, PM10, and exposure to tobacco smoke at home, these causal relationships still exist. Additionally, immune infiltration analysis indicated unique immune cell distribution in each type of kidney disease, which are largely consistent with later two step approach. Conclusion: This study uncovered the causal relationship between gut microbiota and three types of kidney diseases. This discovery provides fresh perspectives on how microbes contribute to kidney diseases, paving the way for more in-depth clinical studies.

Ionizing radiation-induced intestinal injury (IRIII) is a catastrophic disease lack of sufficient medical countermeasures currently. Regulation of the gut microbiota through dietary adjustments is a potential strategy to mitigate IRIII. Time-restricted feeding (TRF) is an emerging behavioral nutrition intervention with pleiotropic health benefits. Whether this dietary pattern influences the pathogenesis of IRIII remains vague. We evaluated the impact of TRF on intestinal radiosensitivity in this study and discovered that only daytime TRF (DTRF), not nighttime TRF, could ameliorate intestinal damage in mice that received a high dose of IR. Faecal metagenomic and metabolomic studies revealed that the intestinal creatine level was increased by approximate 9 times by DTRF, to which the Bifidobacterium pseudolongum enrichment contribute. Further investigations showed that creatine could activate the energy sensor AMP-activated protein kinase in irradiated enterocytes and induce phosphorylation of acetyl-CoA carboxylase, resulting in reduced production of polyunsaturated fatty acids and reduced ferroptosis after IR. The administration of creatine mitigated IRIII and reduced bacteremia and proinflammatory responses. Blockade of creatine import compromised the ferroptosis inhibition and mitigation of DTRF on IRIII. Our study demonstrates a radioprotective dietary mode that can reshape the gut microbiota and increase intestinal creatine, which can suppress IR-induced ferroptosis, thereby providing effective countermeasures for IRIII prevention.