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Biomedical subjects

Lei Zhang

Publications and source records attributed to Lei Zhang.

At least 19 recordsLinked to original sources
PubMed2026

Factor IX Padua AAV gene therapy in adolescents with hemophilia B: a phase 1 trial.

Adeno-associated virus (AAV)-mediated factor IX Padua gene therapy has demonstrated good safety and efficacy in adult patients with hemophilia B, but its safety and efficacy in adolescent patients with hemophilia B remain unknown. Here we report a multicenter, single-arm, phase 1 study involving 11 adolescent participants (aged 12-18 years) with severe or moderately severe hemophilia B (factor IX coagulant activity (FIX:C) ≤2 IU dl-1) in China. All of them received the AAV gene therapy BBM-H901 at a dose of 5 × 1012 vector genomes per kilogram of body weight and were then enrolled in a 52-week follow-up. The primary endpoint was safety. No dose-limiting toxicity was observed throughout the study. The most common adverse events included elevation of white blood cell count, elevation of neutrophil count and rash associated with corticosteroid use. One serious adverse event and two grade 3 adverse events occurred. Abnormal liver function was observed in one participant, with elevated alanine aminotransferase (197.0 U l-1) and aspartate aminotransferase (75.0 U l-1) levels, which returned to normal 4 weeks after immunosuppression therapy. The key secondary endpoints included the mean (s.d.) FIX:C at week 52 following infusion, which was 41.8 (30.1) IU dl-1 (one-stage SynthASil method), and the mean annualized bleeding rate, which decreased from 13.9 to 0.5. In this study, we show that the gene therapy drug BBM-H901 for hemophilia B is safe in adolescent patients, providing initial insights into its efficacy. ClinicalTrials.gov identifier: NCT05709288 .

Journal Article↗
PubMed2026

Pan-genome-based resequencing of 2,320 accessions reveals structural variations and accelerates breeding advances in cultivated peanut.

The cultivated peanut is a crucial global legume crop that is essential for food security and nutrition, particularly in developing regions. However, its limited genetic variation hampers breeding progress and yield improvement. Here we constructed a graph-based pan-genome for peanut, incorporating 14 genomes that represent all 6 peanut varieties. Using this pan-genome, we genotyped 2,320 accessions, covering 88.03% of ICRISAT and 59.21% of USDA core germplasm, enriching valuable resources for genomic studies and breeding. We cataloged genomic structural variations and investigated the role of homoeologous exchanges in population divergence. Through our pan-genome approach, we overcame the challenges of genotyping posed by homoeologous exchanges and identified key genes associated with flowering and dwarfism in peanut. By integrating superior haplotypes and germplasm resources guided by the pan-genome, we further developed high-yield dwarf lines. This work provides essential genomic resources to accelerate functional gene discovery and modern peanut breeding.

Journal Article↗
PubMed2026

Surgical outcomes and complications of fixation strategies for distal tibial fractures: a systematic review and network meta-analysis.

BACKGROUND: Multiple fixation options exist for distal tibial fractures, but the optimal approach remains controversial. Common techniques includeopen reduction and internal fixation(ORIF), minimally invasive plate osteosynthesis (MIPO), external fixation combined with limited open reduction and internal fixation (EF + LORIF), intramedullary nailing (IMN), and retrograde tibial nailing (RTN). METHODS: PubMed, Embase, Web of Science, and the Cochrane Library were searched through March 19, 2026. Network meta-analysis (R v4.5.1) assessed operation time, fracture healing time, malunion, delayed union/nonunion, and infection, reporting MDs or RRs with 95% CIs. RESULTS: Eleven randomized controlled trials and 18 cohort studies (2145 patients) were included. MIPO was associated with a longer operative time and a longer time to union than IMN-IP (MD = 8.23, 95% CI 0.44-16.01; and MD = 1.02, 95% CI 0.10-1.93, respectively). For malunion, ORIF had a lower risk than MIPO (RR = 0.30, 95% CI 0.11-0.82), whereas MIPO had a higher risk than EF + LORIF (RR = 3.26, 95% CI 1.08-9.80) and IMN-SP (RR = 4.03, 95% CI 1.30-12.48). ORIF, EF + LORIF, and IMN-SP also showed lower malunion risk than IMN-IP. No significant differences were observed for delayed union and nonunion. Infection risk was generally higher with ORIF and MIPO than with several comparators, particularly EF + LORIF and intramedullary nailing-based strategies. CONCLUSIONS: No single strategy was consistently superior. Operation time and impaired union ( delayed union and nonunion) did not differ significantly among techniques. MIPO may be associated with longer time to union than IMN-IP and higher malunion risk than EF + LORIF and IMN-SP. Infection risk appeared higher with ORIF and MIPO in network estimates, although several comparisons remained uncertain. Findings should be interpreted in light of imprecision and study-level heterogeneity. PROTOCOL REGISTRATION: INPLASY2025120055.

Humans↗
PubMed2026

Chloroplast genome comparative analysis and phylogenetic relationships of 15 Syringa species (Oleaceae).

Syringa is a crucial shrub genus in the family Oleaceae, which has significant ornamental, economic, and medicinal value. However, research on the chloroplast genome (CPG) phylogeny and lineage diversification of this genus remains limited. In this study, all 15 Syringa CPGs exhibited a characteristic quadripartite structure, with genome lengths ranging from 154,019-158,020 bp. These CPGs were highly conserved and moderately differentiated, each containing 130-132 genes. Analysis of inverted repeat (IR) boundaries indicated structural conservation, with six genes: rps19, rpl2, ycf1, trnN, ndhF, and trnH present at the IR/single-copy (SC) junctions. The small single copy (SSC) region displayed greater sequence variability than the IR regions. ycf1, ndhH, trnL-rpl32, ndhF-ycf1, and rbcL-accD were identified as potential molecular markers and rps11, ycf2, and ycf4 may have contributed to the adaptive evolution of Syringa. Phylogenetic reconstruction based on whole CPG data supported the monophyly of the 15 species, which were divided into three distinct subclades. Molecular dating estimated that Syringa diverged from its sister genus approximately 58 million years ago, with most Syringa species diversifying further approximately 47.49 million years ago during the Eocene. Our findings will hopefully stimulate further studies on this genus that may enhance biodiversity knowledge.

Journal Article↗
PubMed2026

Targeting PRMT9 overcomes venetoclax resistance in AML by modulating splicing and inhibiting translation.

Arginine methylation catalyzed by protein arginine methyltransferases (PRMTs) is required for cancer cell proliferation, but whether PRMTs mediate resistance to therapy remains unclear. Here, we performed loss-of-function screens in venetoclax-resistant (VEN-R) acute myeloid leukemia (AML) patient-derived xenograft cells and found that PRMT9 plays a critical role in promoting VEN resistance. Specifically, VEN-R AML samples exhibited high levels of PRMT9, and PRMT9 inhibition resensitized AML cells to VEN treatment. In preclinical resistant models, genetic ablation of PRMT9 synergized with VEN to eradicate AML cells. Consistently, pharmacologic inhibition of PRMT9 combined with VEN produced similar effects in VEN-R AML mouse models. Mechanistically, PRMT9 ablation disrupted RNA splicing by inducing exon skipping in mRNA encoding ALG13, an uridine diphosphate (UDP)-N-acetylglucosaminyltransferase subunit, thereby downregulating expression of the VEN efflux transporter encoded by the adenosine triphosphate-binding cassette subfamily C member 1 gene. PRMT9 inhibition also suppressed protein synthesis, leading to downregulation of short-lived oncoproteins such as MCL1. These findings establish a connection between PRMT9-mediated arginine methylation and poor VEN responsiveness and demonstrate that targeting PRMT9 may represent a viable strategy to overcome VEN resistance.

Protein-Arginine N-Methyltransferases↗
PubMed2026

SGLF-Net:Staged Global-to-Local Cross-Scale Fusion Network for Colonoscopic Polyp Segmentation.

Polyp segmentation in colonoscopy images plays a pivotal role in computer-aided medical diagnosis and the early prevention of colorectal cancer. However, existing methods often suffer from performance degradation when confronted with extreme polyp scale variation and polyp boundary ambiguity. To address these challenges, we propose the Staged Global-to-Local Cross-Scale Fusion Network (SGLF-Net), which adopts a novel staged global-to-local learning paradigm to progressively refine segmentation from coarse global semantics to fine-grained local details. Specifically, the Global Semantic Perception Stage integrates a Swin Transformer Encoder and a Dynamic Attentive Decoder (DAD) to construct comprehensive multi-scale contextual representations. The Local Detail Refinement Stage employs an Edge-aware Dynamic Attentive Decoder (E-DAD) to enhance structural fidelity and boundary precision through explicit edge-guided supervision. Furthermore, we introduce the Cross Spatial-Scale Feature Aggregation and Reconstitution (CSSAR) module, equipped with hybrid attention mechanisms, to facilitate efficient semantic structural interaction between the two cascaded stages. Extensive experiments on five public benchmark datasets demonstrate that SGLF-Net consistently outperforms state-of-the-art methods in both segmentation accuracy and boundary preservation.

Journal Article↗
PubMed2026

An IRAK1-snRNA axis activates ATM to promote accurate repair within transcriptionally active chromatin.

Genomic integrity in transcriptionally active regions is pivotal for suppressing oncogenic mutations, yet the mechanisms that govern precise homologous recombination (HR) repair within these regions remain elusive. Here, we report that the IRAK1-spliceosome axis operates with small nuclear RNA (snRNA) as a central hub, potently promoting accurate repair at DNA double-strand break (DSB) sites within active chromatin in human cancer cells. Mechanistically, IRAK1 phosphorylates spliceosomal serine/arginine (SR)-rich proteins to recruit snRNA to DSBs, inducing robust condensation of the MRE11-RAD50-NBS1 (MRN) complex near transcriptionally active regions to create an ATM activation platform. Collectively, our findings define a prevalent mechanism governing region-specific precise repair in transcriptionally active domains, where snRNA acts as a "transcription repair bridge" to link transcriptional processes to HR repair and ultimately preserves genomic stability. Inhibiting IRAK1 axis impairs HR repair in transcriptionally active regions, causing a marked increase in mutation rates specific to these regions and cancer-cell chemosensitivity.

Humans↗
PubMed2026

DREAMS illuminates spatial DNA and RNA modification landscapes.

DNA and RNA modifications regulate gene expression and RNA processing, but their spatial organization in complex tissues remains elusive. Here we developed DNA RNA Elements Areal Mass Spectrometry (DREAMS), a mass spectrometry imaging platform that spatially maps diverse nucleic acid modifications simultaneously. Applying DREAMS to TET-deficient mouse brains (Tet1Δ/Δ and triple Tet1/2/3Δ/Δ), we uncover TET1's unexpected role in modulating N1-methyladenosine (m1A), a pivotal RNA modification. While DREAMS reveals broad modification landscapes altered across TET knockouts, we identify TET1-mediated changes in m1A that correlate with transcriptome alterations. Our work establishes DREAMS as a transformative tool for spatial epigenomics/epitranscriptomics and suggests that TET enzymes could influence multiple DNA and RNA modifications with potential gatekeeping roles in nucleic acid regulation.

Animals↗
PubMed2026

Epigenetic-epitranscriptomic crosstalk through TaHAG1-TaNSUN2 coordinates thermotolerance in wheat.

High temperature is a primary abiotic stress that severely constrains crop productivity. Deciphering the regulatory pathways underlying heat responses is essential for breeding heat-tolerant crops with stable yields. Although both epigenetic and epitranscriptomic regulations are involved in plant heat adaptation, their mechanistic interplay remains unclear. Here, integrated epigenomic (H3K9Ac/H3K14Ac) and transcriptomic profiling under heat stress identifies the mRNA m⁵C methyltransferase TaNSUN2 as a key regulator of thermotolerance in wheat. We demonstrate that TaNSUN2 is transcriptionally activated by the histone acetyltransferase TaHAG1, which deposits H3K9Ac at the TaNSUN2 promoter and transcription start site. This recruitment is facilitated by the transcription factors TaE2F1 and TaDP1, which interact with TaHAG1 to form a functional complex. Functional assays revealthat TaNSUN2 operates downstream of TaHAG1 and enhances thermotolerance through m⁵C‑dependent mRNA methylation and stabilization of transcripts involved in chloroplast organization. Furthermore, field trials show that TaNSUN2-overexpressing lines exhibit higher grain yield under normal conditions and reduced yield loss under heat stress. Our findings elucidate an integrated regulatory network linking histone acetylation to RNA m⁵C methylation in heat stress adaptation, providing promising targets for molecular breeding of heat‑resilient wheat.

Triticum↗
PubMed2026

Endovascular treatment after stroke beyond 24 h vs 6-24 h: a propensity score-matched cohort study.

BACKGROUND: Endovascular thrombectomy (EVT) is the standard treatment for acute ischemic stroke due to anterior circulation large vessel occlusion (LVO) within 6-24 h. However, the safety and feasibility of EVT for anterior circulation strokes beyond 24 h remain uncertain. METHODS: We conducted a retrospective cohort study of consecutive patients with anterior circulation LVO who underwent EVT at Changhai Hospital from 2018 to 2023. Patients were stratified into late (6-24 h) and very late (>24 h) windows. Propensity score matching (PSM) was performed to adjust for baseline imbalances, including age, sex, NIHSS, ASPECTS, occlusion location, perfusion parameters, and vascular risk factors. The primary outcome was functional independence (modified Rankin Scale [mRS] ≤ 2) at 3 months. Secondary outcomes included successful reperfusion (TICI 2b-3) and symptomatic intracranial hemorrhage (sICH). RESULTS: Among 1043 screened patients, 429 patients with anterior circulation LVO were included after exclusions, comprising 373 in the late window and 56 in the very late window. PSM yielded 42 matched pairs. Compared with the late window group, the very late window group showed no statistically significant differences in functional independence (54.8% vs. 57.1%; OR = 0.908, 95% CI 0.382-2.153, p = 0.830), successful reperfusion (88.1% vs. 92.9%; OR = 1.800, 95% CI 0.481-7.096, p = 0.460), sICH (2.4% vs. 9.5%; OR = 0.232, 95% CI 0.012-1.652, p = 0.200), intraprocedural complications (26.2% vs. 19.0%; OR = 1.508, 95% CI 0.540-4.362, p = 0.440), or postoperative complications (33.3% vs. 35.7%; OR = 0.900, 95% CI 0.363-2.219, p = 0.820). CONCLUSIONS: In this selected, single-center cohort of anterior circulation LVO patients undergoing EVT, treatment initiated beyond 24 h appeared to have comparable effectiveness and safety to treatment initiated within 6-24 h. Definitive evidence requires confirmation from adequately powered randomized controlled trials.

Humans↗
PubMed2026

De novo haplotype-resolved genome assembly of the endemic kiwifruit Actinidia hubeiensis.

The genus Actinidia, which encompasses the widely cultivated kiwifruit, is characterized by its rich species diversity. Wild Actinidia species serve as invaluable germplasm reservoirs for crop improvement. As an important kiwifruit species, Actinidia hubeiensis represents a unique taxonomic group endemic to Hubei Province, contributing valuable genetic diversity to the genus Actinidia. Here, we present a haplotype-resolved genome assembly for A. hubeiensis. The two haplotype assemblies (Hap1 and Hap2) spanned 658.03 Mb (N50 = 23.16 Mb) and 597.19 Mb (N50 = 20.89 Mb), encoding 35,741 and 36,647 high-confidence protein-coding genes, respectively. Based on comprehensive assessments, both haplotypes demonstrated high completeness (BUSCO completeness > 99%), excellent continuity (LAI up to 21.67), low base-error rates (QV > 40), and nearly complete read mapping rates (> 98%). This genome assembly provides crucial genomic resources for the genus, enriching our understanding of kiwifruit biodiversity and offering new insights into the genetic background and evolutionary characteristics of this distinctive species.

Actinidia↗
PubMed2026

Aflatoxins and their biosynthetic precursors in lotus seeds: simultaneous UPLC-MS/MS determination, contamination profiling, and matrix-specific accumulation during Aspergillus flavus infection.

Aflatoxin (AF) contamination poses a severe global threat to food and medicinal material safety, yet existing research focuses on terminal AF metabolites while neglecting residual biosynthetic precursors, leading to potential underestimation of contamination risks. In this study, a UPLC-MS/MS method was established for the simultaneous quantification of six AFs and their five precursors in lotus seeds, with optimization of mass spectrum parameters, chromatographic separation conditions, and sample pretreatment. Method validation confirmed linearity (R2&#xa0;>&#xa0;0.99), LODs (0.03-0.36&#xa0;&#x3bc;g/kg), and recoveries (76.53%-120.0%, RSD&#xa0;<&#xa0;15%). Analysis of 41 natural lotus seed samples revealed a 63.4% AF contamination rate, dominated by B-group AFs, while O-methylsterigmatocystin (OMST) and versicolorin hemiacetal (VOH) were identified as the primary co-residual precursors with co-occurrence rates &#x2265; 50%. Notably, AFM1 was predominantly detected in natural samples with AFB1 concentrations exceeding 100&#xa0;&#x3bc;g/kg. Artificial inoculation experiments further demonstrated that sterilization and sealing conditions modulated AF biosynthesis in lotus seeds, with non-sterilized and non-sealed groups showing delayed fungal metabolism and lower toxin accumulation. A significant linear correlation was observed between AFM1 and AFB1 levels (r&#xa0;=&#xa0;0.94) in infected samples, demonstrating their accumulation levels are coupled with fungal overall metabolic flux. Given the high co-occurrence rate of OMST/VOH with AFB1 in natural samples, their individual and combined toxicities require in-depth investigation. This work deciphers matrix-specific AF dynamics in lotus seeds, supporting regulatory standard refinement (e.g., precursor inclusion) and targeted control (e.g., time-sensitive drying after harvest). Further studies will focus on exploring the molecular mechanisms of substrate-dependent AF synthesis.

Aflatoxins↗
PubMed2026

Methyltransferase METTL1 regulates MSC mRNA stability via m7G modification in acute pancreatitis.

Acute pancreatitis (AP) is a serious inflammatory disease with significant morbidity, yet its underlying molecular mechanisms remain incompletely understood. This study reveals a novel epitranscriptomic pathway in AP pathogenesis centered on METTL1-mediated N7-methylguanosine (m7G) RNA modification. We found that METTL1 expression and global m7G levels were significantly elevated in serum from AP patients, pancreatic tissues of sodium taurocholate-induced AP mice, and in vitro models of LPS-polarized macrophages and STC-injured pancreatic acinar cells. Through integrated multi-omics analysis combining m7G methylome mapping and transcriptome profiling, we identified Musculin (MSC) as a key target whose mRNA stability is enhanced by METTL1-mediated m7G modification. Functional experiments demonstrated that MSC upregulation activates TNF signaling through phosphorylation of NF-&#x3ba;B, JNK, and MAPK proteins, thereby promoting macrophage M1 polarization and pancreatic acinar cell injury. The pathological significance of this pathway was confirmed in vivo, where pancreas-targeted knockdown of Mettl1 significantly attenuated AP severity. Furthermore, mechanistic studies using a catalytic-dead METTL1 mutant established that both the methyltransferase activity of METTL1 and subsequent TNF signaling activation are essential for driving inflammatory responses. Our findings delineate a previously unrecognized METTL1-m7G-MSC-TNF signaling axis that promotes AP progression, highlighting the therapeutic potential of targeting METTL1-mediated epitranscriptomic modification in inflammatory diseases.

Animals↗
PubMed2026

Intraoperative indocyanine green near-infrared fluorescence imaging for assessing testicular viability in pediatric testicular torsion: A retrospective study.

OBJECTIVE: To evaluate the clinical efficacy of indocyanine green near-infrared fluorescence (ICG-NIRF) imaging versus conventional surgery for assessing testicular viability and guiding decision-making in pediatric testicular torsion (TT). METHODS: A retrospective analysis was performed on 225 pediatric patients undergoing emergency scrotal exploration for TT between January 2019 and January 2025. Patients were categorized into a conventional surgery group (n = 118) relying on visual grading and an ICG-NIRF imaging group (n = 107). Primary outcomes included intraoperative testicular preservation rates and postoperative success rates. Multivariate Cox regression was utilized to identify factors influencing testicular preservation. RESULTS: Baseline characteristics were comparable between groups. The ICG-NIRF group demonstrated a significantly higher intraoperative preservation rate (74.77% vs. 61.02%, p = 0.028) and postoperative success rate (88.75% vs. 69.44%, p = 0.003) compared to the conventional group. Additionally, the ICG-NIRF group exhibited significantly lower rates of secondary orchiectomy (1.25% vs. 9.72%, p = 0.027) and 6-month testicular atrophy (7.59% vs. 23.08%, p = 0.02). Multivariate analysis confirmed ICG-NIRF application as an independent protective factor for testicular preservation (HR = 0.556, p < 0.001). CONCLUSION: ICG-NIRF imaging provides an objective, real-time assessment of testicular perfusion, significantly improving testicular preservation rates and postoperative outcomes. This technique overcomes the subjectivity of conventional visual methods, offering substantial clinical value for fertility preservation in pediatric TT.

Humans↗
PubMed2026

Widespread Molecular Imprints in the Serum Proteome of COVID-19 Convalescents Uncovering Immune System Sequelae.

Post-COVID-19 sequelae have become an emerging global health issue, but the mechanisms for the sustained susceptibility of convalescents to the sequelae remain poorly understood. Here we report the use of a restricted open-search approach to explore the molecular imprints of SARS-CoV-2 infection left on the proteome of 412 COVID-19 patients and convalescences. A total of 827 non-standard amino acid variations, chemically modified residues as well as post-translational modifications, termed non-coded amino acids (ncAAs), are found spreading over 29,814 sites in patient's serum proteins. Markedly, widespread ncAAs are induced and sustainedly imprinted on the serum proteome predominately perturbing the immunoglobulin-mediated immune response, complement activation and coagulation regulation even 12 months after recovery. Sustained amino acid variations and chemical modifications are found in the complementary&#x2011;determining regions (CDRs) of the variable region of immunoglobulin contributing to the interactions between the emerging antibody and antigens; durable chemical amino acid modifications found in the hyper ncAA-modified regions of the constant region of immunoglobulin important for the interaction with the complement and regulatory receptors. In the complement system, inducible ncAAs are memorized in the components essential for the complement activation, amplification cascades and membrane attack processes. Thus, the workflow described in this study can be used to identify the molecular imprints of viral infection at the proteomic scale, particularly the specific antibodies and the immune targets left in COVID-19 patients and convalescents.

Humans↗
PubMed2026

Compound Heterozygous PCDH15 Variants Associated With Cone-Rod Dystrophy in a Chinese Pedigree.

BACKGROUND: This study aimed to characterize the clinical and genetic features of a Chinese family with cone-rod dystrophy in which compound heterozygous PCDH15 variants were identified. METHODS: A Chinese pedigree with autosomal recessive cone-rod dystrophy was investigated. A comprehensive ophthalmic assessment was performed in the proband, a 42-year-old woman, together with genetic evaluation of her family members. Candidate variants were identified using whole-exome sequencing and subsequently assessed by Sanger sequencing and family segregation analysis. RESULTS: Ophthalmoscopic examination revealed pigmentary changes and atrophic lesions affecting the posterior pole and peripapillary area bilaterally. Optical coherence tomography (OCT) demonstrated bilateral outer retinal layer atrophy with disruption of the ellipsoid zone at the posterior pole. Multifocal electroretinography (mfERG) revealed attenuated central responses, while full-field electroretinography (ffERG) documented a more pronounced reduction in cone-mediated (photopic) responses. Two novel compound heterozygous variants in PCDH15, namely c.4903_4906del (p.Glu1635Lysfs*4) and c.3470C>A (p.Ala1157Glu), were identified in this autosomal recessive cone-rod dystrophy pedigree. Family co-segregation analysis provided supportive evidence for their potential association with the disease phenotype. Cross-species analysis revealed high evolutionary conservation of the PCDH15 protein. Three-dimensional structural modeling predicted potential alterations in protein structure. CONCLUSION: To our knowledge, this is the first report describing an association between compound heterozygous PCDH15 variants and cone-rod dystrophy, thereby providing preliminary evidence that may broaden the mutational spectrum associated with this gene.

Adult↗
PubMed2025

Altered ruminal microbiome tryptophan metabolism and their derived 3-indoleacetic acid inhibit ruminal inflammation in subacute ruminal acidosis goats.

BACKGROUND: Subacute ruminal acidosis (SARA) is a digestive disorder that often severely jeopardizes the health and lactation performance of ruminants fed a high-energy diet. Different dairy ruminants exhibit varying degrees of inflammation accompanied by variations in the rumen microbiota when SARA occurs. Our understanding of the occurrence of SARA and varying degrees of rumen epithelial inflammation is lacking. Hence, we performed rumen metagenomic, metagenome-assembled genome and metabolomic analyses, with transcriptome and single-nucleus RNA sequence analyses, to explore the microbial mechanism of SARA occurrence and different degrees of inflammation. RESULTS: A total of 36 goats fed two diets with gradually increasing levels of rumen-degradable starch (RDS) were included in this study, and SARA goats fed 70% concentrate diets supplemented with whole corn (HGW-SARA) and SARA goats fed 70% concentrate diets supplemented with crushed corn (HGC-SARA) were identified. Moreover, 11 goats fed a control basal diet, named LGW-CON, were also included. Compared with those in the LGW-CON group, the rumen fermentation capacity was enhanced, accompanied by ruminal epithelial and systemic inflammation, in goats from HGW-SARA and HGC-SARA. Between them, HGC-SARA goats presented less inflammation. Notably, the ruminal inflammation-related pathways were increased only in the HGW-SARA group but not in the HGC-SARA group. Metagenomic analysis revealed that the &#x3b2; diversity of SARA goats was significantly different from that of LGW-CON goats. Ruminococcus significantly increased in both SARA groups, whereas Prevotella and Bacteroidales significantly decreased, which was accompanied by a decrease in cellulose and hemicellulose enzymes and an increase in lysozymes and lipopolysaccharide synthesis enzymes. Multi-omics analysis of the ruminal contents and tissues suggested that epithelial inflammation was caused by disturbed ruminal microbiome-induced Th17 cell differentiation and IL-17 signalling pathway activation. Comparative analyses between the HGW-SARA and HGC-SARA groups highlighted the importance of Selenomonas and Bifidobacterium, as well as bacterial tryptophan metabolism, in the production of 3-indoleacetic acid, which mitigated ruminal epithelial inflammation by modulating Th17 cells and inhibiting IL-17 signalling. Ruminal microbiota transplantation from HGW-SARA goats to healthy dairy goats and mice revealed the role of microbes in epithelial inflammation. Additionally, 3-indoleacetic acid supplementation reduced rumen inflammation and the IL-17 concentration in the serum, improved VFAs absorption, and enhanced milk production. CONCLUSIONS: This study unveiled that after SARA was induced by high-concentrate feeding, the rumen homeostasis was disrupted, and rumen fiber degradation capacity of dairy goats decreased, but the LPS synthesis capacity increased, and inflammation of the rumen epithelium was observed. However, the ruminal microbial species from the Bifidobacterium and Selenomonas genera and bacterial 3-indole acetic acid are pivotal in mitigating ruminal epithelial inflammation during SARA in dairy goats. This could potentially be attributed to the modulation of ruminal Th17 cell proportions and the inhibition of IL-17 signalling pathways. Video Abstract.

Rumen↗