Inflammatory bowel disease (IBD) represents a significant challenge to global health, characterized by intestinal inflammation, impaired barrier function, and dysbiosis, with limited therapeutic options. In this study, we isolated a novel strain of Bacillus subtilis (B. subtilis) and observed promising effects in protecting against disruption of the gut barrier. Our findings indicate that the enhancement of intestinal barrier function is primarily attributed to its metabolites. We identified a novel metabolite, 2-hydroxy-4-methylpentanoic acid (HMP), derived from B. subtilis, that significantly improved intestinal barrier function. We also show that growth arrest and DNA damage 45A (GADD45A) is a key regulator of mucosal barrier integrity, which is activated by HMP and subsequently activates the downstream Wnt/β-catenin pathway. Our findings potentially contribute to the development of probiotics-derived metabolites or targeted “postbiotics” as novel therapeutics for the treatment or prevention of IBD and other diseases associated with intestinal barrier dysfunction.

Time-restricted feeding (TRF) holds promise for alleviating cognitive decline in aging, albeit the precise mechanism via the gut-brain axis remains elusive. In a clinical trial, we observed, for the first time, that a 4-month TRF ameliorated cognitive impairments among Alzheimer's disease (AD) patients. Experiments in 5xFAD mice corroborated the gut microbiota-dependent effect of TRF on mitigating cognitive dysfunction, amyloid-beta deposition, and neuroinflammation. Multi-omics integration linked Bifidobacterium pseudolongum (B. pseudolongum) and propionic acid (PA) with key genes in AD pathogenesis. Oral supplementation of B. pseudolongum or PA mimicked TRF's protective effects. Positron emission tomography imaging confirmed PA's blood-brain barrier penetration, while knockdown of the free fatty acid receptor 3 (FFAR3) diminished TRF's cognitive benefits. Notably, we observed a positive correlation between fecal PA and improved cognitive function in an AD cohort, further indicating that TRF enhanced PA production. These findings highlight the microbiota-metabolites-brain axis as pivotal in TRF's cognitive benefits, proposing B. pseudolongum or PA as potential AD therapies.

Clinical nutritional support is recognized by Klinefner's Surgery as one of the four pivotal advancements in surgical practice during the 20th century. Surgeons regard clinical nutrition as a “life-saving” discipline, pivotal in preserving the lives of numerous critically ill patients and facilitating the success of many surgical procedures. Parenteral nutrition (PN) support serves as a crucial component of clinical nutritional therapy, while a range of complications associated with total parenteral nutrition (TPN) can significantly undermine the efficacy of patient treatment. Impaired intestinal homeostasis is strongly associated with the occurrence and progression of TPN-related infections, yet the underlying mechanisms remain poorly understood. In this study, RNA sequencing and single-cell RNA sequencing (scRNA-Seq) revealed that reduced secretion of interleukin-22 (IL-22) by intestinal Group 3 innate lymphoid cells (ILC3s) is a significant factor contributing to the onset of TPN-related infections. Additionally, through 16S ribosomal RNA (16S rRNA) gene sequencing of the gut microbiota from patients with chronic intestinal failure and metagenomic sequencing analysis of the gut microbiota from mice, we observed that TPN reduced the abundance of Lactobacillus murinus (L. murinus), while supplementation with L. murinus could promote IL-22 secretion by ILC3s. Mechanistically, L. murinus upregulates indole-3-carboxylic acid, which activates the nuclear receptor Rorγt to stimulate IL-22 secretion by ILC3s. This pathway strengthens gut barrier integrity and reduces infection susceptibility. Our findings enhance our understanding of the mechanisms driving the onset of TPN-related infections, highlighting the critical role of gut microbiota in maintaining immune homeostasis and improving clinical outcomes.

Antimicrobial resistance is a major global health concern. However, the source of gut resistome remains unsolved. We aimed to analyze the contribution of environmental antimicrobial resistance genes (ARGs) to colorectal cancer (CRC) patients. Here, we collected metagenomic data from 1,605 human stool samples (CRC = 748; healthy = 857) and 1,035 city-matched environmental samples, in which 110 CRC, 112 healthy, and 56 environmental samples were newly collected. Compared to healthy subjects, CRC patients had significantly higher ARG burden (p < 0.01) with increased levels of multidrug-resistant ARGs. Gut ARGs in CRC also had a closer similarity to environmental ARGs (p < 0.001). By comparing environmental and gut ARGs, 28 environmental ARGs were identified as CRC-specific ARGs, including SUL2 and MEXE, which were not identified in healthy subjects. Meanwhile, more mobile ARGs (mARGs) from the environment were observed in CRC patients compared to healthy subjects (p < 0.05). The hosts of mARGs were mainly pathogenic bacteria (e.g., Escherichia coli (E. coli) and Clostridium symbiosum (C. symbiosum)). Compared to healthy subjects, CRC patients showed elevated horizontal gene transfer efficiency from the environment to gut. Consistently, the abundance of pathobionts carrying specific mARGs (e.g., E. coli-SUL2 and C. symbiosum-SUL2) were significantly increased in CRC patients compared to healthy subjects (p < 0.05). We thus reveal a route of ARG dissemination from the environment into the gut of CRC patients.

Paralogous transcription factors (TFs) frequently recognize highly similar DNA motifs. Homodimerization can help distinguish them according to their different dimeric configurations. Here, by studying R2R3-MYB TFs, we show that homodimerization can also directly change the recognized DNA motifs to distinguish between similar TFs. By high-throughput SELEX, we profiled the specificity landscape for 40 R2R3-MYBs of subfamily VIII and curated 833 motif models. The dimeric models show that homodimeric binding has evoked specificity changes for AtMYBs. Focusing on AtMYB2 as an example, we show that homodimerization has modified its specificity and allowed it to recognize additional cis-regulatory sequences that are different from the closely related CCWAA-box AtMYBs and are unique among all AtMYBs. Genomic sites described by the modified dimeric specificities of AtMYB2 are conserved in evolution and involved in AtMYB2-specific transcriptional activation. Collectively, this study provides rich data on sequence preferences of VIII R2R3-MYBs and suggests an alternative mechanism that guides closely related TFs to respective cis-regulatory sites.

To address the substantial variability in immune checkpoint blockade (ICB) therapy effectiveness, we developed an innovative R package called integrated Machine Learning and Genetic Algorithm-driven Multiomics analysis (iMLGAM), which establishes a comprehensive scoring system for predicting treatment outcomes through advanced multi-omics data integration. Our research demonstrates that iMLGAM scores exhibit superior predictive performance across independent cohorts, with lower scores correlating significantly with enhanced therapeutic responses and outperforming existing clinical biomarkers. Detailed analysis revealed that tumors with low iMLGAM scores display distinctive immune microenvironment characteristics, including increased immune cell infiltration and amplified antitumor immune responses. Critically, through clustered regularly interspaced short palindromic repeats screening, we identified Centrosomal Protein 55 (CEP55) as a key molecule modulating tumor immune evasion, mechanistically confirming its role in regulating T cell-mediated antitumor immune responses. These findings not only validate iMLGAM as a powerful prognostic tool but also propose CEP55 as a promising therapeutic target, offering novel strategies to enhance ICB treatment efficacy. The iMLGAM package is freely available on GitHub (https://github.com/Yelab1994/iMLGAM), providing researchers with an innovative approach to personalized cancer immunotherapy prediction.

Maternal health, specifically changes in the gut microbiota, can profoundly impact offspring health; however, our understanding of how gut microbiota alterations during the preconception period influence the offspring remains limited. In this study, we investigated the impact and mechanisms of preconception maternal gut dysbiosis on the development of the enteric nervous system (ENS) in mice. We found that preconception maternal exposure to antibiotics led to the abnormal development of the ENS in offspring, increasing their susceptibility to water avoidance stress at the adult stage. Metagenomic, targeted metabolomic, and transcriptomic analyses revealed that preconception antibiotic exposure disrupted the expression of genes crucial for embryonic ENS development by altering maternal gut microbiota composition. Multi-omics analysis combined with Limosilactobacillus reuteri and propionate gestational supplementation demonstrated that the maternal gut microbiota and metabolites may influence embryonic ENS development via the GPR41–GDNF/RET/SOX10 signaling pathway. Our findings highlight the critical importance of maintaining a healthy maternal gut microbiota before conception to support normal ENS development in offspring.

Root System Architecture (RSA) plays an essential role in influencing maize yield by enhancing anchorage and nutrient uptake. Analyzing maize RSA dynamics holds potential for ideotype-based breeding and prediction, given the limited understanding of the genetic basis of RSA in maize. Here, we obtained 16 root morphology-related traits (R-traits), 7 weight-related traits (W-traits), and 108 slice-related microphenotypic traits (S-traits) from the meristem, elongation, and mature zones by cross-sectioning primary, crown, and lateral roots from 316 maize lines. Significant differences were observed in some root traits between tropical/subtropical and temperate lines, such as primary and total root diameters, root lengths, and root area. Additionally, root anatomy data were integrated with genome-wide association study (GWAS) to elucidate the genetic architecture of complex root traits. GWAS identified 809 genes associated with R-traits, 261 genes linked to W-traits, and 2577 key genes related to 108 slice-related traits. We confirm the function of a candidate gene, fucosyltransferase5 (FUT5), in regulating root development and heat tolerance in maize. The different FUT5 haplotypes found in tropical/subtropical and temperate lines are associated with primary root features and hold promising applications in molecular breeding. Furthermore, we performed machine learning prediction models of RSA using root slice traits, achieving high prediction accuracy. Collectively, our study offers a valuable tool for dissecting the genetic architecture of RSA, along with resources and predictive models beneficial for molecular design breeding and genetic enhancement.

Code-based data visualization is a crucial tool for understanding and communicating experimental findings while ensuring scalability and reproducibility. However, complex programming interfaces pose a significant barrier for life scientists. To address this challenge, tidyplots provides a user-friendly code-based interface for creating customizable and insightful plots. With its consistent and intuitive syntax, tidyplots empowers researchers to leverage automated data visualization pipelines while minimizing required programming skills.

Metabolic-associated fatty liver disease (MAFLD) has become increasingly widespread. The intestine is the primary site of lipid absorption and is important for the homeostasis of lipid metabolism. However, the mechanism underlying the participation of the intestinal tract in the development of MAFLD requires additional investigation. In this study, analysis of the single-cell transcriptome of intestinal tissue from cynomolgus monkeys found that hepatic leukemia factor (HLF) participated in the genetic regulation of intestinal lipid absorption. Results obtained from normal and intestine-specific Hlf-knockout mice confirmed that HLF alleviated intestinal barrier disorders by inhibiting peroxisome proliferator-activated receptor alpha (PPARα) expression. The HLF/PPARα axis alleviated MAFLD by mediating gut microbiota-derived extracellular vesicles (fEVs), thereby inhibiting hepatocyte ferroptosis. Lipidomics and functional experiments verified that taurochenodeoxycholic acid (TCDCA), a conjugated bile acid contained in the fEVs, had a key role in the process. In conclusion, intestinal HLF activity was mediated by fEVs and identified as a novel therapeutic target for MAFLD.