iMeta最新文献

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.

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.

Recent advances in understanding the modulatory functions of gut and gut microbiota on human diseases facilitated our focused attention on the contribution of the gut to the pathophysiological alterations of many extraintestinal organs, including the liver, heart, brain, lungs, kidneys, bone, skin, reproductive, and endocrine systems. In this review, we applied the “gut–X axis” concept to describe the linkages between the gut and other organs and discussed the latest findings related to the “gut–X axis,” including the underlying modulatory mechanisms and potential clinical intervention strategies.

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.

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.

Cholesterol gallstones (CGS) still lack effective noninvasive treatment. The etiology of experimentally proven cholesterol stones remains underexplored. This cross-sectional study aims to comprehensively evaluate potential biomarkers in patients with gallstones and assess the effects of microbiome-targeted interventions in mice. Microbiome taxonomic profiling was conducted on 191 samples via V3−V4 16S rRNA sequencing. Next, 60 samples (30 age- and sex-matched CGS patients and 30 controls) were selected for metagenomic sequencing and fecal metabolite profiling via liquid chromatography-mass spectrometry. Microbiome and metabolite characterizations were performed to identify potential biomarkers for CGS. Eight-week-old male C57BL/6J mice were given a lithogenic diet for 8 weeks to promote gallstone development. The causal relationship was examined through monocolonization in antibiotics-treated mice. The effects of short-chain fatty acids such as sodium butyrate, sodium acetate (NaA), sodium propionate, and fructooligosaccharides (FOS) on lithogenic diet-induced gallstones were investigated in mice. Gut microbiota and metabolites exhibited distinct characteristics, and selected biomarkers demonstrated good diagnostic performance in distinguishing CGS patients from healthy controls. Multi-omics data indicated associations between CGS and pathways involving butanoate and propanoate metabolism, fatty acid biosynthesis and degradation pathways, taurine and hypotaurine metabolism, and glyoxylate and dicarboxylate metabolism. The incidence of gallstones was significantly higher in the Clostridium glycyrrhizinilyticum group compared to the control group in mice. The grade of experimental gallstones in control mice was significantly higher than in mice treated with NaA and FOS. FOS could completely inhibit the formation of gallstones in mice. This study characterized gut microbiome and metabolome alterations in CGS. C. glycyrrhizinilyticum contributed to gallstone formation in mice. Supplementing with FOS could serve as a potential approach for managing CGS by altering the composition and functionality of gut microbiota.

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.

Dietary fiber influences the composition and metabolic activity of microbial communities, impacting disease development. Current understanding of the intricate fiber-microbe-disease tripartite relationship remains fragmented and elusive, urging a systematic investigation. Here, we focused on microbiota disturbance as a robust index to mitigate various confounding factors and developed the Bio-taxonomic Hierarchy Weighted Aggregation (BHWA) algorithm to integrate multi-taxonomy microbiota disturbance data, thereby illuminating the complex relationships among dietary fiber, microbiota, and disease. By leveraging microbiota disturbance similarities, we (1) classified 32 types of dietary fibers into six functional subgroups, revealing correlations with fiber solubility; (2) established associations among 161 diseases, uncovering shared microbiota disturbance patterns that explain disease co-occurrence (e.g., type II diabetes and kidney diseases) and distinct microbiota patterns that discern symptomatically similar diseases (e.g., inflammatory bowel disease and irritable bowel syndrome); (3) designed a body-site-specific microbiota disturbance scoring scheme, computing a disturbance score (DS) for each disease and highlighting the pronounced capacity of Crohn's disease to disturb gut microbiota (DS = 14.01) in contrast with food allergy's minimal capacity (DS = 0.74); (4) identified 1659 fiber-disease associations, predicting the potential of dietary fiber to modulate specific microbiota changes associated with diseases of interest; (5) established murine models of inflammatory bowel disease to validate the preventive and therapeutic effects of arabinoxylan that notably perturbed the Bacteroidetes and Firmicutes phyla, as well as the Bacteroidetes and Lactobacillus genera, aligning with our model predictions. To enhance data accessibility and facilitate targeted dietary intervention development, we launched an interactive webtool—mDiFiBank at https://mdifibank.org.cn/.

The rapid growth of microbiome research has generated an unprecedented amount of multi-omics data, presenting challenges in data analysis and visualization. To address these issues, we present MicrobiomeStatPlots, a comprehensive platform offering streamlined, reproducible tools for microbiome data analysis and visualization. This platform integrates essential bioinformatics workflows with multi-omics pipelines and provides 82 distinct visualization cases for interpreting microbiome datasets. By incorporating basic tutorials and advanced R-based visualization strategies, MicrobiomeStatPlots enhances accessibility and usability for researchers. Users can customize plots, contribute to the platform's expansion, and access a wealth of bioinformatics knowledge freely on GitHub (https://github.com/YongxinLiu/MicrobiomeStatPlot). Future plans include extending support for metabolomics, viromics, and metatranscriptomics, along with seamless integration of visualization tools into omics workflows. MicrobiomeStatPlots bridges gaps in microbiome data analysis and visualization, paving the way for more efficient, impactful microbiome research.

Shotgun metagenomics has become a pivotal technology in microbiome research, enabling in-depth analysis of microbial communities at both the high-resolution taxonomic and functional levels. This approach provides valuable insights of microbial diversity, interactions, and their roles in health and disease. However, the complexity of data processing and the need for reproducibility pose significant challenges to researchers. To address these challenges, we developed EasyMetagenome, a user-friendly pipeline that supports multiple analysis methods, including quality control and host removal, read-based, assembly-based, and binning, along with advanced genome analysis. The pipeline also features customizable settings, comprehensive data visualizations, and detailed parameter explanations, ensuring its adaptability across a wide range of data scenarios. Looking forward, we aim to refine the pipeline by addressing host contamination issues, optimizing workflows for third-generation sequencing data, and integrating emerging technologies like deep learning and network analysis, to further enhance microbiome insights and data accuracy. EasyMetageonome is freely available at https://github.com/YongxinLiu/EasyMetagenome.