{"title":"Profiling chimeric RNA in prostate cancer in Chinese cohorts reveals similarities and differences compared to Western populations","authors":"Qiong Wang, Shunli Yu, Jirong Jie, Justin Elfman, Zhi Xiong, Sandeep Singh, Samir Lalani, Yiwei Wang, Kaiwen Li, Bisheng Cheng, Ze Gao, Xu Gao, Hui Li, Hai Huang","doi":"10.1002/imt2.70014","DOIUrl":"https://doi.org/10.1002/imt2.70014","url":null,"abstract":"<p>Chimeric RNAs from chromosomal rearrangements have long been validated as cancer markers and therapeutic targets for many years. Recently, trans-splicing and cis-splicing between adjacent genes are also shown to generate chimeric RNAs. They influence tumor progression by coding fusion proteins, acting as long noncoding or circular RNAs, or altering parental gene expression. Here, we analyzed chimeric RNAs from The Cancer Genome Atlas and Chinese Prostate Cancer Genome and Epigenome Atlas, identifying similarities and differences between Western and Chinese prostate cancer (PCa) cohorts. We confirmed distinct chimeric RNA expression patterns among cancer epithelial cells, cancer-associated fibroblasts, tumor-associated macrophages, and T cells. We unraveled how these chimeras impact tumor cell growth, stromal cell transformation, and intercellular communication within the microenvironment. This comprehensive study establishes a chimeric transcriptome atlas for Chinese PCa patients, highlights population-specific disparities, and presents validated chimeric RNAs with diagnostic, prognostic, and therapeutic potential.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":73342,"journal":{"name":"iMeta","volume":"4 2","pages":""},"PeriodicalIF":23.7,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/imt2.70014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bicheng Ye, Jun Fan, Lei Xue, Yu Zhuang, Peng Luo, Aimin Jiang, Jiaheng Xie, Qifan Li, Xiaoqing Liang, Jiaxiong Tan, Songyun Zhao, Wenhang Zhou, Chuanli Ren, Haoran Lin, Pengpeng Zhang
{"title":"iMLGAM: Integrated Machine Learning and Genetic Algorithm-driven Multiomics analysis for pan-cancer immunotherapy response prediction","authors":"Bicheng Ye, Jun Fan, Lei Xue, Yu Zhuang, Peng Luo, Aimin Jiang, Jiaheng Xie, Qifan Li, Xiaoqing Liang, Jiaxiong Tan, Songyun Zhao, Wenhang Zhou, Chuanli Ren, Haoran Lin, Pengpeng Zhang","doi":"10.1002/imt2.70011","DOIUrl":"https://doi.org/10.1002/imt2.70011","url":null,"abstract":"<p>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 (<i>CEP55</i>) 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 <i>CEP55</i> 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.</p>","PeriodicalId":73342,"journal":{"name":"iMeta","volume":"4 2","pages":""},"PeriodicalIF":23.7,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/imt2.70011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"T2T genome, pan-genome analysis, and heat stress response genes in Rhododendron species","authors":"Xiaojing Wang, Ping Zhou, Xiaoyu Hu, Yun Bai, Chenhao Zhang, Yanhong Fu, Ruirui Huang, Niu Suzhen, Xiaoming Song","doi":"10.1002/imt2.70010","DOIUrl":"https://doi.org/10.1002/imt2.70010","url":null,"abstract":"<p>This study reports the first high-quality telomere-to-telomere (T2T) <i>Rhododendron liliiflorum</i> genome with 11 chromosomes that are gap free. The 24 telomeres and all 13 centromeres detected in this genome, which reached the highest quality gold level. In addition, other three <i>Rhododendron</i> species were sequenced and assembled to the chromosomal level. Based on 15 <i>Rhododendron</i> genomes, we conducted a pan-genome analysis of genus <i>Rhododendron</i>. Combining the genome and whole transcriptome sequencing, we identified several key genes and miRNAs related to the heat stress, which were further verified by transgenic experiments. Our findings provide rich resources for comparative and functional genomics studies of <i>Rhododendron</i> species.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":73342,"journal":{"name":"iMeta","volume":"4 2","pages":""},"PeriodicalIF":23.7,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/imt2.70010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Specificity landscapes of 40 R2R3-MYBs reveal how paralogs target different cis-elements by homodimeric binding","authors":"Tian Li, Hao Chen, Nana Ma, Dingkun Jiang, Jiacheng Wu, Xinfeng Zhang, Hao Li, Jiaqing Su, Piaojuan Chen, Qing Liu, Yuefeng Guan, Xiaoyue Zhu, Juncheng Lin, Jilin Zhang, Qin Wang, Honghong Guo, Fangjie Zhu","doi":"10.1002/imt2.70009","DOIUrl":"https://doi.org/10.1002/imt2.70009","url":null,"abstract":"<p>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 <i>cis-</i>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 <i>cis-</i>regulatory sites.</p>","PeriodicalId":73342,"journal":{"name":"iMeta","volume":"4 2","pages":""},"PeriodicalIF":23.7,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/imt2.70009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Weixin Liu, Harry C. H. Lau, Xiao Ding, Xiaole Yin, William Ka Kei Wu, Sunny Hei Wong, Joseph J. Y. Sung, Tong Zhang, Jun Yu
{"title":"Transmission of antimicrobial resistance genes from the environment to human gut is more pronounced in colorectal cancer patients than in healthy subjects","authors":"Weixin Liu, Harry C. H. Lau, Xiao Ding, Xiaole Yin, William Ka Kei Wu, Sunny Hei Wong, Joseph J. Y. Sung, Tong Zhang, Jun Yu","doi":"10.1002/imt2.70008","DOIUrl":"https://doi.org/10.1002/imt2.70008","url":null,"abstract":"<p>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 (<i>p</i> < 0.01) with increased levels of multidrug-resistant ARGs. Gut ARGs in CRC also had a closer similarity to environmental ARGs (<i>p</i> < 0.001). By comparing environmental and gut ARGs, 28 environmental ARGs were identified as CRC-specific ARGs, including <i>SUL2</i> and <i>MEXE</i>, which were not identified in healthy subjects. Meanwhile, more mobile ARGs (mARGs) from the environment were observed in CRC patients compared to healthy subjects (<i>p</i> < 0.05). The hosts of mARGs were mainly pathogenic bacteria (e.g., <i>Escherichia coli</i> (<i>E. coli</i>) and <i>Clostridium symbiosum</i> (<i>C. symbiosum</i>)). 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., <i>E. coli-SUL2</i> and <i>C. symbiosum-SUL2</i>) were significantly increased in CRC patients compared to healthy subjects (<i>p</i> < 0.05). We thus reveal a route of ARG dissemination from the environment into the gut of CRC patients.</p>","PeriodicalId":73342,"journal":{"name":"iMeta","volume":"4 2","pages":""},"PeriodicalIF":23.7,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/imt2.70008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Gut–X axis","authors":"Xu Lin, Zuxiang Yu, Yang Liu, Changzhou Li, Hui Hu, Jia-Chun Hu, Mian Liu, Qin Yang, Peng Gu, Jiaxin Li, Kutty Selva Nandakumar, Gaofei Hu, Qi Zhang, Xinyu Chen, Huihui Ma, Wenye Huang, Gaofeng Wang, Yan Wang, Liping Huang, Wenjuan Wu, Ning-Ning Liu, Chenhong Zhang, Xingyin Liu, Leming Zheng, Peng Chen","doi":"10.1002/imt2.270","DOIUrl":"https://doi.org/10.1002/imt2.270","url":null,"abstract":"<p>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.</p>","PeriodicalId":73342,"journal":{"name":"iMeta","volume":"4 1","pages":""},"PeriodicalIF":23.7,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/imt2.270","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Longchang Huang, Peng Wang, Shuai Liu, Guifang Deng, Xin Qi, Guangming Sun, Xuejin Gao, Li Zhang, Yupeng Zhang, Yaqin Xiao, Tingting Gao, Gulisudumu Maitiabula, Xinying Wang
{"title":"Gut microbiota-derived tryptophan metabolites improve total parenteral nutrition-associated infections by regulating Group 3 innate lymphoid cells","authors":"Longchang Huang, Peng Wang, Shuai Liu, Guifang Deng, Xin Qi, Guangming Sun, Xuejin Gao, Li Zhang, Yupeng Zhang, Yaqin Xiao, Tingting Gao, Gulisudumu Maitiabula, Xinying Wang","doi":"10.1002/imt2.70007","DOIUrl":"https://doi.org/10.1002/imt2.70007","url":null,"abstract":"<p>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 <i>Lactobacillus murinus</i> (<i>L. murinus</i>), while supplementation with <i>L. murinus</i> could promote IL-22 secretion by ILC3s. Mechanistically, <i>L. murinus</i> 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.</p>","PeriodicalId":73342,"journal":{"name":"iMeta","volume":"4 2","pages":""},"PeriodicalIF":23.7,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/imt2.70007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Enhancement of gut barrier integrity by a Bacillus subtilis secreted metabolite through the GADD45A-Wnt/β-catenin pathway","authors":"Shiqi Liu, Peiran Cai, Wenjing You, Mingshun Yang, Yuang Tu, Yanbing Zhou, Teresa G. Valencak, Yingping Xiao, Yizhen Wang, Tizhong Shan","doi":"10.1002/imt2.70005","DOIUrl":"https://doi.org/10.1002/imt2.70005","url":null,"abstract":"<p>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 <i>Bacillus subtilis</i> (<i>B. subtilis</i>) 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 <i>B. subtilis</i>, 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.</p>","PeriodicalId":73342,"journal":{"name":"iMeta","volume":"4 2","pages":""},"PeriodicalIF":23.7,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/imt2.70005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ye Liu, Hexin Li, Tianhan Sun, Gaoyuan Sun, Boyue Jiang, Meilan Liu, Qing Wang, Tong Li, Jianfu Cao, Li Zhao, Fei Xiao, Fangqing Zhao, Hongyuan Cui
{"title":"Gut microbiome and metabolome characteristics of patients with cholesterol gallstones suggest the preventive potential of prebiotics","authors":"Ye Liu, Hexin Li, Tianhan Sun, Gaoyuan Sun, Boyue Jiang, Meilan Liu, Qing Wang, Tong Li, Jianfu Cao, Li Zhao, Fei Xiao, Fangqing Zhao, Hongyuan Cui","doi":"10.1002/imt2.70000","DOIUrl":"https://doi.org/10.1002/imt2.70000","url":null,"abstract":"<p>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 <i>Clostridium glycyrrhizinilyticum</i> 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. <i>C. glycyrrhizinilyticum</i> 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.</p>","PeriodicalId":73342,"journal":{"name":"iMeta","volume":"4 1","pages":""},"PeriodicalIF":23.7,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/imt2.70000","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Time-restricted feeding mitigates Alzheimer's disease-associated cognitive impairments via a B. pseudolongum-propionic acid-FFAR3 axis","authors":"Yihang Zhao, Mengzhen Jia, Chen Ding, Bingkun Bao, Hangqi Li, Jiabin Ma, Weixuan Dong, Rui Gao, Xuhui Chen, Jiao Chen, Xiaoshuang Dai, Yuanqiang Zou, Jun Hu, Lin Shi, Xuebo Liu, Zhigang Liu","doi":"10.1002/imt2.70006","DOIUrl":"https://doi.org/10.1002/imt2.70006","url":null,"abstract":"<p>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 <i>Bifidobacterium pseudolongum</i> (<i>B. pseudolongum</i>) and propionic acid (PA) with key genes in AD pathogenesis. Oral supplementation of <i>B. pseudolongum</i> 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 <i>B. pseudolongum</i> or PA as potential AD therapies.</p>","PeriodicalId":73342,"journal":{"name":"iMeta","volume":"4 2","pages":""},"PeriodicalIF":23.7,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/imt2.70006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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