{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T05:40:08Z","timestamp":1751953208123,"version":"3.41.2"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T00:00:00Z","timestamp":1751932800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p><jats:italic>Clostridioides difficile<\/jats:italic> infection (CDI) poses a significant clinical burden due to its high recurrence rate and life-threatening complications. While gut dysbiosis is central to CDI pathogenesis, mechanisms underlying microbiota-mediated host defense remain underexplored.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study integrated summary-data-based Mendelian randomization (SMR) of cis-expression quantitative trait loci (cis-eQTLs) from blood, transverse colon, and sigmoid colon tissues with CDI genome-wide association study (GWAS) data to identify host genes influencing CDI susceptibility. Bayesian co-localization was employed to validate relationships. Then a germ-free (GF) mice model colonized with <jats:italic>Lactobacillus acidophilus<\/jats:italic> (LA) was used to investigate LA-mediated regulation of possible gene expression and phenotypic changes in the host.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>SMR analysis identified 14 genes associated with CDI risk, primarily clustered in the major histocompatibility complex (MHC) region. Notably, THOC5 exhibited robust associations (P<jats:sub>SMR<\/jats:sub> &amp;lt; 0.05 in all tissues) and co-localization evidence (posterior probability = 82.6%). In GF mice, LA colonization significantly upregulated colonic <jats:italic>Thoc5<\/jats:italic> expression in two independent experiments (fold change = 5.19\/5.00, P = 0.034\/0.031). Subsequent immunofluorescence experiments revealed that LA colonisation enhanced macrophage activation in the colonic tissue.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These findings reveal key host genes, particularly THOC5, that influence susceptibility to CDI, providing new targets for future prevention and treatment research. Additionally, the study suggests a potential mechanism by which host intestinal LA protects against CDI, highlighting the interaction between probiotics and host transcriptional networks in CDI resistance. These insights offer valuable directions for further investigation.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2025.1607476","type":"journal-article","created":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T05:26:40Z","timestamp":1751952400000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The host genes influencing Clostridioides difficile infection and the potential role of intestinal Lactobacillus acidophilus: a Mendelian randomization and animal model study"],"prefix":"10.3389","volume":"15","author":[{"given":"Yuxin","family":"Sun","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenzhen","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Senlin","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiuxin","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yinuo","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanchao","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yifan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kangshuai","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingjiang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gonghao","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhaoming","family":"Shang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junwei","family":"Qian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaofei","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingquan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1007\/s00018-018-2943-4","article-title":"An insight into gut microbiota and its functionalities","volume":"76","author":"Adak","year":"2019","journal-title":"Cell Mol. Life Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1007\/s00251-021-01204-x","article-title":"Major histocompatibility complex (MHC) associations with diseases in ethnic groups of the Arabian Peninsula","volume":"73","author":"Al Naqbi","year":"2021","journal-title":"Immunogenetics"},{"key":"B3","doi-asserted-by":"publisher","first-page":"S135","DOI":"10.1093\/cid\/civ179","article-title":"Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80R, and Lactobacillus rhamnosus CLR2 (Bio-K+): Characterization, Manufacture, Mechanisms of Action, and Quality Control of a Specific Probiotic Combination for Primary Prevention of Clostridium difficile Infection","author":"Auclair","year":"2015","journal-title":"Clin. Infect. Dis."},{"key":"B4","doi-asserted-by":"publisher","first-page":"3177","DOI":"10.1093\/jac\/dkx254","article-title":"A randomized controlled trial of probiotics for Clostridium difficile infection in adults (PICO)","volume":"72","author":"Barker","year":"2017","journal-title":"J. Antimicrob. Chemother."},{"key":"B5","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1093\/infdis\/136.5.701","article-title":"Clindamycin-associated colitis due to a toxin-producing species of Clostridium in hamsters","volume":"136","author":"Bartlett","year":"1977","journal-title":"J. Infect. Dis."},{"key":"B6","doi-asserted-by":"publisher","first-page":"2326","DOI":"10.1128\/AAC.02176-12","article-title":"Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection","volume":"57","author":"Brown","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"B7","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1038\/nature13828","article-title":"Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile","volume":"517","author":"Buffie","year":"2015","journal-title":"Nature"},{"key":"B8","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1002\/gepi.21758","article-title":"Mendelian randomization analysis with multiple genetic variants using summarized data","volume":"37","author":"Burgess","year":"2013","journal-title":"Genet. Epidemiol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1128\/CMR.00016-13","article-title":"Diagnosis of Clostridium difficile infection: an ongoing conundrum for clinicians and for clinical laboratories","volume":"26","author":"Burnham","year":"2013","journal-title":"Clin. Microbiol. Rev."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.1016\/j.chom.2022.07.015","article-title":"Faecalibaculum rodentium remodels retinoic acid signaling to govern eosinophil-dependent intestinal epithelial homeostasis","volume":"30","author":"Cao","year":"2022","journal-title":"Cell Host Microbe"},{"key":"B11","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/j.cellsig.2008.10.018","article-title":"THOC5 couples M-CSF receptor signaling to transcription factor expression","volume":"21","author":"Carney","year":"2009","journal-title":"Cell Signal."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1578","DOI":"10.1016\/j.cell.2012.04.037","article-title":"Gut immune maturation depends on colonization with a host-specific microbiota","volume":"149","author":"Chung","year":"2012","journal-title":"Cell"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1318","DOI":"10.1126\/science.aaz1776","article-title":"The GTEx Consortium atlas of genetic regulatory effects across human tissues","volume":"369","author":"Consortium","year":"2020","journal-title":"Science"},{"key":"B14","doi-asserted-by":"publisher","first-page":"e00567","DOI":"10.1128\/msphere.00567-24","article-title":"Genetic insight into the relationship between inflammatory bowel disease and Clostridioides difficile infection","volume":"9","author":"Cushing-Damm Kelly","year":"2024","journal-title":"mSphere"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.48476.sa2","article-title":"Systematic genetic analysis of the MHC region reveals mechanistic underpinnings of HLA type associations with disease","volume":"8","author":"D\u2019Antonio","year":"2019","journal-title":"Elife"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2024.1302998","article-title":"Lactobacillus acidophilus and its metabolite ursodeoxycholic acid ameliorate ulcerative colitis by promoting Treg differentiation and inhibiting M1 macrophage polarization","volume":"15","author":"Deng","year":"2024","journal-title":"Front. Microbiol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"e0204253","DOI":"10.1371\/journal.pone.0204253","article-title":"Oral probiotic combination of Lactobacillus and Bifidobacterium alters the gastrointestinal microbiota during antibiotic treatment for Clostridium difficile infection","volume":"13","author":"De Wolfe","year":"2018","journal-title":"PloS One"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2021.774916","article-title":"Approaching genetics through the MHC lens: tools and methods for HLA research","volume":"12","author":"Douillard","year":"2021","journal-title":"Front. Genet."},{"key":"B19","doi-asserted-by":"publisher","first-page":"630","DOI":"10.7326\/M14-2693","article-title":"Fecal microbiota transplantation for clostridium difficile infection: A systematic review","volume":"162","author":"Drekonja","year":"2015","journal-title":"Ann. Intern. Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1038\/mi.2012.32","article-title":"Temporal and spatial interplay of microbiota and intestinal mucosa drive establishment of immune homeostasis in conventionalized mice","volume":"5","author":"El Aidy","year":"2012","journal-title":"Mucosal Immunol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"e1000024","DOI":"10.1371\/journal.pgen.1000024","article-title":"Defining the role of the MHC in autoimmunity: a review and pooled analysis","volume":"4","author":"Fernando","year":"2008","journal-title":"PloS Genet."},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2015.01543","article-title":"Antibiotics and the human gut microbiome: dysbioses and accumulation of resistances","volume":"6","author":"Francino","year":"2015","journal-title":"Front. Microbiol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1636","DOI":"10.1038\/ajg.2010.11","article-title":"Dose-response efficacy of a proprietary probiotic formula of Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R for antibiotic-associated diarrhea and Clostridium difficile-associated diarrhea prophylaxis in adult patients","volume":"105","author":"Gao","year":"2010","journal-title":"Am. J. Gastroenterol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1093\/ije\/dyx275","article-title":"An introduction to instrumental variables for epidemiologists","volume":"47","author":"Greenland","year":"2018","journal-title":"Int. J. Epidemiol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1320","DOI":"10.1056\/NEJMoa1910215","article-title":"Trends in U.S. Burden of clostridioides difficile infection and outcomes","volume":"382","author":"Guh","year":"2020","journal-title":"N Engl. J. Med."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.1261\/rna.2607011","article-title":"Identification of mRNAs that are spliced but not exported to the cytoplasm in the absence of THOC5 in mouse embryo fibroblasts","volume":"17","author":"Guria","year":"2011","journal-title":"Rna"},{"key":"B27","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1080\/19490976.2017.1290756","article-title":"Dietary fiber and prebiotics and the gastrointestinal microbiota","volume":"8","author":"Holscher","year":"2017","journal-title":"Gut Microbes"},{"key":"B28","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1038\/s41467-023-35808-6","article-title":"Deciphering genetic causes for sex differences in human health through drug metabolism and transporter genes","volume":"14","author":"Huang","year":"2023","journal-title":"Nat. Commun."},{"key":"B29","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1038\/nri3430","article-title":"Role of the gut microbiota in immunity and inflammatory disease","volume":"13","author":"Kamada","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"B30","first-page":"434","article-title":"Effect of Lactobacillus acidophilus & epidermal growth factor on experimentally induced Clostridium difficile infection","volume":"133","author":"Kaur","year":"2011","journal-title":"Indian J. Med. Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1111\/1469-0691.12046","article-title":"Can we identify patients at high risk of recurrent Clostridium difficile infection","author":"Kelly","year":"2012","journal-title":"Clin. Microbiol. Infect."},{"key":"B32","doi-asserted-by":"publisher","first-page":"100849","DOI":"10.1016\/j.jhepr.2023.100849","article-title":"JMJD2D stabilises and cooperates with HBx protein to promote HBV transcription and replication","volume":"5","author":"Kong","year":"2023","journal-title":"JHEP Rep."},{"key":"B33","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1016\/j.immuni.2019.08.011","article-title":"MHC class II antigen presentation by the intestinal epithelium initiates graft-versus-host disease and is influenced by the microbiota","volume":"51","author":"Koyama","year":"2019","journal-title":"Immunity"},{"key":"B34","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1038\/s41586-022-05473-8","article-title":"FinnGen provides genetic insights from a well-phenotyped isolated population","volume":"613","author":"Kurki","year":"2023","journal-title":"Nature"},{"key":"B35","doi-asserted-by":"publisher","first-page":"E4485","DOI":"10.1073\/pnas.1415174111","article-title":"Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity","volume":"111","author":"Leclercq","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1539","DOI":"10.1056\/NEJMra1403772","article-title":"Clostridium difficile infection","volume":"372","author":"Leffler","year":"2015","journal-title":"N Engl. J. Med."},{"key":"B37","doi-asserted-by":"publisher","first-page":"156492","DOI":"10.1016\/j.phymed.2025.156492","article-title":"Beta-hydroxy-beta-methylbutyrate (HMB) ameliorates DSS-induced colitis by inhibiting ERK\/NF-\u03baB activation in macrophages","volume":"139","author":"Liu","year":"2025","journal-title":"Phytomedicine"},{"key":"B38","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/j.ajhg.2016.12.008","article-title":"The genetic architecture of gene expression in peripheral blood","volume":"100","author":"Lloyd-Jones","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1693","DOI":"10.1056\/NEJMoa1012413","article-title":"Host and pathogen factors for Clostridium difficile infection and colonization","volume":"365","author":"Loo","year":"2011","journal-title":"N Engl. J. Med."},{"key":"B40","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1056\/NEJMoa0910812","article-title":"Fidaxomicin versus vancomycin for Clostridium difficile infection","volume":"364","author":"Louie","year":"2011","journal-title":"N Engl. J. Med."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1732","DOI":"10.1056\/NEJMoa1801550","article-title":"Changes in prevalence of health care-associated infections in U.S. hospitals","volume":"379","author":"Magill","year":"2018","journal-title":"N Engl. J. Med."},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens11070781","article-title":"Gut microbiota composition associated with Clostridioides difficile colonization and infection","volume":"11","author":"Martinez","year":"2022","journal-title":"Pathogens"},{"key":"B43","doi-asserted-by":"publisher","first-page":"151248","DOI":"10.1016\/j.ejcb.2022.151248","article-title":"THOC5 regulates human osteoclastogenesis","volume":"101","author":"Mun","year":"2022","journal-title":"Eur. J. Cell Biol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"994","DOI":"10.1126\/science.1183605","article-title":"A catalog of reference genomes from the human microbiome","volume":"328","author":"Nelson","year":"2010","journal-title":"Science"},{"key":"B45","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1111\/j.1365-2141.2008.07090.x","article-title":"THOC5 spliceosome protein: a target for leukaemogenic tyrosine kinases that affects inositol lipid turnover","volume":"141","author":"Pierce","year":"2008","journal-title":"Br. J. Haematol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1093\/ije\/dyr233","article-title":"Two-step epigenetic Mendelian randomization: a strategy for establishing the causal role of epigenetic processes in pathways to disease","volume":"41","author":"Relton","year":"2012","journal-title":"Int. J. Epidemiol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1093\/jac\/dkt477","article-title":"Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis","volume":"69","author":"Slimings","year":"2014","journal-title":"J. Antimicrob. Chemother."},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2017.02086","article-title":"Biofilm structures in a mono-associated mouse model of Clostridium difficile infection","volume":"8","author":"Soavelomandroso","year":"2017","journal-title":"Front. Microbiol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"2505","DOI":"10.1128\/JB.01765-07","article-title":"Bile salts and glycine as cogerminants for Clostridium difficile spores","volume":"190","author":"Sorg","year":"2008","journal-title":"J. Bacteriol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1159\/000007633","article-title":"Pseudomembranous colitis: causes and cures","volume":"60","author":"Surawicz","year":"1999","journal-title":"Digestion"},{"key":"B51","doi-asserted-by":"publisher","first-page":"2392872","DOI":"10.1080\/19490976.2024.2392872","article-title":"Prevention and cure of murine C. difficile infection by a Lachnospiraceae strain","volume":"16","author":"Tejada","year":"2024","journal-title":"Gut Microbes"},{"key":"B52","doi-asserted-by":"publisher","first-page":"3114","DOI":"10.1038\/ncomms4114","article-title":"Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection","volume":"5","author":"Theriot","year":"2014","journal-title":"Nat. Commun."},{"key":"B53","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/1478-811X-12-3","article-title":"THOC5, a member of the mRNA export complex: a novel link between mRNA export machinery and signal transduction pathways in cell proliferation and differentiation","volume":"12","author":"Tran","year":"2014","journal-title":"Cell Commun. Signal."},{"key":"B54","doi-asserted-by":"publisher","first-page":"e879","DOI":"10.1038\/cddis.2013.409","article-title":"Transcriptional regulation of immediate-early gene response by THOC5, a member of mRNA export complex, contributes to the M-CSF-induced macrophage differentiation","volume":"4","author":"Tran","year":"2013","journal-title":"Cell Death Dis."},{"key":"B55","doi-asserted-by":"publisher","first-page":"1441","DOI":"10.1016\/j.cell.2020.08.027","article-title":"Diet diurnally regulates small intestinal microbiome-epithelial-immune homeostasis and enteritis","volume":"182","author":"Tuganbaev","year":"2020","journal-title":"Cell"},{"key":"B56","doi-asserted-by":"publisher","first-page":"1300","DOI":"10.1038\/s41588-021-00913-z","article-title":"Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression","volume":"53","author":"Vosa","year":"2021","journal-title":"Nat. Genet."},{"key":"B57","doi-asserted-by":"publisher","first-page":"e1009440","DOI":"10.1371\/journal.pgen.1009440","article-title":"A more accurate method for colocalisation analysis allowing for multiple causal variants","volume":"17","author":"Wallace","year":"2021","journal-title":"PloS Genet."},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.00887","article-title":"Core gut bacteria analysis of healthy mice","volume":"10","author":"Wang","year":"2019","journal-title":"Front. Microbiol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"4154","DOI":"10.3760\/cma.j.issn.0366-6999.20130744","article-title":"Role of Lactobacillus in the prevention of Clostridium difficile-associated diarrhea: a meta-analysis of randomized controlled trials","volume":"126","author":"Wu","year":"2013","journal-title":"Chin. Med. J. (Engl.)"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1016\/j.xinn.2021.100141","article-title":"clusterProfiler 4.0: A universal enrichment tool for interpreting omics data","volume":"2","author":"Wu","year":"2021","journal-title":"Innovation"},{"key":"B61","doi-asserted-by":"publisher","first-page":"4745","DOI":"10.3168\/jds.2014-7921","article-title":"Lactobacillus acidophilus modulates the virulence of Clostridium difficile","volume":"97","author":"Yun","year":"2014","journal-title":"J. Dairy Sci."},{"key":"B62","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1038\/ng.3538","article-title":"Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets","volume":"48","author":"Zhu","year":"2016","journal-title":"Nat. Genet."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2025.1607476\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T05:26:42Z","timestamp":1751952402000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2025.1607476\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,8]]},"references-count":62,"alternative-id":["10.3389\/fcimb.2025.1607476"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2025.1607476","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,8]]},"article-number":"1607476"}}