title: Survey of 800+ data sets from human tissue and body fluid reveals xenomiRs are likely artifacts.
abstract: miRNAs are small 22-nucleotide RNAs that can post-transcriptionally regulate gene expression. It has been proposed that dietary plant miRNAs can enter the human bloodstream and regulate host transcripts; however, these findings have been widely disputed. We here conduct the first comprehensive meta-study in the field, surveying the presence and abundances of cross-species miRNAs (xenomiRs) in 824 sequencing data sets from various human tissues and body fluids. We find that xenomiRs are commonly present in tissues (17%) and body fluids (69%); however, the abundances are low, comprising 0.001% of host human miRNA counts. Further, we do not detect a significant enrichment of xenomiRs in sequencing data originating from tissues and body fluids that are exposed to dietary intake (such as liver). Likewise, there is no significant depletion of xenomiRs in tissues and body fluids that are relatively separated from the main bloodstream (such as brain and cerebro-spinal fluids). Interestingly, the majority (81%) of body fluid xenomiRs stem from rodents, which are a rare human dietary contribution but common laboratory animals. Body fluid samples from the same studies tend to group together when clustered by xenomiR compositions, suggesting technical batch effects. Last, we performed carefully designed and controlled animal feeding studies, in which we detected no transfer of plant miRNAs into rat blood, or bovine milk sequences into piglet blood. In summary, our comprehensive computational and experimental results indicate that xenomiRs originate from technical artifacts rather than dietary intake.
authors.affiliation: Science for Life Laboratory, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, S-10691 Stockholm, Sweden.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Kang
authors.affiliation: Center for Non-Coding RNA in Technology and Health, University of Copenhagen, 1870 Copenhagen, Denmark.|Department of Diabetes Biology, Novo Nordisk, 2760 Måløv, Denmark.|National Food Institute, Technical University of Denmark, 2800 Lyngby, Denmark.
authors.forename: Claus Heiner
authors.initials: CH
authors.lastname: Bang-Berthelsen
authors.affiliation: Molecular Sleep Laboratory, Department of Clinical Biochemistry, Rigshospitalet, 2600 Glostrup, Denmark.
authors.forename: Anja
authors.initials: A
authors.lastname: Holm
authors.affiliation: Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, 08003 Barcelona, Spain.|Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain.
authors.forename: Anna J S
authors.initials: AJ
authors.lastname: Houben
authors.affiliation: Department of Clinical Experimental Research, Glostrup Research Institute, Rigshospitalet, 2600 Glostrup, Denmark.
authors.forename: Anne Holt
authors.initials: AH
authors.lastname: Müller
authors.affiliation: Comparative Pediatrics and Nutrition, Department of Veterinary and Animal Science, University of Copenhagen, 1870 Frederiksberg C, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Thymann
authors.affiliation: Center for Non-Coding RNA in Technology and Health, University of Copenhagen, 1870 Copenhagen, Denmark.|Department of Paediatrics, Herlev Hospital, University of Copenhagen, 2730 Copenhagen, Denmark.|Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Flemming
authors.initials: F
authors.lastname: Pociot
authors.affiliation: Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, 08003 Barcelona, Spain.|Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.affiliation: Science for Life Laboratory, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, S-10691 Stockholm, Sweden.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Friedländer
mesh_terms: D000818:Animals; D016477:Artifacts; D001826:Body Fluids / Q000737:chemistry*; D001923:Brain Chemistry; D002417:Cattle; D004032:Diet; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008099:Liver / Q000737:chemistry* / Q000378:metabolism; D035683:MicroRNAs / Q000097:blood / Q000134:cerebrospinal fluid / Q000145:classification / Q000302:isolation & purification*; D010944:Plants / Q000737:chemistry; D018749:RNA, Plant / Q000097:blood / Q000134:cerebrospinal fluid / Q000145:classification / Q000302:isolation & purification*; D051381:Rats
chemical_list: D035683:MicroRNAs; D018749:RNA, Plant
keywords: artifacts; contamination; exogenous miRNAs; meta-study; miRNA; microRNA; next-generation sequencing