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Biol."],"published-print":{"date-parts":[[2026,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>16S ribosomal RNA (rRNA) gene sequencing is a standard tool for microbial community analysis. Challenges can occur, particularly in low\u2010biomass samples, when host DNA triggers off\u2010target amplification. Low\u2010biomass microbiome studies are particularly vulnerable to contamination from host DNA, which can obscure microbial signals and bias interpretation. This contamination presents a significant barrier to accurately characterizing microbial communities, especially in clinical or environmental samples with limited bacterial DNA. To systematically quantify and mitigate host DNA interference, we constructed a bacterial mock community dilution series spiked with controlled proportions of human DNA. Using 16S rRNA gene sequencing, we assessed how increasing host DNA affects microbial community profiles and evaluated several computational approaches for removing host\u2010derived sequences, including pre\u2010clustering filtering, post\u2010clustering operational taxonomic unit (OTU) filtering, and the R package Decontam. We found that off\u2010target amplification was more prevalent when the bacterial content was less than 10% relative to host DNA. Total DNA concentration induced minimal bias. Post\u2010clustering OTU filtering and reference genome mapping effectively reduced host contamination. Among the tested correction strategies, post\u2010clustering OTU filtering proved most effective and computationally sustainable, achieving nearly complete removal of host\u2010derived reads with minimal effect on microbial diversity estimates. Although 16S rRNA gene sequencing remains a cost\u2010effective and high\u2010throughput technology, it requires rigorous methodological controls in low\u2010biomass contexts. Our study offers a systematic evaluation of off\u2010target amplification effects and practical mitigation strategies to improve the accuracy of microbial community analysis. The presented framework provides a robust and scalable approach for identifying and removing host contamination from low\u2010biomass 16S rRNA sequencing data.<\/jats:p>","DOI":"10.1002\/qub2.70055","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T05:08:43Z","timestamp":1789448923000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Systematic quantification and removal of host DNA contamination in 16S rRNA gene sequencing"],"prefix":"10.1002","volume":"14","author":[{"given":"Till","family":"Birkner","sequence":"first","affiliation":[{"name":"Host\u2010Microbiome Factors in Cardiovascular Disease Lab Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association  Berlin Germany"},{"name":"Experimental and Clinical Research Center A Cooperation of Charit\u00e9\u00a0\u2013\u00a0Universit\u00e4tsmedizin Berlin and Max Delbr\u00fcck Center for Molecular Medicine  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Berlin Institute of Health  Berlin Germany"},{"name":"German Centre for Cardiovascular Research Partner Site Berlin  Berlin Germany"},{"name":"Department of Bioscience Centre for Ecological and Evolutionary Synthesis (CEES) University of Oslo  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"McParland","sequence":"additional","affiliation":[{"name":"Host\u2010Microbiome Factors in Cardiovascular Disease Lab Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association  Berlin Germany"},{"name":"Experimental and Clinical Research Center A Cooperation of Charit\u00e9\u00a0\u2013\u00a0Universit\u00e4tsmedizin Berlin and Max Delbr\u00fcck Center for Molecular Medicine  Berlin Germany"},{"name":"Charit\u00e9\u00a0\u2013\u00a0Universit\u00e4tsmedizin Berlin Corporate Member of Freie Universit\u00e4t Berlin Humboldt\u2010Universit\u00e4t zu Berlin and Berlin Institute of Health  Berlin Germany"},{"name":"German Centre for Cardiovascular Research Partner Site Berlin  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia Kirke","family":"Forslund\u2010Startceva","sequence":"additional","affiliation":[{"name":"Host\u2010Microbiome Factors in Cardiovascular Disease Lab Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association  Berlin Germany"},{"name":"Experimental and Clinical Research Center A Cooperation of Charit\u00e9\u00a0\u2013\u00a0Universit\u00e4tsmedizin Berlin and Max Delbr\u00fcck Center for Molecular Medicine  Berlin Germany"},{"name":"Charit\u00e9\u00a0\u2013\u00a0Universit\u00e4tsmedizin Berlin Corporate Member of Freie Universit\u00e4t Berlin Humboldt\u2010Universit\u00e4t zu Berlin and Berlin Institute of Health  Berlin Germany"},{"name":"German Centre for Cardiovascular Research Partner Site Berlin  Berlin Germany"},{"name":"Berlin Institute of Health (BIH)  Berlin 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