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An additional potential mechanism is intestinal barrier dysfunction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>This case\u2013control study aimed to detect and associate microbial taxa in blood with disease state.<\/jats:p><\/jats:sec><jats:sec><jats:title>Study Design<\/jats:title><jats:p>Areas known for a high prevalence of tick\u2010borne diseases in humans were chosen to survey horses with FUO, which was defined as fever of 101.5\u00b0F or higher with no signs of respiratory illness or other recognisable diseases. Blood samples and clinical parameters were obtained from 52 FUO cases and also from matched controls from the same farms. An additional 23 febrile horses without matched controls were included.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Broadly targeted polymerase chain reaction (PCR) amplification directed at conserved sequence regions of bacterial 16S rRNA, parasite 18S rRNA, coronavirus RdRp and parvovirus NS1 was performed, followed by deep sequencing. To control for contamination and identify taxa unique to the cases, metagenomic sequences from the controls were subtracted from those of the cases, and additional targeted molecular testing was performed. Sera were also tested for antibodies to equine coronavirus.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Over 60% of cases had intestinal microbial DNA circulating in the blood. Nineteen percent of cases were attributed to infection with <jats:italic>Anaplasma phagocytophilum<\/jats:italic>, of which two were subtyped as human\u2010associated strains. A novel <jats:italic>Erythroparvovirus<\/jats:italic> was detected in two cases and two controls. Serum titres for equine coronavirus were elevated in some cases but not statistically different overall between the cases and controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Main Limitations<\/jats:title><jats:p>Not all pathogens are expected to circulate in blood, which was the sole focus of this study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The presence of commensal gut microbes in blood of equine FUO cases is consistent with a compromised intestinal barrier, which is highlighted as a direction for future study.<\/jats:p><\/jats:sec>","DOI":"10.1002\/vms3.70272","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T15:27:50Z","timestamp":1741706870000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Investigation of the Blood Microbiome in Horses With Fever of Unknown Origin"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-7806-4992","authenticated-orcid":false,"given":"Yining","family":"Sun","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine Cornell University  Ithaca New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3191-1682","authenticated-orcid":false,"given":"Y. 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