Abstract
BACKGROUND: Circulating microbial DNA (cmDNA) is a significant biomarker involved in normal physiology, immunity, disease diagnosis, and pathogenesis. Its origin in peripheral blood has sparked extensive discussions and generated numerous hypotheses. AIM: This review explores four potential sources of cmDNA in the blood and analyzes research limitations and future prospects. RESULTS: Four potential sources are collated and analyzed: exogenous microbes or DNA entering the peripheral blood after barrier damage; residual pathogen DNA remaining after infectious diseases; microbial translocation from sites such as the oral and intestinal mucosa into the bloodstream; and the extracellular vesicle delivery system, where microorganisms release vesicles to transfer DNA. CONCLUSIONS: The potential sources of cmDNA in the blood are not mutually exclusive and may be multifaceted, depending on an individual's health condition, sampling time, and contamination control. In-depth study of these sources will open new avenues for early disease detection, precise diagnosis, and prognosis assessment, and encourage further exploration in this promising field.