The origin of circulating microbial DNA in the blood: where does it come from?

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. This review explores four potential sources of cmDNA in the blood and analyzes research limitations and future prospects. 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. 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.