Microbial signals in traditionally sterile and low-biomass human tissues and compartments: current evidence, controversies, and future challenges

Microbial DNA and structures have been detected in blood, adipose tissue, tumors, and reproductive tissues long regarded as sterile or sparsely populated. Whether these findings indicate transient material, viable organisms, or a resident community depends on the specimen and the methods used. This critical narrative review examines mainly bacterial evidence from selected tissues and fluid compartments, using endometriosis to show how anatomical sampling affects interpretation. We assess identity, quantity, localization, viability or activity, persistence, and function as distinct lines of evidence, with contamination controls relevant to each. Studies of healthy blood have not established a common resident microbiota. Adipose findings vary by depot and disease, inflamed mesenteric tissue has yielded cultured isolates, whereas metabolic adipose surveys mainly report DNA and spatial signals. Selected tumor studies support local bacterial detection and experimental effects, but neither finding generalizes to all cancers. Endometriosis studies sample different reproductive compartments, and independent reports disagree on Fusobacterium enrichment. We set out practical requirements for collection, controls, quantification, spatial analysis, and causal experiments. The central task is to separate artifacts from biomarkers and active contributors to disease.