Intestinal barrier dysfunction (""leaky gut"") has been linked to ageing and chronic disease, but evidence of its prevalence at the population scale remains scarce. Human whole-genome sequencing (WGS) routinely yields reads that fail to map to the host genome and are otherwise discarded. We asked whether these unmapped reads can be repurposed as a signal of gut leakiness. To assess the sensitivity of our approach, we spiked sterile blood with a mock microbial community and identified a detection limit of roughly 100 cells/mL for kraken2-based classification, with measurable background in negative controls. In a preliminary analysis of a pilot cohort from the UK Biobank, following normalisation and filtration informed by these sensitivity estimates, we detected putative gut-associated microbial presence in approximately 37% of individuals. Having established the workflow and characterised its detection sensitivity, we aim to investigate whether microbial content in blood WGS is associated with markers of systemic inflammation, frailty indices, and age-related phenotypes and diseases. Together, these results suggest that unmapped reads from existing human WGS data may offer a useful proxy for microbial translocation.

Co-authors: Handan Melike Donertas