Abstract Background The resistome, the collection of antibiotic resistance genes (ARGs) in a microbiome, is increasingly recognised as relevant to the development of clinically relevant antibiotic resistance. Many metagenomic studies have reported resistome differences between groups, often in connection with disease and/or antibiotic treatment. However, the consistency of resistome associations with antibiotic- and non-antibiotic–treated diseases has not been established. In this study, we re-analysed human gut microbiome data from 26 case-control studies to assess the link between disease and the resistome. Results The human gut resistome is highly variable between individuals both within and between studies, but may also vary significantly between case and control groups even in the absence of large taxonomic differences. We found that for diseases commonly treated with antibiotics, namely cystic fibrosis and diarrhoea, patient microbiomes had significantly elevated ARG abundances compared to controls. Disease-associated resistome expansion was found even when ARG abundance was high in controls, suggesting ongoing and additive ARG acquisition in disease-associated strains. We also found a trend for increased ARG abundance in cases from some studies on diseases that are not treated with antibiotics, such as colorectal cancer. Conclusions Diseases commonly treated with antibiotics are associated with expanded gut resistomes, suggesting that historical exposure to antibiotics has exerted considerable selective pressure for ARG acquisition in disease-associated strains. Video Abstract
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