Antimicrobial resistance is widespread among intestinal and extra-intestinal <i>Bacteroides fragilis</i> strains

<i>Bacteroides fragilis</i> is an important member of the human gut microbiota, where it contributes to immune modulation, intestinal barrier integrity, and colonization resistance. Despite its beneficial roles as a symbiont in the gut, <i>B. fragilis</i> is also the most commonly isolated anaerobe in clinical infections, implicated in intra-abdominal abscesses, bloodstream infections, and soft tissue infections. Antimicrobial resistance (AMR) is increasingly recognized as a major factor in its transition from symbiont to opportunist; however, the relationship between resistance and anatomical site of isolation remains poorly defined. Here, we compared AMR phenotypes and genotypes between intestinal and extra-intestinal <i>B. fragilis</i> isolates to assess whether clinical strains are enriched for resistance determinants. Surprisingly, we found comparable susceptibility profiles and AMR gene content between the two groups. Minimal inhibitory concentrations (MICs) were broadly similar, and β-lactamase activity was detected in ~70% of the isolates regardless of the isolation site. We found that resistance genes were similarly distributed across both intestinal and clinical strains. A microbial genome-wide association study (mGWAS) confirmed the known resistance markers, such as <i>ermF</i>, <i>aadS</i>, and <i>tetQ,</i> and identified novel associations with conjugative transposons, efflux transporters, regulatory genes, and previously uncharacterized loci. These findings suggest that intestinal strains serve as a reservoir of clinically relevant resistance determinants that may be mobilized under selective pressure. Although prior work has largely focused on clinical isolates, our findings highlight the need to surveil AMR within the gut microbiota, where widespread resistance in commensal bacteria has the potential to complicate treatment of extra-intestinal infections.