Cultivation and genomic characterization of human gut-associated Bdellovibrio reveals natural predatory bacteria with specialized prey interactions

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ABSTRACT Predatory bacteria from the Bdellovibrio and Like Organisms (BALOs) group represent promising alternatives to conventional antibiotics, yet their presence in the human microbiome has remained unconfirmed through cultivation. While molecular detection methods have identified Bdellovibrionaceae DNA in human-associated environments, viable predatory bacteria had never been successfully isolated from human samples, limiting our understanding of their ecology and therapeutic potential. Here, we report the first successful isolation and characterization of viable Bdellovibrio strains from human fecal samples. Despite extremely low natural abundance requiring enrichment protocols for detection, two of five pooled samples yielded viable predators with characteristic lytic activity. Whole-genome sequencing of two isolates revealed >99% average nucleotide identity to the reference strain HD100 with only 26 total single nucleotide polymorphisms, indicating minimal genomic divergence between human-associated and environmental strains. Comparative genomic analysis of 163 publicly available Bdellovibrio genomes demonstrated that only 10.4% represented true B. bacteriovorus sensu stricto, highlighting substantial cryptic diversity within this genus. Pangenome analysis across 41 genomes revealed a highly conserved core genome (∼2,500-2,650 genes) contrasting with an expanding accessory genome, reflecting functional constraints of obligate predation alongside ecological adaptation. Notably, human-associated isolates exhibited narrower prey ranges, including some multidrug-resistant isolates. These findings establish that predatory bacteria are naturally associated with the human intestinal environment without acquiring novel virulence factors, support their biosafety profile for therapeutic development, and reveal prey specialization that may reflect adaptation to human microbiome ecology. IMPORTANCE This work demonstrates that bacterial predation operates as an active ecological process within the human microbiota. The successful isolation of viable Bdellovibrio establishes that predatory bacteria are viable microbiota members maintaining their predatory phenotype. Genomic conservation (>99% ANI to environmental strains) indicates that predation imposes stringent functional constraints superseding niche-specific adaptations. Our findings reframe microbiome understanding by revealing that predation (a top-down regulatory mechanism) operates in human-associated communities, potentially functioning as a keystone ecological process maintaining diversity through predator-prey dynamics. For microbiome research, this establishes a novel framework for host-microbe-microbe interactions where rare predators may exert disproportionate impacts on community assembly and dysbiosis pathogenesis. This work opens unprecedented opportunities for developing ecologically-informed therapeutics that harness natural predation to simultaneously combat multidrug-resistant infections while restoring microbiota homeostasis, positioning predatory bacteria as a cornerstone strategy for antimicrobial resistance management through ecological microbiota restoration.

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