An ubiquitous antibacterial toxin from human gut bacteria engenders neonatal colonization advantage

Bacteroides fragilis is a common member of the human colonic microbiota. In children, the B. fragilis Type 6 Secretion System (T6SS) has been suggested to mediate dominance between coexisting strains. We sequenced nearly 900 clinical isolates and characterized their T6SS toxin repertoire. The T6SS effector Bte3 was identified as one of the most prevalent effectors within this human isolate cohort. Bte3 exhibited the ability to intoxicate both B. fragilis and Enterobacteriaceae in vitro, and was defined as a periplasmic-intoxicating effector that employs previously unknown adaptor proteins for its secretion. The role of bte3 in early life competition was interrogated via a murine model in which neonates were exposed upon birth to two T6SS-isogenic strains. We observed that T6SS-engineered strains and human isolates containing bte3-based toxin combinations displaced competing B. fragilis strains unless these strains manifest immunity to bte3. These studies suggest that the landscape of T6SS effectors in the human population may be shaped not only by temporal exposure to distinct strains, but by potency of effector function. Our work underscores the relevance of T6SS diversity in B. fragilis early life competition and provides a potential roadmap to design microbial interventions in the context of neonatal acquisition of colonic commensals.