Phage endolysin enables targeted manipulation of the small intestinal microbiota and uncovers niche overlap between oral and butyrate-producing taxa

Small intestinal oral bacterial overgrowth (SIOBO) is associated with impaired nutrient absorption and is a key contributor to environmental enteric disorder (EED) and stunted child growth. Here, we explore the use of a phage-derived lysin as a precision antimicrobial to selectively target Streptococcus salivarius within complex microbial communities. Using a newly developed bioinformatic and wet-lab pipeline, we identified, cloned, and produced a prophage-encoded lysin from S. salivarius and demonstrated its potent and specific lytic activity against 49 S. salivarius strains isolated from stunted children, while sparing related species such as S. mitis , S. parasanguinis, and S. thermophilus . Application of the lysin to human stool-derived in vitro communities and to mice colonized with S. salivarius led to an approximate 2–3 log reduction in S. salivarius abundance while preserving overall bacterial community. We observed a negative correlation between S. salivarius and Coprococcus (now Allocoprococcus ) comes in vitro, and Eubacterium xylanophilum, Akkermansia, Lactobacillus and Ruminococcus in vivo. Spent-medium assays confirmed niche overlap between 10 clinical strains of S. salivarius and 28 taxa commonly recognized as butyrate producers. These results suggest that phage-derived lysins offer multiple benefits by selectively removing ectopically colonized oral taxa and indirectly promoting beneficial anaerobes.