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

Abstract

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.