Phage-steering permits antibody-mediated clearance of E. coli K1 from the gut

E. coli strains expressing the capsule serotype K1 (E. coli K1) are prevalent causes of neonatal sepsis and meningitis. The gut microbiota of healthy adults is a natural reservoir of E. coli K1, from where they can spread to extra-intestinal sites or transmit from mother to infant during birth. Correspondingly, shifting gut colonization from potentially pathogenic E. coli strains to more benign strains would reduce disease risk. Here we leverage knowledge of selective pressures exerted by bacteriophage and mucosal antibodies to limit gut colonization by E. coli K1 and to prevent its transmission. K1-specific bacteriophages (phages) rapidly drive a within-host evolution of capsule-less mutants with exposed surface O-antigens. These mutants become susceptible to vaccine-induced intestinal IgA targeting the bacterial O-antigen, allowing competitive exclusion by the probiotic strain E. coli Nissle. When translated to a murine vertical transmission model, 77% of pups were protected from transmission of E. coli K1 when the mother was vaccinated and treated with phages, whereas E. coli K1 was detected in most pups by day 10 of life if the mother was treated with vaccination or phage-therapy alone. Although the huge diversity of E. coli makes generalization challenging, combining vaccination and phage-steering represents a promising approach for further exploration in eliminating infectious reservoirs.