Outer membrane barrier impairment by deletion reduces gut colonization of Crohn's disease pathobiont .

Adherent-invasive (AIEC) has been implicated in the aetiology of Crohn's disease (CD), a chronic inflammatory disorder of the gastrointestinal tract. The presence of , including AIEC, is heightened in the intestines of CD patients. Therefore, inhibiting AIEC colonization in the gastrointestinal tract could be a promising therapeutic intervention for CD. This study aims to assess the potential of EnvC as a novel therapeutic target, examining how disrupting EnvC activity through the deletion of the gene decreases AIEC gut colonization levels. EnvC serves as a catalyst for peptidoglycan (also called murein) amidases, facilitating bacterial cell division. An AIEC mutant lacking the gene exhibited impaired cell division. Furthermore, deletion led to a diminished outer membrane barrier, as seen in our finding that the mutant became susceptible to vancomycin. Finally, we found that the mutant is impaired in competitive gut colonization in a dysbiotic mouse model. The colonization defects might be attributable to reduced resistance to colonic bile acids, as evidenced by our finding that increased colonic levels of bile acids inhibited the colonization of the gastrointestinal tract by AIEC strains. The present findings suggest that targeting bacterial cell division through the inhibition of EnvC activity could represent a promising intervention for CD.