Enteric infections during colitis and the effect of immunoregulatory interleukin-4-treated- macrophages

Abstract

Inflammatory bowel disease (IBD) is an umbrella term for chronic inflammatory conditions in the gastrointestinal tract and patients exhibit dysregulated immune systems and weakened mucosal defenses. Clinical studies indicate that enteric infections are highly prevalent in IBD populations, but the mechanism for this susceptibility is not well studied. Additionally, certain therapeutics were associated with increased risk of infection, highlighting the need for novel therapeutics that preserve antimicrobial defense and efficacy in managing IBD. Interleukin-4-treated macrophages (M(IL-4))s show promising anti-colitic effects in murine models of chemically-induced colitis. However, their effect during enteric infection, specifically in active colitis, remains elusive. This thesis aimed to investigate the increased susceptibility to enteric infections during active colitis and determine whether M(IL-4) macrophages maintain an anti-colitic effect during infectious colitis. Citrobacter rodentium (CR) is a murine attaching and effacing pathogen that mimics enteropathogenic and enterohemorrhagic E. coli in humans. Using a novel co-treatment model of dextan sulfate sodium (DSS) and CR, we demonstrated increased bacterial load in mice with DSS-induced colitis during the establishment phase of CR infection. This correlated with increased bacterial colonization of the distal colon in co-treated mice during CR establishment. Investigation of the mucus layer revealed increased goblet cell numbers and alterations in mucin glycosylation in co-treated groups that could provide CR with a better niche for establishment and colonization. Clearance was unaffected by DSS colitis with both groups expelling the bacteria by day 25. However, colitis resolution was impaired as co-treated mice still exhibited elevated fecal lipocalin-2, MPO, and disease activity. Treatment with M(IL-4)s neither alleviated nor exacerbated CR infection during colitis, but still retained anti-colitic effects, showing reduced colon shortening and improved intestinal barrier integrity compared with untreated groups. M(IL-4) delivery into CR-infected mice also did not impact CR infection kinetics and inflammation with both groups showing similar shedding, dissemination, and clearance. Altogether, this thesis explores a novel murine model to study enteric infection during active colitis and demonstrates that active colitis predisposes mice to increased CR colonization while prolonging colitis resolution. M(IL-4) treatment did not improve nor aggravate CR infection, highlighting its potential as a therapeutic for IBD.