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Crohn’s disease (CD) is a chronic inflammatory condition of diverse etiology. Exposure to foodborne pathogens causing acute gastroenteritis produces a long-term risk of CD well into the post-infectious period but the mechanistic basis for this ongoing relationship to disease onset is unknown. We developed two novel models to study the comorbidity of acute gastroenteritis caused by Salmonella Typhimurium or Citrobacter rodentium in mice colonized with adherent-invasive Escherichia coli (AIEC), a bacterial pathobiont linked to CD. Here, we show that disease activity in the post-infectious period after gastroenteritis is driven by the tissue-associated expansion of the resident AIEC pathobiont, with an attendant increase in immunopathology, barrier defects, and delays in mucosal restitution following pathogen clearance. These features required AIEC resistance to host defense peptides and a fulminant inflammatory response to the enteric pathogen. Our results suggest that individuals colonized by AIEC at the time of acute infectious gastroenteritis may be at greater risk for CD onset. Importantly, our data identify AIEC as a tractable disease modifier, a finding that could be exploited in the development of therapeutic interventions following infectious gastroenteritis in at-risk individuals., Author Summary Western societies have a disproportionately high rate of inflammatory bowel disease (IBD), with growing incidence especially in the adolescent population. A large body of evidence supports the view that bacteria in the gut participate in the pathophysiology of human bowel diseases. The unifying concept is chronic inflammation that is driven by microbial stimulation of the mucosal immune system. However, the mechanisms by which pathogenic or commensal microbes work in concert with each other and with host responses to perpetuate this inflammation is not well known. Adherent-invasive E. coli (AIEC) are Crohn’s disease (CD)-associated bacteria that are implicated in disease pathology. AIEC are pro-inflammatory and may play a central role in maintaining chronic inflammation in response to other CD risk factors, such as acute infectious gastroenteritis. Here, we show that indeed, acute infectious gastroenteritis creates an inflammatory environment in the gut that drives AIEC expansion and worsens disease severity. The increase in disease severity strictly correlates with this AIEC bloom because blocking this bloom by sensitizing AIEC to host defenses also improves the health status of the host. The long time period between recovery from acute gastroenteritis and new onset CD may allow for targeted interventions to mitigate the risk of CD in AIEC-positive individuals.

Crohn's disease (CD) is a chronic inflammatory condition of diverse etiology. Exposure to foodborne pathogens causing acute gastroenteritis produces a long-term risk of CD well into the post-infectious period but the mechanistic basis for this ongoing relationship to disease onset is unknown. We developed two novel models to study the comorbidity of acute gastroenteritis caused by Salmonella Typhimurium or Citrobacter rodentium in mice colonized with adherent-invasive Escherichia coli (AIEC), a bacterial pathobiont linked to CD. Here, we show that disease activity in the post-infectious period after gastroenteritis is driven by the tissue-associated expansion of the resident AIEC pathobiont, with an attendant increase in immunopathology, barrier defects, and delays in mucosal restitution following pathogen clearance. These features required AIEC resistance to host defense peptides and a fulminant inflammatory response to the enteric pathogen. Our results suggest that individuals colonized by AIEC at the time of acute infectious gastroenteritis may be at greater risk for CD onset. Importantly, our data identify AIEC as a tractable disease modifier, a finding that could be exploited in the development of therapeutic interventions following infectious gastroenteritis in at-risk individuals.