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Title: Acute Infectious Gastroenteritis Potentiates a Crohn's Disease Pathobiont to Fuel Ongoing Inflammation in the Post-Infectious Period}
Article:
Abstract:
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.
Introduction:
Inflammation in Crohn’s disease( CD) can involve the small and large bowel and is accompanied by changes in the microbial composition and distribution at these sites[1–3]. Clinical observations have been consistent in finding increased numbers of bacteria associated with the epithelial mucosa in Crohn’s patients, including members of the Enterobacteriaceae that are enriched in virulence and secretion pathways as determined by culture and molecular methods[4–6]. Although a detailed microbiologic analysis of this population has not been done and their role in disease has not been described, these data imply that the environment favoring bacterial expansion at the mucosal surface is inflammatory in nature and that this particular bacterial bloom is of pathogenic significance in the disease. Among bacteria linked to CD, adherent-invasive E. coli( AIEC) have emerged as having likely pathogenic significance. Since its discovery in 1998[7], several laboratories have reported a higher prevalence of AIEC in CD patients compared to healthy subjects and confirmed their pro-inflammatory potential[5, 8, 9]. Although AIEC share evolutionary ancestry with extraintestinal pathogenic E. coli[10], their infection biology suggests a pathobiont lifestyle that is distinct from frank enteric pathogens. A growing body of work indicates that different host environments can select for AIEC. For example, AIEC isolated from adults[5, 10–12], children[13, 14], and companion animals[15] exhibit a degree of genetic diversity that has made it difficult to discriminate this E. coli pathotype at a molecular level. AIEC can also be isolated from seemingly healthy individuals( albeit much less frequently than in CD), implying that interactions between AIEC and other microbes or host genes might be needed to elicit their pathogenic character. CD is more common in individuals exposed to acute infectious gastroenteritis caused by Salmonella and other enteric pathogens, sometimes with onset times on the order of years after the infectious episode[16–18]. The mechanistic basis for this long-term risk association following an acute event lasting ~2 weeks is unresolved, however one possibility is that resident gut microbes could perpetuate inflammatory reactions in the post-infectious period. This relates to several clinical observations[19, 20]. First, acute infectious gastroenteritis increases the risk of CD onset, often through an intermediate state of post-infectious-irritable bowel syndrome( IBS)[16–18]; second, gastroenteritis causes inflammation that selectively disrupts the resident intestinal microbiota in favor of some members of the Enterobacteriaceae[21, 22]; and third, intestinal infections with frank enteric pathogens have been implicated as a probable cause of relapse in inflammatory bowel disease( IBD) patients[23, 24]. We developed two new models to study comorbidity following acute infectious gastroenteritis in hosts colonized by an AIEC pathobiont from a Crohn’s disease patient. We show that AIEC-colonized mice that develop infectious gastroenteritis in response to either Salmonella enterica serovar Typhimurium( S. Typhimurium), or the attaching and effacing mouse pathogen Citrobacter rodentium, have a worsened outcome compared to AIEC-naïve animals exposed to the same infection stimuli. Bacterial gastroenteritis induced an AIEC bloom in the ileum and colon accompanied by an increase in disease severity. The increase in disease severity strictly correlated with this AIEC bloom because blocking AIEC expansion by sensitizing the bacteria to host defenses ameliorated disease status, providing a direct correlation between AIEC and host damage. These data are the first to show that acute gastroenteritis modulates AIEC levels in the colonized gut, and establish AIEC as an active yet tractable disease modifier in response to acute infectious gastroenteritis.
Discussion:
Despite decades of research, a unifying etiologic pathway to CD has been elusive. Genome-wide association studies have now revealed close to 200 IBD susceptibility alleles. However, in aggregate these loci account for only ~30% of CD heritability with a dominant contribution of three common NOD2 variants[39]. The discordance rate of CD among monozygotic twins also highlights the importance of environmental factors in disease pathogenesis[30]. Thus, while genetic susceptibility remains a key consideration for risk assessment it must be considered among a constellation of other additive risk factors. Recent attention has turned towards a ‘multi-hit’ model of CD pathogenesis that reflects this conceptual framework[19]. In this model the cumulative effects of several factors presents a ‘tipping point’ between homeostasis and protracted intestinal inflammation, a concept that was recently validated in a mouse model involving a genetic TLR1 deficiency[40]. Another risk factor in this multi-hit framework is acute infectious gastroenteritis caused by exposure to relatively common zoonotic pathogens[16–18]. Although such infections tend to be self-limiting, these episodes confer long-term risk of CD well into the post-infectious period, suggesting a sustained imbalance of intestinal homeostasis. Given that healthy subjects can carry AIEC as part of the microbial composition in their gut[41], one possibility is that infectious gastroenteritis elicits the pathogenic character of quiescent AIEC that subsequently exacerbates host damage. Indeed, our report suggests that Crohn’s-associated AIEC exploit the unique host environment imprinted by the action of pathogenic microbes that have been linked to short- and long-term risk of IBD. AIEC expansion and host damage following S. Typhimurium gastroenteritis required the resistance of AIEC to host defense peptides. One of the first CD susceptibility genes was NOD2/CARD15, in which loss-of-function mutations increase the risk of disease[42, 43]. Early studies reported that loss of NOD2 signaling produced defects in the manufacture of some human defensins by Paneth cells and offered a mechanism to account for the altered microbial composition in CD. However these data have been challenged based on human[44, 45] and better-controlled mouse studies[46] that show antimicrobial peptide production by Paneth cells appears to be independent of NOD2 status. This is more in keeping with observations that many antimicrobial peptides are instead increased in inflamed Crohn’s lesions[47, 48]. It also implies that bacteria living at the mucosal surface with an active role in Crohn’s pathogenesis would require mechanisms to resist antimicrobial peptides in the inflamed gut, at least in some patients. Indeed, we found that when AIEC were rendered susceptible to host defense peptides they could no longer expand following infectious gastroenteritis and produced moderating effects on disease severity. Previous work found that, among AIEC isolates from IBD patients that were phenotypically resistant to antimicrobial peptides( MIC >8 μg/ml), many of these strains contained at least one resistance gene from the arlABC locus[34]. Interestingly, none of the E. coli isolated from healthy subjects were resistant to host defense peptides, suggesting that the host might imprint a selective pressure for the evolution of such traits. Whether this selective host environment arises as a result of genetics, the endogenous microbiota, or even xenobiotics used in the management of CD remains an open question. The fact that AIEC are genetically diverse[12] suggests that a number of different founder populations are capable of giving rise to this pathobiont type and understanding what shapes this evolutionary trajectory will be an important topic for future studies. The effect of infectious gastroenteritis on eliciting the pathobiont characteristics of AIEC is consistent with other inflammation models using either chemical colitis or host genetic deficiencies. For example, mouse colon injured by the sodium salt of dextran sulfate produces pan-colitis that is further aggravated by AIEC strain LF82[49, 50]. A genetic deficiency model using TLR5-/- mice that can develop spontaneous colitis showed that transient colonization by AIEC strain LF82 promoted the development of a colitic microbiota that persisted after AIEC was cleared by the host[51, 52]. At this time, we cannot rule out wholesale changes in the microbiota of our co-infection model in favor of a more proinflammatory composition, however our data suggests this is not the main driver. The expansion of tissue-associated AIEC and its direct correlation with pathological outcomes in our study is consistent with human studies showing that the severity of ileal CD is directly correlated with the tissue-associated E. coli burden[3–5]. Thus, if global changes in the microbiota are present, it does not alter the disease course in the absence of AIEC expansion. In summary, exposure to pathogens that trigger acute gastroenteritis creates an environment favorable to colonization by AIEC in otherwise uncontrived hosts. AIEC can be detected in a proportion of healthy individuals, which bears relevance to the finding that infectious gastroenteritis in the general population is a risk factor for IBD. This work provides rationale for the development of novel diagnostic methods that could help identify AIEC-colonized individuals who may be at greater risk following an episode of acute gastroenteritis. It is also possible that infectious gastroenteritis in humans renders them more susceptible to de novo acquisition of AIEC through vulnerabilities created by the disruption of the resident microbiota, a loss of so-called colonization resistance. If so, efforts to understand the provenance of AIEC and its transmission mechanisms should be intensified. Finally, the often long prodromal period for CD[53] and the observed latency between recovery from acute gastroenteritis and CD onset may create intervention opportunities to mitigate or neutralize disease risk in a subset of individuals.
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 .