An adherent-invasive <i>Escherichia coli</i>-colonized mouse model to evaluate microbiota-targeting strategies in Crohn's disease

Sivignon, Adeline; Chervy, Mélissa; Chevarin, Caroline; Elia, Ragot; Billard, Elisabeth; Denizot, Jérémy; Barnich, Nicolas

doi:10.1242/dmm.049707

“…These two genes have been previously characterized in vivo and in vitro , and thus we reasoned that characterizing their phenotypes would allow us to benchmark our model against published in vivo and in vitro AIEC models. Prior studies show that the burden of AIEC LF82Δ fimH is significantly decreased at 2 and 10 dpi in two different mouse models that express mammalian CEACAM6 in the intestine (8, 57). Deletion of ibeA did not impact the burden of AIEC strain NRG857c in mice, although it did contribute to invasion and intracellular survival in vitro (20).…”

Section: Discussionmentioning

confidence: 99%

Colonization of larval zebrafish (Danio rerio) with adherent-invasiveEscherichia coliprevents recovery of the intestinal mucosa from drug-induced colitis

Flores,

Dutta,

Bosserman

et al. 2023

Preprint

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Inflammatory bowel disease (IBD) is a broad term for a range of chronic intestinal disorders, including Crohn’s disease and ulcerative colitis. The global prevalence of IBD is rising, with over one million patients affected in the US alone. Adherent-invasive E. coli (AIEC) is a pathobiont frequently found in IBD biopsies. AIEC adhere to and invade epithelial cells, and can survive inside phagocytes in vitro. However, how AIEC contribute to IBD in vivo remains unclear. Here, we established a larval zevbrafish (Danio rerio) model to study the interplay between pre-existing intestinal inflammation and AIEC colonization of the gut. We used the pro-inflammatory drug dextran sulfate sodium (DSS) to induce colitis. This was followed by food-borne infection of larvae with AIEC using the protozoan Paramecium caudatum, a natural prey, as a vehicle. We show that AIEC more robustly colonizes the zebrafish gut, and persists for longer, compared to non-pathogenic E. coli. In addition, DSS induced colitis increases both bacterial burden and persistence in the larval gut. We benchmark our model against existing rodent models using two mutants deficient in the known AIEC virulence factors FimH and IbeA, which have virulence defects in both rodent and the larval zebrafish model. Finally, we show that AIEC colonization exacerbates DSS induced colitis and prevents recovery from inflammation. In conclusion, we established a high-throughput, genetically tractable model to study AIEC–host interactions in the context of chronic inflammation.

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“…Both fimH and ibeA have been extensively characterized in vivo and in vitro , and thus we used them to benchmark our model against published in vivo and in vitro AIEC models. Deletion of fimH significantly decreased LF82 colonization in two different mouse models that express mammalian CEACAM6 in the intestine ( 8 , 56 ). Deletion of ibeA did not impact the burden of AIEC strain NRG857c in mice, although it did contribute to invasion and intracellular survival in vitro ( 20 ).…”

Section: Discussionmentioning

confidence: 99%

Colonization of larval zebrafish ( Danio rerio ) with adherent-invasive Escherichia coli prevents recovery of the intestinal mucosa from drug-induced enterocolitis

Flores,

Dutta,

Bosserman

et al. 2023

mSphere

2

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Inflammatory bowel disease (IBD) is a broad term for a range of chronic intestinal disorders, including Crohn’s disease and ulcerative colitis. The global prevalence of IBD is rising, with over one million patients affected in the United States alone. Adherent-invasive Escherichia coli (AIEC) is a pathobiont frequently found in IBD biopsies. AIEC adhere to and invade epithelial cells, and can survive inside phagocytes in vitro . However, how AIEC contribute to IBD in vivo remains unclear. Here, we established a larval zebrafish ( Danio rerio ) model to study the interplay between pre-existing intestinal inflammation and AIEC colonization of the gut. We used the pro-inflammatory drug dextran sulfate sodium (DSS) to induce intestinal inflammation. This was followed by food-borne infection of larvae with AIEC using the protozoan Paramecium caudatum , a natural prey, as a vehicle. We show that AIEC more robustly colonize the zebrafish gut and are cleared slower than non-pathogenic E. coli . In addition, DSS-induced enterocolitis increases bacterial burden and decreases bacterial clearance in the larval gut. We benchmark our model against existing rodent models using two mutants deficient in the known AIEC virulence factors FimH and IbeA, which have virulence defects in both rodent and the larval zebrafish model. Finally, we show that AIEC colonization exacerbates DSS-induced enterocolitis and prevents recovery from inflammation-induced damage. In conclusion, we established a high-throughput, genetically tractable model to study AIEC-host interactions in the context of pre-existing inflammation. IMPORTANCE Although inflammatory bowel diseases are on the rise, what factors influence IBD risk and severity, and the underlying mechanisms remain to be fully understood. Although host genetics, microbiome, and environmental factors have all been shown to correlate with the development of IBD, cause and effect are difficult to disentangle in this context. For example, AIEC is a known pathobiont found in IBD patients, but it remains unclear if gut inflammation during IBD facilitates colonization with AIEC, or if AIEC colonization makes the host more susceptible to pro-inflammatory stimuli. It is critical to understand the mechanisms that contribute to AIEC infections in a susceptible host in order to develop successful therapeutics. Here, we show that the larval zebrafish model recapitulates key features of AIEC infections in other animal models and can be utilized to address these gaps in knowledge.

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“…Phage therapy is a biological treatment against bacterial infection; however, it targets only a limited number of bacterial strains. An interesting study showed that LF82-P2, LF82-P6, and LF82-P8 phages were effective against AIEC in a mouse model [67]. Galtier et al [68] found that a single day of oral treatment with bacteriophages significantly decreased intestinal colonization by AIEC strain LF82.…”

Section: -Phage Therapymentioning

confidence: 99%

Antibiotic Therapy for Active Crohn’s Disease Targeting Pathogens: An Overview and Update

Iaquinto,

Mazzarella,

Sellitto

et al. 2024

Antibiotics

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Crohn’s disease (CD) is a multifactorial chronic disorder that involves a combination of factors, including genetics, immune response, and gut microbiota. Therapy includes salicylates, immunosuppressive agents, corticosteroids, and biologic drugs. International guidelines do not recommend the use of antibiotics for CD patients, except in the case of septic complications. Increasing evidence of the involvement of gut bacteria in this chronic disease supports the rationale for using antibiotics as the primary treatment for active CD. In recent decades, several pathogens have been reported to be involved in the development of CD, but only Escherichia coli (E. coli) and Mycobacterium avium paratubercolosis (MAP) have aroused interest due to their strong association with CD pathogenesis. Several meta-analyses have been published concerning antibiotic treatment for CD patients, but randomized trials testing antibiotic treatment against E. coli and MAP have not shown prolonged benefits and have generated conflicting results; several questions are still unresolved regarding trial design, antibiotic dosing, the formulation used, the treatment course, and the outcome measures. In this paper, we provide an overview and update of the trials testing antibiotic treatment for active CD patients, taking into account the role of pathogens, the mechanisms by which different antibiotics act on harmful pathogens, and antibiotic resistance. Finally, we also present new lines of study for the future regarding the use of antibiotics to treat patients with active CD.

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An adherent-invasive Escherichia coli-colonized mouse model to evaluate microbiota-targeting strategies in Crohn's disease

Cited by 9 publications

References 32 publications

Colonization of larval zebrafish (Danio rerio) with adherent-invasiveEscherichia coliprevents recovery of the intestinal mucosa from drug-induced colitis

Colonization of larval zebrafish (Danio rerio) with adherent-invasiveEscherichia coliprevents recovery of the intestinal mucosa from drug-induced colitis

Colonization of larval zebrafish ( Danio rerio ) with adherent-invasive Escherichia coli prevents recovery of the intestinal mucosa from drug-induced enterocolitis

Antibiotic Therapy for Active Crohn’s Disease Targeting Pathogens: An Overview and Update

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