Citrobacter rodentium Relies on Commensals for Colonization of the Colonic Mucosa

Mullineaux-Sanders, Caroline; Collins, James W.; Ruano-Gallego, David; Levy, Maayan; Pevsner‐Fischer, Meirav; Glegola-Madejska, Izabela; Sagfors, Agnes; Wong, Joshua L. C.; Elinav, Eran; Crepin, Valérie F.; Frankel, Gad

doi:10.1016/j.celrep.2017.11.086

Cited by 42 publications

(49 citation statements)

References 35 publications

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“…Analogous to results from Nunez and colleagues attained in germfree mice and antibiotic treated mice model, C rodentium that persists in the lumen does not express its defined virulence genes and, accordingly does not appear to elicit gut inflammation [9,29]. Yet, as shown herein, such persisting C. rodentium was still associated with a phenotype, namely that of exacerbating insulin resistance induced by WSD.…”

Section: Discussionsupporting

confidence: 77%

Western-style diet impedes colonization and clearance of gut bacterial pathogens

Gewirtz

Zou

Zhao³

et al. 2020

Preprint

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Western-style diet (WSD), which is high in fat and low in fiber, lacks nutrients to support gut microbiota. Consequently, WSD promotes microbiota encroachment and reduces microbiota density, potentially influencing colonization resistance, immune system readiness, and, consequently host defense against pathogenic bacteria. Additionally, the low-nutrient colonic environment resulting from WSD might impact bacterial pathogens. Hence, we examined the impact of WSD on infection and colitis in response to gut bacterial pathogens. Mice fed grain-based chow (GBC), WSD, or various versions thereof, were orally infected with Citrobacter rodentium or C. difficile. Colonization and its consequences, including inflammation and death were monitored. We observed that WSD delayed Citrobacter growth, reduced its virulence gene expression and ameliorated inflammation. However, while GBC-fed mice uniformly cleared Citrobacter and were impervious to subsequent Citrobacter challenges, most WSD-fed mice remained chronically infected with Citrobacter while those that cleared it were highly prone to re-infection. Such persistent proneness to Citrobacter infection did not reflect reduced immune responsiveness but rather reflected reduced colonization resistance likely from the low microbiota density resulting from WSD feeding. While persistent Citrobacter infection did not cause overt inflammation, it was associated with low-grade inflammation in colon and adipose tissue that was associated with insulin resistance. An analogous pattern was seen in response to C. difficile with WSD resulting in delayed colonization and mortality while enriching WSD with fiber hastened colonization but afforded clearance and survival. Thus, altering microbiota via diet can profoundly impact the course and consequence of infection following exposure to gut bacterial pathogens.

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Section: Discussionsupporting

confidence: 77%

Western-style diet impedes colonization and clearance of gut bacterial pathogens

Gewirtz

Zou

Zhao³

et al. 2020

Preprint

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“…To examine whether the observed shifts in the susceptibility of our mutants could be accounted for by a shift in commensal microbiota we analyzed its composition in fecal matter derived from uninfected and infected mice using a proteomic approach. We restricted our analyses to the percentile representation of the bacterial phyla of Firmicutes and Becteroidetes since these are the most predominant in the mouse intestine ( 56 – 58 ), and correlated our measurements with the representation of C. rodentium itself since its colonizing properties alters the ratio of Firmicutes to Bacteroidetes (F/B ratio; Figure 3E ). In our analysis we could not identify any changes in F/B ratio either in IEC-HuRko or in M-HuRko mice; this suggests that their cell-restricted deletion does not alter significantly the composition of the commensal microbiota.…”

Section: Resultsmentioning

confidence: 99%

Divergent Innate and Epithelial Functions of the RNA-Binding Protein HuR in Intestinal Inflammation

Christodoulou-Vafeiadou

Ioakeimidis

Ανδρεάδου

et al. 2018

Front. Immunol.

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HuR is an abundant RNA-binding protein acting as a post-transcriptional regulator of many RNAs including mRNAs encoding inflammatory mediators, cytokines, death signalers and cell cycle regulators. In the context of intestinal pathologies, elevated HuR is considered to enhance the stability and the translation of pro-tumorigenic mRNAs providing the rationale for its pharmacological targeting. However, HuR also possesses specific regulatory functions for innate immunity and cytokine mRNA control which can oppose intestinal inflammation and tumor promotion. Here, we aim to identify contexts of intestinal inflammation where the innate immune and the epithelial functions of HuR converge or diverge. To address this, we use a disease-oriented phenotypic approach using mice lacking HuR either in intestinal epithelia or myeloid-derived immune compartments. These mice were compared for their responses to (a) Chemically induced Colitis; (b) Colitis- associated Cancer (CAC); (c) T-cell mediated enterotoxicity; (d) Citrobacter rodentium-induced colitis; and (e) TNF-driven inflammatory bowel disease. Convergent functions of epithelial and myeloid HuR included their requirement for suppressing inflammation in chemically induced colitis and their redundancies in chronic TNF-driven IBD and microbiota control. In the other contexts however, their functions diversified. Epithelial HuR was required to protect the epithelial barrier from acute inflammatory or infectious degeneration but also to promote tumor growth. In contrast, myeloid HuR was required to suppress the beneficial inflammation for pathogen clearance and tumor suppression. This cellular dichotomy in HuR's functions was validated further in mice engineered to express ubiquitously higher levels of HuR which displayed diminished pathologic and beneficial inflammatory responses, resistance to epithelial damage yet a heightened susceptibility to CAC. Our study demonstrates that epithelial and myeloid HuR affect different cellular dynamics in the intestine that need to be carefully considered for its pharmacological exploitation and points toward potential windows for harnessing HuR functions in intestinal inflammation.

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“…In order to determine whether this fitness defect of ΔpduA-J was a result of the inability to use 1,2-propanediol as an energy source or a signal for T3SS regulation, we compared colonization dynamics of mice infected with C. rodentium P ler -const (a strain constitutively expressing the T3SS through a single base pair deletion in the −30 residue of the ler promoter) and a ΔpduA-J P ler -const derivative 54 . Colonization of mice ( n = 10) by C. rodentium P ler -const followed comparable dynamics as the WT for the duration of the infection.…”

Section: Resultsmentioning

confidence: 99%

Host-associated niche metabolism controls enteric infection through fine-tuning the regulation of type 3 secretion

et al. 2018

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Niche-adaptation of a bacterial pathogen hinges on the ability to recognize the complexity of signals from the environment and integrate that information with the regulation of genes critical for infection. Here we report the transcriptome of the attaching and effacing pathogen Citrobacter rodentium during infection of its natural murine host. Pathogen gene expression in vivo was heavily biased towards the virulence factor repertoire and was found to be co-ordinated uniquely in response to the host. Concordantly, we identified the host-specific induction of a metabolic pathway that overlapped with the regulation of virulence. The essential type 3 secretion system and an associated suite of distinct effectors were found to be modulated co-ordinately through a unique mechanism involving metabolism of microbiota-derived 1,2-propanediol, which dictated the ability to colonize the host effectively. This study provides novel insights into how host-specific metabolic adaptation acts as a cue to fine-tune virulence.

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Citrobacter rodentium Relies on Commensals for Colonization of the Colonic Mucosa

Cited by 42 publications

References 35 publications

Western-style diet impedes colonization and clearance of gut bacterial pathogens

Western-style diet impedes colonization and clearance of gut bacterial pathogens

Divergent Innate and Epithelial Functions of the RNA-Binding Protein HuR in Intestinal Inflammation

Host-associated niche metabolism controls enteric infection through fine-tuning the regulation of type 3 secretion

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