The interplay between microbiome dynamics and pathogen dynamics in a murine model of<i>Clostridium difficile</i>Infection

Reeves, Angela E.; Theriot, Casey M.; Bergin, Ingrid L.; Huffnagle, Gary B.; Schloss, Patrick D.; Young, Vincent B.

doi:10.4161/gmic.2.3.16333

Cited by 250 publications

(316 citation statements)

References 65 publications

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“…[15][16][17][18] This creates difficulties in interpreting the results of studies investigating models of pathogenesis where it is not possible to differentiate between the initial microbiome of those animals that succumb to disease and those that do not. Furthermore, with only pre-and post-treatment time points, it is not possible to ascertain whether the post-treatment sample represented a stable condition or whether the community was still experiencing perturbations imposed by the treatment.…”

Section: Introductionmentioning

confidence: 99%

Stabilization of the murine gut microbiome following weaning

et al. 2012

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Section: Introductionmentioning

confidence: 99%

Stabilization of the murine gut microbiome following weaning

et al. 2012

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“…2). 14,15,[18][19][20][21][22][23][24] The US Food and Drug Administration (USFDA) already aims to limit the use of antibiotics to reduce the number of Clostridium difficile infections in the USA. 25 Since PPIs are often prescribed, and these prescriptions renewed, without evidence-based indication, a reduction of unnecessary PPI use could also contribute to this aim.…”

Section: Consequences Of Gut Microbiota Changes Caused By Medicationmentioning

confidence: 99%

The influence of proton pump inhibitors and other commonly used medication on the gut microbiota

et al. 2017

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Proton pump inhibitors (PPIs), used to treat gastro-esophageal reflux and prevent gastric ulcers, are among the most widely used drugs in the world. The use of PPIs is associated with an increased risk of enteric infections. Since the gut microbiota can, depending on composition, increase or decrease the risk of enteric infections, we investigated the effect of PPI-use on the gut microbiota. We discovered profound differences in the gut microbiota of PPI users: 20% of their bacterial taxa were statistically significantly altered compared with those of non-users. Moreover, we found that it is not only PPIs, but also antibiotics, antidepressants, statins and other commonly used medication were associated with distinct gut microbiota signatures. As a consequence, commonly used medications could affect how the gut microbiota resist enteric infections, promote or ameliorate gut inflammation, or change the host's metabolism. More studies are clearly needed to understand the role of commonly used medication in altering the gut microbiota as well as the subsequent health consequences.KEYWORDS gut microbiota; medication; proton pump inhibitors Proton pump inhibitors affect the gut microbiotaProton pump inhibitors (PPIs), used to treat gastroesophageal reflux and to prevent gastric ulcers, are among the most commonly used drugs in the world.1,2 In the Netherlands, one PPI alone (omeprazole) was the fourth most prescribed drug in 2015. In observational studies, the use of PPIs has been associated with an increased risk of enteric infections caused by Clostridium difficile, Salmonella spp., Shigella spp and Campylobacter spp. [3][4][5] Since the gut microbiota can, depending on composition, increase or decrease the risk of enteric infections, we investigated the effect of PPI use on the gut microbiota. 6 Using the 16S rRNA sequences of stool samples from 1815 individuals spanning 3 independent cohorts, we observed profound changes in the gut microbiota of PPI users. In PPI users the relative abundance of 20% of the bacterial taxa, whereof 18 bacterial families, was statistically significantly different (either increased or decreased) compared with abundances in samples from non-users. 6 Concurrently with our research, other research groups were also investigating the influence of PPIs on the gut microbiota. A small intervention study was published a few months before ours and a similar observational study was published in the same issue of Gut. 7,8 In Table 1, the bacterial alterations associated with PPI use from all 3 studies are presented at the family level. There are many similarities between the results of all 3 studies and, when associations at different taxonomical levels are taken into account (e.g. the decrease of order Clostridiales and increases of class Gammaproteobacteria and order Actinomycetales), a consistent profile of alterations in gut microbiota associated with PPI use emerges. Other commonly used drugs and the gut microbiotaTo ensure that our observed alterations in gut microbiota associated wi...

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“…Pretreatment of mice with a cocktail of five antibiotics, followed by an intraperitoneal injection of clindamycin changes the gut microbiota and renders animals susceptible to colonization with C. difficile vegetative cells. 15,16 Unlike the uniformly fatal hamster model, disease severity can vary with the size of the bacterial inoculum administered and the strain of C. difficile used for infection. 16 We recently demonstrated that the broad-spectrum cephalosporin cefoperazone is sufficient to make mice susceptible to infection with C. difficile strain VPI 10463.…”

Section: Introductionmentioning

confidence: 99%

“…16 We recently demonstrated that the broad-spectrum cephalosporin cefoperazone is sufficient to make mice susceptible to infection with C. difficile strain VPI 10463. 15 This C. difficile strain produces high amounts of toxin and experimental infection with this strain is lethal in hamsters and, with increased dose, in mice. [16][17][18] Since we demonstrated a dose-response to inoculum size with VPI 10463 in cefoperazone-treated mice, we hypothesized that this model could be used as a platform to examine differential virulence of C. difficile strains and isolates.…”

Section: Introductionmentioning

confidence: 99%

Cefoperazone-treated mice as an experimental platform to assess differential virulence ofClostridium difficilestrains

et al. 2011

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The toxin-producing bacterium C. difficile is the leading cause of antibiotic-associated colitis, with an estimated 500,000 cases C. difficile infection (CDI) each year in the US with a cost approaching 3 billion dollars. Despite the significance of CDI, the pathogenesis of this infection is still being defined. The recent development of tractable murine models of CDI will help define the determinants of C. difficile pathogenesis in vivo. To determine if cefoperazone-treated mice could be utilized to reveal differential pathogenicity of C. difficile strains, 5-8 week old C57BL/6 mice were pretreated with a 10 d course of cefoperazone administered in the drinking water. Following a 2-d recovery period without antibiotics, the animals were orally challenged with C. difficile strains chosen to represent the potential range of virulence of this organism from rapidly fatal to nonpathogenic. Animals were monitored for loss of weight and clinical signs of colitis. At the time of harvest, C. difficile strains were isolated from cecal contents and the severity of colitis was determined by histopathologic examination of the cecum and colon. Cefoperazone treated mice challenged with C. difficile strains VPI 10463 and BI1 exhibited signs of severe colitis while infection with 630 and F200 was subclinical. This increased clinical severity was correlated with more severe histopathology with significantly more edema, inflammation and epithelial damage encountered in the colons of animals infected with VPI 10463 and BI1. Disease severity also correlated with levels of C. difficile cytotoxic activity in intestinal tissues and elevated blood neutrophil counts. Cefoperazone treated mice represent a useful model of C. difficile infection that will help us better understand the pathogenesis and virulence of this re-emerging pathogen.

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The interplay between microbiome dynamics and pathogen dynamics in a murine model ofClostridium difficileInfection

Cited by 250 publications

References 65 publications

Stabilization of the murine gut microbiome following weaning

Stabilization of the murine gut microbiome following weaning

The influence of proton pump inhibitors and other commonly used medication on the gut microbiota

Cefoperazone-treated mice as an experimental platform to assess differential virulence ofClostridium difficilestrains

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