The gut microbiome diversity of Clostridioides difficile-inoculated mice treated with vancomycin and fidaxomicin

Yamaguchi, Tetsuo; Konishi, Hiroe; Aoki, Kotaro; Ishii, Yoshikazu; Chono, Koji; Tateda, Kazuhiro

doi:10.1016/j.jiac.2019.12.020

Cited by 25 publications

(24 citation statements)

References 33 publications

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“…We obtained C57BL/6 mice from 6 different sources: two colonies from the University of Michigan that were split from each other in 2010 (the Young and Schloss lab colonies) and four commercial vendors: the Jackson Laboratory, Charles River Laboratories, Taconic Biosciences, and Envigo (which was formerly Harlan). These 4 vendors were chosen because they are commonly used for murine CDI studies (25,(33)(34)(35)(36)(37)(38)(39). Two experiments were conducted, approximately 3 months apart.…”

Section: Resultsmentioning

confidence: 99%

The Initial Gut Microbiota and Response to Antibiotic Perturbation Influence Clostridioides difficile Clearance in Mice

Tomkovich

Stough

Bishop

et al. 2020

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The gut microbiota has a key role in determining susceptibility to Clostridioides difficile infections (CDIs). However, much of the mechanistic work examining CDIs in mouse models uses animals obtained from a single source. We treated mice from 6 sources (2 University of Michigan colonies and 4 commercial vendors) with clindamycin, followed by a C. difficile challenge, and then measured C. difficile colonization levels throughout the infection. The microbiota were profiled via 16S rRNA gene sequencing to examine the variation across sources and alterations due to clindamycin treatment and C. difficile challenge. While all mice were colonized 1 day postinfection, variation emerged from days 3 to 7 postinfection with animals from some sources colonized with C. difficile for longer and at higher levels. We identified bacteria that varied in relative abundance across sources and throughout the experiment. Some bacteria were consistently impacted by clindamycin treatment in all sources of mice, including Lachnospiraceae, Ruminococcaceae, and Enterobacteriaceae. To identify bacteria that were most important to colonization regardless of the source, we created logistic regression models that successfully classified mice based on whether they cleared C. difficile by 7 days postinfection using community composition data at baseline, post-clindamycin treatment, and 1 day postinfection. With these models, we identified 4 bacterial taxa that were predictive of whether C. difficile cleared. They varied across sources (Bacteroides) or were altered by clindamycin (Porphyromonadaceae) or both (Enterobacteriaceae and Enterococcus). Allowing for microbiota variation across sources better emulates human interindividual variation and can help identify bacterial drivers of phenotypic variation in the context of CDIs. IMPORTANCE Clostridioides difficile is a leading nosocomial infection. Although perturbation to the gut microbiota is an established risk, there is variation in who becomes asymptomatically colonized, develops an infection, or has adverse infection outcomes. Mouse models of C. difficile infection (CDI) are widely used to answer a variety of C. difficile pathogenesis questions. However, the interindividual variation between mice from the same breeding facility is less than what is observed in humans. Therefore, we challenged mice from 6 different breeding colonies with C. difficile. We found that the starting microbial community structures and C. difficile persistence varied by the source of mice. Interestingly, a subset of the bacteria that varied across sources were associated with how long C. difficile was able to colonize. By increasing the interindividual diversity of the starting communities, we were able to better model human diversity. This provided a more nuanced perspective of C. difficile pathogenesis.

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Section: Resultsmentioning

confidence: 99%

The Initial Gut Microbiota and Response to Antibiotic Perturbation Influence Clostridioides difficile Clearance in Mice

Tomkovich

Stough

Bishop

et al. 2020

mSphere

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“…Many newly developed therapeutic agents are aimed at preserving microbiota during CDI treatment to prevent disease recurrence; for this purpose, two major kinds of therapeutic strategy were investigated: first, the development of narrow-spectrum antimicrobial agents, such as fidaxomicin [ 66 , 67 , 68 , 69 ], ridinidazole [ 70 , 71 ], or cadazolid [ 72 , 73 ]; second, developing antimicrobial agents specifically targeting some distinct structure of C. difficile , such as anti-sense antimicrobial agents [ 74 , 75 ], anti-toxin antibodies [ 76 , 77 ], and agents targeting the pathway of bacterial fatty acid synthesis [ 78 ].…”

Section: Therapeutic Agents Preserving Microbiota During C Difficile Infection Treatmentmentioning

confidence: 99%

“…Fidaxomicin, a minimally absorbed macrocyclic antibiotic, as well as vancomycin, are both drugs of choice for CDI treatment, but the former has less disturbance in the microbiota and, thus, is associated with less recurrent rates compared to vancomycin [ 9 , 66 , 67 , 68 , 69 ]. In the mice model, fidaxomicin reduced the proportion of Clostridial growth to a lesser extent, but increased that of Bacteroidia, and it resulted in less disturbance in microbiota diversity [ 66 ].…”

Section: Therapeutic Agents Preserving Microbiota During C Difficile Infection Treatmentmentioning

confidence: 99%

Application of Microbiome Management in Therapy for Clostridioides difficile Infections: From Fecal Microbiota Transplantation to Probiotics to Microbiota-Preserving Antimicrobial Agents

et al. 2021

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Oral vancomycin and metronidazole, though they are the therapeutic choice for Clostridioides difficile infections (CDIs), also markedly disturb microbiota, leading to a prolonged loss of colonization resistance to C. difficile after therapy; as a result, their use is associated with a high treatment failure rate and high recurrent rate. An alternative for CDIs therapy contains the delivery of beneficial (probiotic) microorganisms into the intestinal tract to restore the microbial balance. Recently, mixture regimens containing Lactobacillus species, Saccharomyces boulardii, or Clostridium butyricum have been extensively studied for the prophylaxis of CDIs. Fecal microbiota transplantation (FMT), the transfer of (processed) fecal material from healthy donors to patients for treating CDIs, combined with vancomycin was recommended as the primary therapy for multiple recurrent CDIs (rCDIs). Either probiotics or FMT have been utilized extensively in preventing or treating CDIs, aiming at less disturbance in the microbiota to prevent rCDIs after therapy cessation. Otherwise, many newly developed therapeutic agents have been developed and aim to preserve microbiota during CDI treatment to prevent disease recurrence and might be useful in clinical patients with rCDIs in the future.

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“…A pooled analysis of individual patient data from two randomized controlled trials demonstrated bovine lactoferrin supplementation protects against late-onset sepsis in infants < 1500 g, especially among infants not receiving human milk [62]. Study by using probiotic and lactoferrin prebiotic were administered in mice showed both Clostridioides difficile inoculation and treatment with vancomycin or fidaxomicin reduced microbiota diversity; however, dysbiosis associated with fidaxomicin was milder than with vancomycin [63]. The use of lactoferrin, or short peptide derivatives that retain the cationic N-terminal moiety that is essential for the anti-microbial and anti-inflammatory activity, may prove to be a promising versatile class of agents for managing the complications that arise from HSCT [64].…”

Section: Lactoferrinmentioning

confidence: 99%

Applications of gut microbiota in patients with hematopoietic stem-cell transplantation

Sun

Cao

et al. 2020

Exp Hematol Oncol

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Studies of the gut microbiota (GM) have demonstrated the close link between human wellness and intestinal commensal bacteria, which mediate development of the host immune system. The dysbiosis, a disruption of the microbiome natural balance, can cause serious health problems. Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) may cause significant changes in GM due to their underlying malignancies and exposure to extensive chemotherapy and systemic antibiotics, which may lead to different disorders. There are complex and multi-directional interactions among intestinal inflammation, GM and immune reactivity after HSCT. There is considerable effect of the human intestinal microbiome on clinical course following HSCT. Some bacteria in the intestinal ecosystem may be potential biomarkers or therapeutic targets for preventing relapse and improving survival rate after HSCT. Microbiota can be used as predictor of mortality in allo-HSCT. Two different strategies with targeted modulation of GM, preemptive and therapeutic, have been used for preventing or treating GM dysbiosis in patients with HSCT. Preemptive strategies include enteral nutrition (EN), prebiotic, probiotic, fecal microbiota transplantation (FMT) and antibiotic strategies, while therapeutic strategies include FMT, probiotic and lactoferrine usages. In this review, we summarize the advance of therapies targeting GM in patients with HSCT.

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The gut microbiome diversity of Clostridioides difficile-inoculated mice treated with vancomycin and fidaxomicin

Cited by 25 publications

References 33 publications

The Initial Gut Microbiota and Response to Antibiotic Perturbation Influence Clostridioides difficile Clearance in Mice

The Initial Gut Microbiota and Response to Antibiotic Perturbation Influence Clostridioides difficile Clearance in Mice

Application of Microbiome Management in Therapy for Clostridioides difficile Infections: From Fecal Microbiota Transplantation to Probiotics to Microbiota-Preserving Antimicrobial Agents

Applications of gut microbiota in patients with hematopoietic stem-cell transplantation

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