Dataset Information

Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation.

ABSTRACT: The indigenous human microbiota is essential to the health of the host. Although the microbiota can be affected by many features of modern life, we know little about its responses to disturbance, especially repeated disturbances, and how these changes compare with baseline temporal variation. We examined the distal gut microbiota of three individuals over 10 mo that spanned two courses of the antibiotic ciprofloxacin, analyzing more than 1.7 million bacterial 16S rRNA hypervariable region sequences from 52 to 56 samples per subject. Interindividual variation was the major source of variability between samples. Day-to-day temporal variability was evident but constrained around an average community composition that was stable over several months in the absence of deliberate perturbation. The effect of ciprofloxacin on the gut microbiota was profound and rapid, with a loss of diversity and a shift in community composition occurring within 3-4 d of drug initiation. By 1 wk after the end of each course, communities began to return to their initial state, but the return was often incomplete. Although broadly similar, community changes after ciprofloxacin varied among subjects and between the two courses within subjects. In all subjects, the composition of the gut microbiota stabilized by the end of the experiment but was altered from its initial state. As with other ecosystems, the human distal gut microbiome at baseline is a dynamic regimen with a stable average state. Antibiotic perturbation may cause a shift to an alternative stable state, the full consequences of which remain unknown.

SUBMITTER: Dethlefsen L

PROVIDER: S-EPMC3063582 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation.

Dethlefsen Les L Relman David A DA

Proceedings of the National Academy of Sciences of the United States of America 20100916

The indigenous human microbiota is essential to the health of the host. Although the microbiota can be affected by many features of modern life, we know little about its responses to disturbance, especially repeated disturbances, and how these changes compare with baseline temporal variation. We examined the distal gut microbiota of three individuals over 10 mo that spanned two courses of the antibiotic ciprofloxacin, analyzing more than 1.7 million bacterial 16S rRNA hypervariable region sequen ...[more]

PMID: 20847294

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Project description:Diet plays an important role in shaping the structure and function of the gut microbiota. The microbes and microbial products in turn can influence various aspects of host physiology. One promising route to affect host function and restore health is by altering the gut microbiome using dietary intervention. The individuality of the microbiome may pose a significant challenge, so we sought to determine how different microbiotas respond to the same dietary intervention in a controlled setting. We modeled gut microbiotas from three healthy donors in germfree mice and defined compositional and functional alteration following a change in dietary microbiota-accessible carbohydrates (MACs). The three gut communities exhibited responses that differed markedly in magnitude and in the composition of microbiota-derived metabolites. Adjustments in community membership did not correspond to the magnitude of changes in the microbial metabolites, highlighting potential challenges in predicting functional responses from compositional data and the need to assess multiple microbiota parameters following dietary interventions. IMPORTANCE Dietary modification has long been used empirically to modify symptoms in inflammatory bowel disease, irritable bowel syndrome, and a diverse group of diseases with gastrointestinal symptoms. There is both anecdotal and scientific evidence to suggest that individuals respond quite differently to similar dietary changes, and the highly individualized nature of the gut microbiota makes it a prime candidate for these differences. To overcome the typical confounding factors of human dietary interventions, here we employ ex-germfree mice colonized by microbiotas of three different humans to test how different microbiotas respond to a defined change in carbohydrate content of diet by measuring changes in microbiota composition and function using marker gene-based next-generation sequencing and metabolomics. Our findings suggest that the same diet has very different effects on each microbiota's membership and function, which may in turn explain interindividual differences in response to a dietary ingredient.

Project description: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.

Dataset Information

Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation.

Publications

Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation.

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