Reducing versus Embracing Variation as Strategies for Reproducibility: The Microbiome of Laboratory Mice

Witjes, Vera M; Boleij, Annemarie; Halffman, Willem

doi:10.3390/ani10122415

Cited by 22 publications

(19 citation statements)

References 76 publications

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“…The work presented here has empirical value in clarifying that macronutrient-matched pulse-free versus pulse-containing diets can be expected to differentially impact the gut microbiome and that pulse-type is an important variable that needs to be considered in both the design and interpretation of human studies. However, while advancing the concept of a pulse-induced ecosystem, it should be anticipated that the three components of the ecosystem will be populated by different microbial taxa in results emerging from different studies, and particularly those reported by different laboratories, in part due to factors such as a source of animals and differences among studies in animal husbandry practices [67]. Our data imply that the positive effects of pulse consumption on health may, in part, be mediated by the gut microbiota based on the magnitude of their pulse-driven community differences despite the obesogenic environment.…”

Section: Discussionmentioning

confidence: 99%

Compositional Changes of the High-Fat Diet-Induced Gut Microbiota upon Consumption of Common Pulses

et al. 2021

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The gut microbiome is involved in the host’s metabolism, development, and immunity, which translates to measurable impacts on disease risk and overall health. Emerging evidence supports pulses, i.e., grain legumes, as underutilized nutrient-dense, culinarily versatile, and sustainable staple foods that promote health benefits through modulating the gut microbiota. Herein, the effects of pulse consumption on microbial composition in the cecal content of mice were assessed. Male mice were fed an obesogenic diet formulation with or without 35% of the protein component comprised by each of four commonly consumed pulses—lentil (Lens culinaris L.), chickpea (Cicer arietinum L.), common bean (Phaseolus vulgaris L.), or dry pea (Pisum sativum L.). Mice consuming pulses had distinct microbial communities from animals on the pulse-free diet, as evidenced by β-diversity ordinations. At the phylum level, animals consuming pulses showed an increase in Bacteroidetes and decreases in Proteobacteria and Firmicutes. Furthermore, α-diversity was significantly higher in pulse-fed animals. An ecosystem of the common bacteria that were enhanced, suppressed, or unaffected by most of the pulses was identified. These compositional changes are accompanied by shifts in predicted metagenome functions and are concurrent with previously reported anti-obesogenic physiologic outcomes, suggestive of microbiota-associated benefits of pulse consumption.

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Section: Discussionmentioning

confidence: 99%

Compositional Changes of the High-Fat Diet-Induced Gut Microbiota upon Consumption of Common Pulses

et al. 2021

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“…Altered intestinal bacterial loads in the mice do not account for the differences in RVwa replication, as no differences were found in bacterial numbers in the feces from groups that substantially differed in RVwa infection. It has been discussed that variations in the microbiome of experimental animals at different laboratories may affect mice phenotypes, which can be at the basis of reproducibility issues [23]. This situation would have minor effects in our case, as we showed that the sole fact of depleting the microbiota with antibiotics allowed RVwa replication.…”

Section: Discussionmentioning

confidence: 61%

Microbiota Depletion Promotes Human Rotavirus Replication in an Adult Mouse Model

et al. 2021

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Intestinal microbiota-virus-host interaction has emerged as a key factor in mediating enteric virus pathogenicity. With the aim of analyzing whether human gut bacteria improve the inefficient replication of human rotavirus in mice, we performed fecal microbiota transplant (FMT) with healthy infants as donors in antibiotic-treated mice. We showed that a simple antibiotic treatment, irrespective of FMT, resulted in viral shedding for 6 days after challenge with the human rotavirus G1P[8] genotype Wa strain (RVwa). Rotavirus titers in feces were also significantly higher in antibiotic-treated animals with or without FMT but they were decreased in animals subject to self-FMT, where a partial re-establishment of specific bacterial taxons was evidenced. Microbial composition analysis revealed profound changes in the intestinal microbiota of antibiotic-treated animals, whereas some bacterial groups, including members of Lactobacillus, Bilophila, Mucispirillum, and Oscillospira, recovered after self-FMT. In antibiotic-treated and FMT animals where the virus replicated more efficiently, differences were observed in gene expression of immune mediators, such as IL1β and CXCL15, as well as in the fucosyltransferase FUT2, responsible for H-type antigen synthesis in the small intestine. Collectively, our results suggest that antibiotic-induced microbiota depletion eradicates the microbial taxa that restrict human rotavirus infectivity in mice.

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“…In this context, Wuerbel et al proposed to intentionally introduce a certain level of controlled variation, to test a phenotype for its robustness against natural confounders and therefore increase the translational value for further clinical studies [219]. An excellent review published by Witjes et al discussed the pros and cons of standardization in the context of microbiome variation and concluded that standardization has to be increased when researchers conduct fundamental studies, especially those who aim at identifying disease mechanisms, to reduce study confounders, whereas more translational studies require robustness tests using mice with different microbiomes to ensure generalization and to increase the external validity of study results [220]. Possible solutions for inducing variation are either the intentional diversification of the microbiome using rather extreme measures such as the re-wilding of laboratory rodents (see Section 6.2.2) or using the microbiome as a co-factor in scientific studies (see Section 6.2.3), e.g., in multi-center studies.…”

Section: Measure To Ensure "Validity"mentioning

confidence: 99%

“…Since reproducibility is closely related to research validity, it can be seen as a measure for the generalizability and translational value of results [217], thus determining relevance of findings [218]. Re-enhancing the level of microbiological standardization increases the so-called "internal validity", which can be achieved by accounting for reciprocal host-microbiome interactions aiming at minimizing variation due to microbiological confounders [220,221]. However, the factors influencing the animal's microbiome are countless and range from housing-related factors such as food, water, caging systems, bedding material (and of course their decontaminative treatments such as autoclavation, irradiation or acidification) to host-related factors such as the animal's genetics, age and gender.…”

Section: Standardizing the Microbiomementioning

confidence: 99%

Health Monitoring of Laboratory Rodent Colonies—Talking about (R)evolution

Buchheister

Bleich

2021

Animals

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The health monitoring of laboratory rodents is essential for ensuring animal health and standardization in biomedical research. Progress in housing, gnotobiotic derivation, and hygienic monitoring programs led to enormous improvement of the microbiological quality of laboratory animals. While traditional health monitoring and pathogen detection methods still serve as powerful tools for the diagnostics of common animal diseases, molecular methods develop rapidly and not only improve test sensitivities but also allow high throughput analyses of various sample types. Concurrently, to the progress in pathogen detection and elimination, the research community becomes increasingly aware of the striking influence of microbiome compositions in laboratory animals, affecting disease phenotypes and the scientific value of research data. As repeated re-derivation cycles and strict barrier husbandry of laboratory rodents resulted in a limited diversity of the animals’ gut microbiome, future monitoring approaches will have to reform—aiming at enhancing the validity of animal experiments. This review will recapitulate common health monitoring concepts and, moreover, outline strategies and measures on coping with microbiome variation in order to increase reproducibility, replicability and generalizability.

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Reducing versus Embracing Variation as Strategies for Reproducibility: The Microbiome of Laboratory Mice

Cited by 22 publications

References 76 publications

Compositional Changes of the High-Fat Diet-Induced Gut Microbiota upon Consumption of Common Pulses

Compositional Changes of the High-Fat Diet-Induced Gut Microbiota upon Consumption of Common Pulses

Microbiota Depletion Promotes Human Rotavirus Replication in an Adult Mouse Model

Health Monitoring of Laboratory Rodent Colonies—Talking about (R)evolution

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