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      Heterogeneity of the gut microbiome in mice: guidelines for optimizing experimental design

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          Abstract

          Targeted manipulation of the gut flora is increasingly being recognized as a means to improve human health. Yet, the temporal dynamics and intra- and interindividual heterogeneity of the microbiome represent experimental limitations, especially in human cross-sectional studies. Therefore, rodent models represent an invaluable tool to study the host–microbiota interface. Progress in technical and computational tools to investigate the composition and function of the microbiome has opened a new era of research and we gradually begin to understand the parameters that influence variation of host-associated microbial communities. To isolate true effects from confounding factors, it is essential to include such parameters in model intervention studies. Also, explicit journal instructions to include essential information on animal experiments are mandatory. The purpose of this review is to summarize the factors that influence microbiota composition in mice and to provide guidelines to improve the reproducibility of animal experiments.

          Abstract

          Given the unmet need for standardizing the experimental work flow related to gut microbial research in animals, guidelines are required to isolate true effects from confounding factors.

          Abstract

          Graphical Abstract Figure.

          Given the unmet need for standardizing the experimental work flow related to gut microbial research in animals, guidelines are required to isolate true effects from confounding factors.

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          Most cited references 112

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          Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis.

          Toll-like receptors (TLRs) play a crucial role in host defense against microbial infection. The microbial ligands recognized by TLRs are not unique to pathogens, however, and are produced by both pathogenic and commensal microorganisms. It is thought that an inflammatory response to commensal bacteria is avoided due to sequestration of microflora by surface epithelia. Here, we show that commensal bacteria are recognized by TLRs under normal steady-state conditions, and this interaction plays a crucial role in the maintenance of intestinal epithelial homeostasis. Furthermore, we find that activation of TLRs by commensal microflora is critical for the protection against gut injury and associated mortality. These findings reveal a novel function of TLRs-control of intestinal epithelial homeostasis and protection from injury-and provide a new perspective on the evolution of host-microbial interactions.
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            The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis.

            Decreased expression of the Nlrp3 protein is associated with susceptibility to Crohn's disease. However, the role of Nlrp3 in colitis has not been characterized. Nlrp3 interacts with the adaptor protein ASC to activate caspase-1 in inflammasomes, which are protein complexes responsible for the maturation and secretion of interleukin-1beta (IL-1beta) and IL-18. Here, we showed that mice deficient for Nlrp3 or ASC and caspase-1 were highly susceptible to dextran sodium sulfate (DSS)-induced colitis. Defective inflammasome activation led to loss of epithelial integrity, resulting in systemic dispersion of commensal bacteria, massive leukocyte infiltration, and increased chemokine production in the colon. This process was a consequence of a decrease in IL-18 in mice lacking components of the Nlrp3 inflammasome, resulting in higher mortality rates. Thus, the Nlrp3 inflammasome is critically involved in the maintenance of intestinal homeostasis and protection against colitis.
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              Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis.

              Intestinal homeostasis is critical for efficient energy extraction from food and protection from pathogens. Its disruption can lead to an array of severe illnesses with major impacts on public health, such as inflammatory bowel disease characterized by self-destructive intestinal immunity. However, the mechanisms regulating the equilibrium between the large bacterial flora and the immune system remain unclear. Intestinal lymphoid tissues generate flora-reactive IgA-producing B cells, and include Peyer's patches and mesenteric lymph nodes, as well as numerous isolated lymphoid follicles (ILFs). Here we show that peptidoglycan from Gram-negative bacteria is necessary and sufficient to induce the genesis of ILFs in mice through recognition by the NOD1 (nucleotide-binding oligomerization domain containing 1) innate receptor in epithelial cells, and beta-defensin 3- and CCL20-mediated signalling through the chemokine receptor CCR6. Maturation of ILFs into large B-cell clusters requires subsequent detection of bacteria by toll-like receptors. In the absence of ILFs, the composition of the intestinal bacterial community is profoundly altered. Our results demonstrate that intestinal bacterial commensals and the immune system communicate through an innate detection system to generate adaptive lymphoid tissues and maintain intestinal homeostasis.
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                Author and article information

                Journal
                FEMS Microbiol Rev
                FEMS Microbiol. Rev
                femsre
                femsre
                FEMS Microbiology Reviews
                Oxford University Press
                0168-6445
                1574-6976
                30 August 2015
                January 2016
                30 August 2015
                : 40
                : 1
                : 117-132
                Affiliations
                [1 ]Department of Gastroenterology, Ghent University, B-9000 Ghent, Belgium
                [2 ]Inflammation Research Center, VIB, B-9052 Ghent, Belgium
                [3 ]Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium
                [4 ]Center for the Biology of Disease, VIB, B-3000 Leuven, Belgium
                [5 ]Department Microbiology and Immunology, KU Leuven, B-3000 Leuven, Belgium
                [6 ]Methusalem Program, Ghent University, B-9000 Ghent, Belgium
                Author notes
                [* ] Corresponding author: Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, B-9052 Ghent, Belgium. Tel: +32(0)93313710; E-mail: Peter.Vandenabeele@ 123456irc.vib-ugent.be
                []Equal contribution.
                Article
                10.1093/femsre/fuv036
                4703068
                26323480
                © FEMS 2015.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com

                Page count
                Pages: 16
                Product
                Categories
                Review Article
                Custom metadata
                January 2016

                Microbiology & Virology

                microbiota, confounding factors, animal facility, animal models, microbiome

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