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. 2018 Jul 4;9(4):374-381.
doi: 10.1080/19490976.2017.1421888. Epub 2018 Apr 19.

Inflammasomes Make the Case for Littermate-Controlled Experimental Design in Studying Host-Microbiota Interactions

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Free PMC article

Inflammasomes Make the Case for Littermate-Controlled Experimental Design in Studying Host-Microbiota Interactions

Michail Mamantopoulos et al. Gut Microbes. .
Free PMC article

Abstract

Several human diseases are thought to evolve due to a combination of host genetic mutations and environmental factors that include alterations in intestinal microbiota composition termed dysbiosis. Although in some cases, host genetics may shape the gut microbiota and enable it to provoke disease, experimentally disentangling cause and consequence in such host-microbe interactions requires strict control over non-genetic confounding factors. Mouse genetic studies previously proposed Nlrp6/ASC inflammasomes as innate immunity regulators of the intestinal ecosystem. In contrast, using littermate-controlled experimental setups, we recently showed that Nlrp6/ASC inflammasomes do not alter the gut microbiota composition. Our analyses indicated that maternal inheritance and long-term separate housing are non-genetic confounders that preclude the use of non-littermate mice when analyzing host genetic effects on intestinal ecology. Here, we summarize and discuss our gut microbiota analyses in inflammasome-deficient mice for illustrating the importance of littermate experimental design in studying host-microbiota interactions.

Keywords: ASC; DSS colitis; Nlrp6; caspase-1; dysbiosis; gut microbiota; inflammasomes; innate immunity; interleukin; littermates.

Figures

Figure 1.
Figure 1.
Littermate-controlled, F2 and ex-GF experimental approaches to evaluate host genetic impacts on the gut microbiota. (A) Breeding scheme used for generating Nlrp6−/− and Nlrp6+/+ littermates from non-littermate Nlrp6−/− and WT mice with a suspected Nlrp6-imposed dysbiosis, with generation of F2 mice for evaluating potential host genetic effects during pre-weaning time. Neither the Nlrp6−/− and Nlrp6+/+ littermates, nor the F2 Nlrp6−/− and Nlrp6+/+ mice reproduced the dysbiosis observed in non-littermate Nlrp6−/− and WT mice. (B) Breeding scheme used to generate ex-GF ASC−/− and ASC+/+ littermates from a GF ASC−/− male and an SPF WT female, in which the latter was the sole gut microbiota donor. Ex-GF ASC−/− and ASC+/+ littermates were allowed to colonize their intestines naturally after birth, and did not show differential gut microbiota compositions.

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