Stability and vertical transmission of synthetic human gut microbiomes and effect of genetic background in mice

University Of Missouri-Columbia, Columbia MO

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Abstract

Applied Research section 1 – Project Summary Research performed using mouse models is often influenced by the resident gut microbiome (GM). Past research demonstrated the significant difference in composition of the GM in specific pathogen-free (SPF) mice from different suppliers, and the significant effects of those GMs on model phenotypes. To identify features of the GM associated with disease in humans, fecal microbiome transfer (FMT) of human fecal material into germ- free (GF) recipient mice is often performed. While potentially informative, use of native human samples presents multiple challenges including only partial knowledge of their composition, lack of uniformity, risk of pathogen or pathobiont exposure, and limited experimental tractability. Synthetic microbial communities made from a mixture of known bacterial isolates address these issues but typically fail to recapitulate the richness or structure of native human microbiomes. Recently, two synthetic human microbiomes were developed, each comprising over 100 bacterial isolates and thus reaching the same order of magnitude in richness as native microbiomes. These microbiomes, hCom1 and hCom2, share functional and compositional differences with supplier-origin SPF microbiomes and reach highly reproducible equilibrium in vitro and in vivo. While the value of these synthetic human microbiomes is immense, there are still several major knowledge gaps including; the long-term stability and vertical transmission of these microbiomes over multiple generations, the effect of genetic background on their composition, and the effect of these communities on baseline and disease-associated phenotypes. The long-term objectives of this research are to address those fundamental questions following reconstitution of germ-free Swiss Webster (SW) mice with hCom1 or hCom2. Aim 1 will test the stability and natural transmission of hCom1 and hCom2 across multiple generations of male and female mice, and the influence of those microbiomes on several baseline phenotypes in unmanipulated, wild-type mice. In Aim 2, SW mice colonized with hCom1 or hCom2 will be used as surrogate dams during embryo transfer rederivation of Non-obese diabetic (NOD) mice and C57BL/6J (B6) mice. Incidence of diabetes in NOD mice and severity of colitis in B6 mice administered dextran sodium sulfate (DSS) will be assessed in offspring colonized with hCom1 or hCom2, relative to mice colonized with suppler-origin SPF microbiomes. We hypothesize that hCom1 and hCom2 will transmit between parent and offspring mice in SW, NOD, and B6 mice, but that host genetic background will influence the relative proportions of individual bacteria in the gut. While we do not anticipate dramatically different phenotypes in hCom-colonized mice relative to traditional SPF mice, we do expect differences in disease severity between hCom1 and hCom2 mirroring the differences observed between different supplier-origin microbiomes. These synthetic human GMs combine complexity, control, and translatability of the microbiome used in mouse models, and the proposed experiments are ultimately intended to enable and inform their use among the biomedical research community.