A Microbe Associated with Sleep Revealed by a Novel Systems Genetic Analysis of the Microbiome in Collaborative Cross Mice

Bubier, Jason A.; Philip, Vivek M.; Quince, Christopher; Campbell, James H.; Zhou, Yanjiao; Vishnivetskaya, Tatiana A.; Duvvuru, Suman; Blair, Rachael Hageman; Ndukum, Juliet; Donohue, Kevin D.; Foster, Carmen M.; Mellert, David J.; Weinstock, George M.; Culiat, Cymbeline T.; O’Hara, Bruce F.; Palumbo, Anthony V.; Podar, Mircea; Chesler, Elissa J.

doi:10.1534/genetics.119.303013

Cited by 23 publications

(33 citation statements)

References 55 publications

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“…model, we identified a range of microbial profiles associated with specific genotypes, suggesting that PWD alleles at specific loci modulate gut microbiome composition. This notion is supported by previous studies demonstrating a strong divergence between gut microbiomes of B6 and PWK/PhJ mice (a close relative of the PWD strain) (80), and strong genetic effects on the microbiome composition in Collaborative Cross mice, which carry B6 and PWK/PhJ alleles (81). Nonetheless, our experiments were not designed to exclude potential founder/strain isolation effects on the microbiome that can be prevalent in mouse studies (82,83), and we cannot rule out a contribution of such effects to the observed microbiome diversity of our consomic strains.…”

Section: Discussionsupporting

confidence: 76%

Interactions between host genetics and gut microbiota determine susceptibility to CNS autoimmunity

Montgomery

Künstner

Kennedy

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. The etiology of MS is multifactorial, with disease risk determined by genetics and environmental factors. An emerging risk factor for immune-mediated diseases is an imbalance in the gut microbiome. However, the identity of gut microbes associated with disease risk, their mechanisms of action, and the interactions with host genetics remain obscure. To address these questions, we utilized the principal autoimmune model of MS, experimental autoimmune encephalomyelitis (EAE), together with a genetically diverse mouse model representing 29 unique host genotypes, interrogated by microbiome sequencing and targeted microbiome manipulation. We identified specific gut bacteria and their metabolic functions associated with EAE susceptibility, implicating short-chain fatty acid metabolism as a key element conserved across multiple host genotypes. In parallel, we used a reductionist approach focused on two of the most disparate phenotypes identified in our screen. Manipulation of the gut microbiome by transplantation and cohousing demonstrated that transfer of these microbiomes into genetically identical hosts was sufficient to modulate EAE susceptibility and systemic metabolite profiles. Parallel bioinformatic approaches identified Lactobacillus reuteri as a commensal species unexpectedly associated with exacerbation of EAE in a genetically susceptible host, which was functionally confirmed by bacterial isolation and commensal colonization studies. These results reveal complex interactions between host genetics and gut microbiota modulating susceptibility to CNS autoimmunity, providing insights into microbiome-directed strategies aimed at lowering the risk for autoimmune disease and underscoring the need to consider host genetics and baseline gut microbiome composition.

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Section: Discussionsupporting

confidence: 76%

Interactions between host genetics and gut microbiota determine susceptibility to CNS autoimmunity

Montgomery

Künstner

Kennedy

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Comprehensive gene mapping studies of behavioral, physiological, circadian, and molecular phenotypes, as well as microbial abundance, conducted in a genetically diverse Collaborative Cross (CC; see Table 1 for a detailed description) mouse colony (Bubier et al, 2020), reported 41 disease-related behavioral and physiological phenotypes associated with microbial abundance and with sleep phenotypes. Over half of them ( 22) included differential abundance of Odoribacter spp.…”

Section: Alterations In Sleep-wake Cyclesmentioning

confidence: 99%

Circadian rhythms and the gut microbiome synchronize the host’s metabolic response to diet

et al. 2021

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The molecular circadian clock and symbiotic host-microbe relationships both evolved as mechanisms that enhance metabolic responses to environmental challenges. The gut microbiome benefits the host by breaking down diet-derived nutrients indigestible by the host and generating microbiota-derived metabolites that support host metabolism. Similarly, cellular circadian clocks optimize organismal physiology to the environment by influencing the timing and coordination of metabolic processes. Host-microbe interactions are influenced by dietary quality and timing, as well as daily light/dark cycles that entrain circadian rhythms in the host. Together, the gut microbiome and the molecular circadian clock play a coordinated role in neural processing, metabolism, adipogenesis, inflammation, and disease initiation and progression. This review examines the bidirectional interactions between the circadian clock, gut microbiota, and host metabolic systems and their effects on obesity and energy homeostasis. Directions for future research and the development of therapies that leverage these systems to address metabolic disease are highlighted.

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“…This resource has been used to identify novel candidate genes and variants associated with drug-induced adverse effects (32,33), responses to pollutants (34), and respiratory innate immunity (35)(36)(37). Additionally, the CC has been used to study transcriptional correlates of disease features (38)(39)(40). Thus, this population is appropriate for understanding genetic contributions to complex disease phenotypes and dissecting causal mechanisms of O3 toxicity.…”

Section: Introductionmentioning

confidence: 99%

Integrative phenotypic and genomic analyses reveal strain-dependent responses to acute ozone exposure and their associations with airway macrophage transcriptional activity

Tovar

Crouse

et al. 2021

Preprint

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Acute ozone (O3) exposure is associated with multiple adverse cardiorespiratory outcomes, the severity of which varies across human populations and rodent models from diverse genetic backgrounds. However, molecular determinants of response, including biomarkers that distinguish which individuals will develop more severe injury and inflammation (i.e., high responders), are poorly characterized. Here, we exposed adult, female and male mice from 6 strains, including 5 Collaborative Cross (CC) strains, to filtered air (FA) or 2 ppm O3 for 3 hours, and measured several inflammatory and injury parameters 21 hours later. Additionally, we collected airway macrophages and performed RNA-seq analysis to investigate influences of strain, treatment, and strain-by-treatment interactions on gene expression as well as transcriptional correlates of lung phenotypes. Animals exposed to O3 developed airway neutrophilia and lung injury, with varying degrees of severity. We identified many genes that were altered by O3 exposure across all strains, and examination of genes whose expression was influenced by strain-by-treatment interactions revealed prominent differences in response between the CC017/Unc and CC003/Unc strains, which were low- and high-responders, respectively (as measured by cellular inflammation and injury). Further investigation of this contrast indicated that baseline gene expression differences likely contribute to their divergent post-O3 exposure transcriptional responses. We also observed alterations in chromatin accessibility that differed by strain and with strain-by-treatment interactions, lending further plausibility that baseline differences can modulate post-exposure responses. Together, these results suggest that aspects of the respiratory response to O3 exposure may be mediated through altered airway macrophage transcriptional signatures, and further confirms the importance of gene-by-environment interactions in mediating differential responsiveness to environmental agents.

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A Microbe Associated with Sleep Revealed by a Novel Systems Genetic Analysis of the Microbiome in Collaborative Cross Mice

Cited by 23 publications

References 55 publications

Interactions between host genetics and gut microbiota determine susceptibility to CNS autoimmunity

Interactions between host genetics and gut microbiota determine susceptibility to CNS autoimmunity

Circadian rhythms and the gut microbiome synchronize the host’s metabolic response to diet

Integrative phenotypic and genomic analyses reveal strain-dependent responses to acute ozone exposure and their associations with airway macrophage transcriptional activity

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