Abstract
The profound impact of the gut microbiome on host health has led to a revolution in biomedical research, motivating researchers from disparate fields to define the specific molecular mechanisms that mediate host-beneficial effects. The advent of genomic technologies allied to the use of model microbiomes in gnotobiotic mouse models has transformed our understanding of intestinal microbial ecology and the impact of the microbiome on the host. However, despite incredible advances, our understanding of the host-microbiome dialogue that shapes host physiology is still in its infancy. Progress has been limited by challenges associated with developing model systems that are both tractable enough to provide key mechanistic insights while also reflecting the enormous complexity of the gut ecosystem. Simplified model microbiomes have facilitated detailed interrogation of transcriptional and metabolic functions of the microbiome but do not recapitulate the interactions seen in complex communities. Conversely, intact complex communities from mice or humans provide a more physiologically relevant community type, but can limit our ability to uncover high-resolution insights into microbiome function. Moreover, complex microbiomes from lab-derived mice or humans often do not readily imprint human-like phenotypes. Therefore, improved model microbiomes that are highly defined and tractable, but that more accurately recapitulate human microbiome-induced phenotypic variation are required to improve understanding of fundamental processes governing host-microbiome mutualism. This improved understanding will enhance the translational relevance of studies that address how the microbiome promotes host health and influences disease states. Microbial exposures in wild mice, both symbiotic and infectious in nature, have recently been established to more readily recapitulate human-like phenotypes. The development of synthetic model communities from such “wild mice” therefore represents an attractive strategy to overcome the limitations of current approaches. Advances in microbial culturing approaches that allow for the generation of large and diverse libraries of isolates, coupled to ever more affordable large-scale genomic sequencing, mean that we are now ideally positioned to develop such systems. Furthermore, the development of sophisticated in vitro systems is allowing for detailed insights into host-microbiome interactions to be obtained. Here we discuss the need to leverage such approaches and highlight key challenges that remain to be addressed.
Highlights
As a species, humans are surrounded by and inhabited by trillions of microorganisms, encompassing bacteria, fungi, archaea, other eukaryotic organisms such as parasites and protists, as well as viruses (Gill et al, 2006; Parfrey et al, 2011; Hallen-Adams and Suhr, 2017; Koskinen et al, 2017; Nkamga et al, 2017; Gregory et al, 2020) that are collectively referred to as the microbiome
While the Specific Pathogen Free (SPF) mouse was adopted with the intention of allowing for more reproducible results, it has been shown that microbiome and phenotypic variability exists between SPF mouse colonies from commercial vendors, as SPF only determines what is excluded, but not what should be present (Smith et al, 2007; Ivanov et al, 2009; Denning et al, 2011; Rosshart et al, 2017)
In spite of all the advantages of the in vivo mouse models we describe, it is a system with limitations that demands alternative approaches that augment our understanding
Summary
Humans are surrounded by and inhabited by trillions of microorganisms, encompassing bacteria, fungi, archaea, other eukaryotic organisms such as parasites and protists, as well as viruses (Gill et al, 2006; Parfrey et al, 2011; Hallen-Adams and Suhr, 2017; Koskinen et al, 2017; Nkamga et al, 2017; Gregory et al, 2020) that are collectively referred to as the microbiome. Animal model systems have proven essential in determining causal roles for the microbiome in shaping disease susceptibility and facilitating the precise delineation of hostmicrobiome interactions that mediate these effects on host physiology As such, they remain an irreplaceable component of the microbiome researcher’s toolkit. It is increasingly clear that intestinal fungi, viruses, archaea, and other eukaryotic species can profoundly impact host phenotypes, such as promoting intestinal immune system maturation and regulating disease susceptibility, often able to imprint phenotypic responses equivalent to gut bacteria (Kernbauer et al, 2014; Chudnovskiy et al, 2016; Escalante et al, 2016; Lin et al, 2020; Yeung et al, 2020; Dallari et al, 2021) These agents do not act in isolation, and their direct or indirect interactions may regulate host health as has been demonstrated in murine models of inflammatory bowel disease (IBD) and parasitic infection (Cadwell et al, 2010; Hayes et al, 2010). While the SPF mouse was adopted with the intention of allowing for more reproducible results, it has been shown that microbiome and phenotypic variability exists between SPF mouse colonies from commercial vendors, as SPF only determines what is excluded, but not what should be present (Smith et al, 2007; Ivanov et al, 2009; Denning et al, 2011; Rosshart et al, 2017)
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