Rosshart SP, Vassallo BG, Angeletti D, Hutchinson DS, Morgan AP, Takeda K, Hickman HD, McCulloch JA, Badger JH, Ajami NJ, Trinchieri G, Pardo-Manuel de Villena F, Yewdell JW, Rehermann B. Wild Mouse Gut Microbiota Promotes Host Fitness and Improves Disease Resistance. Cell. 2017 Oct 17; PubMed.
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The University of Florida College of Medicine
Emory University
Emory University School of Medicine
Our understanding of complex disorders has been immeasurably advanced with the use of model organisms such as mice. The use of inbred strains maintained under highly controlled conditions necessarily limits potential variables that typically confound in vivo experimentation. In addition, recent years have seen the increasing realization that the gut microbiota can influence a wide range of host immune and homeostatic processes, and variations in microbiota community structure can have profound effects on experimental outcomes. Thus, laborious efforts, such as mice maintained in isolator facilities in a germ-free state or with a minimal defined (gnotobiotic) microbiota, have been touted as necessary controls to standardize and reduce the complexity of the murine microbiota in an effort to reduce this variable. However, this work by Rosshart et al. vividly illustrates a limitation of this trend.
The authors evaluated 101 wild-caught mice (Mus musculus domesticus) trapped from locations in the District of Columbia and Maryland. They took a comprehensive approach in comparing microbiota of numerous wild-type mice separated geographically and temporally and lab mice from different suppliers. They found that the microbiota compositions of different populations of wild-type mice were surprisingly similar and also distinct from those of lab mice. Specifically, taxonomic 16s analysis of ileocecal microbiota from the animals revealed distinct grouping of the wild microbiomes relative to the microbiota of standard laboratory animals. Then they reconstituted pregnant germ-free laboratory mice with wild-mouse microbiota so that pups would experience microbe-mediated effects before birth as well as vertical transmission of the microbiota. This design helps alleviate concerns about abnormal immune development that arise when adult germ-free mice are colonized and then evaluated in experiments. Importantly, transfer of the wild murine microbiota into germ-free mice was shown to be stable across generations, retaining specific operational taxonomic units (OTUs) characteristic of wild or laboratory mice. This is intriguing given that the environmental conditions in which wild-mouse microbiomes developed were not recapitulated in the lab. Remarkably, these “wild-mouse microbiome-reconstituted” animals show markedly increased resistance to challenge with a mouse-adapted influenza virus as well as reduced-inflammation-associated neoplasia development (DSS-AOM model). The protective effects of wild-mouse microbiota were associated with abrogation of hyperinflammatory responses and immune-mediated damage, suggesting that the wild microbiota stimulates the effective activation of mechanisms which regulate the resolution of inflammatory responses and epithelial homeostasis.
In addition, it has been shown that pathogen exposure can alter immune activity in laboratory mice to more closely resemble that found in adult humans (Beura et al., 2016; Abolins et al., 2017; Reese et al., 2016), but a novel feature of this study was their use of wild-mouse microbiota that met typical specific pathogen-free facility standards. This specific pathogen-free wild microbiota clearly altered immune responses in recipient mice compared to a standard laboratory mouse microbiota. This wild-microbiota mouse model should be tested to see if its responses to such interventions as vaccinations or drugs recapitulate human responses more accurately than in typical laboratory mice, as has been shown for pathogen-exposed mice. If so, then this would present the exciting possibility that laboratory mouse models could be rendered more representative with immune responses that more closely resemble those in humans without the logistical challenges and experimental confounds associated with pathogen infections.
The implication of these observations is that a naturally occurring microbiota community structure (i.e., not selected for experimental convenience or rigor) has intrinsic benefits for the host, presumably as a result of longstanding mutual co-evolution. Additionally, these data suggest the search for beneficial members of the microbiota may find a productive source in previously understudied natural populations.
With regard to human populations, the data are consistent with current notions of the “hygiene hypothesis,” wherein many disorders of the modern human condition may result from divergence of our microbiota from that of people in traditional societies, whose diet and proximity to domestic animals supports a more ancestral and “wild like” microbiota.
References:
Beura LK, Hamilton SE, Bi K, Schenkel JM, Odumade OA, Casey KA, Thompson EA, Fraser KA, Rosato PC, Filali-Mouhim A, Sekaly RP, Jenkins MK, Vezys V, Haining WN, Jameson SC, Masopust D. Normalizing the environment recapitulates adult human immune traits in laboratory mice. Nature. 2016 Apr 28;532(7600):512-6. Epub 2016 Apr 20 PubMed.
Abolins S, King EC, Lazarou L, Weldon L, Hughes L, Drescher P, Raynes JG, Hafalla JC, Viney ME, Riley EM. The comparative immunology of wild and laboratory mice, Mus musculus domesticus. Nat Commun. 2017 May 3;8:14811. PubMed.
Reese TA, Bi K, Kambal A, Filali-Mouhim A, Beura LK, Bürger MC, Pulendran B, Sekaly RP, Jameson SC, Masopust D, Haining WN, Virgin HW. Sequential Infection with Common Pathogens Promotes Human-like Immune Gene Expression and Altered Vaccine Response. Cell Host Microbe. 2016 May 11;19(5):713-9. Epub 2016 Apr 20 PubMed.
View all comments by Andrew NeishThe Jackson Lab
Rosshart et al. have made a great contribution to our understanding of the role of gut microbiome in determining disease phenotypes in mouse models.
This work highlights the importance of reporting experimental details, and raises an issue that the field will need to address—if we want to simulate more natural microbiota in animal models, how can we standardize the bacterial gut microbiome so that work can be replicated?
Improved fitness due to a more natural microbiota could be either beneficial or detrimental, as a useful experimental disease model may lose its utility in a more “fit” model. For example, the typical lab mouse model of colitis-induced tumorogenesis in Figure 7B-D may be more useful for some experimental applications than the wild-mouse microbiome-reconstituted model that gets far fewer tumors.
In terms of models of neurodegeneration of interest to the Alzforum audience, there already have been a few papers showing a role for microbiome in altering disease-like phenotypes (e.g. Sampson et al., 2016), and I expect we will see many more soon. Given our growing appreciation for the role of neuroinflammation in neurodegenerative diseases, it will be essential to understand both the mechanisms that are common and those that are specific to each.
In all cases we need to pay more attention to the choice and health status of our experimental models, ideally be able to both replicate results in more than one distinct model and in a single model at more than one experimental site, and be careful not to generalize our interpretation of results too broadly. We need to work toward using multiple complementary model systems that take into account not only disease-related genetic variants but also genetic and epigenetic context and environmental and health/microbiome status. There is also a lot of work to be done to understand how genetic context interacts with environment to alter the microbiome. Of course, these are all logistically complex and make projects more costly, so funding agencies need to appreciate the importance of supporting these efforts.
References:
Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, Challis C, Schretter CE, Rocha S, Gradinaru V, Chesselet MF, Keshavarzian A, Shannon KM, Krajmalnik-Brown R, Wittung-Stafshede P, Knight R, Mazmanian SK. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease. Cell. 2016 Dec 1;167(6):1469-1480.e12. PubMed.
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