Structural & functional consequences of chronic psychosocial stress on the microbiome & host
Introduction
There is abundant evidence demonstrating the adverse impact of stress on physiology and neurocognitive correlates during development and adulthood: trauma or abuse during early life increase the risk of psychiatric conditions and can impair the development of the stress response (Heim et al., 2008), while inadequate coping behavior contributes to the etiology of diseases such as gastrointestinal disorders and increased risk of depression (Dinan, 2005, Mayer, 2000). Amidst the efforts to elucidate the mechanisms underpinning this association, there has been a growing recognition of the importance of the microbiota to normal development and function of several physiological processes, including metabolism, immunity, and behavior. Indeed, so integral are these symbionts to host function that it has been suggested that almost all animals, including humans, should be viewed as multi-species organisms or “holobionts” (Gilbert et al., 2012).
The body of work demonstrating the systemic role of the microbiome, especially in neural development and function, is extensive. Disruption or absence of the microbiome impairs behavior and its development, leading to increased exploration, decreased apprehension, and impaired social behavior (Bercik et al., 2011, Desbonnet et al., 2014). Conversely, chronic administration of Lactobacillus rhamnosus (JB-1) alters GABAR expression in the brain, and reduces anxiety-like and depressive behavior (Bravo et al., 2011). Particularly, there is compelling evidence of bidirectional interaction between stress and the microbiome. Exposure to stress alters the structural composition of the intestinal microbiota (Bailey et al., 2011, O’Mahony et al., 2009), while germ-free (GF) status and intestinal colonization alter the developmental trajectory of the stress response (Neufeld et al., 2011, Sudo et al., 2004). Within the context of the holobiont paradigm, the influence exerted by these microorganisms on brain development and behavior is a consequence of the evolution of a multi-species organism. To provide clearer insight into the implications of the concept of the collective “self” for health and disease, and understand the functional relationship between the microbiota and stress-induced alterations, we need greater insight into the mechanisms, pathways, and consequences of communication along the microbiota-gut-brain axis.
Here, an anthropomorphic model is used to examine the impact of psychosocial stress on host-microbiota interactions, and the relationship between the microbiome and stress-induced behavioral deficits. We profile the community structure and species-level shifts in the intestinal microbiota, including in the relative abundance of Akkermancia muciniphilia and Coriobacteriaceae. These specific taxa have been previously reported to be associated with healthy and stress-exposed microbiome communities, respectively (Bendtsen et al., 2012, Everard et al., 2013). Accordingly, in an effort to investigate the use of specific microbial community markers to predict adverse consequences on the host, we examined whether such alterations are retained, amidst broader shifts in the microbiota, across experimental studies. We also examine the nature of the stress-induced dysbiosis—specifically, the Firmicutes/Bacteroidetes ratio, which signals the status of the human gut microbiota in models of obesity and antibiotic-induced dysbiosis (Mariat et al., 2009, Sanderson et al., 2006, Thompson et al., 2015).
Given evidence of immune-mediated signaling along the microbiota-gut-brain axis in the literature (Desbonnet et al., 2010, Forsythe et al., 2010), we profile the immunoregulatory and innate immune phenotype, as well as the function of the peripheral immune system. Moreover, using a computational approach, we address the biological pathways that may be driving the effects of the microbiome on brain and behavior by profiling the predicted functional implications of structural shifts in the microbiome.
Section snippets
Animals
Male C57BL/6 mice, eight-weeks old, and male CD-1 mice, retired breeders, were acquired from Charles River (Montreal, QC, Canada). All animals were allowed to acclimatize to the housing facility for seven days prior to beginning the experiment. Animals were housed in standard conditions (12-h light–dark (LD) cycle, lights on at 07:00) with ad libitum access to standard rodent chow and water. All experiments followed the guidelines of the Canadian Council on Animal Care and were approved by the
Exposure to chronic social defeat induces deficits in social and exploratory behavior
In order to characterize changes in the behavioral phenotype following exposure to chronic stress, animals were subjected to measures that evaluate social, exploratory, and anxiety-like behaviors. Socially defeated mice exhibited pronounced avoidance of a novel CD1 aggressor mouse during the aggressor interaction test, opting to spend the majority of the time in the non-interaction zone of the field (Fig. 1A; Welch-corrected t = 15.74, df = 27, P < 0.0001). Defeated mice also exhibited marked
Discussion
In this study, we offer a structural and functional analysis of the consequences of chronic social defeat stress the murine microbiome and the host. We demonstrate that psychosocial stress induces complex and nuanced OTU-level shifts in the structural composition of the intestinal microbiota, including changes in the relative abundance of microbial groups that are sensitive to the state of the host (Bendtsen et al., 2012, Everard et al., 2013); these shifts are associated with the
Conflict of interest
The authors declare no conflicts of interest.
Funding
This research was funded by a grant from the Office of Naval Research (#N00014-14-1-0787). The sponsor had no role in study design; the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.
Authors contribution
P.F., J.B., & A.B. conceptualized the study. P.F., J.B., A.B. & J.A.F. designed experiments. A.B. performed animal experiments. A.B. and M.F.M. prepared samples and carried out FACS analysis. M.G.S. performed 16S rRNA DNA sequencing. A.B. acquired and analyzed the data and wrote the initial draft of the manuscript. A.B., M.F.M., J.A.F., M.G.S., J.B., & P.F. contributed to data interpretation and revised the manuscript. All authors approved the final version of this article.
Acknowledgments
This project is funded by a grant from the Office of Naval Research (#N00014-14-1-0787). A.B. gratefully acknowledges funding support from the Canadian Institutes of Health Research (GSM-136180). P.F. is supported by a Career Award from the Department of Medicine, McMaster University. Equipment support was provided by funds from the Canadian Foundation for Innovation to J.A.F., M.G.S. is supported as a Canada Research Chair.
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