Response of the commensal microbiota to host physiological stress

Project Summary In the last decade, the role of the commensal microbiota in host health has become well-established. For instance, gut microbiota are intimately involved in nutrient extraction, energy efficiency, and host metabolism, as well as the initial priming and maintenance of the host immune system. Dysbiosis, in which gut microbiota become imbalanced or disrupted, has been linked to the onset and progression of disease in nearly every human organ system. Emerging cross-disciplinary research suggests that the host physiological stress response may be a powerful but relatively understudied contributor to microbial dysbiosis, with wide-reaching implications for host health and quality of life. Yet, how gut microbiota respond to activation of the host stress response–and the molecular mechanisms underlie these responses–remain poorly understood. Uncovering the biological processes that transduce signals of host stress to the commensal gut microbiota is thus of paramount importance to advancing our understanding of complex disease. This early-stage investigator-led team utilizes a novel and tractable non-model rodent system, free-living North American red squirrels (Tamiasciurus hudsonicus), to identify the molecular underpinnings of microbial responses to host stress and determine the specificity and scope of these responses. As rodents, red squirrels offer high translational value for humans with physiological responses to stress that are evolutionarily conserved. In the wild, red squirrels are easily trapped, tracked, and manipulated. This facilitates investigations of host-microbial ecology in subjects with intact and ecologically-relevant rather than artificially-engineered microbiota, illuminating microbial responses and underlying mechanisms favored by natural selection. During the course of this five- year award, the team will use a series of controlled experimental manipulations to induce physiological stress, and subsequently 1) identify the precise microbial traits that respond to activation of the host stress response, and 2) interrogate top-down molecular mechanisms related to gut barrier function that underlie these responses. The team will take an integrative approach that combines amplicon sequencing, metagenomics, metabolomics, immunoglobulin sequencing and physiological surveys to interrogate microbial responses across multiple scales of the microbiota (e.g., genetic, phenotypic, ecological) and capture stress-induced change in gut barrier function (e.g., mucosal immunity, barrier integrity). The proposed work will contribute to the team’s overall vision of integrating the commensal microbiota into a broader understanding of the physiological cascades associated with the host stress response. By establishing a free-living rodent model of the gut-brain axis, this proposal will generate unprecedented insight into the potential adaptive value of the biological processes that govern multidimensional microbial responses to host stress. Findings generated by this work may substantially inform clinical and therapeutic approaches aimed at preventing or reversing stress- induced dysbiosis in the human microbiota by increasing the precision of microbial targets.