Distinct cecal and fecal microbiome responses to stress are accompanied by sex-and diet-dependent changes in behavior and gut serotonin

Authors: Lyte, Joshua - Josh; KOESTER, LUCAS - Iowa State University; DANIELS, KARRIE - Iowa State University; LYTE, MARK - (NCE, CECR)networks Of Centres Of Exellence Of Canada, Centres Of Excellence For Commercilization A

Submitted to: Frontiers in Neuroscience
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/7/2022
Publication Date: 4/12/2022
Citation: Lyte, J.M., Koester, L., Daniels, K., Lyte, M. 2022. Distinct cecal and fecal microbiome responses to stress are accompanied by sex-and diet-dependent changes in behavior and gut serotonin. Frontiers in Neuroscience. 16. Article 827343. https://doi.org/10.3389/fnins.2022.827343.
DOI: https://doi.org/10.3389/fnins.2022.827343

Interpretive Summary: The microbiome, which is the collection of bacteria that reside in the gut and other areas on the body, have important implications for animal and human health. Susceptibility of physical and mental health to environmental stress is partly dependent on the microbiome. Moreover, many stress-associated health conditions, such as irritable bowel syndrome or anxiety disorders, are well-recognized to be affected by the microbiome and are disproportionately reported between male and female subjects. Together this indicates the microbiome and stress uniquely interact in different sexes and microbiome-based solutions will likely need to take into account sex-specific differences. Little is known, however, regarding the differences in the microbiome between male and female animals, and whether these differences may mediate mental or physical susceptibility or resilience to stress. Diet is one common route to cause changes in the microbiome, and by tailoring an animal's diet may increase or decrease certain types of bacteria that cause changes in host reaction to stress. As such we sought to identify whether differences exist in the male and female microbiome , are uniquely tailorable through diet, and if these distinctions predict sex-specific susceptibility to environmental stress. We found that sex-specific stress responses were associated with sex-related differences in the microbiome, thereby indicating microbiome-based strategies to reduce the effects of stress need to consider both sexes and should consider using male and female animals in microbiome studies.

Technical Abstract: Background: Although diet- and stress-induced perturbations in the microbiome associate with changes in host behavior via the microbiota-gut-brain axis, few mechanisms have been identified. The identification of causative pathways by which the microbiome influences host behavior therefore would benefit from the application of evidence-based conceptual frameworks. One such causal framework is microbial endocrinology which is the study of neuroendocrine axes as avenues of bi-directional neurochemical-based host-microbe crosstalk. As such, we investigated the relationship between diet- and stress-induced alterations in behavior, regional gut serotonergic response, and concomitant changes in the cecal and fecal microbiomes of male and female mice. Results: Our results demonstrate that sex is a dominant factor in determining the susceptibility of the gut microbiome to stress and diet. Intestinal serotonergic responses to stress were observed in both sexes but the ability of diet to confer region-specific resilience was dependent on sex . Likewise, behavioral alterations diverged between male and female mice. Together, these results demonstrate distinct sex-dependent relationships between cecal and fecal microbial taxa and behavioral- and serotonergic-responses to stress and diet. Conclusions: The present study underscores the inclusion of both male and female sexes in the examination of the microbiota-gut-brain axis. As different microbial taxa were identified to associate with the behavioral and gut serotonergic responses of male and female mice, certain bacterial species may hold sex-dependent functional relevance for the host. Future investigations seeking to develop microbiome-based strategies to afford host stress resilience should include sex-based differences in the microbiome.