Gut-brain axis serotonergic responses to acute stress exposure are microbiome-dependent

Authors: Lyte, Joshua - Josh; GHEORGHE, CASSANDRA - University College Cork; GOODSON, MICHAEL - Wright-Patterson Afb; KELLEY-LOUGHNANE, NANCY - Wright-Patterson Afb; DINAN, TIMOTHY - University College Cork; CRYAN, JOHN - University College Cork; CLARK, GERARD - University College Cork

Submitted to: Neurogastroenterology & Motility
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/17/2020
Publication Date: 5/11/2020
Citation: Lyte, J.M., Gheorghe, C.E., Goodson, M.S., Kelley-Loughnane, N., Dinan, T.G., Cryan, J.F., Clark, G. 2020. Gut-brain axis serotonergic responses to acute stress exposure are microbiome-dependent. Neurogastroenterology & Motility. 00:e13881. https://doi.org/10.1111/nmo.13881.
DOI: https://doi.org/10.1111/nmo.13881

Interpretive Summary: A critical need exists for the effective management and reduction of deleterious stress-induced changes in people as well as food production animals. The gut microbiota is increasingly appreciated to impact host health via the microbiota-gut-brain axis as well as to play a role in defining host stress response. As such, it is highly likely that the gut microbiota and the microbiota-gut-brain axis represent promising targets in the development of valuable treatments to combat stress. The serotonergic system in the brain and gut plays important roles in influencing host behavior, inflammation, and other physiologically-important aspects. However, little is known whether the host serotonergic response to acute stress is influenced by the gut microbiota. This research revealed how an acutely stressful situation alters the host serotonergic stress response within the gut and in the brain. Our findings demonstrate that the microbiota may play key roles in affecting host serotonergic response to acute stress both within the gut and the brain. This research will help inform future investigations of points wjere host-microbiota interaction may be targeted to improve host health and response to stress.

Technical Abstract: Background: Serotonin is a key-signaling molecule across the microbiota-gut-brain axis and is increasingly recognized as a mediator of stress-induced alterations in host behaviour and gastrointestinal function. Many critical aspects of stress-related alterations in gut-brain axis signaling begin in the gastrointestinal tract although the precise impact of acute and chronic stress on regional serotonergic system dynamics is poorly appreciated, particularly when viewed through the lens of emerging gut microbiome research. Although the gut microbiome is known to modulate host gastrointestinal serotonin synthesis under constitutive non-stressful conditions, it is unknown whether the microbiota also shapes a host serotonergic responses to acute stress. We therefore sought to define a role of the microbiome in regulating the gastrointestinal and brain serotonergic system responses to acute stress. Results: Corticosterone response to acute stress was exaggerated in germ-free (GF) male but not female mice when compared to same-sex conventional mice. The microbiota was found to regulate gastrointestinal serotonergic response to acute stress in a sex- and region-dependent manner. Male-specific post-stress increases in colonic serotonin were absent in GF mice but normalised following colonisation. Conversely, ileal serotonergic concentrations were elevated only in male animals in the absence of a microbiome. mRNA expression of genes involved in tryptophan metabolism within the gut were differentially expressed in the colon and ileum of germ-free mice on a sex-dependent basis. Within the frontal cortex, the absence of the microbiome altered basal serotonin, its main metabolite 5-hydroxyindoleacetic acid, and prevented stress-induced increases in serotonin turnover. Conclusions: The gut microbiome defines the set points of the brain and gastrointestinal serotonergic systems and regulates their response to acute stress in a sex- and region-dependent manner.