COMMENSAL GUT MICROBE MODULATES STRESS-INDUCED GUT DYSMOTILITY THROUGH GUT-DERIVED METABOLITES AND SYMPATHETIC NERVOUS SYSTEM

Stress is a pivotal environmental risk factor for the development of mental disorders. While the impact of stress can vary among individuals, gut dysmotility is a common characteristic in response to acute stress. Mounting evidence suggests that the commensal microbiota residing in the gut plays a crucial role in modulating gut motility. Recent investigations have highlighted the ability of gut microbiota to influence tryptophan metabolism, thereby impacting gut motility. Moreover, studies investigating the gut-brain axis have revealed that the absence of gut microbiota leads to activation of gut-innervated sympathetic neurons. Intriguingly, our previous research demonstrated that colonization of specific commensal gut bacteria, Enterococcus (E.) faecalis, in microbiome-depleted mice can suppress the hypothalamic-pituitary-adrenal (HPA) axis, thereby regulating the release of the stress hormone corticosterone. This pathway exhibits a close association with stress, which has been shown to significantly affect gut motility.

Despite the recognition of the gut microbiota as a crucial regulator of the gut-brain axis, the precise mechanisms through which specific microbes in the intestine remotely influence the HPA axis remain unclear. In this study, we hypothesize that commensal gut microbe modulates stress-induced gut dysmotility via colonic tryptophan metabolism and the sympathetic nervous system.

To investigate this hypothesis, we established an experimental model of acute stress exposure in mice colonized with specific commensal microbes and evaluated their stress response by assessing gut motility.

Our findings indicate that E. faecalis selectively restores gut dysmotility and corticosterone levels following stress exposure, both of which are profoundly disrupted by gut microbiota depletion. Furthermore, metabolomic profiling of serum after microbiota depletion and E. faecalis colonization revealed alterations in metabolites involved in tryptophan and tyrosine metabolisms, accompanied by changes in the expression of key rate-limiting enzymes associated with these pathways. Immunostaining of c-Fos demonstrated that colonization of E. faecalis diminishes neural activity in brain regions implicated in the HPA axis and autonomic nervous system following acute stress exposure, including the paraventricular nucleus of the hypothalamus (PVN), area postrema (AP), and lateral paragigantocellular reticular nucleus/rostral ventrolateral medulla (LPGi/RVLM). Lastly, administration of E. faecalis to mice with complete microbiome effectively restores stress-induced gut dysmotility.

Collectively, our findings provide valuable insights into the intricate mechanisms by which intestinal bacteria influence the host through the gut-brain axis and strongly suggest a novel mechanism through which intestinal commensal bacteria regulate the host's stress response and its subsequent consequences.