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Unravelling the role of circadian rhythmicity in microbiota-gut-brain axis signalling
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Date
2023
Authors
Tofani Sousa e Silva, Gabriel
Journal Title
Journal ISSN
Volume Title
Publisher
University College Cork
Published Version
Abstract
Modern habits are becoming more and more disruptive to health. Our days are often filled with circadian disruption and stress exposure. We need to understand how our responses to these external stimuli are shaped and how they can be targeted to promote health. A growing body of research demonstrates the role of the gut microbiota in influencing brain function and behavior. The stress and circadian systems, which are essential to maintaining appropriate responses to the environment, are known to be impacted by the gut microbiota. Although gut microbes have been shown to modulate circadian rhythms and stress response, such studies were conducted in an independent manner. Since these systems are interconnected through the hypothalamic-pituitary-adrenal (HPA) axis, there is a need to examine how the gut microbiota may play a role in regulating the integration of stress and circadian signals.
In this thesis, I aimed to investigate the influence of circadian rhythmicity in the microbiota-gut-brain axis communication and the consequences of that to stress responsivity. To this end we developed a computational tool, Kronos, that allows us to determine rhythmicity of genes and metabolites in brain regions important to stress and circadian regulation under different microbial status. Moreover, we investigate the interplay of the circadian and stress systems in the absence of the microbiota to dissect its role in the modulation of these systems.
Using transcriptomics, and applying Kronos, we demonstrate that microbial depletion by antibiotic administration or germ-free status disrupts the molecular clock in the superchiasmatic nucleus (SCN). Such alterations to the master clock were accompanied with disruptions in the rhythmicity of circulating corticosterone. Furthermore, multi-omics analysis in the hippocampus and amygdala, indicated that microbial status disrupted the diurnal oscillations in genes and metabolites that compose pathways important for the stress response. We then investigate the expression of genes related to circadian rhythms and HPA-axis in the paraventricular nucleus, pituitary, and adrenal glands across the day. This, together with alterations in corticosterone demonstrates a hyper-activation of the HPA-axis at the sleep/wake transition in microbial depleted animals. Such disruption to the rhythmic function of the HPA-axis resulted in a time-of-day specific impairment of the stress response and stress-sensitive behaviors.
Lastly, we identify changes in the rhythmic profile of the gut microbiota following microbial depletion. This manifested as peak of bacterial load at the same time the impairments in HPA-axis function were observed. Furthermore, by conducting fecal microbiota transplantation we confirm that the diurnal oscillations in gut microbes after antibiotic treatment regulates glucocorticoids secretion and explore the microbial compositional changes underlying it.
This work provides compelling evidence that the gut microbiota regulates stress responsivity via the circadian system. Moreover, we identify the gut microbiota as an important regulator of HPA-axis rhythmic function, demonstrating that the microbiota is essential to adaptively respond to psychological stressors throughout the day.
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Keywords
Circadian rhythm , Gut microbiota , Stress , Gut-brain axis
Citation
Tofani Sousa e Silva, G. 2023. Unravelling the role of circadian rhythmicity in microbiota-gut-brain axis signalling. PhD Thesis, University College Cork.