Unravelling the role of tryptophan metabolism in the microbiota-gut-brain axis: focus on the effects of stress and exercise

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Gheorghe, Cassandra Elise
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University College Cork
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The involvement of the microbiota-gut-brain axis communication in brain function and behaviour has enabled a paradigm shift in neuroscience, neurogastroenterology and psychiatric research. Two key routes of this bidirectional communication are impaired in stress-related disorders: the hypothalamic-pituitary-adrenal axis and tryptophan metabolism. This crosstalk has been widely characterised following chronic stress, in stress-related disorders and gastrointestinal disorders comorbid with psychological distress. The acute transitory reaction to an acute stressor and the associated adaptation over time, however, is not well understood. In this work, we investigated this neglected topic by evaluating the response to a psychological and a physical s stress exposure in terms host and microbial tryptophan metabolism and other pillars of the microbiota-gut-brain axis. For this purpose, we used well-recognised pre-clinical models (germ-free and antibiotic-treated mice) to decipher the role of gut microbes in the regulation of tryptophan metabolism and availability at baseline and following hypothalamic-pituitary-adrenal axis activation. We found that a 15-min acute stressor was sufficient to upregulate colonic 5-HT concentrations in conventional and re-colonised male mice while serotonin level was unaltered in GF male mice. We have identified novel region- and sex- dependent effects of the microbiota in modulating the expression of host rate-limiting enzyme of tryptophan metabolism following acute stress at both terminals of the gut-brain axis communication network (Chapter 2). We found that acute stress induced functional alterations visible as increased intestinal permeability in the ileum (ex vivo and in vitro) depending on time of day. In the colon, alterations in the rate-limiting enzyme of tryptophan breakdown towards serotonin synthesis, TPH-1, was reduced by stress in conventional mice but increased in antibiotic treated mice following stress (Chapter 3). Furthermore, both microbial and host tryptophan metabolism were altered in the caecum of conventional mice following an acute stressor, which was disturbed in germ-free mice and partially restored following colonisation of germ-free animals (Chapter 3). Then, we assessed in sedentary humans transient and adaptive changes to exercise along the microbiota-gut-brain axis at different exercise intensities. We discovered intensity-dependent effects on various pillars of the microbiota-gut-brain axis. While high-intensity training increased the cortisol awakening response chronically, it also led to an increase in peripheral serotonin level directly following a maximal exhaustion test. Light-intensity exercise lead to marked compositional alterations at the species level. Lastly, our work provides the first piece of evidence that the relative abundance of exercise-responsive bacteria with saccharolytic potential decreases with exercise intensity. Together, these results contribute to a deeper comprehension of the host-microbe dialogue driving the spatial and temporal dynamics of the physiological response and adaptation to various types of stress exposure. These observations open future research avenues and encourages a move towards the integrated physiological perspectives essential for the development of precision treatment options in stress-related disorders.
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Tryptophan metabolism , Microbiota-gut-brain axis , Acute stress , Gut function , Gut permeability , Circadian rhythms
Gheorghe, C. E. 2023. Unravelling the role of tryptophan metabolism in the microbiota-gut-brain axis: focus on the effects of stress and exercise. PhD Thesis, University College Cork.