The microbiota drives diurnal rhythms in tryptophan metabolism in the stressed gut

Authors: GHEORGHE, CASSANDRA - University College Cork; LEIGH, SARAH-JANE - University College Cork; TOFANI, GABRIEL - University College Cork; BASTIAANSSEN, THOMAZ - University College Cork; Lyte, Joshua - Josh; GARDELLIN, ELISA - University College Cork; MARTINEZ-HERRERO, SONIA - University College Cork; GOODSON, MICHAEL - Wright-Patterson Afb; KELLEY-LOUGHNANE, NANCY - Wright-Patterson Afb; CRYAN, JOHN - University College Cork; CLARKE, GERARD - University College Cork

Submitted to: Cell Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/13/2023
Publication Date: 4/23/2024
Citation: Gheorghe, C.E., Leigh, S., Tofani, G.S., Bastiaanssen, T.F., Lyte, J.M., Gardellin, E., Martinez-Herrero, S., Goodson, M.S., Kelley-Loughnane, N., Cryan, J.F., Clarke, G. 2024. The microbiota drives diurnal rhythms in tryptophan metabolism in the stressed gut. Cell Reports. 43(4). Article 114079. https://doi.org/10.1016/j.celrep.2024.114079.
DOI: https://doi.org/10.1016/j.celrep.2024.114079

Interpretive Summary: Tryptophan is an amino acid that is commonly consumed in a normal diet. How the body uses tryptophan is important for the healthy function of many organs, including the brain and gut. Moreover, tryptophan metabolism is dependent on the circadian rhythm, which generally describes when the body is awake and when it is asleep. The gut bacteria, called the microbiota, can affect the body's use of tryptophan, however it is not known how this occurs and if the microbiota can differentially affect tryptophan metabolism when the body is awake and when it is asleep. Tryptophan metabolism and availability in the host is essential for neuropsychiatric, gastrointestinal, immune and metabolic health. As such, this study sought to determine how the microbiota can affect the body's tryptophan useage when the body is awake and when it is asleep, in order to benefit host health. This study identified molecular pathways through which the gut microbiota affect host tryptophan metabolism, and that this regulation can directly impact host gut barrier function. Together, the findings of this study provide novel insight into how the gut microbiota can be harnessed to improve host health via tryptophan metabolism.

Technical Abstract: Tryptophan is a precursor of key molecules involved in stress-related disorders and circadian rhythmicity; playing a key role along the gut-brain axis signaling. Physiological effects of chronic stress often manifest as a disruption in circadian rhythms and a dysregulated of host-microbiota crosstalk. However, little is known about the effects of acute stress on the gut. Here we show in mice that a 15-min acute stressor is sufficient to alter gut paracellular permeability in vivo and to alter tryptophan metabolite production through microbiota-dependent mechanisms. We demonstrate that tryptophan-metabolizing bacteria and their predicted metabolites exhibit circadian rhythmicity; and that microbiota depletion affects gut tissue rhythmicity and expression of genes involved in host tryptophan metabolism. Germ-free status and depletion by antibiotics differentially affected circadian rhythmicity of genes involved in host tryptophan degradation. We then show that time-of-day interacts with microbial depletion to alter the gut response to acute stress in a region-dependent manner. Together, these findings highlight a new role for the gut microbiota in regulating circadian rhythms of tryptophan metabolism and barrier function in the gut with implications for host-microbe crosstalk in the gut-brain axis.