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. 2023 Jan 27;28(7):2645–2673. doi: 10.1038/s41380-023-01964-w

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© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 5 — There are direct (synthesis or degradation of neurotransmitters and their precursors) and indirect (synthesis of microbial metabolites with systemic pleiotropic effects) actions. In the indirect actions the main metabolites, SCFAs and tryptophan (trp) derived metabolites, are represented. Red arrows represent the result of pathological condition of BD, meaning the increased or decreased level in certain metabolic routes. Decreased levels of butyrate and propionate besides increased levels of acetate have been related to higher depressive symptoms. Tryptamine levels are risen whereas tryptophan levels are decreased in BD. Kynurenine pathway is also altered in BD and it seems to be related to neuroinflammation, bacterial translocation, HPA dysfunction, neuromodulation. As shown, a peripheral decrease in many metabolites of the Kyn pathway is shown, with specific differences in manic versus depressive stages and inversely correlated with certain gut microbiota populations (Oscillibacter genera). Glutamate concentration, abnormal SCFAs production and decreased trp, all confluence in less enteric serotonin (5HT) production due to decreased stimulation of enteroendocrine cells (EECs). All these mechanisms disruption contribute to bidirectional intestinal inflammation-neuroinflammation. Central nervous system (CNS) also sends signals activating vagus nerve. Studying local and systemic levels of SCFAs in patients with BD can be of aid to better understand microbiota–gut–brain (MGB) axis disruption in this malady. More studies focusing on its different phases and types are needed. This scenario is just the beginning of new therapeutical approaches. GM gut microbiota, DA dopamine, AC acetylcholine, NE norepinephrine, his histamine, GABA gamma-aminobutyric acid, EECs enteroendocrine cells, 5HT serotonin, SCFAs short-chain fatty acids, trp tryptophan, kyn kynurenine, KYNA Kynurenic acid, XA Xanthurenic acid, QA Quinolic acid, Tregs T regulator cells, ILC innate lymphoid cell, BBB blood–brain barrier, CNS central nervous system; (+): activates.