MoodBugs: "How our gut microbes influence how we feel – bacterial metabolites and inflammation as mediators of human microbiota-affect relationships"

Do our gut microbes influence our emotions? This sounded far-fetched a decade ago, but rodent research has shown that the gut microbiota causally impacts affective processes. The underlying microbiota-gut-brain signaling mechanisms include the capacity of the microbiota to produce short-chain fatty acids (SCFA) from dietary fiber (DOI: 10.1038/s41575-019-0157-3), and to regulate inflammation. These rodent findings have great potential to identify new modifiable players in the (patho)physiology of affective processes and disorders, which is urgently needed given the stalled revolution in affective science, but human translation is needed to fulfill this potential. MoodBugs aims to fill this gap by investigating the relationship between the gut microbiota and stress sensitivity and fear learning, two affective endophenotypes, and the microbiota-gut-brain (SCFA, inflammation) and neur(ochemic)al mechanisms underlying it, in an interdisciplinary hypothesis-driven fashion. The project directly builds on two of our key earlier findings. In a population-based study, we showed a cross-sectional association between a specific microbiota profile (B2 enterotype) and mental well-being (DOI: 10.1038/s41564-018-0337-x). In the present project, we aim to test directionality of this association [WP1], as well as causality of microbiota-affect relationships [WP2] in humans. In a placebo-controlled trial, we showed that SCFA administration (1 week) attenuates the cortisol response to psychosocial stress (DOI: 10.1038/s41386-020-0732-x). In the MoodBugs project, we aim to test for whom and how SCFA work (at the level of the brain), and to investigate microbiota composition as a predictor of response to SCFA [WP3]. Finally, we aim to test the causal effect of inflammation on stress and fear, a putative mediating role of neuroinflammation in the underlying neural circuitry, and the potential of SCFA to dampen these inflammation-induced effects [WP4].