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 microbial ecosystem in the gut (the gut microbiota) causally impacts affective processes. The underlying microbiota-gut-brain signalling mechanisms include the capacity of the microbiota to produce short-chain fatty acids (SCFA) from dietary fiber 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.In a population-based study, my team showed a cross-sectional association beteen a specific microbiota profile (B2 enterotype) and mental well-being. To test directionality of this association, I propose a longitudinal and mechanistic population-based study[WP1]. To test causality, I will study the effect of depleting the gut microbiota using an antibiotic intervention on fear learning and its brain basis[WP2].In a placebo-controlled trial, I showed that SCFA administration (1 week) attenuates the cortisol response to psychosocial stress. To test for whom and how SCFA work, I will investigate microbiota composition as a predictor of response to SCFA, and gene expression in affective circuits as the neural mechanism mediating their effect[WP3]. I will induce systemic inflammation to test its causal effect on stress and fear, and on neuroinflammation in the underlying neural circuitry as hypothesized mediator. I will also test the potential of SCFA to dampen these inflammation-induced effects[WP4].