Mental health problems are placing a heavy and continuously growing burden on public health, calling for a resolution. Animal studies and a small number of human studies support the idea that the diverse microbial communities in the intestinal tract (i.e. the gut microbiota) are crucial in supporting optimal brain functioning; the bidirectional microbiota-gut-brain axis provides a paradigm shift with potential for promoting mental functioning. Research points at a number of physiological and cognitive processes involved. Focusing on transdiagnostic factors, I am evaluating the role of the gut microbiome and manipulations thereof in cognitive perseveration and the processing, and recognition of, emotions. Animal studies point at a potential key role of the vagal nerve (i.e. the direct link between the gut and the brain) in modulating the microbiota-gut-brain axis, but little direct evidence in humans is available. Correlational evidence from studies assessing heart rate variability, i.e. a reliable marker of activity of the vagal nerve, indeed confirm such a potential role. Using transcutaneous stimulation of the vagal nerve, furthermore confirms the key role of the vagal nerve in cognitive flexibility, considered to be the opposite of perseverance, and the processing and recognition of emotions. The next question, as such, is whether, and if so, how the vagal nerve connects (manipulations of) the gut microbiota to cognitive and emotional effects.