Recent accumulating evidence indicates that the gut microbiome can affect the development and regulation of the hypothalamic-pituitary-adrenal axis and behavior, with central integrative systems being crucial in the successful physiological adaptation of the organism to external stressor. In contrast, host-derived hormones increase the bacterial proliferative capacity and pathogenicity. In the gut lumen, this type of cross-talk between microorganisms and the host is presumed to be performed continually through various kinds of luminal molecules, as numerous types of bacteria and host cells are in close proximity in the gastrointestinal tract of mammals.We herein focus on bidirectional signaling between the gut microbiome and the host in terms of commensal microbiota affecting the hypothalamic-pituitary-adrenal HPA axis response and behaviors and further discuss the role of gut luminal catecholamines and γ-aminobutyric acid, both of which are presumed to be involved in this signaling.