There is now an expanding volume of evidence to support the view that commensal organisms within the gut play a role in early programming and later responsivity of the stress system. The gut is inhabited by 10¹³–10¹⁴ micro-organisms, which is ten times the number of cells in the human body and contains 150 times as many genes as our genome. It has long been recognised that gut pathogens such as Escherichia coli, if they enter the gut can activate the HPA. However, animals raised in a germ-free environment show exaggerated HPA responses to psychological stress, which normalises with monocolonisation by certain bacterial species including Bifidobacterium infantis. Moreover, increased evidence suggests that animals treated with probiotics have a blunted HPA response. Stress induces increased permeability of the gut allowing bacteria and bacterial antigens to cross the epithelial barrier and activate a mucosal immune response, which in turn alters the composition of the microbiome and leads to enhanced HPA drive. Increasing data from patients with irritable bowel syndrome and major depression indicate that in these syndromes alteration of the HPA may be induced by increased gut permeability. In the case of irritable bowel syndrome the increased permeability can respond to probiotic therapy. Detailed prospective studies in patients with mood disorders examining the gut microbiota, immune parameters and HPA activity are required to throw further light on this emerging area. It is however clear that the gut microbiota must be taken into account when considering the factors regulating the HPA.