Background:Gut microbiotahas emerged as an environmental factor that modulate the host function and is linked to various psychiatric and organic diseases. Objectives: The current study aimed to review the literature to answer the question: Is microbiota affecting the structure or function of the hypothalamus-pituitary axis [HPA]? Methods: Eligibility criteria were experimental or human studies in English language assessing the effects of microbiota on hypothalamus-pituitary axis published during the period from 2008-2018. A manual search in PubMed and Google scholar was conducted using the terms microbiota, effects, modulation, hypothalamus-pituitary axis. Among the two hundred and forty articles identified, 33 were assessed and eighteen[15 experimental and three human studies ] were included. The author name, year of publication, country, methods of the study and the conclusions were reported. Results: There were 240 articles, 33 were assessed for eligibility and 18 were included in the systematc review. The microbiota disruption altered neurotransmitters and vasopressin receptor 1a mRNA expression in the hypothalamus, ameliorated the HPA response to acute stress, reduced insulin and leptin resistance, increased IFNγ, IL2 and IL4 at the expense of TNFα and IL6, modified specific gene expression, and induced inflammation in the hypothalamus. Conclusion: Gut microbiota disturbances induced structural and functional changes in the hypothalamus and can be targeted as a useful affordable intervention in various diseases including stress, anxiety, and depression. Keyword: Gut microbiota, Effects, Hypothalamus-Pituitary, Axis.