The Relationship Between the Gut Microbiome-Immune System-Brain Axis and Major Depressive Disorder

Abstract

Major depressive disorder (MDD) is a prominent cause of disability worldwide. Current antidepressant drugs produce full remission in only about one-third of MDD patients and there are no biomarkers to guide physicians in selecting the best treatment for individuals. There is an urgency to learn more about the etiology of MDD and to identify new targets that will lead to improved therapy and hopefully aid in predicting and preventing MDD. There has been extensive interest in the roles of the immune system and the gut microbiome in MDD and in how these systems interact. Gut microbes can contribute to the nature of immune responses, and a chronic inflammatory state may lead to increased responsiveness to stress and to development of MDD. The gut microbiome-immune system-brain axis is bidirectional, is sensitive to stress and is important in development of stress-related disorders such as MDD. Communication between the gut and brain involves the enteric nervous system (ENS), the autonomic nervous system (ANS), neuroendocrine signaling systems and the immune system, and all of these can interact with the gut microbiota. Preclinical studies and preliminary clinical investigations have reported improved mood with administration of probiotics and prebiotics, but large, carefully controlled clinical trials are now necessary to evaluate their effectiveness in treating MDD. The roles that several gut microbe-derived molecules such as neurotransmitters, short chain fatty acids and tryptophan play in MDD are reviewed briefly. Challenges and potential future directions associated with studying this important axis as it relates to MDD are discussed.

Keywords: axis; brain; depression; gut microbiome; immune system; prebiotics; probiotics; vagus nerve.

Figure 1

Gut-brain Axis. The gut-brain axis is the bidirectional communication between the gut and the brain, and its communication is associated by different pathways with the autonomic nervous system, the enteric nervous system, the neuroendocrine system, and the immune system. Trillions of gut microbes and their metabolites reside in the lumen of the gastrointestinal tract and influence the local mucosal system (visualized in the inset for the barrier in the colon). Signaling pathways between the gut microbiota and the brain include neural pathways such as the vagus nerve, immune pathways, and humoral pathways. Gut microbiota influence host metabolism through local interactions, peripheral systems, and bidirectional communication with the liver. Schematic created with BioRender.com.