Recently, the role of the gut microbiome has become more prominent in gut-brain interactions. The microbiota-gut-brain axis homeostasis is responsible for our emotional behavior, stress response, and brain neurotransmitter balance. This bidirectional communication axis between the gut and the brain is influenced by the effect of the microbiome on the metabolic pathways of the host. Intestinal bacteria intervene directly in Trp metabolism, generating signaling molecules and specific metabolites with physiological effects on both the brain and the intestine. Trp is also metabolized under the influence of the microbiome and suffers three major pathways in the organism: The serotonin (5-HT), kynurenine, and indole pathway resulting in the production of neuro-active metabolites. This current chapter aims to cover the most recent data referring to the Trp metabolites and the microbiome-gut-brain axis in major gut disorders, such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and celiac disease. These diseases are frequently associated with mood disorders.