The complex bidirectional communication between the gut and the brain is finely 
orchestrated by different systems, including the endocrine, immune, autonomic, 
and enteric nervous systems. Moreover, increasing evidence supports the role of 
the microbiome and microbiota-derived molecules in regulating such interactions; 
however, the mechanisms underpinning such effects are only beginning to be 
resolved. Microbiota-gut peptide interactions are poised to be of great 
significance in the regulation of gut-brain signaling. Given the emerging role 
of the gut-brain axis in a variety of brain disorders, such as anxiety and 
depression, it is important to understand the contribution of bidirectional 
interactions between peptide hormones released from the gut and intestinal 
bacteria in the context of this axis. Indeed, the gastrointestinal tract is the 
largest endocrine organ in mammals, secreting dozens of different signaling 
molecules, including peptides. Gut peptides in the systemic circulation can bind 
cognate receptors on immune cells and vagus nerve terminals thereby enabling 
indirect gut-brain communication. Gut peptide concentrations are not only 
modulated by enteric microbiota signals, but also vary according to the 
composition of the intestinal microbiota. In this review, we will discuss the 
gut microbiota as a regulator of anxiety and depression, and explore the role of 
gut-derived peptides as signaling molecules in microbiome-gut-brain 
communication. Here, we summarize the potential interactions of the microbiota 
with gut hormones and endocrine peptides, including neuropeptide Y, peptide YY, 
pancreatic polypeptide, cholecystokinin, glucagon-like peptide, 
corticotropin-releasing factor, oxytocin, and ghrelin in microbiome-to-brain 
signaling. Together, gut peptides are important regulators of 
microbiota-gut-brain signaling in health and stress-related psychiatric 
illnesses.