Anxiety, Depression, and the Microbiome: A Role for Gut Peptides

Abstract

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.

Keywords: Anxiety; Depression; Gut microbiota; Gut peptides; Gut–brain axis.

Fig. 1

Major communication pathways of the microbiota–gut–brain axis. There are numerous mechanisms through which the gut microbiota may signal the brain to control physiological processes. These include the release of gut peptides by enteroendocrine cells (EECs) where they activate cognate receptors of the immune system and on vagus terminals in the gut. Gut peptides such as neuropeptide Y (NPY) can also be released by cytokines under immune stimulation. There have been numerous reports of alterations in the gut microbiota in neuropsychiatric conditions, where gut peptides may play a key signaling role. Only a few examples of gut–brain pathway and gut peptides are represented in this figure CCK = cholecystokinin; GLP-1 = glucagon-like peptide; CRF = corticotropin-releasing factor; PYY = peptide YY; GABA = γ-aminobutyric acid; SCFA = short-chain fatty acid

Fig. 2

Gut peptide distribution in the gastrointestinal tract. Gut peptides are released from different subgroups of enteroendocrine cells (EECs) following appropriate stimulation. The stomach is rich in ghrelin expression from A cells (brown circles), cholecystokinin (CCK) is expressed in the proximal segment of the small intestine by I cells (blue circles). The small and large intestine secretes glucagon-like peptide (GLP-1) and peptide YY (PYY) from L cells (red and green circles, respectively). Only some examples of EEC subgroups and relative hormones secreted are represented in the figure