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

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.

Neuropeptide Y (NPY) prevents depressive-like behavior, spatial memory deficits and oxidative stress following amyloid-ß (Aß(1-40)) administration in mice.

Neuropeptide Y (NPY) is a 36-amino acid peptide widely distributed in the central nervous system (CNS) that has been associated with the modulation of several functions including food intake, learning and memory, mood and neuroprotection. There is great interest in understanding the role of NPY in the deleterious effects induced by the central accumulation of amyloid-ß (Aß) peptides, a pathological hallmark of Alzheimer's disease (AD). Herein, we evaluated the effects of a single intracerebroventricular (i.c.v.) administration of NPY (0.0234 µmol/µL) 15 min prior to the i.c.v. injection of aggregated Aß1-40 peptide (400 pmol/mouse) in behavioral and neurochemical parameters related to oxidative stress in mice. Pretreatment with NPY prevented Aß1-40-induced depressive-like responses and spatial memory impairments evaluated in the tail suspension and object location tasks, respectively. The protective effects of NPY on spatial memory of Aß1-40-treated mice were abolished by the pretreatment with the selective Y2 receptor antagonist BIIE0246. On the other hand, the administration of NPY and Aß1-40 did not alter the performance of the animals in the elevated plus-maze and open field arena, indicating lack of effects on anxiety state and locomotor function. Although Aß1-40 infusion did not change hippocampal and cortical glutathione peroxidase (GPx) activity and glutathione (GSH) levels, Aß1-40-infused animals showed an increased lipid peroxidation in hippocampus and prefrontal cortex that were blunted by NPY administration. These findings indicate that central administration of NPY prevents Aß1-40-induced depressive-like behavior and spatial memory deficits in mice and that this response is mediated, at least in part, by the activation of Y2 receptors and prevention of oxidative stress.