The gut microbiota is comprised of a vast variety of microbes that colonize the gastrointestinal tract and exert crucial roles for the host health. These microorganisms, partially via their breakdown of dietary components, are able to modulate immune response, mood, and behavior, establishing a chemical dialogue in the microbiota–gut–brain interphase. Changes in the gut microbiota composition and functionality are associated with multiple diseases, in which altered levels of gut-associated neuropeptides are also detected. Gut neuropeptides are strong neuroimmune modulators; they mediate the communication between the gut microbiota and the host (including gut–brain axis) and have also recently been found to exert antimicrobial properties. This highlights the importance of understanding the interplay between gut neuropeptides and microbiota and their implications on host health. Here, we will discuss how gut neuropeptides help to maintain a balanced microbiota and we will point at the missing gaps that need to be further investigated in order to elucidate whether these molecules are related to neuropsychiatric disorders, which are often associated with gut dysbiosis and altered gut neuropeptide levels.
The gut microbiota comprises a complex community of metabolically active microorganisms that have a strong influence on a wide range of physiological processes, such as immune and nervous system development, food metabolism, cell growth and differentiation, or mood and behavior. Though the composition of the gut microbiota is unique for each individual and therefore it is not possible to determine what defines a “healthy microbiota,” it seems clear that alterations in the composition of the gut microbiota, known as dysbiosis, are associated with multiple diseases, including neuropsychiatric disorders and inflammatory gastrointestinal diseases. Thus, it is of great significance to investigate the mechanisms involved in the interplay between the microbiota and the host.
One of the ways by which the gut bacteria establish their intimate relationship with their host is through the production of biologically active molecules. Bacteria produce these molecules by breaking down dietary compounds that reach the intestine and/or the indigenously produced compounds that are expelled from the intestine. Products of bacterial breakdown range from immunomodulatory to antimicrobial and neuroactive compounds that not only have a local action on the host but can also reach the blood stream to have an impact on distant parts of the body.
Neuropeptides are now in the spotlight as one of the potential mediators of the exchange of information between gut bacteria and other tissues and organs. Their role as modulators of neuronal and immune functions is well known and reveals a strikingly complex network through which neuropeptides exert multiple functions. Although the term “neuropeptide” is commonly used in the context of the central nervous system (CNS), the enteric nervous system (ENS) is another major source of production of these peptides. Therefore, in this article, we will use the term “gut neuropeptides” to specifically refer to neuropeptides which are produced in the ENS, as opposed to other gut peptides which are also produced in the intestinal epithelium. This term also reinforces the idea that gut neuropeptides are able to exert an extraintestinal action by signaling to distant organs, such as the brain. Interestingly, several gut neuropeptides also have antimicrobial activity; for instance, neuropeptide Y (NPY) and substance P (SP), which have been shown to inhibit the growth of Escherichia coli. However, the antimicrobial activity of gut neuropeptides has not been studied in detail yet. Considering that gut antimicrobial neuropeptides are produced not only in the CNS but also in the ENS and their respective receptors are widely expressed along the gastrointestinal tract (GIT), it is important to unravel the function of these peptides in the context of gut microbiota homeostasis, which is key for a healthy state of the host. Finally, gut neuropeptides might also be key regulators of the so-called microbiota–gut–brain axis; for example, through their receptors expressed on the vagus nerve, the main communication route between the gut and the CNS. In this review article, we will describe the different types of antimicrobial peptides (AMPs) that are present in the gut and their mode of action. Thereafter, we will focus on gut neuropeptides and will address their direct and indirect function in maintaining homeostasis.
The GIT is a major entry point of microbes, and so, the organ has developed a complex defense mechanism to protect the host from diseases, as part of the innate immune system. One of the components of this defense barrier is the AMPs. In the GIT, AMPs are produced not only by the intestinal epithelium but also by the gut microbiota in the lumen. As presented in Table 1, human defense peptides have a rather broad spectrum of action, whereas their bacterial counterparts display a much narrower spectrum. This is due to a very specific mode of action of bacterial AMPs where the antimicrobial action takes place upon high-affinity binding to receptors in the cell envelope.
Gut bacteria represent a major source of AMPs production in the GIT. These bacteria synthesize the so-called bacteriocins. Similar to AMPs produced by human cells, bacteriocins are small, cationic peptides that can easily interact with bacterial membranes. So far, 177 bacteriocins have been identified and sequenced; 88% of them are produced by Gram-positive bacteria, whereas the remaining 12% are produced by Gram-negative bacteria and Archaea. It is also remarkable that most of the reported Gram-positive bacteriocins producers belong to the group of lactic acid bacteria, which carry out fermentation of sugar into lactic acid. However, it cannot be concluded that lactic acid bacteria are the only bacteriocin producers; instead, given the interest that they pose for the food industry, it is likely that most of the research has been focused on this group of bacteria and accordingly more bacteriocins have been reported to be produced by lactic acid bacteria.
Bacteriocins are classified into many different subgroups due to the heterogenicity of this group of molecules. Bacteriocins that are produced by Gram-negative bacteria are referred to as microcins, small peptides, or colicins, which are larger proteins. Microcins are subsequently divided into class I (< 5 kDa, containing post-translational modifications) and class II (5–10 kDa, without post-translational modifications). Despite their structural diversity, microcins share an interesting mechanism of action that has been named the “Trojan Horse” strategy. Some microcins such as MccJ25 and MccE492 mimic the structure of essential bacterial molecules and take advantage of the natural receptors for these ligands, which allow them to enter and kill the target bacteria. On the other hand, MccC7 and MccC59 are secreted as harmless molecules and further transformed into toxic derivatives once they enter the susceptible bacteria. An interesting example of how microcins are relevant for the host was shown recently using a mouse model of intestinal inflammation. In the study of Sassone-Corsi et al., probiotic E. coli Nissle 1917, which produces microcins, was able to restrict the expansion of other competing Enterobacteriaceae during inflammation, including pathogenic E. coli and Salmonella enterica. Also, therap
