Immunomodulatory and anti-inflammatory neuropeptides: Production by specific gut microbiota genera – in silico evidence

Immunomodulatory anti-inflammatory gut
Immunomodulatory and anti-inflammatory neuropeptides – gut

Researches from Spain and Portugal showed, for the first time, the production of neuropeptides by gut microbiota with potential immunomodulatory and anti-inflammatory properties.

Several probiotic species of Lactobacillus and Bifidobacterium have been found to increase the cytotoxic activity of natural killer cells and the phagocytosis of macrophages, as well as mediate the adaptive immune responses elicited by subsets of dendritic cells (DCs), B- and T-cells, and enterocytes.

However, beyond their direct contact with mucosal systems, microbiota might also regulate host immunity by soluble chemical mediators. It has beensuggested that the microbiota modulate gut immunity not only by direct contact with the mucosa, but also through soluble mediators including short-chain fatty acids derived from the metabolism of dietary fiber, as well as by peptides encrypted in the intestinal microbial exoproteome.

These immune molecular effectors include cell wall components, exopolysaccharides, short-chain fatty acids, conjugated linoleic acid, bacteriocins, extracellular bacterial proteins, and bioactive peptides. In this regard, bioactive peptides derived from food, gut microbiota, or probiotics have already been recognised as immunomodulatory compound.

Hidalgo-Cantabrana and colleagues recently identified peptide derived from Bacteroides fragilis YCH46 (peptide B12), which polarized Th17 and Th22 responses in human peripheral blood mononuclear cells (PBMCs) from healthy controls.

Increasing body of evidence indicate the involvement of gut microbiota and the nervous system in the gut-brain axis and cross-talk. Various neuropeptides, such as substance P, neuropeptide Y, calcitonin gene-related peptide, vasoactive intestinal polypeptide, etc., released by peripheral neurons alongside with endocrine cells in the gastrointestinal tract, play an essential role in the gut-brain communication. On the other side, some immunomodulatory peptides were found to be encrypted in the human gut metaproteome.

So far, however, it appears that the potential existence of neuropeptides encrypted in the proteins produced by human intestinal microbes has not been explored.

In the study published in the Food Research International journal, Blanco-Míguez and colleagues, in a collaboration between Spanish and Portuguese research institutes, performed a large-scale screening of the human gut microbiome in search for specific bacterial genus that produces bioactive neuropetides.

The authors used the amino acid sequences of the 5949 neuropeptides from the Neuropep database. In addition, all the 91.325.790 sequences of potential bioactive peptides from the bioactive section of Mechanism of Action of the Human Microbiome (MAHMI) database were screened. From 91,325,790 potential bioactive peptides, only 581 returned a match when crossed against the 5949 neuroactive peptides from the NeuroPep database and the 15 digestive hormones. 

From the screening, 581 peptides matched human neuropeptides, non-human peptides, or digestive hormones. From the 581 peptides, 258 could be found in human neuropeptide databases, 313 in non-human neuropeptide databases, and 10 as digestive hormones.

Immunomodulatory and anti-inflammatory neuropeptidesConsidering the potential bacterial genus that produces potential neuropeptides, 14% were members of the genera Ruminococcus, 10% members of genera Clostridium, 7% members of genera Firmicutes, and 3% from the genera Lactobacillus, Streptococcus, and Escherichia. Some of these genera are known to expand regulatory T Cells (Treg) population of lymphocytes and are important in intestinal homeostasis (Atarashi et al., Nature, 500, 232–236, 2013).

Thus, this study appears to provide the first in silico evidence indicating the production of peptides with a double bioactivity: neuropeptide or digestive-related, and immunomodulatory or anti-inflammatory by specific genus of gut bacteria.

Interestingly, and as stated by the authors, “Classical (Lactobacillus sp.) and next-generation (Faecalibacterium sp.) probiotics are shown to produce these peptides, which are proposed as a potential mechanism of action of psychobiotics”.

This may also indicate that different gut microbiotas, via the release of these neuropetides can influence host immunity, and the gut-brain cross-talk, which in turn, may have important implications for conditions such as depression,pain, etc.

Source: Food Res Int, 2018. 119:221-226. doi: 10.1016/j.foodres.2019.01.069

Read more: Food Research International