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Commentary: The Potential Role of the Dipeptidyl Peptidase-4-Like Activity From the Gut Microbiota on the Host Health.

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PubMed ID: 30687289

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Da Silva RR

Front Microbiol. 2018. doi: 10.3389/fmicb.2018.03313

COMMENT: Dipeptidyl peptidase-4 (DPP-4) is an aminopeptidase involved in protein digestion. In humans, these enzymes are present either as membrane proteins or as soluble enzymes. In commensal bacteria, Dipeptidyl peptidase-4 is present as a membrane protein (S9B family). In addition, a similar type of cytosolic Dipeptidyl peptidase-4 is found in some bacteria, such as Lactobacillus helveticus (PepX, S15 family).

This commentary focuses on the work reported by Olivares et al., 2018, in which they have investigated the activity of the DPP-4 present in the gut microbiota of mice, and have hypothesized about its effect on the host organism. The authors base their arguments on the fact that the cecal content of gnotobiotic mice colonized with the gut microbiota of a healthy subject showed increased proteolytic activity of DPP-4 as compared to germ-free mice (GFM). Additionally, cecal tissue mRNA analyzed in both study groups did not demonstrate significant differences in Dpp-4 gene expression between them. This indicates that significant DPP-4-like activity occurs in the gut microbiota.

Olivares et al., sought to determine the origin of the enzyme and the mechanism by which it is present in plasma. The hypothesis raised by the authors is that DPP-4 is translocated from the gut microbiota through the intestinal wall.

The aim of this commentary is to discuss the hypothesis formulated by Olivares et al., 2018, and to propose further experiments to validate it.

(1) as mentioned by the authors, for the enzyme to be translocated, the microbiota would require to secrete a soluble isoform of the peptidase; (2) the intestinal wall is recognized to be an impermeable barrier to macromolecules, and therefore, increased permeability is associated with intestinal disorder, inflammation, and disease.

It has not yet been verified whether microbes can also secrete DPP-4. Additionally to the active secretion of DPP-4, this enzyme could be also released outside microbial cells by cellular lysis following microbial death in the intestine. This finding would be necessary to support the hypothesis of translocation of the enzyme through the intestinal wall.

Another important aspect to be considered is the permeability of the intestinal wall. A suitable transport membrane system for translocation of these enzymes would be required, without being necessarily accompanied by detrimental effects on the host.

In part, to verify if the dipeptidyl aminopeptidase activity in KO mice for Dpp-4 gene is a PepX-like, it may possibly be investigated by comparative analysis of the sequence of the enzyme present in the plasma and a gene library of the gut microbiota. Metagenomics approaches could be useful to validate the presence of this enzyme in the gut microbiota. 

Finding a relationship between the DPP-4 activity present in the plasma of KO mice for Dpp-4 gene and the enzyme expressed by the gut microbiota is a challenge that may contribute to reinforce the concept of enzyme translocation

CONCLUSION

Despite further research is necessary to validate the hypothesis made by Olivares et al., 2018  the results along with the information available in the literature, make possible to associate the gut microbial Dipeptidyl peptidase-4 (DPP-4) activity with effects on the host health.

Referenced article: Olivares M., Schüppel V., Hassan A. M., Beaumont M., Neyrinck A. M., Bindels L. B., et al. . (2018). The potential role of the dipeptidyl peptidase-4-like activity from the gut microbiota on the host health. Front. Microbiol. 9:1900. 10.3389/fmicb.2018.01900

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Diana López-Farfán