Gut microbiota DPP4-like enzymes are increased in type-2 diabetes and contribute to incretin inactivation.

BACKGROUND: The gut microbiota controls broad aspects of human metabolism and feeding behavior, but the basis for this control remains largely unclear. Given the key role of human dipeptidyl peptidase 4 (DPP4) in host metabolism, we investigate whether microbiota DPP4-like counterparts perform the same function. RESULTS: We identify novel functional homologs of human DPP4 in several bacterial species inhabiting the human gut, and specific associations between Parabacteroides and Porphyromonas DPP4-like genes and type 2 diabetes (T2D). We also find that the DPP4-like enzyme from the gut symbiont Parabacteroides merdae mimics the proteolytic activity of the human enzyme on peptide YY, neuropeptide Y, gastric inhibitory polypeptide (GIP), and glucagon-like peptide 1 (GLP-1) hormones in vitro. Importantly, administration of E. coli overexpressing the P. merdae DPP4-like enzyme to lipopolysaccharide-treated mice with impaired gut barrier function reduces active GIP and GLP-1 levels, which is attributed to increased DPP4 activity in the portal circulation and the cecal content. Finally, we observe that linagliptin, saxagliptin, sitagliptin, and vildagliptin, antidiabetic drugs with DPP4 inhibitory activity, differentially inhibit the activity of the DPP4-like enzyme from P. merdae. CONCLUSIONS: Our findings confirm that proteolytic enzymes produced by the gut microbiota are likely to contribute to the glucose metabolic dysfunction that underlies T2D by inactivating incretins, which might inspire the development of improved antidiabetic therapies.

The microbiota composition drives personalized nutrition: Gut microbes as predictive biomarkers for the success of weight loss diets.

The investigation of the human gut microbiome during recent years has permitted us to understand its relevance for human health at a systemic level, making it possible to establish different functional axes (e.g., the gut-brain, gut-liver, and gut-lung axes), which support the organ-like status conferred to this microecological component of our body. The human gut microbiota is extremely variable but modifiable via diet, a fact that allows targeting of microbes through defined dietary strategies to uncover cost-effective therapies to minimize the burden of non-communicable diseases such as pandemic obesity and overweight and its metabolic comorbidities. Nevertheless, randomly controlled dietary interventions regularly exhibit low to moderate degrees of success in weight control, making their implementation difficult in clinical practice. Here, we review the predictive value of the baseline gut microbiota configurations to anticipate the success of dietary interventions aimed at weight loss, mostly based on caloric restriction regimes and oral fiber supplementation. This emergent research concept fits into precision medicine by considering different diet patterns and adopting the best one, based on the individual microbiota composition, to reach significant adiposity reduction and improve metabolic status. We review the results from this fresh perspective of investigation, taking into account studies released very recently. We also discuss some future outlooks in the field and potential pitfalls to overcome with the aim of gaining knowledge in the field and achieving breakthroughs in personalized nutrition.