Microbiome research often focuses on which microbes are present in the gut and what small molecules they produce. But gut bacteria also make enzymes that can act directly on molecules produced by the host. Researchers from Peking University and collaborating institutions now report that one such bacterial enzyme can weaken a protective intestinal signal and aggravate colitis in a preclinical model.
Published in Science China Life Sciences, the study focuses on dipeptidyl peptidase 4 (DPP4). DPP4 is produced by the host, but DPP4-like enzymes are also made by gut microbes. Because these microbial enzymes can perform functions similar to host enzymes, the researchers describe them as “microbial-host-isozymes.” An important unanswered question has been whether different microbial DPP4s act on the same targets, or whether their substrate preferences give them distinct biological effects.
To address this question, the team screened DPP4 enzymes from different gut microbes for enzymatic activity and substrate adaptability. The analysis highlighted DPP4 from Bacteroides vulgatus , or BvDPP4, which showed a specific regulatory effect on glucagon-like peptide-2 (GLP-2). The researchers found that BvDPP4 inactivated GLP-2 and, in doing so, disrupted the intestinal barrier and aggravated colitis.
These results link a specific bacterial enzyme with a defined host substrate and a disease-related phenotype. They also suggest that enzyme activity and substrate preference are useful factors to consider when studying microbiome-host interactions.
The researchers next asked whether BvDPP4 could be directly inhibited. A screen of natural products identified theaflavin as an inhibitor of BvDPP4 that also regulated GLP-2 levels. In a preclinical model, theaflavin treatment ameliorated the worsening of colitis induced by BvDPP4. The results do not establish theaflavin as a treatment for inflammatory bowel disease in people; its clinical efficacy and safety would require further study. Further work is also needed to determine the relevance of BvDPP4 and related microbial enzymes to human disease.
Overall, the study characterizes an interaction between BvDPP4 and GLP-2 and provides evidence that microbial enzyme activity can influence intestinal inflammation in this preclinical model.
Science China Life Sciences