Bacterial enzyme found to weaken gut protective hormone signal

Gut microbiome research has traditionally examined which microbes live in the intestine and the small molecules they produce. However, a new study is suggesting that researchers may also need to consider another way bacteria interact with their hosts: through enzymes that act directly on molecules produced by the body.

Researchers from Peking University and collaborating institutions have identified a bacterial enzyme that can weaken a protective intestinal signal and aggravate colitis in a preclinical model.

The study focuses on dipeptidyl peptidase 4 (DPP4), an enzyme produced by the host. DPP4-like enzymes are also made by gut bacteria and can carry out similar functions to their host counterparts. The researchers refer to these enzymes as ’microbial-host-isozymes.’

However, bacterial DPP4 enzymes may not all act on the same molecules. The researchers wanted to determine whether differences in their substrate preferences could lead to distinct effects on intestinal health.

Bacterial DPP4 affects GLP-2

The team screened DPP4 enzymes produced by different gut microbes, assessing their enzymatic activity and ability to act on different substrates.

This analysis identified DPP4 from Bacteroides vulgatus, known as BvDPP4, as having a specific regulatory effect on glucagon-like peptide-2 (GLP-2). GLP-2 is an intestinal hormone involved in maintaining the gut barrier.

The researchers found that BvDPP4 could inactivate GLP-2. This reduced the protective effects of the intestinal signal, disrupting the intestinal barrier and aggravating colitis in the preclinical model.

The findings establish a connection between a specific bacterial enzyme, a defined host molecule and a disease-related effect. They also highlight the potential importance of enzyme activity and substrate preference when investigating interactions between the microbiome and its host.

Natural product inhibits bacterial enzyme

The researchers then investigated whether BvDPP4 could be directly inhibited. Screening natural products identified theaflavin as an inhibitor of BvDPP4. The compound also affected GLP-2 levels, suggesting that inhibiting the bacterial enzyme could help preserve the intestinal signal.

In a preclinical model, treatment with theaflavin ameliorated the worsening of colitis caused by BvDPP4.

The researchers say that these findings do not establish theaflavin as a treatment for inflammatory bowel disease in people. Its effectiveness and safety in humans would need to be assessed through further research.

Additional studies will also be needed to establish whether BvDPP4 and related microbial enzymes have a significant role in human disease.

Overall, the findings suggest that understanding the microbiome may require more than identifying which bacteria are present and which metabolites they produce. Examining the enzymes made by those microbes and the host molecules they can modify could provide another way of understanding how gut bacteria influence intestinal health and disease.