Microbes dwelling in the human gut sometimes produce molecules that mimic host functions. These bugs synthesize androgens that complicate prostate cancer treatment and neurotransmitters that modulate sensory decisions such as attraction or aversion to odors or food choice (1,2). These functions, along with the influence of microbial molecules on health, inspired Peking University School of Basic Medical Sciences physiologist Changtao Jiang and his colleagues to devise tools to identify microbial-human isozymes: microbial enzymes with the same functions as but different structures from human enzymes. 

“Many of these microbial-host isozymes lack sequence conservation, making it difficult to identify [them] through sequencing-based technology,” wrote Jiang in an email. His team developed a screening platform that detects the activity of these enzymes in gut bacterial communities. Their workflow identified a microbial dipeptidyl peptidase 4 (DPP4), where the human equivalent is a therapeutic target for treating type 2 diabetes, suggesting a potential new way to improve diabetes treatment (3).

To develop their isozyme identification tool, Jiang’s team first collected fecal samples from ten healthy human volunteers and cultured them in an optimized medium that supports and maintains microbial growth, composition, and diversity. Then they selected 110 enzymes relevant to various human diseases. They measured the activity of protein extracts from the stool-derived bacterial communities using the corresponding enzymatic assays. 

This is a really nice example of how an enzyme in the gut microbiome can contribute to human health. 
- Catherine Abbott, Flinders University

Microbial DPP4 (mDPP4) activity stood out. Human DPP4 degrades glucagon-like peptide-1 (GLP-1), a hormone promoting insulin secretion in certain conditions. Because GLP-1 improves glycemic control, the FDA approved DPP4 inhibitors as a way to help treat type 2 diabetes. However, DPP4 inhibitors can have variable effectiveness.

Jiang and his colleagues observed that the mDPP4 isozyme decreases GLP-1 activity in mice with leaky guts derived from high-fat diets. GLP-1 levels remained unaffected by mDPP4 in  mice fed normal diets. 

“It was surprising to us that mDPP4 could degrade host GLP-1 in vivo,” wrote Jiang. As a macromolecule, mDPP4 may face challenges crossing the intestinal barrier to access GLP-1 under normal conditions, he added, so it made sense that it only becomes relevant in mice with a leaky gut. 

The team then tested whether clinically relevant human DPP4 inhibitors could also impair mDPP4. They found that the drugs’ inhibitory effects were significantly weaker for the microbial form of the enzyme. “mDPP4 is an important explanation for the variation in the responses [to] DPP4 inhibitors,” Jiang wrote.

Since these results place mDPP4 as a therapeutic target for diabetes, Jiang’s team screened for potential inhibitors. They found that daurisoline (Dau), a small molecule present in some medicinal herbs, showed strong inhibitory effects against mDPP4. Treating a mouse model of diabetes with Dau-d4, an optimized Dau derivative, significantly improved their glucose metabolism. Jiang and his colleagues are now interested in translating these findings to humans. Yet, he acknowledged, they need to first provide more evidence of Dau derivatives’ effects and safety and are currently planning experiments to achieve that. 

Catherine Abbott, a molecular biologist at Flinders University who did not participate in this study, said that the evidence supporting the team’s conclusion is very solid. “They’ve done a lot of work,” she added. “This is a really nice example of how an enzyme in the gut microbiome can contribute to human health.”

References

1. Pernigoni, N. et al. Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis. Science  374, 216-224 (2021).
2. O’Donnell, M. P. et al. A neurotransmitter produced by gut bacteria modulates host sensory behaviour. Nature  583, 415-420 (2020).
3. Wang, K. et al. Microbial-host-isozyme analyses reveal microbial DPP4 as a potential antidiabetic target. Science  381, eadd5787 (2023).