Current methods for modulating the gut microbiota, such as FMT and antibiotics, generally alter the microbial community indiscriminately and come with challenges including infection risks or drug resistance. Thus, can we regulate specific microbial strains without affecting the overall community structure? Gut microbial enzymes are key players of microorganisms, but their nuanced roles in host metabolism, including their potential for coevolutionary mimicry of host enzymes, remain largely unexplored. Here, we introduce the concept of 'Microbial-Host-Isozyme' and uncovers a wide variety of isozymes from microbiota, capable of mimicking host enzyme functions and even cross-species regulation of metabolic diseases. Microbial DPP4 degrades active GLP-1, impacting glucose tolerance. Host DPP4 inhibitors like Sitagliptin are ineffective against microbial DPP4, unveiling a new variable in treatment outcomes. Through high-throughput screening, we identified Dau-d4, a potent microbial DPP4 inhibitor that ameliorates glucose imbalances in mice. Our work offers the prospect of targeted microbial strain regulation, providing new avenues for the precision treatment of metabolic diseases.