Studies of the putative functional relationships between the gut microbiota and host cardiometabolic diseases (CMDs), including atherosclerosis, diabetes, and metabolic dysfunction-associated steatohepatitis (MASH), have garnered unprecedented attention in recent years.1,2 Although causality has not yet been unequivocally established, interventions targeting the gut microbiota, such as antibiotics and fecal microbiota transplantation, have been demonstrated to improve health.3 Although such interventions show unique clinical value in specific scenarios such as recurrent Clostridioides difficile infection,4 they typically show interindividual variability in efficacy and raise safety concerns, altogether underscoring the need for safer, more precise, and targeted strategies.5 A deeper understanding of the molecular mechanisms by which gut microbiota exert their functions in health and disease will be crucial to such goals.
Enzymes are intracellular proteins that perform defined biological processes, and enzyme-targeting drugs constitute a significant proportion of current therapeutics.6 In recent years, growing evidence has indicated that gut microbial enzymes are key mediators of microbiota-derived functions.7 Such enzymes contribute to CMDs pathogenesis primarily through 3 mechanisms: generating bioactive metabolites that influence intestinal barrier integrity, inflammation, and other essential physiological processes; regulating the homeostasis of critical host metabolites, such as ceramides and cholesterol; and metabolizing xenobiotics derived from diet and drugs, thereby modulating nutrient absorption and drug efficacy.
Given the complexity of the functions of gut microbiota, it is arguably overly simplistic to categorize them as symbionts that are probiotic or pathogenic. Rather, by identifying and characterizing key microbial enzymes, we will be able to precisely modulate gut microbiota functions in health and disease. When a clear enzymatic cause is identified, therapies targeting microbial enzymes capitalize on a function-driven mechanism. This allows for precision that is independent of taxonomy and avoids off-target consequences stemming from compositional heterogeneity of the functional microbes across individuals. The operational feasibility and druggability of these therapies are further supported by mature enzyme-based therapy development paradigms. Ultimately, enzyme-targeted interventions are expected to work alongside conventional whole-microbiota or strain-level approaches, thereby enriching the toolkit for developing gut microbiome-based therapeutics.
