Lactobacillus-Based Therapy for Ulcerative Colitis: From Strain Heterogeneity and TCM-Mediated Modulation to Engineered Delivery and Precision Translation

Although Lactobacillus sensu lato is widely considered a promising microecological intervention for ulcerative colitis, its clinical translation remains severely constrained by strain-specific efficacy, host microenvironmental dependency, and the risk of opportunistic systemic translocation across a compromised intestinal barrier. The historical assumption of genus-level therapeutic uniformity is increasingly inadequate, as even closely related strains can exhibit divergent or occasionally adverse clinical outcomes. This functional heterogeneity is rooted in distinct genomic architectures encoding carbohydrate-active enzymes, bile salt hydrolases, and surface adhesins, which collectively govern the metabolic and colonization behavior of live biotherapeutics. Furthermore, selectively expanding target strains within a competitive, exclusionary gut microbiota represents a major clinical bottleneck. To address these barriers, this review synthesizes the common protective networks of lactobacilli and the taxonomic heterogeneity that defines their efficacy and safety boundaries. We review how traditional Chinese medicine constituents may selectively modulate target strains through the potential substrate-enzyme compatibility and summarize advanced bioengineering platforms, including postbiotics (inactivated-cell preparations) and cell-free effector components, and responsive biomaterials, designed to protect these metabolic pathways. By deconstructing the molecular logic of functional divergence and pharmacological targeting, we argue that a promising direction for precision microecological therapy may involve moving beyond broad taxonomic classification toward quantitative matching of strain-specific functional and enzymatic fingerprints. This paradigm shift demands rigorous causal validation, context-responsive delivery systems, and a regulatory transition toward quality control standards incorporating biochemical effector activity units alongside, rather than instead of, viable-cell enumeration. Schematic representation of precision Lactobacillus-based therapy for ulcerative colitis, integrating strain heterogeneity and shared metabolite–receptor networks, traditional Chinese medicine (TCM)-mediated targeted enzymatic modulation, bioengineered delivery platforms, and the restoration of colonic mucosal homeostasis