Engineered Lactobacillus rhamnosus Producing 3-Hydroxybutyrate: A Dual-Action Therapeutic Strategy for Colon Cancer Cachexia.

3-hydroxybutyrate (3-HB), an essential endogenous metabolite, shows significant therapeutic potential in several disease contexts. However, its clinical application has been hampered by limitations, such as adverse effects on the gut microbiota. This study introduces a genetically engineered strain of Lactobacillus rhamnosus GG (LGGK) that integrates the benefits of 3-HB production with the probiotic properties of LGG. Using a murine colon cancer cachexia (CAC) model, LGGK supplementation significantly improved survival, reduced tumor progression, and alleviated muscle wasting. LGGK restored gut microbial diversity, increased the abundance of beneficial bacteria, and increased the production of short-chain fatty acids while reducing harmful microbial populations. In addition, LGGK supplementation demonstrated anti-inflammatory effects, effectively reducing elevated pro-inflammatory cytokines in serum and skeletal muscle. These findings highlight LGGK as a dual-action therapeutic approach that utilizes the metabolic benefits of 3-HB and the gut-modulating properties of LGG. This innovation offers a promising strategy for the treatment of CAC and potentially other metabolic and inflammatory disorders, and highlights the potential of engineered probiotics in advanced therapeutic applications.