Lachnospiraceae and Its Metabolite Malate Act in Concert to Repair Gut Microbiota Imbalance and Block Colorectal Cancer Progression

Background:Gut microbiota dysbiosis is a crucial driver of the initiation and progression of colorectal cancer (CRC), where functional gut microbes and their metabolites play key roles in the microecological regulation of CRC. Currently, the association between Lachnospiraceae and CRC progression, as well as the underlying mechanisms, remains incompletely understood and warrants further investigation.Methods:Bioinformatics analysis was performed to explore the co-pathway association between gut microbiota and metabolites in CRC patient samples. In vivo animal models were established to assess the regulatory effects of Lachnospiraceae on CRC tumorigenesis and gut microbiota homeostasis. The anti-CRC activities of Lachnospiraceae and its metabolite malate were investigated using in vitro experiments that measured cell viability, proliferation, apoptosis, and colony formation. Western blotting was performed to detect the expression levels of key proteins in the Wingless/Integrated (Wnt)/β-catenin signaling pathway.Results:Bioinformatics analysis revealed that malate was significantly downregulated in CRC patients, accompanied by gut microbiota dysbiosis driven predominantly by short-chain fatty acid (SCFA)-related Firmicutes such as Lachnospiraceae and Ruminococcaceae. In vivo, Lachnospiraceae restored gut microbiota homeostasis, reduced tumor number, and decreased tumor load. In vitro, Lachnospiraceae suppressed colorectal tumorigenesis and increased colonic D-malate levels. Conclusion:Lachnospiraceae bacterium biologics abstracts accession-2278 (BAA-2278) is associated with anti-CRC effects in preclinical models, potentially mediated through regulation of gut microbiota homeostasis and inhibition of Wnt/β-catenin signaling via its metabolite malate.