Colon cancer cachexia remodels gut microbiota and metabolite profiles in a murine model

Background: Cancer cachexia is a multifactorial syndrome involving involuntary weight loss, muscle atrophy, and systemic inflammation, contributing significantly to mortality in advanced cancers. Although gut microbiota dysbiosis has been implicated in metabolic and inflammatory disturbances relevant to cachexia, the functional metabolic consequences remain poorly understood. Using a murine model of colon carcinoma 26 (C26)-induced cachexia, we integrated metagenomic sequencing and non-targeted metabolomics to delineate cachexia-specific microbial and metabolic alterations compared to non-cachexia tumor-bearing and healthy controls. Methods: To investigate colon cancer cachexia-induced remodeling of the gut ecosystem, we established mouse models using cachexia-inducing and non-cachexia-inducing colon carcinoma 26 cells. Food intake, body weight, muscle and fat weight were monitored. Cecal content was collected for metagenomic sequencing and non-targeted metabolome analysis. Results: Colon cancer cachexia models were successfully established as evidenced by reduced food intake, decreased body weight, and loss of muscle and fat mass. Metagenomic sequencing revealed decreased microbial diversity and distinct structural separation in colon cancer cachexia mice, with enriched genera including Bacteroides, Phocaeicola, Escherichia, Enterobacter, Helicobacter, and Proteus, and depletion of butyrate- and bile acid-producing taxa including Alistipes, Eubacterium, Roseburia, Clostridium, and Hungatella. Functional analysis indicated significant alterations in metabolic pathways. Metabolomic profiling identified reduced levels of ursodeoxycholic acid (UDCA), hyodeoxycholic acid (HDCA), branched-chain amino acids, and bacterial amino acid metabolites (bAAms), alongside enrichment in nucleotide and steroid hormone metabolism. Correlation analyses demonstrated significant associations between specific microbial genera and altered metabolites. Conclusions: Colon cancer cachexia remodeled the gut microbiota and metabolite landscape in a murine model. These findings suggested specific bacterial taxa and metabolites as potential biomarkers and therapeutic targets, offering new directions for the prevention and treatment of cancer cachexia. This study reveals distinct taxonomic and functional shifts in the gut microbiota alongside associated metabolic disruptions, offering new insights into cachexia pathophysiology and potential therapeutic targets.