Metabolomics-based and functional validation to explore the effect of the gut microbe-associated metabolite guanidinoacetic acid on rectal adenocarcinoma

ABSTRACT:

Objective: The gut microbiota plays a crucial role in rectal adenocarcinoma (READ). Nonetheless, little is known about corresponding changes in gut microbiota–host interactions. This study aimed to identify the structure of the gut microbiota and the characteristics of faecal metabolites in patients with READ.

Methods: Faecal samples were collected from 33 individuals with READ and 34 healthy controls (HC), with post-neoadjuvant treatment faecal samples also collected from the 5 READ patients, and 16S rRNA gene amplification sequencing and untargeted liquid chromatography-mass spectrometry metabolomics analysis were performed. Methods such as weighted correlation network analysis (WGCNA) and molecular docking to determine target gene–related information, and to explore the effects of guanidinoacetic acid (GAA) on colorectal cancer cell lines through in vitro experiments.

Results: Firmicutes, Proteobacteria, Actinobacteria, and Bacteroidetes were the most abundant phyla in patients with READ and healthy controls (HC). At the genus level, Peptostreptococcus exhibited marked enrichment in the READ cohorts, whereas Faecalibacterium was dominant in the HC group. The predicted microbial functional analysis indicated a significant increase in the metabolism of betaine, guanidinoacetic acid (GAA), L-tryptophan, arachidonic acid, and arachidic acid. Moreover, by comparing the faecal metabolites between the HC and READ groups,Pearson’s correlation analysis demonstrated significant interactions between six microbiota taxa and nine metabolites, suggesting specific human metabolic pathways. The cellular function results demonstrated that GAA promoted the proliferation, invasion, and migration of colorectal cells while inhibiting apoptosis. Further analysis revealed that GAA may might promote CRC progression of colorectal cancer by affecting molecules such as KLB, CA2, CSTG, CYP4F12, and GZBM.

Conclusion: This study provides a foundational guide for the systematic and multidimensional evaluation of the contribution of the gut microbiota and its metabolites to READ and identifies a metabolite (namely, GAA) that may be of important in the occurrence, development, and treatment of READ, offering a new perspective for further research on READ.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS12620 | MetaboLights | 2025-06-29

REPOSITORIES: MetaboLights