Modelling Fusobacterium lifestyles transitions by integrating transcriptomics and growth data

Area of Science:

• Microbiology
• Cancer Biology
• Metabolic Engineering

Background:

• Bacteria within the tumor microenvironment significantly influence cancer development and progression.
• Fusobacterium nucleatum enrichment in colorectal cancer (CRC) is linked to increased mortality.
• The metabolic adaptability of F. nucleatum is crucial for its survival in dynamic environments, but its mechanistic link to virulence and cancer phenotypes remains unclear.

Purpose of the Study:

• To characterize the basal physiology of F. nucleatum.
• To develop a genome-scale metabolic model (GEM) for simulating F. nucleatum phenotypes under various nutritional conditions.
• To investigate the metabolic adaptations of F. nucleatum during interactions with human cells using gene expression data.

Main Methods:

• Reconstruction of an experimentally validated genome-scale metabolic model (GEM) for F. nucleatum.
• Simulation of bacterial phenotypes under different nutritional conditions using the GEM.
• Integration of in vitro gene expression data to contextualize the metabolic model and simulate cell-interaction phenotypes.

Main Results:

• Bacterial adhesion to human cells induces metabolic rewiring, including suppressed branched-chain amino acid catabolism and increased methionine and serine uptake.
• Bacterial invasion prompts partial reactivation of central carbon and nitrogen metabolic pathways.
• Shifts in short-chain fatty acid production and redox balance were identified, potentially influencing bacterial persistence and the tumor microenvironment.

Conclusions:

• F. nucleatum exhibits significant metabolic plasticity in response to host cell interactions.
• Metabolic rewiring during adhesion and invasion suggests mechanisms for bacterial persistence and modulation of the tumor microenvironment.
• This study provides a mechanistic framework for understanding F. nucleatum's role in CRC through its metabolic adaptations.