Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer

Area of Science:

• Oncology
• Microbiome Research
• Metabolomics

Background:

• Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer mortality with limited treatment efficacy.
• Genetic factors alone do not fully explain patient responses to chemotherapy.
• The influence of diet and the gut microbiome on PDAC treatment remains largely unexplored.

Purpose of the Study:

• To investigate the role of microbiota-derived metabolites in PDAC treatment response.
• To identify specific metabolites that correlate with chemotherapy efficacy.
• To elucidate the mechanisms by which these metabolites influence cancer cell behavior and treatment outcomes.

Main Methods:

• Shotgun metagenomic sequencing and metabolomic profiling of PDAC patients.
• Faecal microbiota transplantation and dietary manipulation in humanized gnotobiotic mouse models.
• Loss- and gain-of-function experiments to determine the role of myeloperoxidase and indole-3-acetic acid (3-IAA).
• Analysis of reactive oxygen species (ROS) and autophagy pathways in cancer cells.

Main Results:

• The tryptophan metabolite indole-3-acetic acid (3-IAA) was enriched in patients responding to PDAC treatment.
• Administration of 3-IAA or modulation of the gut microbiota enhanced chemotherapy efficacy in preclinical models.
• Neutrophil-derived myeloperoxidase was essential for 3-IAA's therapeutic effect, leading to ROS accumulation and suppressed autophagy in cancer cells.
• Elevated 3-IAA levels correlated with improved therapy outcomes in independent human PDAC cohorts.

Conclusions:

• Microbiota-derived 3-IAA is a key factor influencing PDAC chemotherapy response.
• The mechanism involves myeloperoxidase-mediated oxidation of 3-IAA, ROS generation, and autophagy inhibition.
• These findings highlight the potential of targeting the gut microbiome and nutritional interventions to improve pancreatic cancer treatment.