Strain-level genetic heterogeneity and colonization dynamics drive microbiome therapeutic efficacy

Area of Science:

• Oncology
• Immunotherapy
• Microbiome Research

Background:

• Fecal microbiota transplantation (FMT) shows promise in immunotherapy.
• Efficacy of FMT in non-small-cell lung cancer (NSCLC) is not well understood.
• Previous studies show inconsistent results regarding microbiome's role in cancer therapy.

Purpose of the Study:

• To investigate the efficacy of FMT in advanced PD-L1-negative NSCLC.
• To explore the role of specific bacterial strains within species in therapeutic outcomes.
• To identify mechanisms driving variable responses to FMT and immunotherapy.

Main Methods:

• Conducted a single-arm trial of FMT in advanced NSCLC patients.
• Analyzed over 2,000 metagenomes using a high-resolution strain-tracking framework.
• Correlated bacterial strain engraftment with clinical outcomes and identified species-intrinsic traits.

Main Results:

• FMT improved anti-PD-1 efficacy and progression-free survival in NSCLC patients.
• Identified distinct strains within species having opposing therapeutic effects, resolving prior inconsistencies.
• Successful colonization by specific beneficial strain variants correlated with positive clinical outcomes.

Conclusions:

• FMT can enhance immunotherapy in PD-L1-negative NSCLC.
• Bacterial strain-level analysis is crucial for understanding microbiome-mediated therapeutic effects.
• Identified 38 priority species for developing next-generation microbiome-based precision therapeutics.