Causal relationships between gut microbiota and programmed cell death protein 1/programmed cell death-ligand 1: A...

Area of Science:

• Microbiome research
• Immunotherapy
• Genetics

Background:

• Clinical studies suggest gut microbiota impacts immune checkpoint blockade (ICB) therapy efficacy.
• The precise causal relationship and specific microbial players remain unclear due to confounding factors.
• Identifying these microbes is crucial for optimizing ICB treatment outcomes.

Purpose of the Study:

• To establish a causal link between the gut microbiota and PD-1/PD-L1 expression.
• To identify specific microbial species that could serve as biomarkers for ICB therapy.
• To enhance the predictive power of immunotherapy response through microbiome analysis.

Main Methods:

• Utilized bidirectional two-sample Mendelian randomization (MR) to investigate causality.
• Employed two distinct data thresholds for robust analysis.
• Conducted species-level microbiota genome-wide association studies (GWAS) for validation.

Main Results:

• Genus_Holdemanella negatively correlated with PD-1; Genus_Prevotella9 positively correlated with PD-1.
• Several bacteria, including Rhodospirillales, Ruminococcaceae_UCG005, and Coprococcus_2, showed positive correlations with PD-L1.
• Firmicutes and specific ClostridialesvadinBB60group, Ruminococcaceae, and Ruminococcaceae_UCG014 showed negative correlations with PD-L1.
• Species_Parabacteroides_unclassified was identified as a significant species in further analysis.

Conclusions:

• Established causal relationships between specific gut bacteria and PD-1/PD-L1 levels.
• Identified potential microbial biomarkers for predicting response to immune checkpoint blockade therapy.
• MR analyses were robust, with no significant heterogeneity or pleiotropy detected.