Causal relationships between gut microbiota and programmed cell death protein 1/programmed cell death-ligand 1: A bidirectional Mendelian randomization study

Abstract

BackgroundMultiple clinical studies have indicated that the gut microbiota influences the effects of immune checkpoint blockade (ICB) therapy comprising PD-1/PD-L1 inhibitors, but the causal relationship is unclear. Because of numerous confounders, many microbes related to PD-1/PD-L1 have not been identified. This study aimed to determine the causal relationship between the microbiota and PD-1/PD-L1 and identify possible biomarkers for ICB therapy.MethodWe used bidirectional two-sample Mendelian randomization with two different thresholds to explore the potential causal relationship between the microbiota and PD-1/PD-L1 and species-level microbiota GWAS to verify the result.ResultIn the primary forward analysis, genus_Holdemanella showed a negative correlation with PD-1 [βIVW = -0.25; 95% CI (-0.43 to -0.07); PFDR = 0.028] and genus_Prevotella9 showed a positive correlation with PD-1 [βIVW = 0.2; 95% CI (0.1 to 0.4); PFDR = 0.027]; order_Rhodospirillales [βIVW = 0.2; 95% CI (0.1 to 0.4); PFDR = 0.044], family_Rhodospirillaceae [βIVW = 0.2; 95% CI (0 to 0.4); PFDR = 0.032], genus_Ruminococcaceae_UCG005 [βIVW = 0.29; 95% CI (0.08 to 0.5); PFDR = 0.028], genus_Ruminococcus_gnavus_group [βIVW = 0.22; 95% CI (0.05 to 0.4); PFDR = 0.029], and genus_Coprococcus_2 [βIVW = 0.4; 95% CI (0.1 to 0.6); PFDR = 0.018] were positively correlated with PD-L1; and phylum_Firmicutes [βIVW = -0.3; 95% CI (-0.4 to -0.1); PFDR = 0.031], family_ClostridialesvadinBB60group [βIVW = -0.31; 95% CI (-0.5 to -0.11), PFDR = 0.008], family_Ruminococcaceae [βIVW = -0.33; 95% CI (-0.58 to -0.07); PFDR = 0.049], and genus_Ruminococcaceae_UCG014 [βIVW = -0.35; 95% CI (-0.57 to -0.13); PFDR = 0.006] were negatively correlated with PD-L1. The one significant species in further analysis was species_Parabacteroides_unclassified [βIVW = 0.2; 95% CI (0-0.4); PFDR = 0.029]. Heterogeneity (P > 0.05) and pleiotropy (P > 0.05) analyses confirmed the robustness of the MR results.

Causality between gut microbiota and gastroesophageal reflux disease: A two-sample Mendelian randomization analysis

“…Moreover, individuals with Barrett's esophagus exhibit reduced esophageal microbial diversity, and gram-negative bacteria, such as Prevotella species and H. pylori, may contribute to the pathogenesis of the disease [58]. A Mendelian analysis revealed a positive correlation between the abundance of genus Prevotella 9 and PD-1 expression [59]. PD-1 expression is signi cantly upregulated in gastrointestinal diseases, such as GERD, peptic ulcer disease, and gastritis-duodenitis [60].…”

Causal effects of gut microbiota on autism spectrum disorder: A two-sample mendelian randomization study

“…Since the number of eligible IVs ( P < 5 × 10 -8 ) was extremely small, a relatively more comprehensive threshold ( P < 5 × 10 -5 ). [21,22] To satisfy the MR hypothesis, we performed a linkage disequilibrium (LD) analysis (R2 < 0.001, clumping distance = 10,000kb) and removed the non-compliant SNPs. Palindrome SNPs were removed to prevent alleles from influencing causality results between the GM taxa and ASD.…”

The causal relationship of colorectal cancer on schizophrenia: A Mendelian randomization study

“…Subsequently, the SNPs with effect allele frequency (EAF) < 0.01 were excluded. [21] After harmonization in the 2 GWASs, 6 SNPs (rs72746180, rs12135286, rs16892766, rs6066825, rs6983267, and rs33087967) were selected as IVs (Supplementary Table S1, http://links.lww.com/MD/K155).…”