An Alpha-Defensin Gene Single Nucleotide Polymorphism Modulates the Gut Microbiota and May Alter the Risk of Acute Graft-Versus-Host Disease

Abstract

α‐defensin‐5 (HD5) accounts for 70% of the bactericidal peptide activity of Paneth cells and regulates gut microbial homeostasis. We previously reported that the G allele of rs4415345, a single nucleotide polymorphism (SNP) in the gene for HD5, was associated with approximately 40% lower risk of grade II-IV aGVHD (PMID: 30004111). Considering the role of microbiota disruptions in aGVHD, we hypothesized that rs4415345G may have a specific gut microbiota signature. First, we analyzed linked host-microbiota genetic data from 248 subjects in the Human Microbiome Project to test our hypothesis in healthy individuals. With the assumption that many microbial taxa have no association with a given SNP, we used 10-fold cross-validated Lasso regression as a test of association between rs4415345 and taxon relative abundance. A single taxon (Odoribacter splanchnicus) was retained in 99% of the simulations, always with a positive association with the G allele. Next, we evaluated whether O. splanchnicus is associated with less aGVHD in 226 patients with a 16S rRNA gene-sequenced research stool sample collected between days -30 and -6 of allo-HCT. O. splanchnicus was present in 65 (29%) patients. The univariate hazard ratio (HR) of O. splanchnicus detectability for grade II-IV aGVHD was 0.70, with a 95% confidence interval (95%CI) of 0.44-1.10 (P = 0.12). Multivariable analysis, adjusted for anti-anaerobic antibiotic exposure between days -7 and +14 yielded a similar result (HR: 0.70, 95%CI: 0.44-1.11, P = 0.13). In summary, the G allele of rs4610776 is associated with the higher relative abundance of O. splanchnicus in healthy individuals and less aGVHD in allo-HCT recipients. In an independent dataset, O. splanchnicus presence was associated with a 30% reduction in risk for aGVHD, though this association did not reach statistical significance. O. splanchnicus is a weakly butyrogenic bacterium also capable of producing indole, and depleted in patients with IBD. Both butyrate and indole can limit aGVHD. In addition, O. splanchnicus correlates with less TNFα production in response to inflammatory stimuli. We propose that O. splanchnicus may reduce aGVHD risk in rs4415345G individuals.