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.

α-防御素-5（HD5）占Paneth细胞杀菌肽活性的70％，并调节肠道微生物的体内稳态。我们先前曾报道过，rs4415345的G等位基因是HD5基因中的一个单核苷酸多态性（SNP），与II-IV级aGVHD的风险降低了约40％（PMID：30004111）。考虑到微生物群破坏在aGVHD中的作用，我们假设rs4415345G可能具有特定的肠道微生物群特征。

首先，我们分析了人类微生物组计划中来自248位受试者的相关宿主微生物群遗传数据，以检验我们在健康个体中的假设。假设许多微生物分类群与给定的SNP没有关联，我们使用10倍交叉验证的Lasso回归作为rs4415345与分类群相对丰度之间关联的测试。在99％的模拟中，保留了一个单一的分类单元（Odoribacter splanchnicus），并且始终与G等位基因呈正相关。接下来，我们评估了226例异基因HCT的第30天到第-6天之间收集的16S rRNA基因测序的研究粪便样本中的葡萄球菌是否与较少的aGVHD相关。65例（29％）患者出现内脏稻。的单变量风险比（HR）II-IV级aGVHD的内脏稻检出率为0.70,95％置信区间（95％CI）为0.44-1.10（P  = 0.12）。在-7天至+14天之间针对抗厌氧抗生素暴露进行调整的多变量分析得出了相似的结果（HR：0.70、95％CI：0.44-1.11，P  = 0.13）。

总之，rs4610776的G等位基因与健康个体中内脏稻的相对丰度较高，而同种HCT受体的aGVHD较低。在一个独立的数据集中，内脏稻的存在与aGVHD的风险降低了30％相关，尽管这种关联没有统计学意义。内脏O. splanchnicus是一种弱产热细菌，也能够产生吲哚，并在IBD患者中耗竭。丁酸酯和吲哚均可限制aGVHD。另外，响应于炎症刺激，内脏稻与较少的TNFα产生相关。我们建议O. splanchnicus可以降低rs4415345G个人的aGVHD风险。