Prolonged Suppression of Butyrate-Producing Bacteria Is Associated With Acute Gastrointestinal Graft-vs-Host Disease and Transplantation-Related Mortality After Allogeneic Stem Cell Transplantation
Prolonged Suppression of Butyrate-Producing Bacteria Is Associated With Acute Gastrointestinal Graft-vs-Host Disease and Transplantation-Related Mortality After Allogeneic Stem Cell Transplantation
复制标题
DOI：
10.1093/cid/ciab500
复制
发表时间：
2021-07-10
影响因子：
11.8
通讯作者：
Weber, Daniela
中科院分区：
文献类型：
--
作者：
Meedt, Elisabeth;Hiergeist, Andreas;Weber, Daniela
异基因造血干细胞移植后早期脂肪酸减少。这是重要的，因为细菌代谢物如丁酸盐具有重要的抗炎功能和对肠上皮完整性的稳定作用。因此，产酪菌的损失与移植物抗宿主病的严重程度增加和移植相关死亡率增加相关。背景产酪菌在肠道微生物组稳态和肠上皮完整性中起重要作用。先前的研究已经证明了在异基因干细胞移植（ASCT）后给予短链脂肪酸（如丁酸盐）和保护免受急性移植物抗宿主病（GvHD）之间的关联。方法在本研究中，我们检测了28例健康供体和201例ASCT后患者的产丁酸菌丰度和产丁酸能力。我们前瞻性地收集了一系列粪便样本，并对粪便核酸提取物中的丁酸盐产生细菌酶丁酰辅酶A（CoA）：乙酸CoA转移酶（BCoAT）进行了聚合酶链反应分析。结果我们的数据表明，在ASCT过程中的早期，产丁酸菌的强有力的和长期的抑制。在多变量分析中，第0天（移植当天）前早期使用广谱抗生素被确定为与低BCoAT拷贝数相关的独立因素（比值比，0.370 [95%置信区间，0.175 - 0.783]; P = 0.009）。减少的酪酸与微生物多样性的其他生物标志物相关，如低3-吲哚硫酸酯水平，梭菌目丰度降低以及低逆辛普森指数和有效香农指数（均P < .001）。GvHD发作时低BCoAT拷贝数与GI-GvHD严重程度相关（P = .002），并与显著较高的GvHD相关死亡率相关（P = .04）。此外，第30天低BCoAT拷贝数与显著较高的移植相关死亡率相关（P = 0.02）。结论我们的研究结果与以下假设一致，即微生物组的改变在GvHD发病机制中起重要作用，微生物参数如BCoAT可能作为生物标志物来识别具有致死性GI-GvHD高风险的患者。
Butyrogenic commensals diminish early after allogeneic stem cell transplantation. This is significant because bacterial metabolites such as butyrate have important anti-inflammatory functions and stabilizing effects on gut epithelial integrity. Accordingly, loss of butyrogenic bacteria is associated with increased severity of graft-vs-host disease and increased transplantation-related mortality.Background Butyrogenic bacteria play an important role in gut microbiome homeostasis and intestinal epithelial integrity. Previous studies have demonstrated an association between administration of short-chain fatty acids like butyrate and protection from acute graft-vs-host disease (GvHD) after allogeneic stem cell transplantation (ASCT). Methods In the current study, we examined the abundance and butyrogenic capacity of butyrate-producing bacteria in 28 healthy donors and 201 patients after ASCT. We prospectively collected serial stool samples and performed polymerase chain reaction analysis of the butyrate-producing bacterial enzyme butyryl-coenzyme A (CoA):acetate CoA-transferase (BCoAT) in fecal nucleic acid extracts. Results Our data demonstrate a strong and prolonged suppression of butyrogenic bacteria early in the course of ASCT. In a multivariable analysis, early use of broad-spectrum antibiotics before day 0 (day of transplantation) was identified as an independent factor associated with low BCoAT copy numbers (odds ratio, 0.370 [95% confidence interval, .175-.783]; P = .009). Diminished butyrogens correlated with other biomarkers of microbial diversity, such as low 3-indoxylsulfate levels, reduced abundance of Clostridiales and low inverse Simpson and effective Shannon indices (all P < .001). Low BCoAT copy numbers at GvHD-onset were correlated with GI-GvHD severity (P = .002) and associated with a significantly higher GvHD-associated mortality rate (P = .04). Furthermore, low BCoAT copy numbers at day 30 were associated with a significantly higher transplantation-related mortality rate (P = .02). Conclusions Our results are consistent with the hypothesis that alterations in the microbiome play an important role in GvHD pathogenesis and that microbial parameters such as BCoAT might serve as biomarkers to identify patients at high risk of lethal GI-GvHD.