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Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice

机译：在人类和小鼠的异基因造血干细胞移植后使用广谱抗生素与GVHD相关的死亡率增加

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After allogeneic hematopoietic stem cell transplantation (allo-HSCT), intestinal bacteria modulate risks of infection and graft-versus-host disease (GVHD). Neutropenic fever is common and treated with a choice of clinically equivalent antibiotics that target obligately anaerobic bacteria (anaerobes) to varying degrees. We retrospectively examined 857 allo-HSCT recipients and found that treatment of neutropenic fever with imipenem-cilastatin and piperacillin-tazobactam was associated with increased GVHD-related mortality at 5 years (21.5% in imipenem-cilastatin-treated patients vs. 13.1% in untreated patients, p=0.025, and 19.8% in piperacillin-tazobactam-treated patients vs. 11.9% in untreated patients, p=0.007). However, two other antibiotics also used to treat neutropenic fever, aztreonam and cefepime, were not associated with GVHD-related mortality (p=0.78 and p=0.98, respectively). Analysis of stool microbiota composition showed that piperacillin-tazobactam administration was associated with increased compositional perturbation. Studies in mouse models demonstrated similar effects of these antibiotics, as well as aggravated GVHD mortality with imipenem-cilastatin or piperacillin-tazobactm compared to aztreonam (p<0.01 and p<0.05, respectively). We found pathological evidence for increased GVHD in the colon of imipenem-cilastatin-treated mice (p<0.05), but no differences in short-chain fatty acid concentrations or regulatory T cells numbers. Notably, imipenem-cilastatin treatment of mice with GVHD led to loss of the protective lining of mucus in the colon (p<0.01) and intestinal barrier function was compromised (p<0.05). Sequencing of mouse stool specimens showed expansion of Akkermansia muciniphila (p<0.001), a commensal bacterium with mucus-degrading capabilities, raising the possibility that mucus degradation can contribute to murine GVHD. We demonstrate an underappreciated risk for antibiotics with activity against anaerobes to exacerbate colonic GVHD after transplant.
机译：同种异体造血干细胞移植（allo-HSCT）后，肠道细菌调节感染和移植物抗宿主病（GVHD）的风险。嗜中性白血球减少症很普遍，并且可以选择多种临床上等效的抗生素治疗，这些抗生素可以不同程度地靶向专性厌氧细菌（厌氧菌）。我们回顾性检查了857名异源HSCT接受者，发现用亚胺培南-西司他丁和哌拉西林-他唑巴坦治疗中性粒细胞低热与5年时GVHD相关死亡率增加有关（亚胺培南-西司他丁治疗组为21.5％，未治疗组为13.1％）。在接受哌拉西林-他唑巴坦治疗的患者中，p = 0.025和19.8％，而在未治疗的患者中为11.9％，p = 0.007）。然而，另外两种也用于治疗中性粒细胞减少的抗生素，氨曲南和头孢吡肟，与GVHD相关的死亡率无关（分别为p = 0.78和p = 0.98）。粪便微生物群组成的分析表明，哌拉西林-他唑巴坦的给药与组成扰动增加有关。在小鼠模型中的研究表明，与氨曲南相比，亚胺培南-西司他丁或哌拉西林-他唑巴特姆对这些抗生素的作用相似，并且加重了GVHD的死亡率（分别为p <0.01和p <0.05）。我们发现在经亚胺培南-西司他丁治疗的小鼠结肠中GVHD升高的病理学证据（p <0.05），但短链脂肪酸浓度或调节性T细胞数量无差异。值得注意的是，亚胺培南-西司他丁对GVHD小鼠的治疗导致结肠粘液保护层的丧失（p <0.01），肠屏障功能受损（p <0.05）。小鼠粪便标本的测序显示，有黏液降解能力的共生细菌Akkermansia muciniphila（p <0.001）扩增，增加了黏液降解可能导致鼠GVHD的可能性。我们证明了具有抗厌氧菌活性的抗生素在移植后加重结肠GVHD的风险被低估。

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