Khuat Lam T, Le Catherine T, Pai Chien-Chun Steven, Shields-Cutler Robin R, Holtan Shernan G, Rashidi Armin, Parker Sarah L, Knights Dan, Luna Jesus I, Dunai Cordelia, Wang Ziming, Sturgill Ian R, Stoffel Kevin M, Merleev Alexander A, More Shyam K, Maverakis Emanual, Raybould Helen E, Chen Mingyi, Canter Robert J, Monjazeb Arta M, Dave Maneesh, Ferrara James L M, Levine John E, Longo Dan L, Abedi Mehrdad, Blazar Bruce R, Murphy William J
Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.
Department of Biology, Macalester College, Saint Paul, MN 55105, USA.
Sci Transl Med. 2020 Nov 25;12(571). doi: 10.1126/scitranslmed.aay7713.
The efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is limited by acute and chronic graft-versus-host disease (GVHD). The impact of obesity on allo-HSCT outcomes is poorly understood. Here, we report that obesity had a negative and selective impact on acute gut GVHD after allo-HSCT in mice with diet-induced obesity (DIO). These animals exhibited increased gut permeability, endotoxin translocation across the gut, and radiation-induced gastrointestinal damage after allo-HSCT. After allo-HSCT, both male and female DIO mouse recipients showed increased proinflammatory cytokine production and expression of the GVHD marker ST2 (IL-33R) and MHC class II molecules; they also exhibited decreased survival associated with acute severe gut GVHD. This rapid-onset, obesity-associated gut GVHD depended on donor CD4 T cells and occurred even with a minor MHC mismatch between donor and recipient animals. Retrospective analysis of clinical cohorts receiving allo-HSCT transplants from unrelated donors revealed that recipients with a high body mass index (BMI, >30) had reduced survival and higher serum ST2 concentrations compared with nonobese transplant recipients. Assessment of both DIO mice and allo-HSCT recipients with a high BMI revealed reduced gut microbiota diversity and decreased Clostridiaceae abundance. Prophylactic antibiotic treatment protected DIO mouse recipients from endotoxin translocation across the gut and increased inflammatory cytokine production, as well as gut pathology and mortality, but did not protect against later development of chronic skin GVHD. These results suggest that obesity-induced alterations of the gut microbiota may affect GVHD after allo-HSCT in DIO mice, which could be ameliorated by prophylactic antibiotic treatment.
异基因造血干细胞移植（allo-HSCT）的疗效受到急性和慢性移植物抗宿主病（GVHD）的限制。肥胖对allo-HSCT结果的影响尚不清楚。在此，我们报告肥胖对饮食诱导肥胖（DIO）小鼠allo-HSCT后的急性肠道GVHD有负面且选择性的影响。这些动物在allo-HSCT后表现出肠道通透性增加、内毒素跨肠道转运以及辐射诱导的胃肠道损伤。allo-HSCT后，雄性和雌性DIO小鼠受体均显示促炎细胞因子产生增加以及GVHD标志物ST2（IL-33R）和MHC II类分子的表达增加；它们还表现出与急性严重肠道GVHD相关的存活率降低。这种快速发作的、与肥胖相关的肠道GVHD依赖于供体CD4 T细胞，即使供体和受体动物之间存在轻微的MHC不匹配也会发生。对接受来自无关供体的allo-HSCT移植的临床队列进行回顾性分析发现，与非肥胖移植受者相比，体重指数（BMI，>30）高的受者存活率降低且血清ST2浓度更高。对DIO小鼠和BMI高的allo-HSCT受者的评估均显示肠道微生物群多样性降低以及梭菌科丰度降低。预防性抗生素治疗可保护DIO小鼠受体免受内毒素跨肠道转运的影响，并增加炎性细胞因子的产生以及肠道病理学改变和死亡率，但不能预防慢性皮肤GVHD的后期发展。这些结果表明，肥胖诱导的肠道微生物群改变可能影响DIO小鼠allo-HSCT后的GVHD，预防性抗生素治疗可能会改善这种情况。
