The microbiota and allograft rejection: novel investigations into the consequences of obesity

微生物群和同种异体移植排斥：对肥胖后果的新研究

• 批准号: 10204895
• 负责人: Maria-Luisa Alegre
• 金额: $ 40.38万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10204895
• 关键词: Affect; Alloantigen; Antibiotics; Antigen-Presenting Cells; Bacteroidetes; Bile Acids; Biological; Blood; Clinical; Communities; Data; Diet; Environmental Risk Factor; Enzymes; Experimental Models; Feces; Firmicutes; GPBAR1 gene; Gastrectomy; Genetic; Germ-Free; Graft Rejection; Graft Survival; High Fat Diet; Hydrolase; Image; Immune system; Immunosuppressive Agents; In Vitro; Intestines; Investigation; Kinetics; Link; Mediating; Metabolic; Metagenomics; Modality; Modification; Mus; Obese Mice; Obesity; Organ; Outcome; Oxides; Phenotype; Reporting; Role; Secondary to; Serum; Shapes; Shotgun Sequencing; Solid; Supplementation; T-Lymphocyte; Testing; Therapeutic; Thinness; Transplantation; Valine; allograft rejection; bacterial metabolism; bariatric surgery; base; clinically relevant; diet-induced obesity; dysbiosis; gut microbes; gut microbiota; host microbiota; human study; improved; in vivo; isoimmunity; microbial; microbial community; microbial composition; microbiome research; microbiota; novel; obese patients; organ transplant rejection; receptor; response; restoration

The extent of genetic disparities between donor and recipients constitutes the main driver that determines the strength of alloimmunity and subsequent kinetics of graft rejection. In recent years, a role for environmental factors has emerged. Our preliminary results have identified 2 inter-related environmental factors that can modulate the strength of the alloimmune response. The first is the microbiota, represented by the communities of microbes that inhabit the body. Here, we reported that the elimination of microbiota through the use of germ- free (GF) mice, or a decrease of microbial diversity induced by broad-spectrum antibiotics (Abx) in both donor and recipient mice prior to transplantation resulted in a reduction of alloreactivity and prolonged graft survival. Mechanistically, antigen-presenting cells (APCs) from GF and Abx-pre-treated mice had a reduced capacity to prime donor-reactive T cells. The second environmental factor is high fat diet (HFD). We showed that obese mice mounted an augmented alloimmunity and rejected transplants faster than lean mice. Mechanistically, APCs from obese mice had a greater capacity to present alloantigen to T cells compared with APCs from lean mice, a mirror image of the phenotype observed in GF and Abx-treated mice. Based on established links between obesity and the gut microbiota, we propose that obesity-dependent dysbiosis super-activates APCs, which, in turn, induces a more potent priming of alloreactive T cells leading to accelerated kinetics of transplant rejection. Using metagenomic shotgun sequencing, we have identified increased proportions of Firmicutes and decreased proportions of Bacteroidetes and Verrucomicrobia in diet-induced obese (DIO) mice. Interestingly, these changes were reversed in mice treated with bariatric surgery (sleeve gastrectomies, SGx), and in mice treated with TDCA/valine, co-metabolites that we found to be reduced in the serum of obese mice and restored by SGx. Of clinical relevance, we detected high levels of B. vulgatus, a commensal species that can metabolize TDCA, in the stool of an obese patient. Based on these preliminary data, we propose that shaping of microbial communities by diet modulates alloimmunity. Specifically, we hypothesize that obesity, via its alteration of the microbiota and through changes of co-metabolites in host/microbiota, enhances DC poising that results in increased priming of alloreactive T cells and accelerated graft rejection; those effects are reverted by bariatric surgery or through the restoration of metabolite levels. This hypothesis will be tested in the context of the following Specific Aims. Specific Aim 1. To determine if the microbiota shaped by HFD before and after bariatric surgery differentially modulates alloimmunity and the kinetics of graft rejection. Specific Aim 2. To investigate the mechanisms by which the microbiota-dependent metabolites TDCA and valine that are decreased in obesity and restored by SGx, modulate alloimmunity and graft rejection. Specific Aim 3. To determine the effects of bariatric surgery on the microbiota, TDCA/valine serum levels, and APC tuning in a pilot human study.

捐赠者和接受者之间的遗传差异程度构成了决定的主要驱动因素 同种免疫的强度和随后的移植物排斥动力学。近年来，环保的作用 因素已经显现。我们的初步结果确定了两个相互关联的环境因素 调节同种免疫反应的强度。第一个是微生物群，以群落为代表 居住在体内的微生物。在这里，我们报道了通过使用细菌来消除微生物群 游离 (GF) 小鼠，或广谱抗生素 (Abx) 引起的供体微生物多样性减少 移植前的受体小鼠导致同种异体反应性降低和移植物存活时间延长。 从机制上讲，来自 GF 和 Abx 预处理小鼠的抗原呈递细胞 (APC) 的能力降低 主要供体反应性 T 细胞。第二个环境因素是高脂肪饮食（HFD）。我们证明肥胖 小鼠比瘦小鼠更快地获得增强的同种免疫并排斥移植物。从机械上来说， 与瘦小鼠的 APC 相比，肥胖小鼠的 APC 向 T 细胞呈递同种异体抗原的能力更强 小鼠，是在 GF 和 Abx 处理的小鼠中观察到的表型的镜像。基于已建立的链接 在肥胖和肠道微生物群之间，我们提出肥胖依赖性生态失调会超级激活 APC， 反过来，诱导同种异体反应性 T 细胞更有效地启动，从而加速移植动力学 拒绝。使用宏基因组鸟枪法测序，我们发现厚壁菌门和 饮食诱导肥胖（DIO）小鼠中拟杆菌门和疣微菌门的比例降低。有趣的是， 这些变化在接受减肥手术（袖状胃切除术，SGx）治疗的小鼠和小鼠中得到逆转 用 TDCA/缬氨酸治疗，我们发现肥胖小鼠血清中的共代谢物减少并恢复 由 SGx 提供。具有临床意义的是，我们检测到高水平的普通双歧杆菌（B. vulgatus），这是一种可以代谢的共生物种 TDCA，存在于肥胖患者的粪便中。基于这些初步数据，我们建议微生物的塑造 社区通过饮食调节同种免疫。具体来说，我们假设肥胖通过改变 微生物群并通过宿主/微生物群中的共代谢物的变化，增强 DC 平衡，从而导致 增加同种异体反应性 T 细胞的启动并加速移植物排斥；这些影响可以通过减肥药恢复 手术或通过恢复代谢水平。这一假设将在以下背景下得到检验： 遵循具体目标。 具体目标 1. 确定减肥手术前后 HFD 是否塑造了微生物群 差异调节同种免疫和移植物排斥的动力学。具体目标 2. 调查 肥胖时微生物群依赖性代谢物 TDCA 和缬氨酸减少的机制 并通过 SGx 恢复，调节同种免疫和移植物排斥。具体目标 3. 确定效果 在一项人体试验研究中，减肥手术对微生物群、TDCA/缬氨酸血清水平和 APC 调整进行了影响。

项目成果

Association of balanced abdominal organ transplant center volumes with patient outcomes.

平衡腹部器官移植中心体积与患者预后的关系。

• DOI: 10.1111/ctr.14217
• 发表时间: 2021
• 期刊: Clinical transplantation
• 影响因子: 2.1
• 作者: Adler,JoelT;Tsai,ThomasC;Jin,Ginger;Cron,DavidC;Ross-Driscoll,KatherineH;Malek,SayeedK;Tullius,StefanG;Weissman,JoelS
• 通讯作者: Weissman,JoelS

Global Impact of the COVID-19 Pandemic on Solid Organ Transplant.

• DOI: 10.1016/j.transproceed.2022.02.009
• 发表时间: 2022-07
• 期刊: Transplantation proceedings
• 影响因子: 0.9
• 作者: Kute VB;Tullius SG;Rane H;Chauhan S;Mishra V;Meshram HS
• 通讯作者: Meshram HS

Accelerated chronic skin changes without allograft vasculopathy: A 10-year outcome report after face transplantation.

无同种异体移植血管病变的加速慢性皮肤变化：面部移植后 10 年结果报告。

• DOI: 10.1016/j.surg.2020.01.010
• 发表时间: 2020
• 期刊: Surgery
• 影响因子: 3.8
• 作者: Kollar,Branislav;Rizzo,NatalieM;Borges,ThiagoJ;Haug,Valentin;Abdulrazzak,Obada;Kauke,Martin;Safi,Ali-Farid;Lian,ChristineG;Marty,FranciscoM;Rutherford,AnnaE;Mitchell,RichardN;Murphy,GeorgeF;Tullius,StefanG;Riella,Leonard
• 通讯作者: Riella,Leonard