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.

供体和受体之间基因差异的程度构成了决定

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