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Reducing innate inflammation in new onset T1D with Lactobacillus plantarum

使用植物乳杆菌减少新发 T1D 的先天炎症

基本信息

批准号：
10626065
负责人：
Susanne M Cabrera
金额：
$ 61.33万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-21 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10626065
关键词：
Acceleration Animals Antibiotic Therapy Antibiotics Autoantibodies Beta Cell Biological Assay Cell physiology Cellular Stress Child Controlled Environment Coronary Arteriosclerosis Dependence Development Diabetes Mellitus Diet Disease Disease Progression Environmental Risk Factor Equilibrium Event Exhibits Exposure to Family Fostering Frequencies Genetic Genetic Risk Genetic Transcription Genotype Human Hypoglycemia Immune Incidence Inflammation Inflammatory Insulin Insulin-Dependent Diabetes Mellitus Interleukin-1 Interleukin-10 Intestinal permeability Lactobacillus plantarum Major Histocompatibility Complex Measures Mediating Microvascular Dysfunction Modeling Morbidity - disease rate Neonatal Onset of illness Partial Remission Patients Pattern recognition receptor Pediatric cohort Peripheral Phenotype Placebo Control Plasma Positioning Attribute Predisposition Probiotics Qualifying Randomized Rattus Receptor Activation Regulation Regulatory T-Lymphocyte Replacement Therapy Residual state Resistance Risk Risk Reduction Rodent Rodent Model Siblings Signal Transduction Structure of beta Cell of islet Supplementation T-Lymphocyte Testing Therapeutic Agents Transforming Growth Factor beta Virus Virus Diseases Volatile Fatty Acids age related chemokine clinically significant cytokine design diabetes pathogenesis diabetic dysbiosis environmental change gut microbiota high risk immunoregulation improved insulin dependent diabetes mellitus onset insulin secretion islet autoimmunity juvenile animal metabolome microbiota microorganism antigen monocyte mortality patient population prevent primary outcome proband probiotic supplementation secondary outcome single-cell RNA sequencing systemic inflammatory response western diet

项目摘要

PROJECT SUMMARY Type 1 diabetes (T1D) arises through T-cell mediated killing of the pancreatic beta-cells. It has a strong genetic component, but environmental factors likely influence disease triggering as well as the post-onset disease course. In human T1D families, we have identified an elevated inflammatory state that is consistent with exposure to microbial antigens. In healthy siblings of probands, this familial innate inflammation is supplanted by an age-dependent regulatory state that includes temporal increases in peripheral activated regulatory T-cell frequencies. We have identified a similar inflammatory state in the BioBreeding DR rat model of T1D. DR rats are not spontaneously diabetic, however T1D can be triggered in young animals by viral infection. Importantly, the innate inflammatory state in DR rats is temporally supplanted by an IL-10/TGF-β- mediated regulatory state that coincides with the inability of virus to induce T1D in older animals. In line with studies that implicate an altered gastrointestinal microbiota in T1D pathogenesis, modulation of the microbiota in healthy siblings of T1D probands or DR rats partially normalizes the underlying inflammatory state. In BioBreeding rats, such treatments prevent development of T1D. Our studies suggest that T1D progression is promoted when the genetically controlled but environmentally influenced familial innate state is augmented by additional inflammatory signals prior to the establishment of robust counter-regulatory mechanisms. Our studies have also focused on the persistence of insulin secretion after T1D onset, which is clinically significant as even modest residual beta cell function is associated with reduced risk of complications. These studies have utilized a plasma-based transcriptional bioassay that quantitatively captures inflammatory: regulatory balance. Importantly, new onset T1D patients with short post-onset partial remissions, exhibit plasma based signatures with predictively higher inflammatory bias, as well as reduced peripheral regulatory T-cell abundances. In genetically susceptible healthy subjects and T1D patients, we hypothesize that levels of immune activity are in part governed by composition of the microbiota and systemic microbial antigen exposure. This in turn influences the rate of T1D progression as measured by duration of the post- onset partial remission. With our large patient population and expertise, we are well-positioned to test the hypothesis that the inflammatory state associated with T1D and T1D susceptibility can be partially normalized through probiotic supplementation. We propose the following specific aims. 1. Determine whether Lactobacillus plantarum 299v supplement reduces systemic inflammation and prolongs residual β-cell function in new onset T1D. 2. Define how L. plantarum 299v supplementation alters immune activity in new onset T1D.

项目总结 1型糖尿病(T1D)是通过T细胞介导的对胰岛β细胞的杀伤而发生的。它有一个很强的遗传因素，但环境因素可能影响疾病的触发和发病后病程。在人类T1D家族中，我们发现了一种一致的炎性状态升高暴露在微生物抗原之下。在先证者的健康兄弟姐妹中，这种家族先天炎症是被年龄相关的调节状态所取代，这种状态包括外周激活的暂时性增加调节T细胞频率。我们在生物繁殖的DR大鼠模型中发现了类似的炎症状态 T1D。糖尿病视网膜病变大鼠不是自发性糖尿病大鼠，但幼年动物可通过病毒引发T1D 感染。重要的是，DR大鼠的固有炎症状态被IL-10/转化生长因子-β暂时取代- 介导的调节状态，与病毒不能在老年动物中诱导T1D相一致。与…一致在T1D发病机制中涉及胃肠道微生物区系改变的研究，微生物区系的调节在T1D先证者或DR大鼠的健康兄弟姐妹中，糖尿病大鼠的潜在炎症状态部分正常。在……里面生物饲养的大鼠，这样的治疗可以防止T1D的发展。我们的研究表明，T1D进展是当受基因控制但受环境影响的家庭与生俱来的状态通过在建立强有力的反调节机制之前，有更多的炎症信号。我们的研究还集中在T1D发病后胰岛素分泌的持久性，这具有临床意义。因为即使是适度的残留β细胞功能也与降低并发症的风险有关。这些研究使用了一种基于血浆的转录生物测定，可以定量捕捉炎症：调节平衡。重要的是，新发的T1D患者发病后短期部分缓解，表现出基于血浆的具有更高炎症倾向性以及外周调节性T细胞减少的特征富足。在遗传易感的健康受试者和T1D患者中，我们假设免疫活性的水平在一定程度上是由微生物区系和系统微生物的组成决定的。抗原暴露。这反过来又影响以后持续时间衡量的T1D进展速度开始部分缓解。凭借我们庞大的患者群体和专业知识，我们有能力测试假设与T1D和T1D易感性相关的炎症状态可以部分正常化通过益生菌补充剂。我们提出了以下具体目标。 1.确定植物乳杆菌299v补充剂是否能降低全身炎症和延长新发T1D患者的残留β细胞功能。 2.明确补充植物乳杆菌299v如何改变新发病的T1D的免疫活性。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Role of endoplasmic reticulum stress in impaired neonatal lung growth and bronchopulmonary dysplasia.

DOI：
10.1371/journal.pone.0269564
发表时间：
2022
期刊：
PloS one
影响因子：
3.7
作者：
通讯作者：

Youth Along the T2D Risk Continuum Remain Concerningly Refractory to Therapeutic Interventions.

T2D 风险连续体中的青少年仍然难以接受治疗干预。

DOI：
10.1210/clinem/dgab292
发表时间：
2021
期刊：
The Journal of clinical endocrinology and metabolism
影响因子：
0
作者：
Wolfgram,PeterM;Cabrera,SusanneM
通讯作者：
Cabrera,SusanneM

Probiotic normalization of systemic inflammation in siblings of type 1 diabetes patients: an open-label pilot study.

DOI：
10.1038/s41598-022-07203-6
发表时间：
2022-02-28
期刊：
Scientific reports
影响因子：
4.6
作者：
Cabrera SM;Coren AT;Pant T;Ciecko AE;Jia S;Roethle MF;Simpson PM;Atkinson SN;Salzman NH;Chen YG;Hessner MJ
通讯作者：
Hessner MJ

Lactiplantibacillus plantarum 299v supplementation modulates β-cell ER stress and antioxidative defense pathways and prevents type 1 diabetes in gluten-free BioBreeding rats.