Microbial therapy improves gut permeability to reduce cognitive decline and Alzheimer’s disease

微生物疗法可改善肠道通透性，从而减少认知能力下降和阿尔茨海默病

• 批准号: 10185582
• 负责人: Hariom Yadav
• 金额: $ 112.84万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10185582
• 关键词: APP-PS1; Acceleration; Address; Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Basic Science; Brain; Cell Count; Cell Culture Techniques; Cell Lineage; Cell Wall; Chronic; Cognition; Data; Development; Disease Marker; Disease Progression; Elderly; Encephalitis; Extravasation; G-Protein-Coupled Receptors; Goblet Cells; Health; Human; Impaired cognition; In Vitro; Inflammation; Intervention; Intestinal permeability; Intestines; Knowledge; LGR5 gene; Lactobacillus; Leaky Gut; Leucine-Rich Repeat; Link; Measures; Modification; Mucins; Mucous body substance; Mus; Outcome Study; Pathogenesis; Pathway interactions; Permeability; Population; Probiotics; Process; Production; Public Health; Research Personnel; Risk Factors; Role; Severities; Signal Transduction; Sodium Dextran Sulfate; Source; Structure; TLR2 gene; Testing; Therapeutic; Time; Transgenic Mice; Translational Research; Variant; Work; base; chemical synthesis; comparative; cost; design; effective therapy; feeding; gastrointestinal; gut microbiota; improved; inflammatory disease of the intestine; insight; lipoteichoic acid; microbial; mimetics; mouse model; multidisciplinary; normal aging; novel; probiotic therapy; prophylactic; stem cell differentiation; stem cells; systemic inflammatory response; transcription factor

Project Summary/Abstract This study will test the hypotheses that: (a) increased gut permeability due to loss of mucus barrier accelerates aging-related cognitive decline and AD pathology, and (b) a unique heat-killed human-origin probiotic (Lactobacillus paracasei D3-5 [LpD3-5]) and its lipoteichoic acid (LTA) restores mucin production to reduce gut leakage and thereby ameliorate cognitive decline and AD pathology. Our hypotheses are based on multiple lines of emerging evidence, including our preliminary data indicating that: (i) Chronic inflammation begins several years before cognitive decline/AD appear in humans and mice; (ii) Increased gut permeability and reduced mucus barrier are linked with elevated inflammation in gut and brain, cognitive decline, and AD markers in older and AD mice; (iii) A unique human-origin heat-killed probiotic LpD3-5 reduces gut permeability and inflammation in the gut and brain of older mice by increasing mucin production and goblet cell numbers, and shows promising improvements in cognition; (iv) A specific LTA from the cell wall of LpD3-5 increases both goblet cell numbers and mucin production by activating toll-like receptor 2 (TLR2) signaling, which in turn reduces gut permeability and inflammation; and (v) Mucin-stimulating effects of LTA from LpD3-5 are unique, strain-dependent, and possibly due to variations in D-alanyl modification. These findings raise several important questions: (a) whether increased gut permeability due to loss of mucus barrier accelerates aging-related cognitive decline and AD pathology, and whether LpD3-5 therapy can reverse these changes; (b) how LpD3-5 and its LTA increase goblet cell numbers and thus mucin production, which in turn reduces gut permeability; and (c) why LTA from LpD3-5 differs in its mucin-promoting activity between two Lactobacillus paracasei (Lp) strains. To address these important gaps in the current state of knowledge, in Aim 1, we will define the causative role of elevated gut permeability on the onset and severity of cognitive decline/AD and its reversal by LpD3-5, using both normal aging and AD (APP/PS1) mouse models. In Aim 2, we will determine whether LpD3-5 and its LTA promote differentiation of iSCs into a goblet cell lineage in mice, to define the mechanism by which they increase goblet cell numbers in older and AD gut. In Aim 3, we will examine strain-specific D-alanyl-modification on LTAs using NMR structural analyses, to define the differences in their ability to promote mucin production via activating TLR2/Muc2 axis in vitro. Outcomes of these studies are expected to provide, for the first time, direct evidence that increased gut permeability due to loss of the mucus barrier accelerates both aging-related cognitive decline and AD, and that a unique human-origin probiotic therapy can reverse them. This work could inform a new paradigm to connect aging and AD by means of increased gut permeability as a common mechanism, and open opportunities for rational design of synthetic mimetics of LTAs to reduce gut permeability, cognitive decline, and AD – debilitating public health problems of older adults.

项目摘要/摘要 这项研究将检验以下假设：(A)粘液屏障的丧失导致的肠道通透性增加加速 与衰老相关的认知衰退和AD病理，以及(B)一种独特的热致死人源益生菌 (副乳杆菌D3-5[LpD3-5])及其脂磷壁酸(LTA)恢复粘蛋白的产生以减少肠道 渗漏，从而改善认知能力下降和AD的病理。我们的假设是基于多条线的 包括我们的初步数据表明：(I)慢性炎症开始于几个 在人类和小鼠出现认知衰退/阿尔茨海默病的前几年；(Ii)肠道通透性增加和减少 粘液屏障与老年人肠道和大脑炎症增加、认知能力下降和AD标记物有关 和AD小鼠；(Iii)一种独特的人源性热灭活益生菌LpD3-5降低肠道通透性和炎症 在老年小鼠的肠道和大脑中，通过增加粘蛋白的产生和杯状细胞的数量，并显示出有希望的 认知的改善；(Iv)LpD3-5细胞壁的特定LTA增加两个杯状细胞的数量 通过激活Toll样受体2(TLR2)信号产生粘蛋白，进而降低肠道通透性 和炎症；以及(V)LpD3-5的LTA的粘蛋白刺激作用是独特的，依赖于菌株，并且 可能是由于D-丙氨基修饰的变化。这些调查结果提出了几个重要问题：(A) 粘液屏障丧失导致的肠道通透性增加加速衰老相关的认知衰退和阿尔茨海默病 病理，以及LpD3-5治疗能否逆转这些变化；(B)LpD3-5及其LTA如何增加杯状物 细胞数量，从而产生粘蛋白，从而降低肠道通透性；以及(C)为什么来自LpD3-5的LTA 两株副乳杆菌(Lactobacillusparacasei，LP)的粘蛋白促进活性不同。要解决这些问题 当前知识状态中的重要差距，在目标1中，我们将定义隆起的肠道的致病作用 LpD3-5逆转认知功能衰退/阿尔茨海默病发病和严重程度的通透性 衰老和AD(APP/PS1)小鼠模型。在目标2中，我们将确定LpD3-5及其LTA是否促进 小鼠骨髓间充质干细胞分化为杯状细胞系，以确定其增加杯状细胞的机制 较早和AD肠段的细胞数。在目标3中，我们将研究菌株特异性D-丙氨基对ltas的修饰。 核磁共振结构分析，以确定它们通过激活促进粘蛋白产生的能力的差异 体外培养TLR2/Muc2轴。预计这些研究的结果将首次提供直接证据。 由于粘液屏障的丧失而导致的肠道通透性增加加速了与衰老相关的认知衰退 和AD，一种独特的人类起源的益生菌疗法可以逆转它们。这项工作可能会为一种新的 通过增加肠道通透性作为共同机制来连接衰老和AD的范式，并开放 合理设计LTA的合成模拟物以降低肠道通透性、认知能力下降和 使老年人身体虚弱的公共卫生问题。

项目成果

Unique trans-kingdom microbiome structural and functional signatures predict cognitive decline in older adults.

• DOI: 10.1007/s11357-023-00799-1
• 发表时间: 2023-10
• 期刊: GEROSCIENCE
• 影响因子: 5.6
• 作者: Chaudhari, Diptaraj S.;Jain, Shalini;Yata, Vinod K.;Mishra, Sidharth P.;Kumar, Ambuj;Fraser, Amoy;Kociolek, Judyta;Dangiolo, Mariana;Smith, Amanda;Golden, Adam;Masternak, Michal M.;Holland, Peter;Agronin, Marc;White-Williams, Cynthia;Arikawa, Andrea Y.;Labyak, Corinne A.;Yadav, Hariom
• 通讯作者: Yadav, Hariom

Poor Oral Health Linked with Higher Risk of Alzheimer's Disease.

口腔健康状况不佳与阿尔茨海默病的较高风险有关。

• DOI: 10.3390/brainsci13111555
• 发表时间: 2023-11-07
• 期刊: Brain sciences
• 影响因子: 3.3

A mechanism by which gut microbiota elevates permeability and inflammation in obese/diabetic mice and human gut.

• DOI: 10.1136/gutjnl-2022-327365
• 发表时间: 2023-10
• 期刊: GUT
• 影响因子: 24.5
• 作者: Mishra, Sidharth P.;Wang, Bo;Jain, Shalini;Ding, Jingzhong;Rejeski, Jared;Furdui, Cristina M.;Kitzman, Dalane W.;Taraphder, Subhash;Brechot, Christian;Kumar, Ambuj;Yadav, Hariom
• 通讯作者: Yadav, Hariom

The effects of prebiotics on gastrointestinal side effects of metformin in youth: A pilot randomized control trial in youth-onset type 2 diabetes.

益生元对二甲双胍在青年中的胃肠道副作用的影响：一项试验2型糖尿病的试验随机对照试验。

• DOI: 10.3389/fendo.2023.1125187
• 发表时间: 2023
• 期刊: Frontiers in endocrinology
• 影响因子: 5.2

The Triple Alliance: Microbiome, Mitochondria, and Metabolites in the Context of Age-Related Cognitive Decline and Alzheimer's Disease.

三重联盟：与年龄相关的认知衰退和阿尔茨海默氏病背景下的微生物组、线粒体和代谢物。

• DOI: 10.1093/gerona/glad226
• 发表时间: 2023
• 期刊: The journals of gerontology. Series A, Biological sciences and medical sciences
• 作者: Prajapati,SantoshK;Shah,Ria;Alford,Nicholas;Mishra,SidharthP;Jain,Shalini;Hansen,Barbara;Sanberg,Paul;Molina,AnthonyJA;Yadav,Hariom
• 通讯作者: Yadav,Hariom