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.

项目概要/摘要 这项研究将检验以下假设：(a) 由于粘液屏障的丧失而导致肠道通透性增加 与衰老相关的认知能力下降和 AD 病理学，以及 (b) 独特的热灭活人类来源益生菌 （副干酪乳杆菌 D3-5 [LpD3-5]）及其脂磷壁酸 (LTA) 可恢复粘蛋白产生，从而减少肠道菌群 渗漏，从而改善认知能力下降和 AD 病理。我们的假设是基于多条线。 新出现的证据，包括我们的初步数据表明：（i）慢性炎症开始于数个 人类和小鼠认知能力下降/AD 出现前数年；(ii) 肠道通透性增加并降低 粘液屏障与肠道和大脑炎症升高、认知能力下降以及老年人的 AD 标志物有关 和 AD 小鼠；(iii) 独特的人源热灭活益生菌 LpD3-5 可降低肠道通透性和炎症 通过增加粘蛋白的产生和杯状细胞的数量，在老年小鼠的肠道和大脑中发挥作用，并显示出有希望的 认知能力的改善；(iv) LpD3-5 细胞壁的特定 LTA 增加了杯状细胞的数量 通过激活 Toll 样受体 2 (TLR2) 信号传导来产生粘蛋白，从而降低肠道通透性 (v) LpD3-5 的 LTA 的粘蛋白刺激作用是独特的、依赖于菌株的，并且 可能是由于 D-丙氨酰修饰的变化造成的。这些发现提出了几个重要的问题：(a)是否如此。 由于粘液屏障丧失而导致肠道通透性增加，加速与衰老相关的认知能力下降和 AD 病理学，以及 LpD3-5 治疗是否可以逆转这些变化（b）LpD3-5 及其 LTA 如何增加杯状效应； (c) 为什么 LpD3-5 会产生 LTA； 两种副干酪乳杆菌 (Lp) 菌株之间的粘蛋白促进活性存在差异。 当前知识状况的重要差距，在目标 1 中，我们将定义肠道菌群升高的致病作用 通透性对认知衰退/AD 的发生和严重程度的影响及其 LpD3-5 的逆转，使用正常值和 在目标 2 中，我们将确定 LpD3-5 及其 LTA 是否促进衰老和 AD (APP/PS1) 小鼠模型。 在小鼠体内将 iSC 分化为杯状细胞谱系，以确定它们增加杯状细胞的机制 在目标 3 中，我们将使用 LTA 检查菌株特异性 D-丙氨酰修饰。 NMR 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 这些研究的结果有望首次提供直接证据。 由于粘液屏障的丧失而增加了肠道通透性，加速了与衰老相关的认知能力下降 和AD，并且一种独特的人源益生菌疗法可以逆转它们，这项工作可以为一种新的方法提供信息。 通过增加肠道通透性作为常见机制来连接衰老和 AD 的范例，并开放 合理设计 LTA 合成模拟物以减少肠道通透性、认知能力下降和 AD——老年人衰弱的公共卫生问题。

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 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

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

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