Thursday, December 26, 2024
12/26/2024
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.
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