Hariom Yadav

Research topics

Matched from this investigator's NIH project titles and abstracts.

• Cognitive Aging
• Alzheimer's and Dementia
• Developmental Cognitive Neuroscience

Active NIH awards

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

  5R01AG071762-03

  NIA · FY 2025 · $368K

  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.

• miRNAs in the gut-brain axis to predict the risk of cognitive decline in older adults

  1R21AG085881-01

  NIA · FY 2024 · $425K

  ABSTRACT/SUMMARY Aging population is increasing, and age-related cognitive, Alzheimer’s disease (AD) and its related dementias (ADRD) prevalence sharply rising, with no prognosis, prevention or treatment. This is because we do not fully understand the mechanisms responsible for cognitive decline and ADRD progression during aging. Studies have identified many genes associated with the risk of development of familial AD, however, few have examined how the underlying mechanisms involved with aging-related risk and progression of AD. Studies of microbiota showed strong evidence that gut bacteria and metabolites significantly contribute to the development of AD and AD-related dementias (ADRD). Interestingly, we and others found that the gut microbiome signature in older adults with mild cognitive impairment (MCI), an early stage of AD, and ADRD significantly differs from cognitively healthy age-matched individuals. However, the mechanisms by which the gut microbiome impacts brain health are not well understood. Emerging evidence from literature and our preliminary data suggests that miRNAs produced from gut cells in response to microbial changes can also play important role in AD. miRNAs are known to modulate AD pathogenesis through many pathways, including targeting proteins related to Aβ clearance, neurotoxicity, synaptic loss, and cellular senescence, but the role of gut-derived miRNAs in age- related cognitive decline and ADRD is obscure. Here we propose the hypothesis that novel miRNAs of the gut appear in the blood circulation of older adults with MCI and dementia compared to healthy controls. We also posit that these gut-associated exosomal miRNAs travel through blood to brain and impact gene expression program in specific cell types of brain. To address these translationally important studies, we will use the stools and plasma samples from our ongoing study called Microbiome in aging Gut and Brain (MiaGB) consortium to determine the unique signature of gut-originating miRNAs and their mechanism of action by focusing on the two specific aims. In aim 1, we will determine the miRNA signatures that uniquely originated from gut to blood in older adults with MCI and dementia compared to cognitively healthy. In aim 2, we will determine if the exosomal miRNAs travel from gut to brain, target cell types in brain and impact their gene expression. Our studies will define the unique miRNAs of MCI and dementia compared to healthy controls, as well as establish the mechanism by which these MCI/ADRD-specific miRNAs impact specific neuronal cell functions. Our studies are built as an ancillary of the ongoing large MiaGB study for completing cost-effective, high rigor and timely manner by utilizing expertise of interdisciplinary team.

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

  4R01AG071762-02

  NIA · FY 2024 · $386K

  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.