Investigating the neuroinflammatory and metabolomic mechanisms by which the GUT microbiome modulates parkinson's disease dementia - parkinson's disease (PD), parkinson's disease dementia (PDD), and…

The National Institute of Neurological Disorders and Stroke awarded Brigham & Women's Hospital Inc. $681,377 on August 24, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to investigate the neuroinflammatory and metabolomic mechanisms by which the gut microbiome modulates Parkinson's disease dementia.

The funded research examines how specific gut microbiota contribute to Parkinson's disease versus Parkinson's disease dementia through metabolite secretion that modulates microglial and neuronal function, using mechanistic studies in both familial and sporadic disease models. The research focuses on a family harboring an alpha-synuclein E46K mutation exhibiting varied disease penetrance and preliminary data identifying bacteria associated with disease penetrance, demonstrating that transferring disease-associated microbiota into a mouse model worsened motor and cognitive function, and linking microbiota transfer to increased peripheral IFN-gamma production in T cells and increased microglial inflammatory transcriptional profiles.

The research is performed at Brigham & Women's Hospital in Boston, Massachusetts, with a period of performance extending through June 30, 2031. Brigham & Women's Hospital, a subsidiary of Partners Healthcare System Incorporated, serves as the prime recipient of this Project Grant award.

Investigating the neuroinflammatory and metabolomic mechanisms by which the GUT microbiome modulates parkinson's disease dementia - parkinson's disease (PD), parkinson's disease dementia (PDD), and other alzheimer's disease-related dementias (adrd) are complex diseases involving gene-environment interactions. Studying rare kindreds with inherited forms of neurodegeneration that mimic sporadic disease provides a window into understanding mechanisms in a controlled genetic and environmental context. We are investigating unique mechanistic microbiome determinants of disease penetrance in a family harboring an alpha-synuclein E46>k mutation that exhibits a spectrum of resilience to PD/PDD, develops PD with motor symptoms alone, or PD with dementia. We hypothesize that the specific GUT microbiota contribute to PD VS. PDD through the secretion of metabolites that modulate microglial and neuronal function. While emerging evidence suggests that the GUT microbiota affects PDD by modulating neuroinflammation, mechanistic studies that define the interaction of specific microbes and host pathways are urgently needed, which this proposal rigorously investigates using multiple models of familial and sporadic PDD. In our preliminary data, first, we identified bacteria associated with PDD disease penetrance, several of which are altered in sporadic PD/PDD. Second, transferring the PDD GUT microbiota into the 3KL PD mouse model worsened motor and cognitive function and was linked to microbiota associated with familial E46K PDD and sporadic PDD patients. Third, we colonized 3KL mice with putative protective and detrimental microbes and found differential effects on motor and cognitive function. Fourth, PDD microbiota transfer increased peripheral infg production in t cells and increased microglial inflammatory transcriptional profiles, identifying specific immunologic pathways by which the microbiota contributes to PDD pathogenesis. Fifth, by conditioning human stem cell-derived microglia with supernatants from novel PDD E46K bacteria isolates, we identified specific bacteria that modulate microglial inflammatory and phagocytic function. Sixth, modeling neurons, astrocytes, and microglia in vitro, we identified PDD bacterial supernatants that induce cellular toxicity in E46K PDD neuron-containing TRI-cultures. In this proposal, by using carefully selected in vivo and in vitro models, we will identify microbes and metabolites that affect PDD pathogenesis and test their relevance to both genetic and sporadic PDD. Aim 1 will investigate conserved mechanisms by which the PD/PDD microbiota affect cognitive VS. Motor function in ASO, A53T, GBA, and 3KL PD models. We will identify microbial metabolites, peripheral immune responses, and the impact on brain pathology. Aim 2 will use microglial gene editing technology to mechanistically investigate the role of microbiome-microglia crosstalk in driving PDD proinflammatory states. Aim 3 will investigate intercellular mechanisms by which the PDD microbiota induces neuronal pathogenesis in diverse stem cell-derived microglia-astrocyte-neuronal TRI-cultures, and in vivo using spatial transcriptomics. These studies have the potential to uncover novel pathways by which the microbiome influences cognitive impairments in PD, which may ultimately lead to innovative treatments for PDD and adrd.