Integrative host microbiota multi-omics analysis reveals distinctive systemic inflammation and metabolic disorder across Alzheimer's disease continuum.

Abstract

There is a growing appreciation that systemic factors, such as chronic inflammation, metabolic disorders, vascular dysfunction and gut microbiota dysbiosis, are highly connected and traverse a complex route across multiple pathophysiological processes that play crucial roles in Alzheimer's disease (AD) pathogenesis. Yet, understanding the pathophysiology of the disease is still lacking. Herein, we used 16s sequencing and short-gun metagenomics for gut microbiota structure and functional analysis, employed mass cytometry technology to examine the blood immune cell profiles, applied antibody array to quantify the expression level of 440 plasma proteins and applied targeted metabolomics approach to detect up to 630 metabolites in the blood. Through these multi-omics analysis, we unraveled the complex interplay among these systemic factors that were functionally linked to brain insults in the discrete stages along disease continuum, and delineated stage-specific systemic characteristics associated with the clinical-pathological changes. Notably, amnesic mild cognitive impairment (aMCI) exhibited a Th1-skewed profile, whereas mild-to-moderate AD showed a higher Th17/Treg ratio, which accompanies the structural and functional alteration of gut microbiota and blood metabolic and protein changes to disease-specific immune response. We further developed diagnostic models discriminating the discrete disease stages and revealed heterogeneity of AD by integrating the systemic factors, which empowered the prediction of aMCI subset at high-risk of progression into AD, and early stage of AD to a more severe one. Our study uncovered a complex interplay of systemic factors in AD development, and provided valuable information for developing the disease-modifying drug in future.