The Emerging Link between Microbial Derived DPP-4 and Cognitive Health: The Gut-Microbiome Perspective

Abstract

As a pivotal microbial-host isozyme and counterpart to human dipeptidyl peptidase-4 (hDPP-4), microbial dipeptidyl peptidase-4 (mDPP-4) holds significant potential for understanding and treating metabolic and cognitive disorders across diverse demographic groups including aging populations. Chapter 1 introduces the research problem and evidence of gut microbiome involvement in cognitive aging, emphasizing how host-microbe interactions can regulate and maintain host homeostasis. Chapter 2 provides clinical evidence from a double- blind, placebo-controlled, randomized clinical trial by examining variations and their links to cognitive decline in aging populations. The study focused on middle-aged and older adults diagnosed with mild cognitive impairment (MCI) and compared their gut microbiome compositions to those of neurologically healthy individuals. A key aspect of our finding was the identification of specific microbial species, Prevotella ruminicola, Bacteroides thetaiotaomicron, and Bacteroides xylanisolvens, which showed a significant correlation with MCI at baseline; notably, both genera Prevotella and Bacteroides are among the main groups that carry mDPP-4 genes. The intervention with probiotic Lactobacillus rhamnosus GG (LGG) significantly reduced the absolute abundance of Prevotella sp. and correlated with improved cognitive scores in the MCI group. These findings suggest that targeted microbial interventions serve as effective strategies for enhancing cognitive function and slowing the progression of cognitive decline in compromised populations. Chapter 3 reviews the properties of hDPP-4 and introduces mDPP-4, underscoring the need for more research on its role in human health. We analyze mDPP-4's structure, compare it with human analogs, and discuss the potential impact of conventional hDPP-4 inhibitors on the gut microbiome, proposing the need for personalized microbiome interventions. In Chapter 4, we conduct an in-depth examination of mDPP-4, emphasizing its enzymatic functions, similarities, and differences with hDPP-4. We propose a novel classification for mDPP-4, which defines distinct classes and clades that differ significantly from hDPP-4. Finally, Chapter 5 highlights the main findings of this study and delineates future research directions in the field of mDPP-4 research. This body of work highlights the potential of mDPP-4 as a viable target for therapeutic development, extending to systemic conditions involving hDPP-4. It underscores the efficacy of personalized microbiome-targeted interventions, setting the stage for precision medicine across a spectrum of metabolic and cognitive disorders through microbiome research.