Bone-Brain Crosstalk in Alzheimer’s: Key Mechanisms

Abstract

Previous studies have shown a bidirectional communication between human gut microbiota and the brain, known as the microbiota–gut–brain axis (MGBA). The MGBA influences the host’s nervous system development, emotional regulation, and cognitive function through neurotransmitters, immune modulation, and metabolic pathways. Factors like diet, lifestyle, genetics, and environment shape the gut microbiota composition together. Most research have explored how gut microbiota regulates host physiology and its potential in preventing and treating neurological disorders. However, the individual heterogeneity of gut microbiota, strains playing a dominant role in neurological diseases, and the interactions of these microbial metabolites with the central/peripheral nervous systems still need exploration. This review summarizes the potential role of gut microbiota in driving neurodevelopmental disorders (autism spectrum disorder and attention deficit/hyperactivity disorder), neurodegenerative diseases (Alzheimer’s and Parkinson’s disease), and mood disorders (anxiety and depression) in recent years and discusses the current clinical and preclinical gut microbe‐based interventions, including dietary intervention, probiotics, prebiotics, and fecal microbiota transplantation. It also puts forward the current insufficient research on gut microbiota in neurological disorders and provides a framework for further research on neurological disorders.

Keywords: Alzheimer’s disease, autism, fecal microbiota transplantation, gut microbiota–brain axis, neurological disorders, Parkinson’s disease, probiotics

Gut microbiota driving neurological disorders. Gut microbiota may drive neurodevelopmental disorders (ASD and ADHD), neurodegenerative disorders (AD and PD), and mood disorders (anxiety and depression) through gastrointestinal disorders, gut microbiota disorders, decreased diversity of gut microbiota, delayed development of gut microbiota, and so on.

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1. INTRODUCTION

Microbes are the oldest life on Earth and have coevolved with their human hosts for millions of years. In the past few decades, accelerated research on the microbiome has revealed that microbiota is a key determinant of human health and disease, maintaining host homeostasis and regulating host physiological state. At the genetic level, 99% of the genes in the human body are microbial genes, and there is unique microbiome colonization in human skin, respiratory tract, urogenital tract, gastrointestinal tract (GI), and so on. 1 Among them, the human GI is the host of most microbiota; there are trillions of microbes, and over time, they coevolve with the host organisms and depend on each other. 1 These microbial communities present in the human gut are called the gut microbiome. In the course of the lifespan, the gut microbiota exhibits dynamic fluctuations influenced by factors such as age, psychological disposition, lifestyle, and GI health status of the host. This dynamic and diverse microbial community actively shapes and modulates the host’s pathophysiological processes, thereby underscoring its significant potential for clinical diagnosis and therapeutic intervention. 3 It also promotes the human microbiome project that is put forward, in order to understand our microbial components in genetic and metabolic landscape. 7 With the progress of research on the intersection of gut microbiota and neuroscience, some evidence has clarified the existence of bidirectional communication pathways between gut microbiota and the central nervous system (CNS), which affect the synthesis and release of neurotransmitters in the brain. These studies highlight the close association between gut health and neural health, suggesting a potential impact on neurodevelopmental disorders. 1 The biphasic communication between gut microbes and the CNS is known as the “microbiota–gut–brain axis” (MGBA). 9 Current cellular models, mouse models, and human experimental studies consistently demonstrate that the gut microbiome plays a critical role in various aspects of nervous system development, neuroinflammation, cognitive processes, emotion regulation, and behavioral regulation. 10 11 12 Therefore, the gut microbiota is a personalized, multifunctional target with great potential in the diagnosis and treatment of neurological disorders.

The purpose of this review is to elaborate on the functional role of the MGBA and the current research progress in neurological disorders (such as autism spectrum disorders [ASD], attention‐deficit/hyperactivity disorder [ADHD], Alzheimer’s disease [AD], Parkinson’s disease [PD], depression, and anxiety), so as to provide a summary framework for this rapidly developing research field.

We have summarized the following key points regarding the role of MBGA in several neurological disorders described here: (1) it has been reported that the gut microbiota of patients with neurological disorders is different from that of healthy individuals, and some even have the common characteristic of gut microbiota disorder; (2) depletion or delayed development of gut microbes may cause neurodevelopmental disorders, and higher inflammatory markers are both associated with a decrease in beneficial bacteria and an increase in proinflammatory bacteria; (3) neurodegenerative diseases are associated with decreased diversity of gut microbiota, and the deposition of some characteristic proteins is also regulated by gut microbiota; (4) GI disorders are seen as complications or prodromal symptoms in most neurological disorders, which also implies the role of MGBA in neurological disorders; (5) although some studies have shown beneficial results, the limitations and complexity of the intervention treatment of gut microbiota in the above neurological disorders by probiotics, fecal material transplant (FMT), diet, and other means need to be discussed and further studied.

This review explores the diversity of gut microbes and the factors influencing them (dietary, genetic, and environmental) and the bidirectional communication of the MGBA. It mainly summarizes the role of the MGBA in the pathogenesis and risk factors of neurological disorders, particularly based on human and animal models, including differences in microbiome and metabolites. Furthermore, the review delves into the modulation of gut microbes in clinical treatments (such as probiotics, prebiotics, fecal microbiota transplantation [FMT], and dietary interventions), discussing their potential benefits and limitations.

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2. THE GUT MICROBIOTA

2.1. Composition and diversity of the gut microbiota

The gut microbiota is not only a large number but also a complex community with richness and diversity, including bacteria, archaea, fungi, viruses, parasites, and protozoa, among which bacteria are the most important components. 1 Previous studies on human gut microbiome have shown that the majority of human gut bacteria are anaerobes, dominated by Firmicutes and Bacteroidetes, whereas ActinobacteriaClostridiaCyanobacteriaProteobacteria, and Verrucomicrobia are less common. 13 Bifidobacteria, a member of Firmicutes, are thought to play a role in the development of the immune system in early life and have anti‐inflammatory properties, which are considered to be beneficial bacteria. 14 15 The gut microbiota is diverse and has obvious individual differences. 16 The dysbiosis of gut commensal microbiota and the increase of pathogenic microbiota can affect GI function, homeostasis, and overall health, thereby serving as pivotal contributors to disease pathogenesis. 2 16 In general, gut microbial diversity increases between childhood and adulthood and decreases with aging. 17 The diversity of gut microbiota is a potential marker of healthy aging, and the alpha diversity of the gut microbiota decreases with age and is associated with frailty in the elderly. 18 However, the diversity of gut microbiota is not reduced in all elderly people, and the diversity of gut microbiota is high in long‐lived people. 19

Gut fungi and bacteria appear to exhibit a synergistic relationship in the occurrence of diseases. 20 21 CandidaSaccharomyces, and Cladosporium are the most abundant genera in the gut fungal flora of healthy adults. 20 There are also a certain number of viruses in the gut, including bacteriophages and other viruses, and phage deployment is involved in the mechanism of colonization resistance. 17 Phages can drive evolutionary changes in bacterial communities by creating gene flow networks that promote ecological adaptation. 22 In addition, host assignment showed that virus diversity was highest in Firmicutes. 22 The gut microbiome also contains methanogenic archaea (mainly Methanobrevibacter smithii). 16 Overall, the structure and diversity of gut microbes need to be further revealed.

2.2. Factors influencing the gut microbiota

The composition of the human gut microbiota is subject to numerous influences. Initial colonization of gut microbes occurs during the early stages of human birth, with microbial transmission from the mother’s birth canal, skin, and breast milk establishing the infant’s nascent gut microbiota. 23 After weaning, the development of infant gut microbiota enters a transitional stage, and enters a stable stage in childhood. Its composition, diversity, and function gradually resemble those of adults and become the original bacteria. 24 25 Some viewpoints suggest that the human microbiota may be exposed at earlier stages, potentially influenced by the placental microbiota during maternal pregnancy. 23 26 Subsequent studies have indicated that the placenta in healthy human pregnancies do not harbor microbes, suggesting that the detected “placental microbes” may be common contaminants. 27 28 The idea of the existence of “placental microbes” is currently controversial and needs further exploration.

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