Gastrointestinal Changes and Alzheimer's Disease

Abstract

Background: There is a well-described mechanism of communication between the brain and gastrointestinal system in which both organs influence the function of the other. This bi-directional communication suggests that disease in either organ may affect function in the other.

Objective: To assess whether the evidence supports gastrointestinal system inflammatory or degenerative pathophysiology as a characteristic of Alzheimer's disease (AD).

Methods: A review of both rodent and human studies implicating gastrointestinal changes in AD was performed.

Results: Numerous studies indicate that AD changes are not unique to the brain but also occur at various levels of the gastrointestinal tract involving both immune and neuronal changes. In addition, it appears that numerous conditions and diseases affecting regions of the tract may communicate to the brain to influence disease.

Conclusion: Gastrointestinal changes represent an overlooked aspect of AD, representing a more system influence of this disease.

Keywords: Alzheimer; Microbiome; amyloid; enteric neuron; inflammation; intestine.

Fig. 1.. Interactions between the Gastrointestinal Tract and Brain of Relevance in AD.

The autonomic nervous system innervates the gastrointestinal tract to directly influence the enteric cells, immune cells, and intestinal microbiome. In addition, circulating hormonal secretions can have similar influences on the intestine. In turn, intestine-derived secretions such as bacterial products or metabolites, immune cells, cytokines, neurotransmitters, or enteric hormones may influence nervous communication to the brain directly or travel via the vasculature to affect the brain through mechanisms perhaps involving disruption of the blood-brain barrier (BBB).

Fig. 2.. Possible mechanisms of brain and stomach communication to the brain to potentiate AD pathophysiology.

Periodontitis, characterized by chronic gingival inflammation and bone and tooth loss, increases the risk for AD and dementia. Periodontitis is also positively correlated with increased amyloid plaque load, gliosis, and neuron loss. Increased immune cell activation and circulating cytokines associated with periodontitis may infiltrate through the blood-brain barrier to directly influence disease pathophysiology. Similarly, periodontal pathogens and their components, such as LPS, have been reported to be elevated in AD brains. Rodent studies of oral pathogen infection support the human disease findings by stimulating increased brain cytokines and LPS, memory dysfunction, neuron loss, elevated Aβ, and increased phospho-tau levels. In addition to the inflammatory contributions of changing oral health to the brain in AD, several studies demonstrate that the peripheral inflammatory changes associated with gastric infection and gastritis also induce AD-like changes in rodents, including elevated brain cytokines and altered behavior. This notion is supported by human studies demonstrating an increased association of H. pylori infection with AD patients compared to controls and improved behavior with eradication therapy.

Fig. 3.. Potential contributions of the small and large intestine to AD pathophysiology.

Several studies validate disease-related changes in the small intestines of AD patients and rodent models characterized by Aβ and tau pathology and inflammatory changes. For example, small intestine epithelial cells express APP in response to dietary changes such as a high-fat diet and can secrete Aβ peptide possibly into the intestinal connective tissue and the circulation. In agreement with this, enteric neurons in rodent models and AD patient small intestines have demonstrated intracellular Aβ, immune cell changes, neuron expression differences, and phospho-tau increases. Different rodent models of AD have also identified intestinal motility and permeability changes compared to controls. Although the intestine-related dysfunction represents a disease phenotype, it is possible that enteric-derived Aβ, phospho-tau, activated immune cells, enteric hormones, or cytokines may communicate to the brain to influence disease via the circulation or direct neuronal innervation. Similar contributions to disease may exist for the large intestine. For example, intestinal inflammatory changes such as those associated with IBD may provide a driving force for exacerbating bacterial translocation through a disrupted epithelial layer and immune cell activation and enteric neuron dysfunction that communicates to the brain in AD. Rodent IBD studies validate that intestinal immune and functional compromise and an impaired epithelial barrier communicate to the brain to exacerbate gliosis, cytokine elevations, and increased plaque load using AD mouse models. Age, diet, environment, or disease-associated changes in the intestinal microbiome, largely localized to the large intestine, have also been characterized in human AD patients and rodent models. This dysbiosis correlates with cognitive changes and peripheral inflammatory states. Disease-modifying, unique bacteria or their components and secretory products such as LPS, small chain fatty acids, and secondary bile acids have been examined in human and rodent models to identify therapeutic targets. It is clear from rodent studies that manipulation of the intestinal microbiome is sufficient to alter brain changes such as behavior, gliosis, inflammatory changes, and Aβ levels in rodent models.