Gut Microbiota: From the Forgotten Organ to a Potential Key Player in the Pathology of Alzheimer's Disease

Abstract

More than 300 years ago, Antony van Leewenhoeck first described observing single-celled microorganisms, which he termed "animalcules," examining his saliva under a microscope. Although the idea of the coexistence of microorganisms in our body is not new, we have only recently been able to investigate their ecological relationship to our body, with the development of high-throughput molecular techniques. The diverse microorganism communities residing in our guts are established and maintained by complex interactions among microorganisms and their host. Notably, their alteration has been implicated in influencing various diseases including neurological diseases. Alzheimer's disease (AD) is the most common cause of dementia characterized by a progressive decline in memory and thinking severe enough to interfere with daily life. Despite the great progress in linking genetic risk factors with AD pathogenesis, treatments targeted at AD pathology and its modifiers have not yet resulted in a disease-modifying therapy. There is mounting evidence that the gut microbiota interacts with AD pathogenesis by disrupting neuroinflammation and metabolic homeostasis-the gut microbiota has gone from being the forgotten organ to a potential key player in the AD pathology.

Keywords: Amyloid; Bacteria; Microbiome; Neurodegeneration; Tau.

Figure 1.

Hypothetical model illustrating impact of an altered gut microbiota on AD pathogenesis. A balanced composition of gut microbiota with an abundance of commensal bacteria is essential for healthy brain function (left). In the lower half of each figure, blue color represents symbiont; black color represents harmless commensal microbe; and red color represents pathobiont. In the healthy status of the gut-brain axis, homeostatic astrocytes maintain their extracellular environment and support the integrity of the brain blood barrier protecting the CNS from exposure to peripheral agents/molecules. Pathogens which do enter the CNS are scavenged by microglia. However, as pathobionts become dominant in the gut (dysbiosis), excessive proinflammatory cytokines and neurotoxic bacterial metabolites (eg, lipopolysaccharide) lead to disruption of gut permeability and blood–brain barrier integrity. This then accelerates entry of circulating inflammatory molecules and pathogens into the brain, resulting in excessive activation of innate immunity. In turn, inappropriate glial activity may worsen processes such as Aβ seeding and clearance or local effects of Aβ (a), or exacerbate tau-mediated neurodegeneration in later stages (b). AD = Alzheimer’s disease; CNS = Central nervous system.

Figure 2.

Schematic diagram of dysregulated gut-brain axis and its interaction with AD pathology. Arrows indicate the direction of the effect. Arrows with dashed lines indicate that no studies have explored this putative relationship yet in the AD—gut microbiome field. Multiple risk factors (top), such as genetic variants (eg, ApoE4 allele, which also can directly affect AD pathology and BBB permeability) and environmental factors (eg, aging, alcohol consumption, antibiotic drug treatment) lead to unbalanced gut microbiota composition (dysbiosis). This gut dysbiosis contributes to AD-pathology progression by generating inflammatory agents and bacterial metabolites that associate with increased intestinal barrier and BBB dysfunction. Some cytokines (eg, IL-17) and metabolites (eg, SCFA) can amplify the abundance of plasma T helper type 1 (Th1) cells, which invade the brain parenchyma. These promote neuroinflammation (ie, increase proinflammatory microglial abundance) and contribute to AD pathogenesis: amyloid-β (Aβ) deposition and neurofibrillary tangles (not investigated yet). Hypothetically the CNS-invading pathogens or toxic bacterial metabolites may directly cause or facilitate AD pathology. AD = Alzheimer’s disease; BBB = Blood–brain barrier; CNS = Central nervous system; LPS = Lipopolysaccharide; SCFA = Short-chain fatty acids.