The Microbiota-Gut-Brain Axis and Alzheimer Disease. From Dysbiosis to Neurodegeneration: Focus on the Central Nervous System Glial Cells

Abstract

The microbiota-gut system can be thought of as a single unit that interacts with the brain via the "two-way" microbiota-gut-brain axis. Through this axis, a constant interplay mediated by the several products originating from the microbiota guarantees the physiological development and shaping of the gut and the brain. In the present review will be described the modalities through which the microbiota and gut control each other, and the main microbiota products conditioning both local and brain homeostasis. Much evidence has accumulated over the past decade in favor of a significant association between dysbiosis, neuroinflammation and neurodegeneration. Presently, the pathogenetic mechanisms triggered by molecules produced by the altered microbiota, also responsible for the onset and evolution of Alzheimer disease, will be described. Our attention will be focused on the role of astrocytes and microglia. Numerous studies have progressively demonstrated how these glial cells are important to ensure an adequate environment for neuronal activity in healthy conditions. Furthermore, it is becoming evident how both cell types can mediate the onset of neuroinflammation and lead to neurodegeneration when subjected to pathological stimuli. Based on this information, the role of the major microbiota products in shifting the activation profiles of astrocytes and microglia from a healthy to a diseased state will be discussed, focusing on Alzheimer disease pathogenesis.

Keywords: Toll-like receptor 4; amyloid-β; clasmatodendrosis; cytokines; endotoxin; neurovascular unit; short chain fatty acids; vagus nerve.

Figure 1

Schematic representation of the bottom-to-top regulation of neuroinflammation in AD pathogenesis. (Left panel) In healthy conditions, the microbiota–gut–brain axis modulates key processes, including immune cell maturation and maintenance of the gut epithelium. SCFAs produced by the gut microbiota cross the IB and, via the circulatory system, reach and cross the blood–brain barrier. Once in the brain parenchyma, SCFAs target microglia and regulate their functions. The gut microbiota is one of the main producers of Aβ peptide and LPS, which integrate in CM and cross the BBB. Aβ is readily retro transported to the circulatory system for its disposal. Blue lines represent known beneficial pathways of microbiota. (Right panel) Microbiota overproduction of LPS and cytokines causes modification of the permeability of the gut epithelium, of the NVU and of the glymphatic system. Gut microbiota production of SCFA is reduced in AD, while the production of proinflammatory cytokines, including IL-1β, IL-6, and TNF-α, as well as MAMPs and PAMPs, is increased. These factors translocate to the brain where they modulate microglia via TLR4, and activated M1 microglia release IL-1β, TNF-α, ROS, and NO that cause neuronal damage. In addition, proinflammatory cytokines cause activation of astrocytes (A1), which release cytokines that in turn decrease AQP4 expression and modify NVU permeability. Peripheral Th1, activated by isoleucine (Ile) and phenylalanine (Phe) produced by microbiota, can recognize the bacterial metabolites or MAMPs and migrate to the brain via the damaged BBB. Aβ peptide produced by the microbiota can easily cross the IB or be retrogradely transported to the brain via the vagus nerve. Since disposal of Aβ peptide is impaired by the damage to the BBB, Aβ peptide precipitates to form plaques, which further worsens microgliosis and astrogliosis, increasing the severity of AD pathology. Red lines indicate the bottom-to-top damaging pathways so far demonstrated.