FIGURE 2.

Glymphatic pathway in pathological conditions: a role for the bidirectional gut-brain communication. Alterations of the glymphatic pathway may contribute to the extracellular accumulation of waste products, including altered protein in the brain (black stars). These include alterations in the morphology and drainage capacity of meningeal lymphatic vessels, impairment of CSF influx and efflux, along with the release of several pro-inflammatory cytokines and immune cells. Considering the reciprocal communication which occurs between the brain and the gastrointestinal tract, gut alterations can affect the CNS, and vice-versa. Potentially harmful solutes, including misfolded/aggregated proteins, may spread to the gut through the autonomic nervous system to induce inflammation [brain-first (top-down) type]. In turn, gut dysbiosis, inflammation, and leakage may promote the antidromic spread of potentially harmful molecules to the CNS via the vagal fibers or the bloodstream [body-first (bottom-up) type], bypassing and altering the glymphatic system and the BBB (left insert). These include misfolded/aggregated proteins such as α-synuclein, microorganisms, and also pro-inflammatory cytokines and activated immune cells, such as TREM TREM cells-positive activated macrophages. Extracellular accumulation of waste products related to an altered glymphatic drainage is exacerbated when intracellular clearing systems are impaired (right insert). This is the case of the autophagy pathway, which grants neuronal proteostasis and survival. When autophagy is impaired, extracellular release of undigested, potentially harmful substrates may occur via exosome release.