Fig. 2

Routes by which microbes modulate neurodegenerative diseases. In the immunological pathway, gut microbe-derived products or metabolites (e.g., LPS) pass through the gut barrier and activate innate immune cells, primarily monocytes, and subsequently increase secretion of proinflammatory cytokines (TNF-α, IL-1β, IL-6, etc.) and reduce the phagocytic capacity of monocytes for amyloid proteins, leading to elevated neuroinflammation and amyloid aggregates in the brain. Gut dysbiosis also promotes the conversion of CD4⁺ T cells into proinflammatory phenotypes (Th1 and Th17), which secrete proinflammatory cytokines (IFN-γ, TNF-α, IL-1β, IL-17 A, etc.). These microbes can traverse the impaired blood-brain barrier and interact with microglia in the brain, exacerbating neuroinflammation. In the vagus nerve pathway, neurotransmitters and hormones secreted by enteroendocrine cells upon stimulation by the gut microbiome and its products can activate the vagus nerve. Amyloid-producing bacteria trigger gut amyloid accumulation, which is retrogradely transported to the brain via the vagus nerve. Gut microbe-derived extracellular vesicles can penetrate the brain through the vagus nerve and bloodstream, reducing BNDF expression in neurons and exacerbating neuroinflammation. In the circulatory pathway, microbes, their products, and neurotransmitters and hormones secreted by enteroendocrine cells can enter the peripheral circulation and cross the blood-brain barrier, leading to damage to neurons and microglia, reduced microglial phagocytic capacity, and increased neuroinflammation and amyloid aggregates in the brain. BDNF brain-derived neurotrophic factor, EC enteroendocrine cell, IFN-γ interferon-γ, IL interleukin, LPS lipopolysaccharide, Th T helper cell, TMA trimethylamine, TMAO trimethylamine-N‐oxide, TNF-α tumour necrosis factor-α