Molecular links between inflammatory bowel disease and Alzheimer’s disease through immune signaling and inflammatory pathways

Figure 1 This schematic timeline illustrates the progression of Alzheimer’s disease-related pathologies in the central nervous system and gastrointestinal tracts of APPNL-G-F and amyloid precursor protein/PS1 transgenic mouse models. APP: Amyloid precursor protein; CNS: Central nervous system; GI: Gastrointestinal; Aβ: Amyloid-β.

Figure 2 Detailed schematics of inflammatory bowel disease pathophysiology and its transformation into Alzheimer’s disease pathophysiology: Gut inflammation and increased intestinal permeability lead to systemic transport of inflammatory mediators via peripheral circulation and vagus nerve, resulting in blood-brain barrier disruption, amyloid-β accumulation, tau hyperphosphorylation, and neuroinflammation. SCFAs: Short-chain fatty acids; LPS: Lipopolysaccharides; IBD: Inflammatory bowel disease; AD: Alzheimer’s disease; ROS: Reactive oxygen species; GABA: γ-aminobutyric acid.

Figure 3 Gut-brain axis comparison between healthy individuals and Alzheimer's disease patients with inflammatory bowel disease. Healthy individuals maintain intact blood-brain barrier (BBB), balanced neurotransmitters, and diverse gut microbiota, while Alzheimer’s disease patients with inflammatory bowel disease exhibit disrupted BBB, neuroinflammation, dysbiosis, and reduced short-chain fatty acids. SCFAs: Short-chain fatty acids; GABA: γ-aminobutyric acid.

Figure 4 Gut-brain axis: From dysbiosis to neuroinflammation. Gut dysbiosis leads to a leaky gut and systemic inflammation, releasing pro-inflammatory mediators. These mediators cross a compromised blood-brain barrier, activating resting microglia into a pro-inflammatory M1 phenotype. Activated M1 microglia release cytokines, chemokines, and reactive oxygen species, causing neuronal damage (dystrophic neurons) and contributing to pathologies like amyloid-β plaque formation and microgliosis, highlighting the gut-brain axis's role in neuroinflammation. LPS: Lipopolysaccharides; TLRs: Toll-like receptors; TNF-α: Tumor necrosis factor-alpha; IL: Interleukin; BBB: Blood-brain barrier; TREM2: Triggering receptor expressed on myeloid cells 2; NF-kB: Nuclear factor kappa B; ROS: Reactive oxygen species.