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

Table 2 Key inflammatory and immune signaling pathways shared between inflammatory bowel disease and Alzheimer’s disease

Pathway	Key molecules	Role in IBD	Role in AD	Therapeutic target	Ref.
NLRP3 inflammasome	NLRP3, ASC, caspase-1, IL-1β, IL-18, GSDMD	Drives mucosal inflammation and epithelial barrier damage via IL-1β/IL-18 maturation and pyroptosis	Promotes microglial activation, synaptic dysfunction, and Aβ/Tau pathology via IL-1β/IL-18; pyroptosis amplifies neuroinflammation	NLRP3 inhibitors (e.g., MCC950), IL-1 blockers (anakinra), caspase-1/GSDMD inhibitors	[42,44,47,101]
Proinflammatory cytokines	TNF-α, IL-6, IL-1β, IFN-γ	Central mediators of flare activity; correlate with severity; disrupt tight junctions	Sustain neuroinflammation, impair synaptic plasticity, associate with cognitive decline; disrupt BBB	Anti-TNF (infliximab, adalimumab), anti-IL-6 (tocilizumab), IL-1 blockade; JAK inhibitors	[61,76,80,81]
Tryptophan–kynurenine	IDO1, Tryptophan 2,3-dioxygenase, Kynurenine, 3-Hydroxykynurenine, QA, KA	Inflammation upregulates IDO1; shifts TRP metabolism; impacts gut immunity	Kynurenine Pathway metabolites modulate glutamatergic/cholinergic signaling; QA neurotoxic; KA neuromodulatory	IDO1 inhibitors; KP modulators; microbiota-directed TRP metabolism	[46,67]
Microglia–astrocyte activation	TLR2/4, NF-κB, C/EBPβ, AEP (δ-secretase), GFAP	TLR activation by microbial products fuels cytokines and tissue damage	Glial priming via TLR/NF-κB; C/EBPβ–AEP axis accelerates Aβ/Tau pathology	TLR antagonists; NF-κB inhibitors; AEP inhibitors; glial modulators	[96,97,100-103]
Barrier–adhesion–trafficking	Tight junctions (ZO-1, occludin, claudins), MUC2, HMGB1, ICAM-1/VCAM-1	Barrier loss, mucus alterations, leukocyte adhesion/extravasation	BBB disruption, HMGB1 as alarmin, leukocyte trafficking into brain	Barrier protectants; HMGB1 antagonists; anti-adhesion strategies	[145-147]
Vagus–cholinergic anti-inflammatory	Vagus nerve, α7 nAChR	Modulates intestinal inflammation via vagal tone	Vagal signaling links gut inflammation to brain; α7 nAChR neuroprotective	Vagus nerve stimulation; α7 nAChR agonists	[59,69-72]
Mitochondrial stress-ROS	mtROS, NLRP3 activation, mitophagy	Oxidative stress perpetuates mucosal inflammation	mtROS primes microglia; contributes to Aβ/Tau aggregation	Antioxidants; mitophagy enhancers	[119-124]

IBD: Inflammatory bowel disease; AD: Alzheimer’s disease; IL: Interleukin; Aβ: Amyloid-β; TNF-α: Tumor necrosis factor-alpha; JAK: Janus kinase; QA: Quinolinic acid; KA: Kynurenic acid; TLR: Toll-like receptor; NF-kB: Nuclear factor kappa B; BBB: Blood-brain barrier; α7 nAChR: Α7 nicotinic ACh receptors; ROS: Reactive oxygen species.