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

Table 3 Therapeutic approaches targeting gut-brain axis dysfunction in inflammatory bowel disease and Alzheimer’s disease

	Intervention	Mechanism	Evidence (model or study)	Outcome on AD	Outcome of IBD	Trial No./Ref.
Anti-inflammatory medications	TNF-α inhibitors (infliximab, adalimumab)	Reduce systemic inflammation and BBB permeability by blocking TNF-α	Clinical data from IBD patients; Phase 3 trials	63% reduced risk in CD patients, 36% in UC patients; neuroprotective effects	Widely used IBD treatment; reduces gut inflammation and flare activity	NCT00207766, NCT05090124
	Immunomodulators (azathioprine, mercaptopurine, methotrexate)	Suppress systemic inflammation through immune modulation	Clinical cohort studies in IBD patients	37% reduction in AD risk in both CD and UC patients	Controls inflammation and maintains remission	[37]
	IL-1β blockers (anakinra)	Block IL-1 inflammatory pathway reducing neuroinflammation	ASCOT trial in mild AD patients	Potential cognitive improvement or stabilization	Reduces gut mucosal inflammation and IL-1β-mediated damage	NCT04834388
	IL-6 receptor inhibitors (tocilizumab)	Reduce IL-6 mediated neuroinflammation and amyloidogenesis	Clinical studies in inflammatory conditions	Anti-inflammatory effects; may reduce neuroinflammation	Reduces intestinal IL-6 signaling and inflammation	[151,152]
	JAK inhibitors (tofacitinib)	Inhibit JAK/STAT cytokine signaling pathway	Approved for IBD treatment; potential AD therapy	May reduce glial activation-induced neuroinflammation	Effective in decreasing intestinal inflammation and barrier breakdown	[106,107]
	XPro™ (selective TNF inhibitor)	Selective TNF inhibition targeting neuroinflammation	MINDFuL trial in early AD and MCI patients	Investigated for neuroinflammation reduction in early AD	Potential anti-inflammatory effects on gut mucosa	NCT05318976
	P2X7 Receptor Antagonists	Modulate P2X7 activation, dampen ATP-driven inflammasome signaling, cut downstream IL-1β/TNF-α release	Pre-clinical IBD and AD models show reduced gut and brain inflammation	Lower microglial activation, curb neuroinflammation, protect neurons	Inhibits EGC hyperactivation and cytokine release, reducing gut inflammation	[94-96]
Gut microbiota modulation	Probiotic supplementation (Lactobacillus, Bifidobacterium)	Restore gut microbial balance; reduce gut permeability and systemic inflammation	Preclinical AD models; Probio-AD trial	Improves cognitive function; reduces neuroinflammation	Decreases colitis severity; partially restores gut barrier	NCT05145881
	Fecal microbiota transplantation	Restore healthy gut microbiota and improve gut-brain communication	Animal models (APP/PS1 mice); clinical trial	Decreases Aβ deposition; enhances cognitive performance	Improves gut microbiota composition; reduces inflammation	NCT06920212
Dietary and lifestyle modifications	Mediterranean diet	Rich in polyphenols and omega-3 fatty acids; modulates gut microbiota and reduces inflammation	Clinical studies	Reduces AD risk; lowers proinflammatory cytokines and neuroinflammation	Beneficially alters gut microbiota composition; reduces systemic inflammation	ISRCTN35739639
	Ketogenic diet	Promotes ketone body synthesis; enhances mitochondrial function and reduces oxidative stress	Clinical trials	Neuroprotective effects; potentially slows AD progression	May improve mitochondrial function in gut epithelium	ACTRN12618001450202
Targeting bacterial amyloids	Anti-bacterial amyloids targeting	Prevent bacterial amyloid formation (E. coli, B. subtilis) that accelerates cerebral amyloid aggregation	Preclinical studies on bacterial amyloids	Reduce amyloid pathology and Aβ aggregation	Reduces gut bacterial-derived amyloid formation and inflammation	[160-162]
Neuroimmune modulation	Vagus nerve stimulation and α7nAChR agonists	Enhance CAIP to regulate immune responses	Preclinical and clinical studies in IBD and AD	Neuroprotective by reducing neuroinflammation via α7nAChR activation	Modulates intestinal inflammation through improved vagal tone	[59,68-72]

IBD: Inflammatory bowel disease; AD: Alzheimer’s disease; TNF-α: Tumor necrosis factor-alpha; BBB: Blood-brain barrier; CD: Crohn disease; UC: Ulcerative colitis; IL: Interleukin; IL-1β: Interleukin-1 beta; JAK: Janus kinase; STAT: Signal transducer and activator of transcription; EGC: Enteric glial cell; Aβ: Amyloid-β; APP: Amyloid precursor protein; E. coli: Escherichia coli; B. subtilis: Bacillus subtilis; CAIP: Cholinergic anti-inflammatory pathway; α7 nAChR: Α7 nicotinic ACh receptors; MCI: Mild cognitive impairment.