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

Table 1 Summary of animal model studies on the association between inflammatory bowel disease and Alzheimer’s disease

Animal model	Induced condition	Key observation (outcome measures)	Relevance to IBD-AD link	Ref.
C57BL/6J mice	DSS-induced colitis	Elevated NLRP3-driven neuroinflammation, cognitive deficits, impaired glymphatic clearance	Links colitis-associated inflammation to neurodegeneration via immune signaling	[42]
		Increased IL-1β, caspase-1, gasdermin D, Aβ, HMGB1, BBB disruption, TNF-α, IL-6	Systemic inflammation impairs BBB and enhances neuroinflammation	[45]
		Upregulated IDO-1, increased kynurenine and kynurenic acid, worsened cognitive decline	Systemic inflammation contributes to neuroinflammation and cognitive impairment	[46]
Tg2576 Transgenic mice	DSS-induced colitis	Altered gut microbiota, increased GFAP and microglial activation	Demonstrates that chronic gut dysbiosis worsens cognitive dysfunction and AD pathology	[43]
	Gut dysbiosis before AD	Increased gut permeability, reduced tight junction proteins, and fluorescein isothiocyanate-dextran leakage	Gut barrier dysfunction precedes and contributes to AD pathology	[50]
3XTg-AD transgenic mice	DSS-induced colitis + vagotomy	C/EBPβ/δ-secretase activation, Aβ and Tau fibril propagation to the brain via the vagus nerve	Highlights gut-brain signaling in AD exacerbation due to gut inflammation, with the vagus nerve as the conduit	[44]
	Transgenerational effects on antibiotic-induced dysbiosis	Delayed cognitive decline, reduced Aβ aggregation in the brain	Gut microbiota influences AD pathology via immune modulation across generations	[40]
APP/PS1 transgenic mice	Antibiotic-induced gut dysbiosis	Altered gut microbiota, reduced amyloid pathology, increased T-reg cells, and modified microglial activation	Highlights the gut microbiota's role in AD via immune modulation, even without direct colitis	[53]
	Fecal microbiota transplant	Restoration of microbial balance, reduced amyloid load, and cognitive improvement	Supports microbiota-targeting therapy for AD mitigation	[54]
	Gut dysbiosis	Microglial activation, elevated TNF-α, IL-6, and early gut microbiota changes	Gut dysbiosis precedes and contributes to AD pathology	[8]
	Intestinal barrier alterations	Excessive Aβ accumulation in gut epithelium, increased permeability, inflammatory changes, and mucin2 upregulation[59]	Gut barrier dysfunction linked to AD pathology[59]	[50]
	Germ-free condition	Reduced amyloid plaque deposition compared to control mice	Suggests gut microbiota influence on AD pathogenesis	[39]
SAMP8 mice	Gut dysfunction, colonic motility	Delayed colonic motility, enteric neurodegeneration, early ENS Aβ and Tau aggregates	ENS dysfunction may precede brain AD pathology	[52]
APPNL-G-F transgenic mice	DSS-induced colitis	Increased neutrophil infiltration into the hippocampus and cortex, clustering around Aβ plaques, worsening neuroinflammation	Neutrophils migrate through the GBA and exacerbate AD pathology	[48]
		Significant exacerbation of Aβ plaque deposition, altered CD68, and increased systemic inflammation	Gut inflammation triggers neuroinflammation and worsens AD pathology	[19]
	DSS-induced colitis + probiotics	Reduced colitis severity, partially improved gut permeability, limited effects on neuroinflammation and Aβ	Probiotics have mild protective effects on the gut and brain	[55]
APP/PS1 and AppNL-G-F mice	Studied for gut-brain interactions	Increased amyloid plaque deposition in the intestines and brain, gut motility and permeability changes	Supports the hypothesis that gut inflammation precedes neurodegeneration	[41]
5XFAD transgenic mice	Genetic overexpression of human APP & PS1 mutations (presymptomatic stage)	Reduced IL-17 protein production/secretion in PP and MLN cells of 5xFAD mice, significantly lower miR-155 expression in MLN cells of 5xFAD mice	The observed GALT changes, especially reduced IL-17 (linked to ↓miR-155), mirror AD progression. This might reflect inadequate immune surveillance in the gut, potentially leading to enhanced AD pathology (e.g., via altered microbiota or Aβ clearance)	[49]

IBD: Inflammatory bowel disease; AD: Alzheimer’s disease; DSS: Dextran sodium sulfate; IL: Interleukin; BBB: Blood-brain barrier; Aβ: Amyloid-β; TNF-α: Tumor necrosis factor-alpha; APP: Amyloid precursor protein; ENS: Enteric nervous system; GBA: Gut-brain axis; GALT: Gut-associated lymphoid tissue; MLN: Mesenteric lymph nodes.

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.

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.