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.