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

Abstract

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), has been increasingly associated with the progression of neurodegenerative disorders, particularly Alzheimer's disease (AD). Emerging data from population-based meta-analyses and in vivo experimental models demonstrate that systemic inflammation associated with IBD exacerbates disruption of the gut-brain axis (GBA). This disruption promotes the deposition of amyloid-β (Aβ) plaques, and cognitive decline. Together, these effects contribute to the progression of AD. Chronic colitis, a hallmark of IBD, accelerates Aβ pathology and induces cognitive impairment in transgenic mouse models, providing direct evidence of the detrimental effects of gut inflammation on neurodegeneration. Although numerous clinical and meta-analytical studies have examined the prevalence of AD in IBD patients, the molecular mechanisms underlying this association remain inadequately understood. In particular, the roles of immune regulation and GBA interactions require further investigation. This review aims to critically compile current evidence that elucidates the shared pathophysiological mechanisms underlying this association, such as chronic systemic inflammation, gut dysbiosis, and dysregulated immune responses. Although anti-inflammatory therapies, probiotics, and modulation of the gut microbiota have the potential to reduce the risk of AD and slow its progression, age-related gut inflammation and dysbiosis can aggravate AD pathology. This underscores the necessity for treatments that specifically target IBD-associated inflammation to limit AD progression. In addition, this review also meticulously examines how immune signaling and regulatory pathways in IBD, such as triggering receptor expression via myeloid cell receptor activation; NLRP3 inflammasome-driven inflammation; disrupted interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) signaling; and elevated C-reactive protein levels, contribute to increased amyloidogenesis. This paper proposes a comprehensive framework for therapeutic strategies targeting IBD-related inflammation and elucidates their potential to attenuate the progression of AD.

Keywords: Alzheimer’s disease; Amyloidogenesis; Gut-brain axis; Immune signaling; Inflammatory bowel disease; Inflammatory pathways; Therapeutics.

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.