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.

Core Tip: This review provides evidence regarding the molecular connections between inflammatory bowel disease (IBD) and Alzheimer’s disease (AD). This interaction is facilitated mainly through immune signaling and inflammatory processes through the gut-brain axis. In IBD, chronic inflammation of the gut facilitates systemic inflammation, which may breach the blood-brain barrier and trigger neuroinflammation, amyloid-β accumulation, and cognitive impairment. The common mechanisms are the activation of the NLRP3 inflammasome, cytokine signaling dysregulation, and mitochondrial dysfunction. By inhibiting IBD-related inflammation via drugs or by modulating the microbiota, an approach based on neuroprotection can slow the progression of AD.

INTRODUCTION

Inflammatory bowel disease (IBD) is a persistent inflammatory disease of the gastrointestinal (GI) tract, which encompasses ulcerative colitis (UC) and Crohn’s disease (CD)[1]. The characteristic of UC is superficial inflammation limited to the colonic mucosa, typically resistant to conventional therapies and associated with systemic immune activation. Its pathogenesis is associated with dysfunction of the epithelial barriers, immune cell invasion, and a cytokine storm that causes systemic immune activation linked to extraintestinal manifestations such as neuroinflammation and cognitive impairment[2]. On the other hand, CD mainly affects the distal ileum, though it can manifest throughout the GI tract, and is typified by chronic inflammation, with or without lymphatic infiltrates and granulomas[3]. Genetic predisposition, immune regulation disorder, and gut dysbiosis also play a role in the progression of CD[1,4]. Even though they manifest differently, both UC and CD stimulate the synthesis of proinflammatory cytokines that trigger neuroinflammatory processes leading to neuronal damage[5]. There has been growing interest in the association between IBD and Alzheimer’s disease (AD), and in particular, the role of ongoing gut inflammation on the pathogenesis of neurodegenerative disorders[6]. The discussion of the salient features of AD will aid in understanding such a potential connection. AD is a non-vascular progressive neurodegenerative disorder involving amyloid-β (Aβ) plaques and neurofibrillary tangles, resulting in significant cognitive impairment[7]. However, most importantly, neuroinflammation is a central pathogenic feature of AD, induced by activated glial cells (microglia and astrocytes), which produce proinflammatory cytokines, leading to neuronal damage[8-10]. Additionally, the pathogenesis of AD is associated with significant dysfunction of neurotransmitter systems, which, besides the dysregulation of the gut-brain axis (GBA), may exacerbate neuroinflammatory mechanisms and impair neural functions[11]. Considering these properties, it is proposed that chronic systemic inflammation and immune dysregulation caused by diseases like IBD will affect AD progression through changes in neuroinflammatory and neurochemical environments. Recent studies have shown that the inflammation caused by IBD leads to the onset and progression of AD, partly via gut-derived molecules that stimulate neuroinflammation[12-14]. Gut hyperpermeability, frequently observed in IBD, permits the translocation of inflammatory mediators into the bloodstream, disturbing brain homeostasis and potentially accelerating the progression of AD[15-17]. Furthermore, metabolites originating from the gut can traverse the GBA, impact neural function and lead to synaptic impairment and neuroinflammation[6,18]. Chronic inflammation in IBD compromises gut barrier integrity, allowing proinflammatory cytokines, microbial metabolites [such as short-chain fatty acids (SCFAs) and trimethylamine-N-oxide], and endotoxins [e.g., lipopolysaccharides (LPS)] to enter the systemic circulation[1,19]. Through mechanisms such as receptor-mediated transcytosis and tight junction disruption, endothelial dysfunction facilitates the passage of inflammatory mediators across the blood-brain barrier (BBB). These mediators trigger microglial activation and neuroinflammation. Consequently, Aβ accumulation and tau hyperphosphorylation occur, leading to cognitive decline - a characteristic feature of AD[5,20,21]. Furthermore, epidemiological studies provide additional evidence for the role of gut-derived inflammation in neurodegeneration, demonstrating that individuals with IBD have an increased risk of developing dementia, particularly AD[22,23]. The neurotransmitter dysregulation is a primary molecular correlation between IBD and AD, which plays a significant role in causing GBA dysfunction. Enteric neurotransmitters including glutamate, γ-aminobutyric acid (GABA), serotonin, and acetylcholine (ACh) are important in the maintenance of gut homeostasis and neural communication. In IBD, chronic intestinal inflammation disrupts this balance, often leading to excessive glutamatergic activity and reduced GABAergic signaling, thereby promoting excitotoxicity and neuronal damage[24]. These neurotransmitters regulate the enteric nervous system (ENS), which undergoes changes under the influence of inflammation, resulting in aberrant gut-brain signaling that contributes to neuroinflammation[25]. An ENS malfunction, therefore, increases neuroinflammatory responses by additional impairment of gut barrier function and enhancing immune activation and thus facilitating the neurodegeneration cascade in AD. This paper is dedicated to the role of IBD-related immune signaling pathways, inflammatory mediators, and cellular perturbations in increasing neurodegeneration and systematically examines the molecular and immunological correlations between IBD and AD. The main processes under investigation include GBA dysfunction, alterations in the ENS, neurotransmitter imbalances, and oxidative stress. These factors play critical roles in promoting microglial activation and neuronal damage. This review also discusses shared genetic risk factors, common inflammatory markers, as clinical and preclinical data of the correlation of the two conditions. Lastly, possible treatment interventions, including immune-targeted therapies, microbiota-based therapies, and metabolic modulators, are being explored for their potential to simultaneously address gut and neuroinflammatory processes.

CLINICAL AND METANALYTICAL STUDIES EXTRAPOLATING THE ASSOCIATION OF AD IN IBD PATIENTS

Numerous clinical and meta-analytical studies have explored the association between IBD and AD, providing evidence of a link between chronic gut inflammation and neurodegenerative risk. A large-scale meta-analysis by Liu et al[26] utilized pooled data from over 2.3 million individuals across six studies. It demonstrated a significant increase in the risk of developing dementia after an IBD diagnosis, irrespective of patient age, sex, dementia subtype, or IBD subtype[26]. Another meta-analysis by Zhang et al[23], which was based on data from approximately 1.3 million patients, revealed that the overall risk of dementia was significantly greater in IBD patients than in the general population, including a notably increased risk of AD. To further corroborate these findings, Liu et al[22] conducted a study involving a cohort of over 3 million participants, confirming an increased risk of all-cause dementia in patients with IBD. This study specifically associated UC with both all-cause dementia and AD, whereas CD was associated with only general dementia[22]. A more recent meta-analysis by Zong et al[27] further reinforced the association between IBD and AD, reporting an elevated risk of AD in IBD patients. This study also reported that older individuals (aged 50 years and above) with IBD were more susceptible to both AD and dementia than younger individuals with IBD. In contrast, a meta-analysis of seven studies involving approximately 20000 AD cases by Xing et al[28] revealed no significant association between IBD and AD risk. However, this study showed an inverse correlation, suggesting a potentially reduced AD risk associated with exposure to IBD-related medication, indicating that anti-inflammatory treatments might play a neuroprotective role[28].

Geographic variations in this association have also been documented. For example, one study reported that patients with IBD in Asian populations exhibit a twofold greater risk of developing AD than do those in European and American populations[27]. Moreover, multiple cohort and retrospective population-based studies have demonstrated a connection between IBD and neurodegenerative disorders. A Danish nationwide population-based cohort study by Rønnow Sand et al[29] tracked over 88000 IBD patients over a 40-year period. It revealed a 7.2% increased risk of all-cause dementia among individuals with UC and a 5.8% increased risk among those with CD. This study also revealed a stronger association between AD/all-cause dementia and UC than with CD, suggesting that the inflammatory mechanisms specific to UC may be more closely involved in AD pathogenesis[29]. Similarly, a German cohort study involving nearly 7000 participants (3850 with IBD and 3850 non-IBD controls) over a 15-year period reported varying cumulative incidences of dementia across IBD subtypes. Overall, IBD was associated with a 1.22-fold increased risk of dementia, with UC patients exhibiting a 1.25-fold increase, whereas no significant association was observed for CD patients. These findings further support the hypothesis that UC-related inflammation may play a role in neuroinflammatory processes relevant to AD[14]. In a Korean cohort study by Kim et al[30], which included approximately 25000 patients and 99000 controls, IBD was similarly linked to an elevated risk of neurodegenerative diseases. Notably, among patients aged 65 years or older, those with IBD had a greater risk of developing AD, with female patients showing particularly pronounced susceptibility[30]. Taken together, the consistency of results across diverse large-scale cohort studies and meta-analyses provides compelling evidence for a link between IBD and an increased risk of dementia. This association holds true despite variations in geography, age, environmental exposure, and genetic background. Several studies further indicate a particularly elevated risk of AD.

Genetic analyses and Mendelian randomization (MR) studies have further investigated the associations between IBD and neurodegenerative conditions. Liu et al[26] conducted a meta-analysis of seven studies using a genetic inverse variance approach with a random-effects model. They reported a significantly increased risk of dementia among IBD patients compared with the general population[26]. Subgroup analysis indicated that individuals over the age of 65 with IBD faced a particularly elevated risk. Mechanistically, chronic inflammation in IBD leads to sustained elevations in proinflammatory cytokines, such as tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). These cytokines compromise the integrity of the BBB, thereby promoting persistent neuroinflammation and accelerating neurodegenerative processes[23]. In a subsequent study, Liu et al[26] performed a large-scale meta-analysis incorporating MR data from ten observational cohort studies based on genome-wide association studies (GWAS), encompassing a combined sample size of over 80 million individuals. While this analysis confirmed a positive association between IBD and dementia, it revealed no evidence of a genetic correlation between IBD and AD. This finding suggests that the observed epidemiological link between IBD and AD is more likely driven by immune-mediated mechanisms rather than shared genetic susceptibility. In multiple genetic studies, the absence of overlapping genetic loci between IBD and AD further strengthens this interpretation[31-36].

The retrospective database studies also support a relationship between IBD and AD. Aggarwal et al[37] explored the Explorys electronic medical records database and analyzed over 64 million patients and reported 723540 AD cases, 6730 of which had a previous diagnosis with IBD. In addition, 620 of these IBD patients had AD a year after being diagnosed. This study also indicated that intestinal surgery patients with IBD were more likely to develop AD, enhancing the relationship between gut health and neurodegeneration[37]. These deficits may be a link between neurodegeneration and a possible extraintestinal manifestation of IBD. A meta-analysis of the cognitive performance of 687 active IBD patients revealed notable deficits in working memory, executive function, and attention. This implies that IBD patients may present subclinical cognitive deficits mediated by systemic inflammation and GBA disturbance even before a confirmed diagnosis of dementia or AD[38].

Therapeutic interventions have the potential to reduce the risk of AD in IBD patients. Treatment with TNF-α inhibitors was linked to a much lower risk of AD; specifically, CD patients treated with these agents had a 63% reduced risk, whereas UC patients had a 36% reduced risk. Additionally, the use of immunomodulators (including azathioprine, mercaptopurine, and methotrexate) was associated with a 37% reduction in AD risk in both CD and UC patients. These findings suggest that suppressing systemic inflammation through immunomodulatory therapies may confer neuroprotective benefits and potentially slow the progression of neurodegenerative disease in IBD patients[37]. Although multiple large-scale meta-analyses and cohort studies indicate a robust association between IBD and an increased risk of dementia, particularly in the ageing population, the evidence specifically linking IBD and AD remains uncertain. While collective evidence from clinical studies is compelling, it is crucial to interpret these findings with an awareness of their inherent limitations. Retrospective database studies, although powerful in scale, are susceptible to selection biases, coding inaccuracies, and unmeasured confounding variables that may influence the observed associations between IBD and AD.

Inflammatory pathways and GBA interactions are likely the key elements contributing to this complex relationship, which are discussed below.

PRECLINICAL STUDIES ON ASSOCIATION OF IBD AND AD EXPERIMENTAL INSIGHTS

Preclinical studies have revealed both direct and indirect links between gut dysfunction and AD. Research using AD mouse models has demonstrated that chronic intestinal inflammation exacerbates AD pathology, with evidence suggesting that gut dysfunction may precede neurological changes (Table 1). Chen et al[8] reported that gut dysbiosis in amyloid precursor protein (APP)/PS1 mice occurs before Aβ plaque formation rather than merely a consequence of AD pathology. One month of treatment resulted in significant changes in the microbiome and hippocampal microglial activation. Elevated levels of proinflammatory cytokines (TNF-α and IL-6) were detected well before significant Aβ accumulation. This finding implies that gut dysbiosis is an early event in AD development[8]. Microgliosis, proinflammatory cytokines, and amyloid plaque deposition were significantly decreased in germ-free APP/PS1 mice, as reported by Harach et al[39]. On the other hand, fecal microbiota transplantation (FMT) from conventionally raised APP/PS1 mice into germ-free recipients enhanced amyloid deposition and neuroinflammation, supporting the role of gut dysbiosis in AD pathology[39]. Moreover, Bello-Medina et al[40] noted that dysbiosis caused by long-term antibiotics in 3xTg-AD mice has transgenerational consequences. These findings suggest that the gut flora contributes to neurodegeneration. In the study, the offspring of antibiotic-treated mice exhibited inherited changes in the microbiota accompanied by delayed cognitive decline and reduced Aβ aggregation in the brain[40]. Manocha et al[41] carried out a longitudinal comparison between APP^NL-G-F transgenic mice and wild-type control APP/PS1 mice. They discovered that amyloid pathology first occurred in the intestinal epithelium before the brain, accompanied by microglial activation alongside systemic inflammation, further implicating the GBA link in AD[41].

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.

Chronic intestinal inflammation, often associated with IBD, can exacerbate neurodegeneration beyond gut dysbiosis alone by promoting immune activation and systemic inflammation. Studies utilizing dextran sodium sulfate (DSS)-induced colitis, a model that mimics human UC by damaging the colonic epithelium and disrupting the mucosal barrier in animals, provide significant evidence. He et al[42] demonstrated that in aged C57BL/6J mice, four weeks of chronic DSS-induced colitis resulted in spatial and recognition deficits, activation of microglia and astrocytes, upregulation of the NLRP3 inflammasome, and impaired glymphatic clearance. Interestingly, these effects were prevented in NLRP3 knockout mice in response to DSS induction. These findings emphasize how IBD is linked to AD progression via NLRP3 inflammasome-mediated neuroinflammation[42]. Similarly, Lorenzini et al[43] reported that DSS-induced colitis in young Tg2576 APP mice resulted in gut dysbiosis, reflected by an altered Firmicutes/Bacteroidetes ratio. It also led to elevated systemic neuroinflammatory markers, astrocyte dysfunction, and microglial activation. These findings imply that IBD-induced gut dysbiosis and inflammation are major factors that aggravate AD pathology and cause cognitive decline[43]. Furthermore, Sohrabi et al[19] reported that in DSS-induced colitis AppNL-G-FAD mice, not only increased Aβ plaque deposition but also region-specific changes in microglial CD68 expression were observed. Increased proinflammatory cytokines in both the periphery and the brain accompany this process, strengthening the link between gut inflammation and neuroinflammation[19]. During an investigation of gut-brain communication in 3xTg mice, Chen et al[8] reported that DSS-induced gut inflammation activated the colonic C/EBPβ/δ-secretase pathway. This activation appeared to trigger Aβ and Tau fibril formation in the gut and their subsequent translocation to the brain via the vagus nerve. It was accompanied by neuroinflammation, including microglial and astrocyte activation as well as cytokine expression. Additionally, intestinal barrier integrity was disrupted due to tight junction protein downregulation. Notably, vagotomy prevented the spread of these gut-derived fibrils toward the brain and mitigated AD pathology, confirming that the vagus nerve serves as a key conduit in this process[44].

Systemic inflammation, alongside the vagus nerve pathway, contributes to BBB dysfunction and neuroinflammatory processes. Compelling evidence links chronic intestinal inflammation to impaired neuronal function. Mitchell et al[45] demonstrated that chronic intestinal inflammation in APP/PS1 mice reduced hippocampal activity, induced cognitive deficits, and elevated the levels of inflammatory markers, including IL-1 beta (IL-1β), IL-6, caspase-1, and caspase-11[45]. They also reported elevated levels of high-mobility group box 1 in both the serum and brain, indicating its transit from the inflamed gut, where it triggers microglial pyroptosis. Concurrently, increased BBB permeability allows peripheral inflammatory signals to enter the brain[45]. Similarly, Zhao et al[46] reported that DSS-induced colitis in mice exacerbated cognitive impairment and Aβ deposition. This was accompanied by the upregulation of indoleamine 2,3-dioxygenase 1, an enzyme involved in tryptophan metabolism. This led to increased levels of kynurenine and kynurenic acid, which are well-known regulators of glutamatergic and cholinergic neurotransmission[46].

Tejera et al[47] investigated how LPS-induced systemic challenge in APP/PS1 mice transiently altered microglial shape and exacerbated Aβ deposition by impairing microglial Aβ clearance capacity, thus clarifying how systemic inflammation affects AD. Dependent on the NLRP3 inflammasome, this negative impact is accompanied by decreased beclin-1 expression and increased peripheral myeloid cell infiltration near plaques. Together, these findings highlight a mechanism by which systemic inflammation drives neuroinflammation through NLRP3-mediated microglial dysfunction[47]. Assessing the direct impact of IBD on AD, Kaneko et al[48] reported that DSS-induced colitis in AppNL-G-F mice significantly enhanced the development of Aβ plaques. Particularly, single-cell RNA sequencing revealed a significant increase in immature neutrophils infiltration clustering around Aβ plaques. Systemic depletion of these neutrophils or inhibition of their derived matrix metalloproteinase-9 (MMP-9) during colitis stops Aβ exacerbation. This implies that neutrophils attracted during gut inflammation are engaged in AD pathology through the action of MMP-9[48].

In addition to systemic inflammation, changes in the gut immune system are also linked. Examining gut-associated lymphoid tissue (GALT) in 5xFAD mice, Saksida et al[49] reported that aged mice with established AD pathology presented reduced IL-17 production in Peyer’s patches and mesenteric lymph nodes. This was associated with reduced expression of miR-155, a microRNA critical for Th17 cell differentiation and the stability of IL-17 mRNA. These findings indicate that intestinal immune dysregulation and compromised IL-17 signaling may be linked to the progression of AD. They may also contribute to impaired gut immune surveillance[49]. Emerging evidence also suggests that GI dysfunction precedes the onset of AD pathology. As noted by Honarpisheh et al[50], gut dysregulation, particularly intestinal epithelial barrier impairment, is characterized by increased permeability and downregulation of tight junction proteins ZO-1, occludin, and claudin-5. This dysregulation occurs in Tg2576 mice prior to detectable cerebral Aβ deposition[50]. Consistently, He et al[51] reported similar intestinal barrier disturbances in APP/PS1 mice. These disturbances included excessive intestinal Aβ accumulation, elevated gut permeability, tight junction dysfunction, inflammatory responses, altered populations of intestinal crypt cells (goblet and Paneth cells), and enhanced mucin production[51]. Moreover, Pellegrini et al[52], using the SAMP8 mouse model of accelerated aging and cognitive decline, reported early GI dysfunction (delayed colonic motility) and enteric neurodegeneration (loss of myenteric plexus neurons). Notably, aggregates of Aβ and phosphorylated tau were identified in the ENS prior to significant neuropathology in the brain, suggesting that disruption of the ENS and gut barrier integrity may precede central AD pathology[52].

Given the strong gut-brain link implicated in AD, various microbiota-targeted interventions have been explored as potential therapeutic strategies. Modulating the optimal gut microbiota composition during bacterial infection depends critically on the use of antibiotics. As essential for treating bacterial infections by changing the gut flora, antibiotics can also lead to dysbiosis, immune system changes, and inflammation - conditions related to AD. Minter et al[53], for example, reported that long-term changes in the gut microbiota composition resulted from postnatal (P14-P21) antibiotic treatment in APP/PS1 model mice. Reduced Aβ deposition, increased Foxp3+ T-regulatory cells, and altered microglial and astrocyte activation in the brain all point to gut-driven immune modulation in AD pathology from these microbial changes[53]. Sun et al[54] investigated the therapeutic possibilities of altering the gut flora even more. A better performance on the Morris water maze and new object recognition tests indicated that FMT from healthy donors to APP/PS1 mice enhanced their cognitive ability. The lower hippocampal levels of the glial markers glial fibrillary acidic protein (astrocytosis) and Iba1 (microgliosis) suggested that FMT recipients also displayed reduced neuroinflammation. Furthermore, lower Aβ40 and Aβ42 levels were noted, which indicated a lower amyloid load[54]. Based on such evidence, probiotics have emerged as another potential AD therapy. Sahu et al[55] investigated the effects of probiotic intervention in APP^NL-G-F mice with DSS-induced colitis on colitis-induced AD exacerbation. This study confirmed that colitis exacerbates AD-related neuroinflammation. On the other hand, probiotic supplementation reduced colitis severity and partially improved gut permeability; it had only a limited effect on reducing neuroinflammatory markers and Aβ pathology in this model[55]. These studies collectively underscore the complex interactions involving immune signaling (including GALT, NLRP3, and neutrophils), systemic inflammation, neuroinflammation, and the GBA. However, this preclinical evidence must be contextualized by the significant heterogeneity in experimental design. For example, a variety of transgenic mouse models of AD (e.g., APP/PS1, 5xFAD, 3xTg-AD, and AppNL-G-F) exhibit different pathological timelines and inflammatory responses (Figure 1), whereas variability in DSS colitis protocols - including dosage, duration, and frequency - can lead to different degrees of gut inflammation and barrier permeability[56,57]. These limitations underscore the need for standardized, prospective longitudinal studies to validate the proposed mechanistic links. Further investigations into the specific molecular mechanisms linking gut health and AD are necessary to develop effective therapeutic strategies.

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.

MOLECULAR LINKS BETWEEN IBD AND AD

The intricate relationship between IBD and AD has been increasingly elucidated through various molecular mechanisms, notably involving the GBA, which facilitates bidirectional communication between the GI tract and the central nervous system (CNS). Chronic inflammation in IBD is thought to disrupt this axis and compromise (BBB) integrity, allowing proinflammatory cytokines and microbial metabolites to enter the CNS and exacerbate the neuroinflammatory processes associated with AD. Moreover, dysregulation of neurotransmitters, in particular, serotonin, ACh, and dopamine, highlights the possible effect of GI inflammation on cognitive performance and emotion regulation in AD. Enteric glial cells (EGCs) play a major role in modulating these interactions since ENS malfunction can propagate neuroinflammation related to AD. Moreover, immune signaling pathways, such as those driven by NLRP3 inflammasome activation and key cytokines like TNF-α and IL-1β, are involved in common inflammatory processes in both diseases. Noteworthy pathophysiological connections are oxidative stress and mitochondrial dysfunction as augmented reactive oxygen species (ROS) in IBD can lead to neuronal damage and result in cognitive decline in AD. Lastly, there is genetic overlap, in particular, the genes associated with the immune response and mitochondrial functioning, which underscores the complexity of the interactions that can be underlying both diseases. The importance of this complex interaction is to highlight the importance of conducting additional research to explore treatment strategies in connection to neurodegenerative conditions and GI issues. The next discourse will thus methodically describe these identified molecular mechanisms, clarifying their roles in the pathophysiological interaction between IBD and AD (Figure 2).

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.

GBA AND NEURODEGENERATION

Neural and inflammatory conduits of the GBA

By linking the GI tract and the ENS with the CNS, the GBA constitutes a complex, bidirectional communication network. Immunological signaling, endocrine pathways, neural connections - including the vagus nerve - and microbial metabolites help to mediate this link[20,58]. In IBD, vagus nerve dysfunction, microbiota dysbiosis, and ongoing systemic inflammation all contribute to the elimination of the GBA and lead to neuroinflammation (Figure 3)[24,59]. Key GBA intermediaries, including the ENS, vagus nerve, immune mediators, and gut microbiota-derived metabolites, can cause inflammatory responses that influence neurodegeneration[41,59]. Partially through the cholinergic anti-inflammatory pathway (CAIP), the vagus nerve serves as a critical conduit within the GBA, transmitting signals between the gut and brain to regulate neuroimmune homeostasis. In IBD, however, persistent intestinal inflammation disrupts vagal function, thereby diminishing CAIP activity and potentially leading to dysregulated microglial activation and ensuing neuroinflammation[24,59,60]. The reduced vagal tone observed in IBD is linked to increased TNF-α levels, which can induce neuroinflammation and perhaps hasten AD development[61-63]. In strengthening this link, preclinical studies, including vagotomy, revealed that the gut and neuroinflammation worsened, aggravating AD pathology[9,52,60,64]. GBA dysfunction in IBD is strongly influenced by chronic intestinal inflammation. This causes excessive production of proinflammatory cytokines in the circulation, which causes systemic inflammation that compromises the integrity of the BBB. Within the CNS, these circulating inflammatory mediators can activate microglia, fostering continuous neuroinflammation and neuronal dysfunction linked with neurodegeneration[2,51].

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.

Role of the gut microbiota and microbial metabolites

The gut flora is also vital in GBA functioning because it determines immune regulation, neurotransmitter production, and metabolic communication[59]. Dysbiosis in the gut of patients with IBD is typically observed in the form of depletion of beneficial bacteria and proliferation of proinflammatory species. Such alteration is capable of generating microbial amyloids and increased intestinal LPS that may be absorbed through the gut barrier and ultimately enter the circulation and consequently onto the CNS through the general visceral afferent (GVA). These molecules may trigger microglia once in the CNS, which results in neuroinflammation and worsened loss of cognition[59,65]. Additionally, the neuroprotective effects of SCFAs, in particular, butyrate produced by good bacteria, are generally mediated by changes in microglia and BBB integrity enhancement. Besides decreasing the production of SCFA, IBD-related dysbiosis tends to impair this protective action and can worsen the disruption of the BBB and neuroinflammation, thereby damaging cognitive impairment in AD patients[59,66,67]. Another mechanism by which gut dysbiosis leads to neurodegeneration involves the translocation of microbial metabolites. These include neurotransmitters such as GABA and serotonin, which are produced by gut bacteria via the GBA. They directly influence neuronal signaling, synaptic activity, and cognitive functions[9,63]. In essence, the GBA might represent a basic link between IBD and neurodegeneration.

NEUROTRANSMITTERS IN IBD AND AD

Dysregulation of serotonin, ACh, and dopamine

Bidirectional communication across the GBA depends on neurotransmitters, which regulate digestion, mood, and cognition, and numerous other physiological functions. In both IBD and AD, the dysregulation of important neurotransmitters suggests that altered signaling within the GBA contributes to the pathophysiology and interaction of both diseases[9,24]. Chronic GI tract inflammation in IBD patients alters the levels and actions of several important neurotransmitters, including serotonin, dopamine, and ACh. Serotonin, primarily synthesized in the gut, plays crucial roles in regulating gut motility, immune cell function, and microbial composition. Serotonin signaling is often altered in IBD, which can result in lower levels that support dysbiosis, gut inflammation, reduced motility, and increased permeability[24,59,64,68]. This change in signaling is associated with dysregulated immune activation and the release of gut pro-inflammatory cytokines. Since gut inflammation and microbial changes can impact central serotonin availability, they influence brain function. Brain serotonin deficits are associated with neuroinflammation and cognitive decline in AD. This connection provides a link between IBD and AD neuropsychiatric symptoms. Dysregulation of serotonin signaling along the gut-brain axis affects neurotransmission and neuroplasticity, mechanisms implicated in AD pathology[67-69]. ACh, which primarily functions through the CAIP, is essential for both cognitive function and immune regulation[70]. The CAIP is a crucial neural reflex through which the CNS modulates peripheral immune responses. The vagus nerve specifically releases ACh, which interacts with α7 nicotinic ACh receptors expressed on immune cells, such as macrophages[71,72]. This interaction reduces gut inflammation by inhibiting the synthesis and release of proinflammatory cytokines, including TNF-α. However, in IBD, this protective mechanism is sometimes dysregulated[71]. Factors such as reduced vagal nerve activity or a deficiency in ACh can impair CAIP function, leading to uncontrolled gut inflammation. This chronic local inflammation may escalate to systemic inflammation, potentially contributing to the neuroinflammatory processes relevant to AD[72-74]. Under both conditions, dopamine signaling is also dysregulated. In IBD, altered dopamine levels can influence symptoms and gut motility, whereas dopaminergic dysfunction in AD has been linked to cognitive decline and motor deficits. Common modifications in dopamine pathways may represent a link whereby changes associated with IBD exacerbate AD-related deficits[74-76].

Glutamate-GABA imbalance and influence of microbial metabolites

Although synaptic plasticity depends on glutamate signaling, excessive glutamate induces excitotoxicity. Gut inflammation in IBD may cause excessive glutamate release, which can damage enteric neurons. Proinflammatory cytokines, including IL-6, are partially regulated by glutamate receptors. Increased IL-6 release following the activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, kainite and glutamate receptors suggests their involvement in the inflammatory responses associated with IBD[76]. Glutamatergic signaling and inflammation are related; whereby gut inflammatory processes are mediated by nuclear factor kappa B (NF-κB). Variations in glutamate homeostasis and receptor activity can cause dysregulated pathways, aggravating IBD-related inflammation[1]. Glutamate excitotoxicity mediated by overstimulation of N-methyl-D-aspartate receptors and metabotropic glutamate receptors aggravates neurodegeneration, synaptic loss, and neuronal death[60,77,78]. In contrast, GABA offers an inhibitory balance. Dysregulated GABAergic signaling is linked in IBD to dysbiosis and immune malfunction. In AD, an imbalance between the GABAergic and glutamatergic systems fuels excitotoxicity. Common for both IBD and AD, systemic inflammation can aggravate this imbalance[9,59,67]. The gut flora has a significant influence on neurotransmitter balance. In particular, SCFAs such as butyrate and microbial metabolites alter GABAergic, glutamatergic, and dopaminergic signaling; protect the gut barrier; and lower inflammation. Reduced SCFA generation in dysbiosis linked to IBD compromises these processes, aggravating GI and neurodegenerative symptoms. These metabolites represent potential therapeutic targets that connect gut health to brain function, given the neuroprotective effects of SCFAs observed in AD models[61,64,67]. Thus, a key link between IBD and AD is neurotransmitter dysregulation within the GBA. Understanding these common neurochemical pathways helps elucidate the connection between these two diseases and provides insight into potential treatments that can improve gut and brain health.

THE ROLE OF THE ENS AND EGCS IN IBD-ASSOCIATED AD

ENS dysfunction and the role of EGCs

GI motility and gut-brain communication are controlled by the ENS, a sophisticated network of neurons and glia within the gut wall. Enteric neural loss, synaptic changes, and neuroimmune disturbances define ENS dysfunction in IBD[24,60]. Emerging data suggest that ENS disturbance linked to IBD causes systemic inflammation via the GBA, thus promoting AD progression[2,9,74]. Studies based on IBD models have revealed compromised epithelial barrier integrity and enteric plexus neuroinflammation, including neuronal degeneration. Support for a link between chronic gut inflammation and CNS pathology comes from this structural ENS degradation in IBD being linked to neuronal death, synaptic remodeling, and ongoing glial activation[24,79,80]. EGCs have become increasingly important mediators of these intricate interactions. Understanding the involvement of the GBA in AD depends on the study of EGCs, as they typically play vital roles in preserving intestinal barrier function, modulating local immunity, and regulating neurotransmission[51,81]. Although they are distinct from CNS microglia, EGCs play a similar role as primary immune responders in the gut. In IBD, hyperactivated EGCs produce excessive proinflammatory cytokines (e.g., TNF-α, IL-1β, and IL-6), compromising gut barrier integrity and contributing to neuroinflammation[1,79,82]. The S100B protein, which is largely secreted by activated EGCs, accelerates AD pathology by promoting Aβ aggregation and tau phosphorylation[59,83]. Kaneko et al[48] reported elevated S100B levels in DSS-induced IBD models, which correlated with microglial activation and increased neurodegeneration in AD models[47,48]. Consistent with these findings, the lower levels of neuroprotective glial cell-derived neurotrophic factor (GDNF) observed in IBD patients suggest impaired neuronal survival mechanisms, potentially contributing to both ENS atrophy and cognitive decline[84]. The pathogenesis of IBD is linked to GDNF, the ENS, and the expression of GDNF, and EGCs affect gut homeostasis and control neuronal responses to inflammation. Mostly produced by EGCs, GDNF has a significant on gut homeostasis and neuronal reactions to inflammatory stimuli[27,85]. EGCs release GDNF upon activation by neuroinflammatory stimuli, promoting neuronal protection, neuroplasticity, and immune modulations vital for GBA integrity[85]. Dysregulation of EGCs and GDNF signaling can aggravate IBD symptoms[57].

P2X7 purinergic receptor pathway as a shared inflammatory mechanism

Furthermore, specific molecular pathways involving EGCs may bridge IBD to AD pathogenesis. For example, chronic gut inflammation, a hallmark of IBD, can activate the P2X7 purinergic receptor (P2X7Rs). While P2X7Rs are broadly expressed across various cell types, their activation within the enteric environment - either directly on EGCs or indirectly via neurons influencing EGCs - can lead to several detrimental outcomes. These include ATP-mediated EGC hyperactivation, which contributes to neuronal apoptosis, and the propagation of inflammatory signals from the gut to the CNS, potentially contributing to AD pathology[83,86]. In IBD, cellular stress and tissue damage within the inflamed intestinal environment promote the release of ATP[87]. Elevated ATP subsequently binds to and activates P2X7Rs on resident immune and intestinal epithelial cells (IECs)[88]. This P2X7 activation initiates an inflammatory cascade, including mast cell activation and the release of cytokines (IL-6, TNF-α), which drives inflammation in both CD and UC[89,90]. The upregulation of P2X7 in inflamed bowel tissues suggests that targeting P2X7 may offer therapeutic benefits[84]. In AD, ATP accumulation near Aβ plaques appears to act as a critical trigger for P2X7Rs on microglia[91,92]. When these receptors are overstimulated by excess ATP released from stressed neurons or the plaques themselves, they activate microglia to be in a hyperinflammatory state[93]. This sparks the release of damaging cytokines (such as IL-1β and TNF-α) and creates a self-perpetuating cycle. In this cycle, inflammation drives further neuronal damage, which results in the release of more ATP, leading to even greater P2X7 activation[94,95]. This contributes to neuroinflammation and cognitive decline, as inflammation exacerbates neuronal damage. Targeting P2X7 in AD has shown promise in preclinical models by reducing inflammatory responses[96]. P2X7Rs represent a shared inflammatory mechanism between IBD and AD, reflecting both local and central effects of systemic inflammation. Both conditions involve dysregulated ATP signaling through P2X7[87,88,91]. In addition to P2X7, NLRP3 inflammasome activation within EGCs exacerbates neuroinflammatory cascades, promoting synaptic dysfunction and neurodegeneration[42,44,97]. Thus, ENS dysfunction and EGC hyperactivation in IBD contribute to neuroinflammation and neurodegeneration, establishing a pathological link between gut disturbances and AD progression. This strong association underscores the ENS and EGCs as promising therapeutic targets for attenuating AD progression in the context of IBD.

IMMUNE SIGNALING PATHWAYS IN IBD AND AD

Shared innate immunity and inflammatory cascades

Immune signaling pathways constitute essential molecular links between IBD and AD, with chronic inflammation serving as a fundamental pathological hallmark shared by both conditions. This overlapping inflammatory profile involves immune cells and cytokines as central mediators, and the dysregulation of these pathways in both the gut and brain facilitates their bidirectional interaction through the GBA[25,60]. In IBD, proinflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-17 drive chronic gut inflammation, leading to mucosal damage and increased intestinal permeability (leaky gut)[98]. This barrier breach allows microbial products, such as LPS, to enter systemic circulation, potentially triggering neuroinflammation and neurodegeneration, which are characteristic of AD pathology (Figure 4)[2,79]. Gut macrophages and dendritic cells further amplify this inflammation by secreting more cytokines that can reach the brain, thereby exacerbating neurodegeneration[60,64]. As a key mediator of immune responses in both IBD and AD, toll-like receptor 4 (TLR4) aggravates chronic inflammation in both diseases. Upregulated TLR4 in intestinal cells in IBD causes bacterial LPS to be recognized, triggering signals that produce more proinflammatory cytokines and gut inflammation[99]. Damage-associated molecular patterns (DAMPs) activate microglial TLR4 in AD, thus fostering neuroinflammation[100]. Enhanced gut permeability in IBD through the GBA could enable the translocation of LPS to activate microglial TLR4 in the brain, thus aggravating AD neurodegeneration. Another shared occurrence between IBD and AD is the activation of the NLRP3 inflammasome. In IBD, the activation of immune cells and IECs results in the production of IL-1β and IL-18, aggravating gut inflammation and damage[47,101]. In AD, NLRP3 activation in microglia enhances IL-1β production and contributes to Aβ plaque formation and tau phosphorylation[47,101]. Chronic inflammasome activation in both the gut and brain accelerates neurodegeneration, suggesting that it may be a potential therapeutic target[42,44]. Triggering receptor expressed on myeloid cells 2 (TREM2) modulates inflammatory responses relevant to both conditions. In IBD, TREM2, expressed on intestinal macrophages, helps regulate immune homeostasis, promoting anti-inflammatory responses and tissue repair[102]. In AD, microglial TREM2 facilitates Aβ phagocytosis and influences neuroinflammation[103]. Dysregulated TREM2 signaling in IBD may lead to systemic immune activation that, via the GBA, alters microglial TREM2 function in AD, exacerbating neuroinflammation.

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.

Both disorders are linked to the NF-κB pathway, a major control mechanism of inflammatory gene expression. NF-κB hyperactivation in the gut leads to excessive proinflammatory cytokine generation in IBD, disturbing the barrier and causing chronic inflammation[104]. Similarly, in AD, NF-κB activation in microglia and astrocytes fuels neuroinflammation, cytokine release, Aβ and tau pathology, and BBB disruption[105]. In IBD, ongoing gut NF-κB activation can induce systemic inflammation and compromise neuroprotective systems, thus aggravating AD. Crucially, in the context of inflammation, the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway controls cytokine signaling. Overactivation increases intestinal inflammation and barrier breakdown in IBD[106]. In AD, it exacerbates glial activation-induced neuroinflammation and neuronal damage[107]. This common cascade implies that AD neuroinflammation may be facilitated by gut inflammation in IBD. Moreover, JAK inhibitors applied in IBD - e.g., tofacitinib - may have therapeutic relevance for AD[106].

Dysregulation of adaptive immunity and T-helper cells

Common immune signaling pathways, including TLR4, NLRP3, TREM2, NF-κB, and JAK/STAT, reflect important elements connecting IBD and AD through chronic inflammation mediated via the GVA (Table 2). In the pathogenesis of IBD and its consequences in AD, adaptive immunity plays a crucial role. Within the framework of IBD, a dysregulated immune response toward the gut microbiota causes chronic intestinal inflammation marked by the activation of T cells, B cells, and antigen-presenting cells[108]. Through excessive IL-17 generation, dysregulated Th17 responses driven by IL-23 promote chronic inflammation in IBD, amplifying neutrophil recruitment, epithelial damage, and proinflammatory cytokine cascades (e.g., IL-6 and TNF-α). Th17 plasticity exacerbates intestinal pathology, particularly through the conversion of Th17 cells into IFN-γ-producing cells in response to IL-12/IL-23 stimulation[109,110]. Concurrently, B cells contribute to IBD by producing pathogenic IgG and presenting antigens, thereby perpetuating mucosal inflammation[111,112]. In AD, Th17 cells infiltrate the brain parenchyma, where IL-17 induces neuroinflammation, Fas/FasL-mediated neuronal apoptosis, and BBB disruption, all of which are correlated with cognitive decline[113]. The GBA is implicated in these conditions. IBD-associated dysbiosis increases intestinal permeability, enabling microbial translocation (e.g., LPS via the vagus nerve). This process triggers systemic inflammation and neurotoxic IL-17/IL-23 signaling, thereby accelerating AD pathology[113-115]. Shared genetic susceptibility in immune pathways (e.g., IL-23R and STAT3) and myeloid cell dysfunction further connect IBD and AD[116,117]. Paradoxically, while IBD genetics may confer AD protection through IL23R R381Q-mediated STAT3 attenuation[118], chronic inflammation and microbiota shifts predominantly drive risk, highlighting the dual role of adaptive immunity[117]. Therapeutic strategies targeting Th17 plasticity, IL-17 neutralization, or microbiota restoration (e.g., FMT) show promise in ameliorating both conditions[111,118].

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.

OXIDATIVE STRESS AND MITOCHONDRIAL DYSFUNCTION LINKING IBD AND AD

Mitochondrial dysfunction has emerged as a significant factor in the pathophysiology of various diseases, including IBD and AD. Oxidative stress and mitochondrial dysfunction are key pathophysiological factors linking IBD and AD. In IBD, IECs exhibit structurally abnormal mitochondria with altered cristae and compromised function[119,120]. This has been evidenced by transcriptomic analyses, showing underrepresentation of mitochondrial respiration genes and the downregulation of all 13 mitochondrially encoded respiratory chain complex genes in UC[121-123]. These molecular changes are accompanied by a 50%-60% decrease in the activity of mitochondrial complex I, II, III, and IV[121-123]. Notably, the decreased complex I activity in UC correlates with disease severity[121,122]. This intestinal mitochondrial failure is often driven by chronic intestinal inflammation, generating excessive ROS that damages mitochondria[2,59,67]. This process initiates further mitochondrial ROS (mtROS) production, mitochondrial DNA (mtDNA) damage, and its release as DAMPs. Consequences include disrupted mitochondrial dynamics (e.g., decreased optic atrophy 1[124], prohibitin 1 deficiency[125], impaired NIX-mediated mitophagy, which is essential for intestinal homeostasis[126,127], and defective autophagy in IECs. These alterations lead to the accumulation of damaged organelles/proteins, sustained ROS production, and compromised intestinal barrier integrity, which can contribute to systemic inflammation and mitochondrial dysfunction in other organs, including the brain[61,66].

Concurrently, AD pathogenesis involves profound neuronal mitochondrial dysfunction characterized by bioenergetic collapse in the hippocampal and cortical regions[128,129], which may precede the formation of classical Aβ plaques and tau tangles. This process is bidirectionally reinforced, as mitochondrial stress increases APP processing to Aβ, while accumulated Aβ further impairs mitochondrial function, and tau protein interactions with components such as voltage-dependent anion channel 1 exacerbate dysfunction[129]. In AD, this mitochondrial compromise also generates excessive mtROS, leading to oxidative damage, mtDNA release that stimulates inflammatory responses via DAMP signaling[130], and impaired mitophagy, as observed in the hippocampus and in induced pluripotent stem cell-derived AD neurons[131,132]. Common features of mitochondrial dysfunction under both conditions include an impaired electron transport chain, defective mitophagy, increased mtDNA damage, and impaired oxidative phosphorylation[65,120,133], leading to ATP deficits that hinder essential protein degradation pathways such as the ubiquitin-proteasome system and autophagy. Consequently, this results in the accumulation of misfolded proteins such as Aβ in AD[134] and damaged organelles in IBD.

Both diseases converge on hyperactivation of the NLRP3 inflammasome, triggered by mitochondrial DAMPs (mtDNA, mtROS)[126,130] and elevated ROS levels[47,101]. This process is normally mitigated by effective mitophagy[126,131] but exacerbated by systemic oxidative stress, which also overwhelms key antioxidant systems (e.g., superoxide dismutase (SOD), catalase, and glutathione peroxidase), thereby intensifying neurodegeneration in AD[24,64,67]. This shared mitochondrial pathology is further compounded by the dysregulation of cellular stress response networks. Elevated levels of the mitochondrial chaperone HSP60 have been reported in AD[129]. In addition, interconnected endoplasmic reticulum stress and autophagy dysfunction have been observed in both conditions[120,129]. These findings establish a compelling molecular linkage in which oxidative stress and mitochondrial dysfunction, often originating from IBD-related intestinal inflammation, culminate in systemic inflammation and neuroinflammation, thereby significantly contributing to AD progression[122]. This occurs through the impairment of cellular metabolism and a reduction in ATP production, which are critical for neuronal survival[5,9,24], highlighting mitochondria and their quality control mechanisms as central therapeutic targets.

GENETIC OVERLAPS AND RISK FACTORS LINKING IBD AND AD

Although IBD and AD have clear links according to epidemiological studies, specific genetic studies have yet to identify genes directly connecting them. This result suggests that this link may involve shared genetic elements affecting common pathways or complex interactions. Crucially, genetic overlaps in genes linked to the immune response, inflammation, and cellular homeostasis are subsequently analyzed. Among these, apolipoprotein E (APOE), TREM2, and NLRP3 are fundamental controllers of pathways linked to both diseases[24,64,67]. A main AD risk factor, the APOE4 allele, is also linked to gut barrier dysfunction related to IBD[60,135]. In addition, TREM2 variants compromise microglial function in AD and affect gut macrophage responses, suggesting a common pathophysiological link[61,135-137]. GWAS results revealed that NLRP3 polymorphisms are risk factors for both diseases, highlighting the role that inflammasome activation plays in gut inflammation and neurodegeneration[24,47,101]. In addition to these important genes, human leukocyte antigen (HLA) variants (HLA-DRB1, HLA-DQA1, and HLA-DQB1) linked to both diseases suggest that the major histocompatibility complex is involved in susceptibility via effects on antigen presentation and adaptive immunity[138]. In addition to strengthening the immune-genetic link, polymorphisms in CARD9, a gene engaged in innate immune signaling, have been linked to both IBD and neuroinflammation[139,140]. Furthermore, polymorphisms in IL-6 and TNF-α help explain the BBB dysfunction and microglial activation in IBD and AD patients[9,65]. Owing to genetic variations in PARK7 (DJ-1), SOD2, PINK1, and PGC-1α, mitochondrial dysfunction has been associated with oxidative stress and impaired cellular metabolism in both IBD and AD[24,141-144]. The maintenance of mitochondrial homeostasis depends on these genes; thus, their dysregulation contributes to energy deficits, elevated ROS production, and neuronal loss in AD while exacerbating gut epithelial dysfunction in IBD. Moreover, variants in glycogen synthase kinase 3, a key tau kinase involved in regulating inflammation and tau phosphorylation, have been implicated in both IBD and AD, potentially linking gut inflammation to tau pathology[145,146]. In addition to hereditary associations, polymorphisms in intercellular adhesion molecule 1 (ICAM1), which regulates leukocyte adhesion and migration, have been identified in both IBD and AD, thereby connecting neurovascular dysfunction and gut inflammation[59,147]. Furthermore, single nucleotide polymorphisms in genes that interact with tight junction protein 1 (e.g., MAGI2 and MAGI3) are linked to compromised tight junction integrity. These changes compromise the intestinal barrier and BBB permeability, possibly providing a genetic basis for increased gut and BBB permeability in AD and IBD[51,148,149]. These significant overlaps in pathophysiology and related genetic elements underscore the need for further studies employing genomics, transcriptomics, and epigenetics to comprehensively define the molecular interactions between IBD and AD.

THERAPEUTIC IMPLICATIONS

By targeting immune signaling, gut dysbiosis, and systemic inflammation, the overlapping pathophysiological mechanisms between IBD and AD point to possible therapeutic interventions for treating either or both diseases. For those with IBD, such focused treatments - which reduce neuroinflammation, restore the gut balance, and control immune responses - may slow the course of AD (Table 3). Anti-inflammatory medications targeting key cytokines linked to both diseases show great potential. For example, widely used TNF-α inhibitors (such as adalimumab and infliximab), which treat IBD, have possible neuroprotective effects by lowering systemic inflammation and BBB permeability, thus perhaps lowering the incidence of AD[37,40]. Similarly, IBD patients receiving anti-TNF-α treatment have a much lower incidence of AD than untreated patients do, highlighting the neuroprotective action of this treatment[37,150]. This potential is now being tested in Phase 3 trials for early AD, such as studies investigating the safety and efficacy of infliximab (NCT00207766) and adalimumab (NCT05090124, NCT00408629) in patients with evidence of neuroinflammation. Another trial, MINDFuL (NCT05318976), has already investigated the selective TNF inhibitor XPro™ in early AD and mild cognitive impairment (MCI) patients with inflammation. Potential therapeutic targets include IL-1β and IL-6, which are linked to neuroinflammation and amyloidogenesis. However, the IL-6 receptor inhibitor tocilizumab has demonstrated anti-inflammatory effects that may reduce neuroinflammation. The IL-1 receptor antagonist anakinra is being assessed in the ASCOT trial (NCT04834388) to determine whether it can improve or stabilize cognitive function in participants with mild AD by blocking the IL-1 inflammatory pathway[151,152].

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.

In addition to anti-inflammatory drugs, gut microbiota modulation has emerged as a significant therapeutic target. In particular, probiotic supplementation - especially with Lactobacillus and Bifidobacterium strains - has been shown in preclinical AD models to reduce intestinal permeability, decrease systemic inflammation, and enhance cognitive function[153], an approach being evaluated in studies such as the Probio-AD trial (NCT05145881). Moreover, a clinical study revealed that AD patients presented significantly reduced levels of beneficial bacterial species, which was associated with elevated neuroinflammation markers, supporting the potential use of probiotics to restore GBA integrity[154]. Prebiotic interventions have also been demonstrated to modulate gut flora, enhance gut-brain communication, and exert neuroprotective effects by promoting anti-inflammatory responses and supporting immune homeostasis in AD models[155]. Another method is FMT, which is being clinically assessed in AD patients (NCT06920212) and has been shown to decrease Aβ deposition and enhance cognitive performance in animal models[54,156,157]. However, before its clinical use, more research is needed on the long-term effectiveness and safety of FMT for treating neurodegenerative diseases. Despite the promise of microbiota-targeted approaches such as probiotics and FMT, establishing direct causality remains a significant challenge. The therapeutic efficacy of these interventions is complicated by several factors, including the strain-specific effects of probiotics, where different bacterial strains within the same species can exert distinct immunological and metabolic effects[158]. Furthermore, there is profound host variability in response to microbial interventions, which is dictated by an individual’s unique baseline microbiome, genetic makeup, diet, and immune status[159]. The complexity of the GBA indicates that standardized interventions have limited efficacy. Reliable therapeutic modulation, therefore, depends on personalized strategies that address the system's interacting variables.

Another potential therapeutic target is bacterial amyloids, which are produced by specific gut microbiota and are implicated in the misfolding and aggregation of amyloid proteins in the brain. For example, amyloid-like proteins structurally similar to Aβ are produced by Escherichia coli and Bacillus subtilis, possibly accelerating cerebral amyloid deposition in AD patients[160]. Therapeutic approaches, including antimicrobial peptides or probiotics, aimed at preventing bacterial amyloid formation, could help reduce amyloid pathology[160-162]. In addition to pharmacological treatments, dietary and lifestyle modifications are receiving increasing attention as potential therapeutic approaches. The Mediterranean diet, rich in polyphenols and omega-3 fatty acids, has been shown to beneficially alter gut microbiota composition, thereby reducing AD risk[163,164] and lowering systemic inflammation, including proinflammatory cytokines associated with AD pathology (ISRCTN35739639). Additionally, a ketogenic diet promotes ketone body synthesis, which exerts neuroprotective effects by enhancing mitochondrial function and reducing oxidative stress, potentially slowing AD progression[165,166]. The efficacy of this approach has been evaluated in trials, such as ACTRN12618001450202. In individuals with chronic inflammatory diseases, cognitive training in older adults has been shown to stimulate neuroplasticity and delay cognitive decline, offering an adjunctive approach to AD management[167]. Given these multiple therapeutic avenues, future studies should concentrate on including synergistic treatments in clinical trials to develop an evidence-based therapeutic strategy capable of addressing both AD and IBD simultaneously.

FUTURE PERSPECTIVES

While significant progress has been made in linking IBD and AD, several critical questions remain unanswered, paving the way for future research. It is also critical to acknowledge that the relationship between IBD and AD may be influenced by alternative or interfering mechanisms that extend beyond a direct gut-brain inflammatory axis. For example, depression is a well-established and highly prevalent comorbidity in patients with both IBD and AD, and it may act as a significant confounder or mediator in this association[168,169]. A nationwide population-based study by Choi et al[170] revealed that IBD patients with comorbid depression had a significantly increased risk of developing both dementia and Parkinson's disease compared with IBD patients without depression. This finding strongly suggests that depression is not merely a concurrent condition but may act as a critical mediator or an accelerator in the neurodegenerative process initiated by gut inflammation. Mechanistically, this aligns with the growing recognition of a complex, tripartite relationship between gut inflammation, psychiatric conditions, and neurodegeneration. As highlighted in a recent review by Petracco et al[171], pathologies such as IBD and neuropsychiatric disorders share overlapping pathways - including systemic inflammation, hypothalamic-pituitary-adrenal axis dysregulation, and profound gut dysbiosis - that are also central to AD pathogenesis[172]. Therefore, the neuroinflammatory and cognitive changes observed in patients with IBD could be substantially driven or exacerbated by comorbid depression. Disentangling these intertwined pathologies is a crucial priority for future research, which must carefully control for psychiatric comorbidities when investigating the IBD-AD link. A primary goal should be to move beyond correlational evidence toward establishing causality through prospective, longitudinal cohort studies that track cognitive trajectories in well-characterized IBD patients, carefully controlling for confounders such as medication use, diet, and comorbidities such as depression. Mechanistically, advanced multiomics approaches (genomics, transcriptomics, and metabolomics) applied to both patient samples and sophisticated preclinical models, such as human intestinal organoids coupled with brain organoids, are necessary to identify specific microbial species, metabolites, and immune cell subsets that traverse the GBA to drive neurodegeneration[173]. The discovery of reliable gut-derived biomarkers - such as specific SCFAs, inflammatory cytokines, or microbial DNA signatures in circulation - could enable early risk stratification for cognitive decline in IBD patients. Finally, this deeper mechanistic understanding should inform the design of targeted clinical trials, testing not only novel microbiota-based therapies but also the neuroprotective potential of existing IBD treatments, such as JAK inhibitors or anti-integrin therapies, in at-risk populations.

CONCLUSION

Based on research data emphasizing immune signaling and inflammatory pathways as fundamental modulators, the complex interaction between IBD and AD is becoming increasingly recognized. This review examines how alterations in ENS, GBA impairment, and peripheral immune activation contribute to neurodegeneration. Bidirectional gut-brain communication provides the mechanistic framework for this association, whereby IBD-associated immune dysregulation may accelerate the AD pathogenic process. Proinflammatory cytokines play a central role in this process, driving persistent inflammation in both the brain (AD) and the gut (IBD). Pattern recognition receptors, including TLRs and NOD-like receptors, are activated to intensify immune responses, driving disease progression in both organs. Key conduits allowing gut-derived immune signals to communicate with neuroinflammatory responses are the ENS and vagus nerve. Moreover, converging pathways of oxidative stress and mitochondrial dysfunction offer additional molecular insights into the shared pathogenesis. Additionally, overlapping genetic risk factors support the hypothesis of a common pathogenic framework.

Clinical evidence and meta-analyses corroborate this association, indicating an increased risk of AD among IBD patients. Large-scale studies have demonstrated a significant correlation between chronic gut inflammation and cognitive decline, particularly increased AD susceptibility in older IBD patients. While shared genetic predispositions may not directly link the two diseases, immune-mediated mechanisms - such as elevated proinflammatory cytokines and altered immune cell profiles - appeared to be central drivers. Preclinical studies offer compelling insights, demonstrating that gut dysbiosis, chronic intestinal inflammation, and immune activation exacerbate neuroinflammation and cognitive impairment in AD models. Notably, findings in mouse models suggest that gut dysfunction may precede Aβ accumulation, implicating intestinal disruptions as potential early events in AD pathogenesis. Furthermore, DSS-induced colitis models have confirmed that gut inflammation triggers microglial activation, BBB disruption, and increased cerebral amyloid burden, reinforcing immune-mediated connections. Therapeutic interventions targeting immune responses, restoring gut homeostasis, and reducing inflammation show promise in slowing disease progression in both IBD and AD patients. Clinical data indicate that TNF-α inhibitors and other immunomodulators significantly reduce AD risk in IBD patients, suggesting neuroprotective benefits through managing systemic inflammation. In summary, immune signaling and inflammatory pathways primarily mediate the molecular links between IBD and AD, with the GBA as a critical conduit. Elucidating these shared mechanisms is crucial for enhancing early detection and risk assessment of AD in IBD patients, as well as for developing novel therapeutic strategies to improve outcomes for individuals affected by either or both conditions.