Vascular dementia (VD), the second major category of dementia, also known as vascular cognitive impairment (VCI), is mainly manifested as a progressive and fluctuating decline in memory, language, computation, visuospatial ability, attention, and power of execution (1). VD is caused by multiple factors, which can lead to neurovascular injury, further reducing cerebral blood flow, and cognitive dysfunction. Its main pathogenesis includes a neuroinflammatory response, oxidative stress, destruction of the blood-brain barrier (BBB), uncoupling of neurovascular units, destruction of mitochondrial morphology and function, demyelination and myelin injury, neurotoxicity, etc (2). The absence of well-established and universally accepted neuropathological criteria, along with the diversity and overlapping definitions of cerebrovascular lesions, pose challenges in determining the true prevalence of pure VCI in autopsy studies (3). However, the evidence has shown that the cognitive impairment of VD is more severe in comparison to other neurodegenerative diseases (4). An epidemiological investigation showed that there was significantly higher rate in hospitalization and mortality of VCI patients than those of non-VCI patients, similar to that of Alzheimer’s disease (AD) patients (5).

The evidence that intestinal diseases can affect nervous system function, such as depression, anxiety, dementia, Parkinson’s disease (PD), through the brain-gut axis (6), has been verified, and this relationship may be bidirectional (7–11). Inflammatory bowel disease (IBD), including crohn’s disease (CD) and ulcerative colitis (UC), is a chronic, relapsing, immune-mediated intestinal disease (6, 7). It is characterized by the overlapping effects of genetic mutations (12), environmental factors (13), intestinal microbiota disorders (14), and immune factors (15). The connection between IBD and the nervous system has been extensively studied. For example, a clinical research showed that the prevalence of anxiety and depression in IBD patients is 32.1% and 25.2% respectively (16). Similarly, patients with depression are more commonly diagnosed with IBD, and psychiatric symptoms are significantly associated with adverse disease activity-related outcomes in IBD (17). Furthermore, the relationship between IBD and PD is also bidirectional due to genetic overlap, abnormal transfer of α-synuclein from the gastrointestinal tract to the central nervous system (CNS), and neuroinflammatory responses. This connection has been corroborated by multiple studies and experiments (18–20). In addition, studies on dementia from the direction of the brain-gut axis involve many aspects, such as epidemiology, pathogenesis, and prognosis (21). For example, an epidemiological study showed that IBD might not only be a risk factor for dementia, but also lead to an earlier age of dementia. This was consistent with another study, revealing a positive association between IBD and dementia risk, particularly in patients with UC (8). In addition, a meta-study also uncovered an increased long-term risk of dementia in IBD patients (22). However, the association mechanism between IBD and dementia may be multifactor, which may be related to chronic inflammation, accelerated atherosclerosis, and hypercoagulability (23), especially thromboembolic events, thrombocytosis, hyperlipidemia, and hyperhomocysteinemia. All these factors may further aggravate the occurrence and development of VD (24). On the one hand, a study had shown that the gut microbes might affect neuroinflammatory responses through microglia (25). On the other hand, gut microbes could affect the generation ability of hippocampal neurons through metabolism, endocrine signaling, and nervous system driving mechanisms (26–28), thus affecting cognitive function. These findings uncover a fact that gut microbes can influence the development and impairment of cognitive function.

At present, the brain-gut axis not only connects the brain to the gut itself, but also represents the interaction between the brain-gut axis system and the central nervous system (CNS), endocrine chemical signaling system, immune regulation, microbiome, metabolism, and brain-gut barrier function (29) ( Figure 1 ). Although extensive evidence has shown that gut diseases are closely associated with dementia, the underlying mechanisms have not been fully elucidated. In particular, limited research has been done to discover the relationship between VD and intestinal disease. Based on bioinformatics technology, this study explores the internal relationship between VD and IBD by means of searching for common differentially expressed genes (coDEGs) in VD brain tissue and UC colon tissue. The shared gene signatures identified are expected to elaborate the disease-related biological mechanism. The exploration of the common biological pathways can provide a new perspective for further study and treatment.

The overall design of the study is illustrated in Figure 2 .

Vascular dementia is considered to be a disease that can be prevented and controlled. However, improvements in cognition have not been satisfactory in clinical trials, so medical practitioners have been focusing on innovation in vascular dementia mechanisms, risk factors, and new treatment options. Gut microbiota was considered to be an important influencing factor for stroke, and the bidirectional interaction between intestinal diseases and neurological diseases was still not clear. Integrative bioinformatics analyses are becoming more common in the exploration of new genes, potential diagnostic and prognostic biomarkers, underlying mechanisms, and potential therapeutic targets using big data. This approach can provide valuable insights into various diseases (30, 31).

The brain-gut axis is a bidirectional communication pathway. And all the central, intestinal, autonomic nervous systems, as well as the hypo-pituitary-adrenal (HPA) axis constitute a complete brain-gut axis system. The vagus nerve, immune and neuroendocrine systems, neurotransmitters and metabolites, and gut microbiota are the key nodes that play their respective mechanism effects in the brain-gut axis pathway (32–34). After decades of research by scientists, they have demonstrated a strong connection between the gut and the brain in mechanisms such as neurons, neurotransmitters, hormones, and immune-mediated regulation (35, 36). Whole-gene expression data may give us a hand to better understand the specific pathological links and provide molecular basis for brain-gut axis system. Firstly, 18 common pathways between GSE122063 (VD) and GSE47908 (UC) were shown by using he independent GSEA. Interestingly, the common pathways of both were highly clustered, such as mainly immune diseases and neurodegenerative diseases involved in human diseases, the common biological and organic systems belong to the immune system, and a considerable proportion of environmental information processing pathways, and metabolic pathways, suggesting that there might be a pathogenic correlation between VD and IBD. Next, GO and KEGG enrichment analyses were performed on 167 selected coDEGs. The main pathways of GO: BP function was mainly concentrated in the immune-mediated by leukocyte cells, monocytes, and lymphocytes, and the KEGG function enrichment was mainly concentrated in immune diseases, infectious disease, the immune system, and environmental information processing pathways. This suggested that the mechanism of connection between the two diseases might be related to immune and inflammatory regulation and environmental information processing. Interestingly, in a basic study (37, 38), scientists build a new microbiota-gut-brain axis, indicating that effector T cells migrate from the gut to the brain, specifically localizing in the leptomeninges. This migration enhances ischemic neuroinflammation by secreting interleukin-17 (IL-17), which in turn increases chemokine production in the brain parenchyma and leads to the infiltration of cytotoxic immune cells such as neutrophils. Furthermore, it had been well documented that inflammatory factors can lead to neuronal death resulting in cognitive and emotional dysfunction. In addition, in the study on the impact of ischemic stroke on the gut, cerebral ischemia could quickly cause intestinal ischemia, leading to a disruption in intestinal flora through free radical reactions, and enhance systemic inflammation and aggravate cerebral infarction. Transplantation of primary Intestinal Epithelial Stem Cells (IESCs) from healthy donors into post-stroke models could prevent depression-like behavior and cognitive impairment (39).

To further detect the coDEGs, 8 shared hub genes were selected, and GO/KEGG enrichment analysis was performed on the 8 shared genes. The GO: BP pathway mainly focused on the activation of glial cells, neuroinflammatory response and immune cell regulation, which was consistent with the results of previous studies (38). After verifying the functions of hub genes, we verified them in the IBD validation datasets, which showed the important role of 7 shared hub genes (ITGB2, CYBB, IL1B, TLR2, CASP1, IL10RA, and BTK) in IBD patients with VD and genes IL1B, TLR2, and CASP1 might play an early diagnostic role in IBD complicated with VD. Because gut microbes can directly affect the characteristics of the immune system, immune activation might be the pathway through which gut microbes act on the CNS. Finally, 167 coDEGs were analyzed for immune infiltration and immune correlation, and 8 hub genes were analyzed for immune correlation. The results further confirmed the association between VD and IBD between coDEGs and hub genes and the existence of 16 immune cells in immune activities. This suggests that inflammatory diseases of the gut may affect central nervous system function through a specific immune system, especially in relation to vascular dementia, but of course, there are other factors involved, which need to be further studied.

ITGB2 is predominantly expressed in immune cells and plays a crucial role in various metabolic pathways and immune functions, including leukocyte extravasation (40). ITGB2 plays a critical role in T-cell development and function. Research has also associated ITGB2 with chronic colitis (41, 42). In addition, a study suggested that Itgb2+ microglia were found to function as a time-specific multifunctional immunomodulatory subcluster during ischemia reperfusion injury (CIRI). It has been proved that ITGB2 plays a role in the pathological changes of IBD (43, 44), but the specific mechanism remains to be further explored. TLR2 plays a fundamental role in pathogen recognition and activation of innate immunity. Knockout of TLR2 has been shown to prevent impaired cerebral blood flow in early diabetes and VCI by counteracting overperfusion in long-term diabetes (45). The expression of TLR2 is crucial in enhancing barrier function during injury and preserving tight junctions (46, 47), and are crucial in IBD (48–50). Furthermore, neutrophil extracellular traps (NETs) activated by TLR2 and TLR4 have been shown to worsen colon tissue damage and promote thrombotic events with active inflammatory bowel disease (IBD) (50), resulting in stroke and VD. BTK plays a crucial role in B-cell development and functions as a key player in both innate and adaptive immunity (51). In AD brain tissue, BTK may improve cognition in AD patients by preventing microglia activation and synaptic loss. BTK deficiency has been shown in various experiments to lead to severe colitis. This mechanism includes the activation of the NLRP3 inflammasome due to BTK defects (52), as well as its important role in preserving gut immune balance and preventing inflammation through the regulation of T-cell polarization (53). However, the mechanism of BTK in VD remains to be further explored. CYBB, also known as NADPHoxidase 2 (NOX2), is involved in the generation of reactive oxygen species (ROS) during ischemic stroke (IS) and is found to be significantly increased (54, 55). As has been demonstrated in numerous studies, oxidative stress is an important mechanism of vascular dementia (56, 57). In addition, the inadequate ROS production results in an upregulation of nuclear factor kappa-B (NF-κB)-regulated inflammatory genes, leading to the over activation of NF-κB and inflammasome in phagocytes. This sustained activation triggers the continuous release of pro-inflammatory cytokines and contributes to inflammatory conditions, such as IBD (58). CASP1 plays a pivotal role in cellular immunity as an initiator of the inflammatory response. CASP1 initiates a pro-inflammatory reaction by cleaving the inflammatory cytokines IL1B and IL18, thus participating in various inflammatory processes (59–61). Additionally, CASP1 triggers pyroptosis (62). IL1B (Interleukin 1 Beta) is a member of the interleukin 1 cytokine family, known as a pro-inflammatory cytokine that plays a critical role in inflammatory disorders (63) and is typically regulated by the NLRP3-caspase1 axis (64). A number of studies have shown that the NLRP3/CASP1/IL1B pathway can participate in neuronal apoptosis and autophagy by mediating oxidative stress and neuroinflammatory response (65–67) in VD, leading to impairment and aggravation of cognitive function. Moreover, in IBD, numerous studies have demonstrated the activation of the NLRP3/CASP1/IL1B axis, which plays a crucial role in immune response, hyperinflammatory response, and pyroptosis, contributing to the pathogenesis and progression of the disease (68–71). IL10RA is cell surface receptor for the cytokine IL10 that participates in IL10-mediated anti-inflammatory functions, limiting excessive tissue disruption caused by inflammation. IL10RA modulates the miR15a/16-1/IL10RA/AKT3 axis to reduce brain damage and improve cognition in VD models (72). Intestinal microbial dysbiosis caused by IL10RA dysfunction can lead to early-onset IBD (73, 74) and refractory IBD (75). PTPRC requires for T-cell activation through the antigen receptor. Although there is substantial evidence for the role of T cells in VD and IBD (76, 77), the mechanism of action of PTPRC in both remains unclear. Despite the identification of shared genes using bioinformatics methods, further research is required to elucidate the interactions and relationships between these molecular markers through the brain-gut axis. It is evident that these biological pathways of molecular markers are primarily focused on immunity, inflammation, oxidative stress, microglia activation, among others. However, these pathways do not fully capture the signal transduction mechanisms between them, highlighting the necessity for additional pathway studies from the perspective of the brain-gut axis.

Neuroinflammatory response is mainly mediated by cytokines, chemokines, reactive oxygen species free radical transmitters, which are mainly secreted by microglia, astrocytes, endothelial cells (ECs) and peripheral derived immune cells. This response can be can be triggered by various damaging events, including hypoxia, ischemia, and infection (78). In normal organisms, neuroinflammation can maintain the stability of the immune microenvironment. However, it may also damage CNS due to excessive activation of the inflammatory response (79, 80), leading to cell injury, blood-brain barrier destruction, and other pathological changes, inducing or aggravating the occurrence and development of VD. There has been increasing evidence that the immune system plays a key role in brain-gut signal transduction (81). For example, studies in germ-free mice and mice treated with broad-spectrum antibiotics showed that the gut microbiota was involved in bacteria-related intestinal immunity, which also reflected the microbiota’s ability to locally regulate innate and adaptive immunity in the gastrointestinal tract (GI) and throughout the body (82). As we know, neurons and glia in the enteric nervous system are involved in intestinal immunity (83). Innate immune cells in the gut include dendritic cells, M cells, macrophages, mast cells, NK cells, and type 1, 2, and 3 innate lymphoid cells (ILCs), serving as the first line of defense in the intestinal barrier. Adaptive immune cells are divided into different cell subtypes (84). Cytotoxic CD8+T cells and CD4 effector cells (TH1 cells, TH2 cells, and Th17 cells) and regulatory T cells (Tregcells) are not only involved in action locally, but also migrate to other organs by immune migration, including the brain (85). Under normal conditions, the CNS is isolated from the periphery by the BBB, which is molecularly and cellularly similar to glial cells, and local immune functions are mainly supported by glial cells. Animal experiments had also demonstrated (86, 87) that when the BBB was damaged, its permeability increased, leading to microglia activation. Microglia are the main resident immune cells in the central nervous system, which have the ability of antigen presentation and bind to lymphocytes to limit the invasion of pathogens (88). In addition to cytokines, microglia can recognize neurotransmitters and neuromodulators, which trigger immune responses (88). As the most abundant glial cells in the nervous system, astrocytes play a key role in promoting the integrity of the BBB and participating in the immune response (89).

Blood ECs have long been known to modulate inflammation by regulating immune cell trafficking, activation status and function (90). ECs play a crucial role in BBB vascular biology by upholding permeability, homeostasis, vessel wall integrity, and preventing thrombosis (91), and are involved in peripheral immunity and neuroinflammation (92). In our study, we found that the functions of coDEGs are mainly concentrated in immune regulation and inflammatory response, and the dysfunction of these functions plays an important role in the permeability and function of ECs. For example, during sepsis, ECs enhance the immune response and activate the clotting system, thus shifting from an anticoagulant state to a pro-coagulant state (93, 94). They are both a target and source of inflammation, acting as a link between local and systemic immune responses. Inflammatory mediators also inhibited cAMP/Rac1signalling to increase endothelial cell permeability (95, 96). Severe inflammation can also result in parenchymal infiltration of peripheral immune cells and activation, causing structural damage to the BBB (97). When the BBB is damaged due to various reasons, the leaky BBB is involved in neuroinflammation, oxidative stress and excitotoxicity, leading to perivascular injury, leukocyte infiltration and brain parenchymal changes, leading to VD (98, 99). In addition, ECs can crosstalk with a variety of cells leading to cognitive impairment, for example, loss of endothelial-pericyte crosstalk is a major driving force in dementia pathology (100), and endothelium-macrophage crosstalk mediates BBB dysfunction in hypertension (101). Impaired BBB can cause a variety of neurological dysfunctions, which further leads to the imbalance of peripheral system homeostasis, leading to multiple intestinal complications, such as intestinal flora imbalance (GMD), IBD, necrotizing enterocolitis (NEC), and even colorectal cancer (CRC). In turn, these complications can worsen brain function and, in patients with IS, it can even disrupt the brain’s immune system (102).

Combined with the results of immune infiltration results of 8 hub genes, it can be inferred that intestinal diseases may migrate to the central nervous system through acquired immune cells such as Cytotoxic CD8+T cells, TH2 cells, and regulatory T cells to activate neural immunity. Of course, innate immune cells, especially NK cells, and mast cells are also directly involved in the formation of vascular dementia, which needs further experimental proof. Central memory CD4 T cells in VD and memory B cells in IBD can suppress this abnormal immune response and may provide targets for further intervention. Previous studies have found that intestinal immune cells themselves can also directly regulate neuroimmune homeostasis and brain responses to inflammation. Intestinal antigens stimulate B cells to differentiate into immunoglobulin A (IgA), secreting plasma cells to control the gut microbial community. Autoimmune diseases of the nervous system induce massive migration of intestinal IgA+ plasma cells to the brain and spinal cord (85). These findings are consistent with our results and may open new avenues for the treatment of nervous system disorders by using intestinal antigens to promote IgA+B cell production and promote neuroimmune suppression (103), and thus may provide potential immunotherapy targets for patients with IBD complicated with VD. In addition, evidence from animal studies suggested a potential role for short-chain fatty acids (SCFAs) in communication with the BBB and the brain-gut axis that supported BBB integrity (104), which could link butyric acid to memory, cognition, mood, and metabolism (105). Benakis et al. found that the intestinal flora of mice treated with antibiotics was changed, and the intestinal dysbiosis could increase regulatory T cells and decrease the number of IL-17+γδT cells by changing the activity of dendritic cells, and finally play a brain-protective role by limiting neuroinflammatory response (37). After middle cerebral artery occlusion, γδT cells would quickly infiltrate the lesion area and aggravate the BBB injury by releasing IL-17A.

Many scientists believe that there is a close link between microbial diversity and healthy aging. Studies in mice have shown that fecal microbiota grafts could correct age-related immune deficits (82), and that transplanting gut microbes from older mice into younger mice adversely affects critical CNS functions (106, 107). Neurological studies have shown that the microbiome also plays a role in neurodegeneration. Studies of fecal microbiota transplantation in transgenic mouse models indicated a causal relationship between gut microbiota, protein aggregation, and cognitive problems (108, 109). Animal and human clinical trials had explored dietary additives such as prebiotics, biostime, omega-3 polyunsaturated fatty acids, or phytochemicals to intervene in the intestinal microenvironment (110). For example, a high-fiber diet (which promoted SCFA production in the gut microbiota) was a promising intervention. It could overcome the cognitive and social dysfunction caused by maternal obesity (111). Fecal microbiota transplantation (FMT) was another potential treatment that had been shown to affect high-fat dietary intake in mice and reduce the risk of causing cognitive problems (112). Therefore, intestinal microbiome intervention is another promising target for improving cognitive impairment, which is consistent with the evidence of IBD and VD provided in this study.

This study has certain limitations. Initially, the data utilized in our research was sourced from the GEO database, which did not provide specific clinical details like gender, age, complications, etc. for each sample, resulting in their exclusion from our study. Additionally, the sample size derived from the database was limited, which might lead to false positive results. Moreover, the analysis of genes and pathways has certain limitations and cannot fully reflect the unknown mechanism of the disease. Consequently, further research with larger sample sizes is necessary to elucidate the precise relationship between VD and IBD and its various phenotypes. Finally, due to the difficulty in obtaining samples, we did not conduct in vitro experiments, particularly with regard to how these genes act on immune cells through which pathways and how they affect the occurrence and process of diseases.

This study elucidates the common pathogenesis of VD and IBD and the connection between the two through the brain-gut axis pathway at the molecular level, suggesting that IBD and VD are closely related, and IBD may be an independent risk factor for VD. In addition, the immunoinfiltration analysis of the coDEGs suggests that the two can interact through the innate and adaptive immune system, and the inflammatory response, which provides a new perspective for basic research and clinical research. The identification of 8 hub genes helps us to better search for new targets for the treatment of both, and is of great value for the prediction of IBD-combined VD.

The original data used in this study are all publicly available. This data can be found here: https://www.ncbi.nlm.nih.gov/geo/ under the accession numbers GSE122063, GSE47908, and GSE479285.

Ethical approval was not required for the studies involving humans because All data in this paper are from public databases. The studies were conducted in accordance with the local legislation and institutional requirements. The human samples used in this study were acquired from gifted from another research group. Written informed consent to participate in this study was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and the institutional requirements.

YW: Data curation, Formal analysis, Investigation, Visualization, Writing – original draft. DX: Conceptualization, Funding acquisition, Writing – review & editing. SM: Data curation, Methodology, Validation, Writing – review & editing. NS: Project administration, Resources, Writing – review & editing. XZ: Project administration, Software, Writing – review & editing. XW: Supervision, Validation, Writing – review & editing.