Diabetic kidney disease (DKD) is the most common cause of chronic kidney disease and end-stage renal disease worldwide, affecting approximately 30%–40% of people with diabetes (1). In recent years, the incidence of diabetes worldwide has increased in parallel with the prevalence of DKD due to changes in obesity rates, metabolic syndrome, and lifestyle habits (2). At the same time, due to the high medical cost and poor prognosis in the advanced stage of the disease, DKD has brought a heavy burden to the whole society and families (3).

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract of unknown etiology. IBD has traditionally been viewed as a disease of the Western world. However, data over the past decade have shown that IBD has become a global disease with a dramatic increase in incidence and prevalence in the East (4). Due to the early onset of IBD, complex clinical symptoms (fatigue, diarrhea, and pain), and fluctuating disease course (prolonged disease course, recurrent attacks, and difficult to cure), it has a great impact on the quality of life and psychological state of patients (5). Although the precise cause and pathogenesis of IBD remain unknown and an effective cure is lacking, genetic research is now providing insight into the biological mechanisms behind the disease, which may hold promise for future therapies (6). Recently, extraintestinal symptoms and associated diseases of IBD have attracted increasing attention, most of which are related to autoimmune diseases such as type 1 diabetes mellitus, thyroid disease, and dermatitis herpetiformis (7). DKD and IBD are common and complex chronic diseases that are clinically heterogeneous and progressive. Some studies have shown that DKD and IBD are related disorders that probably share susceptibility genes. Patients with DKD are often associated with gastrointestinal dysfunction and may be more susceptible to IBD (8–10). However, the mechanism of DKD concurrent IBD remains unclear. As DKD and IBD are currently incurable, they represent a major public health challenge worldwide. Therefore, a clear knowledge of the key risk genes implicated in DKD complicated with IBD could help to identify potential therapeutic targets for the development of new drugs, in addition to the possible discovery of new potential diagnostic biomarkers for the early diagnosis of DKD complicated with IBD, while an understanding of the possible molecular mechanisms implicated in DKD and IBD could help improve the prognostic and therapeutic tools leading to a better quality of life of the patients, delaying the progression of the disease.

In recent years, with the continuous development of molecular biotechnology, bioinformatics has played an increasingly important role in exploring the molecular mechanisms of human diseases through systematic analysis of available biomedical data (11). In this study, we systematically explored the key targets and important pathways of DKD combined with IBD using bioinformatics methods, which enhanced our understanding of the underlying molecular mechanisms of DKD and IBD and provided potential targets for further research.

The flowchart of the study based on data mining and bioinformatic analysis is presented in Figure 1 .

Inflammatory bowel disease (IBD) is an autoimmune disease consisting of Crohn’s disease (CD), ulcerative colitis (UC), and indeterminate colitis. IBD is most common in Western countries, especially in North America and northern Europe; its prevalence is increasing year by year, and its cause is still unclear (20, 21). Genetic, environmental, and host-related factors are associated with the exacerbation of gut inflammation (22). The classical presentations of IBD are malabsorption and gastrointestinal symptoms; however, CD is more likely to manifest as watery diarrhea and vague symptoms, whereas UC is more likely to manifest as diarrhea and bleeding (23). The extraintestinal symptoms and associated diseases of IBD have been increasingly recognized in recent years. Many of these are associated with autoimmune diseases such as type 1 diabetes, thyroid disease, and dermatitis herpetiformis (7). There are many reports of combined kidney disease in patients with IBD, especially DKD (8–10). Therefore, in this study, we applied the bioinformatics approach to investigate the possible mechanisms of IBD complicated with DKD from a genetic perspective.

Through data mining, we found that IBD and DKD have many related genes in common, and MMP2, HGF, FGF2, IL-18, IL-13, and CCL5 were identified as the core risk genes for DKD with IBD by PPI analysis. MMP2 is an enzyme with gelatinase activity. Overexpression of MMP2 in glomerulus and tubules can lead to kidney damage and fibrosis by inflammatory processes through various pathologies (24). Meanwhile, mucosal MMP2 activity has been reported to be upregulated in humans with IBD (25). It facilitates remodeling of ECM and degradation of basal membrane type IV collagen, leading to intestinal ulceration, epithelial damage, and fistula formation (26, 27). HGF is a pleiotropic factor with the activities of antiapoptotic, cytoprotective, and modulating central inflammation and immunoreaction in many diseases (28, 29). Elevated serum HGF level is significantly associated with the incidence of type 2 diabetes (T2DM) and the development of insulin resistance (IR) (30). It has a positive effect on the survival of islet β cells and could protect against high-fat diet-induced obesity and regulate IR (31). Many studies have also found that serum HGF levels are higher in IBD patients compared with controls, which may be a good acute phase response biomarker of IBD activity (32, 33). HGF could modulate intestinal epithelial cell proliferation and migration, thus accelerating the repair of the intestinal mucosa (34). Recombinant human HGF and HGF gene therapy eliminates the severity in some animal models of IBD and is considered as a new treatment modality (35). IL-18 and IL-13 are both inflammatory cytokines, and CCL5 is a chemokine; inflammatory processes have been demonstrated to be associated with the development of DKD (36). It has been reported that IL-18 levels in urine and serum are increased in patients with DKD, and the serum IL-18 level is related to renal injury severity in DKD (37, 38). IL-18 could induce the release of interferon γ; lead to the production of other inflammatory cytokines, such as IL-1 and TNF; and induce endothelial cell apoptosis (39). In fact, IL-18 is thought to be more closely related to the progression of DKD than other diabetic complications (40). CCL5 is a potent chemoattractant for macrophages, monocytes, T cells, and granulocytes. CCL5 is significantly upregulated in renal biopsy samples from patients with T2DM and overt nephropathy, and its expression in renal tubular cells has a direct correlation with the interstitial cellular infiltration and the magnitude of proteinuria (41). The production of IL-18 was regarded as a key etiological factor for patients with IBD (42). It has been shown to disrupt the mucosal barrier, trigger inflammation, and amplify damage to the intestinal epithelium during disease (43). CCL5 also plays a crucial role in IBD; its expression is enhanced in the intestine and is closely implicated in the pathophysiology (44–46). These studies on the core risk genes for DKD with IBD validate our findings to some extent. These core risk genes may serve as the potential therapeutic targets for the development of new drugs and possible diagnostic biomarkers for the clinical identification of DKD complicated with IBD.

According to the KEGG terms, the risk genes for DKD complicated with IBD were mainly associated with the PI3K-Akt signaling pathway, AGE-RAGE signaling pathway in diabetic complications, and HIF-1 signaling pathway. Many studies have shown that stimulation of angiogenesis is an active participant in the establishment and maintenance of tissue inflammation in IBD (47, 48). The study by Zhou et al. found that the PI3K-Akt signaling pathway plays a crucial role in the angiogenesis of IBD, which could be activated by placental growth factor and induce the angiogenic effects in IBD (49). In addition, pro−inflammatory cytokines, such as tumor necrosis factor (TNF), are pivotal for the development of IBD (50). The activation of TNF receptor could stimulate the production of reactive oxygen species, which mediates the cell fate regarding senescence and apoptosis through the PI3K/AKT pathway (51). Decreased phosphorylation of PI3K-Akt could give rise to podocytes apoptosis, and many drugs have been reported to exert anti-apoptosis and renal protection effects in DKD through activating PI3K-Akt signaling pathway (52, 53). Therefore, it is reasonable that the dysregulation of the PI3K/AKT pathway is implicated in the induction and progression of DKD complicated with IBD. Hypoxia-induced activation of the HIF signaling pathway is a common feature of inflammatory diseases, including IBD (54). Hypoxia-inducible factor 1-alpha (HIF-1α) acts as a transcription factor that regulates cellular adaptation to low oxygen levels and supports the development and function of the gut barrier, thereby conferring protection against IBD (55), while constitutive activation of HIF-2α leads to the development or exacerbation of IBD in colitis models (56). In DKD, tubular HIF activity is inhibited, and HIF activation protects mitochondrial function and prevents diabetes-induced tissue hypoxia, tubulointerstitial fibrosis, and proteinuria (57). These studies on the signaling pathway for DKD with IBD also validate our findings to some extent.

Our study found that DKD and IBD share many common related genes and pathogenic mechanisms, oxidative stress, chronic inflammatory response, and immune dysfunction were possible mechanisms, and further research on these common targets for DKD complicated with IBD, especially the core targets, is important for the development of new effective drugs and the early diagnosis. Our study is based on the data mining and bioinformatics approach and has limitations due to the lack of experimental validation, mainly in the failure to validate the expression of the identified key risk genes in the blood of the patients with DKD combined with IBD and the changes in potential signaling pathways. Therefore, experiments on the key targets and related pathways of DKD combined with IBD are also needed to be conducted in the future.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary Material .

XZ performed the research, conducted the bioinformatics analysis, and wrote the first draft of the manuscript. HX, SF, and JY participated in data collection and analysis. YC and YJ participated in the project design and manuscript draft preparation and revision. All the authors have approved the final version of the manuscript.