Emerging research posits that chronic tissue inflammation is a central player in the pathogenesis of Type 2 Diabetes Mellitus (T2DM), characterized by a state of low-grade inflammation (1). The disturbance in gut mucosal ecology in individuals with T2DM, combined with the active migration of intestinal flora to mesenteric adipose tissue (MAT) and the bloodstream, results in a continuous influx of inflammatory antigens (2). Ulcerative colitis (UC) is a chronic, nonspecific inflammatory condition characterized by extensive mucosal inflammation in the colon (3), typically arising from an imbalance between the gut flora and the immune system (4). Although T2DM and UC share common features, such as disruptions in gut microbiota and intestinal mucosa inflammation, the precise mechanisms underlying their co-occurrence remain unclear.

Currently, there is no cure for Type 2 diabetes. Despite the recent successful development of numerous antidiabetic drugs, single-target treatments are increasingly seen as inadequate due to individual variations, diverse pathogenesis, and issues related to drug and body resistance (5). Similarly, ulcerative colitis carries a heightened risk of adverse events, treatment resistance, and loss of response over time, highlighting the limitations of current therapies (6). Thus, multi-target drugs offer greater potential advantages over single-target drugs, underscoring the need to continually identify new targets to develop effective and safe therapies. Traditional Chinese medicine formulations are characterized by their multi-component approach, targeting multiple pathways and targets simultaneously.

The venerable Chinese herbal prescription, Gegen Qinlian Decoction (GQD), traces its origins to the era of the Eastern Han Dynasty. This formulation, consisting of four vital herbs—Radix puerariae, Radix scutellariae, Rhizoma coptidis, and Glycyrrhizae Radix, represents a traditional prescription deeply rooted in the principles of Traditional Chinese Medicine (TCM), specifically tailored for addressing intestinal damp-heat syndrome. A large-scale randomized controlled study (RCT) has demonstrated GQD’s efficacy in significantly lowering HbA1c and fasting blood glucose (FBG) levels, offering relief in cases of T2DM (7). Animal experiments suggest that GQD may mitigate systemic and local inflammation by promoting the enrichment of butyrate-producing intestinal flora, thereby ameliorating clinical manifestations associated with T2DM (8). Meta-analyses have shown that GQD effectively alleviates symptoms in individuals with UC, resulting in decreased Ulcerative Colitis Endoscopic Index of Severity (UCEIS) scores and maintaining a low recurrence rate, all while exhibiting minimal adverse events (9). Furthermore, additional animal studies have elucidated the mechanisms underlying GQD’s therapeutic effects in alleviating ulcerative colitis, including the reduction of inflammation and oxidative stress, inhibition of the IL-6/JAK2/STAT3 signaling pathway, restoration of the balance between Treg and Th17 cells in colonic tissues, and enhancement of intestinal barrier function (10, 11).

As bioinformatics advances and the widespread adoption of gene chips continue, their integration into the biomedical domain has become indispensable. The analysis of microarray data emerges as a transformative tool, offering fresh insights into the shared etiological underpinnings of both T2DM and UC. In this investigation, a comprehensive strategy merging bioinformatics and machine learning was employed, drawing upon datasets from the GEO database to unravel the intertwined comorbid mechanisms associated with T2DM and UC. Furthermore, our study delved into network pharmacology, shedding light on the intricate mechanisms governing the utilization of GQD across diverse diseases sharing a common treatment modality (Figure 1).

An increasing body of research is corroborating the association between UC and T2DM. It has been demonstrated that diabetes is the most prevalent co-morbidity of UC (17). A population-based cohort study reveals a significantly heightened risk of T2DM among individuals with UC (18). The association between diabetes and UC holds significant implications across epidemiology, etiology, clinical practice, and therapeutic strategies, signaling profound implications for research and patient care alike (19). Hence, investigating the mechanisms underlying the co-occurrence of UC and T2DM holds clinical significance, aiding in early disease detection and timely intervention. In this study, we conducted analyses on four microarray datasets related to UC and T2DM using diverse bioinformatics approaches. Based on our predictions, inflammatory and immune processes, along with Immunoinflammatory signaling pathways such as IL-17, TNF, chemokine, and Toll-like receptor, may represent potential mechanisms underlying the co-morbidity of T2DM with UC. Following subsequent network pharmacological analyses, pivotal targets of GQD for the concurrent treatment of T2DM and UC were identified, including AKT1, BCL2, EGFR, ESR1, PTGS2, STAT3, and TNF. Notably, GQD predominantly acts on immuno-inflammatory pathways, such as Toll-like receptors, IL-17, TNF, MAPK, and the PI3K-Akt signaling pathways, in the simultaneous treatment of T2DM and UC.

In recent years, the roles of intestinal flora, inflammation, and immune regulation in the pathogenesis of T2DM and UC have attracted increasing attention (20, 21). Single-cell sequencing coupled with immune infiltration analysis underscored the pivotal role of immune cells in driving the pathogenesis of both UC and T2DM. The intestinal mucosal immune system, comprising lymph nodes, lamina propria, and epithelial cells, serves as a vital barrier safeguarding intestinal integrity. The symbiotic relationship between the microbiome and the intestinal immune system is crucial for preserving mucosal homeostasis (22). However, deficiencies and dysbiosis in the intestinal flora can result in significant impairments to the intestinal mucosal immune system, precipitating the onset of T2DM alongside UC (23, 24). UC’s development involves various factors within the gut microbiome, immune system dysfunctions, and compromised intestinal barriers, resulting in abnormal immune reactions to typical gut bacteria (25). UC is characterized by an imbalance between intestinal effector T cells and mucosal Treg, with effector T cells being overly active and Treg cells not expanding sufficiently (26). Balancing the population of Th17 and Treg cells in the intestines of mice markedly improves symptoms and reduces pathological damage in ulcerative colitis (27). In T2DM, disruptions in intestinal immunity and barrier function, alongside alterations in gut microbiota, foster heightened intestinal permeability. Consequently, intestinal bacterial components infiltrate circulation, fueling both local and systemic chronic inflammation, ultimately contributing to insulin resistance (28, 29). Dendritic cells, functioning as autocrine or paracrine modulators, synthesize and release classical neurotransmitters crucial for maintaining intestinal immune balance. Their abundance is markedly elevated in the gut of patients with UC and T2DM (30, 31). In ulcerative colitis, the usual equilibrium of intestinal B-cell reactions is disturbed, resulting in a notable decrease in regulatory B cells (32, 33). In parallel, B cells modulate Th17 proliferation and the production of pro-inflammatory factors in the intestines of T2DM patients (34). Research indicates that managing macrophage metabolism and polarization can alleviate symptoms in DSS-induced UC mice, hinting at the potential of targeting macrophage polarization to restore immune balance as a promising UC treatment strategy (35). In individuals with T2DM, there is a reduction in the quantity of anti-inflammatory T-cell subsets, such as regulatory T-cells (Treg), M2-like macrophages, and IgM-producing B-1 cells, alongside an elevation in the number and/or ratio of inflammatory effector T-cells (36). Individuals diagnosed with T2DM often exhibit irregularities in the frequency and functionality of B cells, potentially resulting in heightened inflammatory reactions and reduced insulin sensitivity. Moreover, the antibodies generated by B cells are pivotal in the progression of T2DM, notably contributing to neuroinflammation and cognitive deterioration (37, 38). In individuals with T2DM, dendritic cells are implicated in vascular dysfunction. Research indicates an elevated accumulation of dendritic cells in the perivascular adipose tissue of diabetic mice, which consequently compromises their anticonstrictive and vasodilatory functions (39). Likewise, macrophages emerge as the primary immune cell driving inflammation within pancreatic islets in T2DM, posing a threat to the insulin-secreting function of β-cells through multiple mechanisms (40). In conclusion, the elevated permeability of intestinal mucosa caused by disturbances in intestinal flora and impairment of the intestinal mucosal immune system contributes to the onset of systemic chronic inflammatory responses, a shared mechanism underlying the development of UC and T2DM (41).

Ulcerative colitis manifests as recurring mucosal inflammation with periods of remission, necessitating treatment to induce and sustain remission (42). Concurrently, the incidence of T2DM is on the rise, contributing to escalating rates of disability and mortality, thereby compounding the burden on families (43). Thus, there is an imperative to discover additional routine serum biomarkers for the early diagnosis and treatment of T2DM and UC. Three distinct machine learning studies identified IGFBP3 as a biomarker for GQD in treating T2DM, while BACE2, EPHB4, and EPHA2 emerged as biomarkers for GQD in UC treatment. IGFBP3 interacts with cellular proteins involved in glucose metabolism regulation, consequently inducing insulin resistance and diminishing glucose uptake in adipose tissue (44). For every one-unit rise in genetically determined IGFBP3 levels, there’s a 26 percent higher likelihood of developing T2DM (45). The degradation of pancreatic β-cells is a pivotal aspect of T2DM, and IGFBP3 signaling contributes to this decline in β-cell function and viability. Suppressing IGFBP3 activity can protect β-cells, potentially delaying or preventing the onset of diabetes, making it a promising therapeutic avenue for diabetes treatment (46). BACE2, a protease regulated by the JAK2/STAT5 signaling pathway, emerges as a pivotal contributor to UC development (47). The activity of IL-1R2, linked to ulcerative colitis, is influenced by the BACE2 gene. Therefore, BACE2 assumes a significant role in the pathogenesis of UC (48). The EphB/ephrin-B system has become a promising focus for tackling gut inflammatory diseases. Suppressing this system seems to provide a therapeutic benefit by regulating immune responses (49). Eph/ephrin proteins are implicated in numerous chronic inflammatory conditions. Targeting EPHB4 to disrupt EphB/ephrin B signaling holds potential as a pharmacological strategy for treating UC (50). In summary, the involvement of Eph/ephrin signaling in maintaining intestinal balance, managing inflammation, and regulating neuroimmune interactions offers exciting possibilities for future investigations and therapeutic advancements in gastrointestinal conditions (51).

In China, GQD is extensively employed for the treatment of both T2DM and UC. Through degree-value analysis of the herbal-chemical-target-protein network, we pinpointed seven active ingredients—Berlamine, Palmatine, Moslosooflavone, Quercetin, Moupinamide, Panicolin, and Baicalein—as potential compounds for treating the combined condition of T2DM and UC. Berlambine accomplishes the alleviation of inflammatory response and intestinal epithelial barrier dysfunction by diminishing the protein levels of TLR4 and MyD88, inhibiting the phosphorylation of I-κB α, and obstructing the translocation of NF-κB p65 from the cytoplasm to the nucleus (52). Concurrently, Berlambine notably increased the mRNA expression of the Nrf2 signaling pathway and elevated the activity of the pancreatic PI3K/Akt signaling pathway (53). Palmatine, a naturally occurring compound known for its anti-inflammatory and antioxidant properties, reverses the dysfunction in the insulin signaling pathway by increasing the expression of IRS-1, PI3K, AKT2, and GLUT4 genes while decreasing the expression of PKC (54). Furthermore, Palmatine alleviates ulcerative colitis symptoms by mitigating colon damage, preserving intestinal flora balance, and modulating tryptophan catabolism (55). Moslosooflavone markedly decreased the concentrations of inflammatory mediators like TNF-α, IL-1β, and IL-6 in mice (56). Quercetin’s renowned anti-inflammatory properties position it as a promising natural remedy for various inflammatory conditions (57). Quercetin ameliorates UC by restoring intestinal barrier function via the activation of AHR-mediated enhancement of tight junctions (58). Additionally, quercetin provides therapeutic benefits in T2DM by inhibiting pancreatic iron accumulation and pancreatic β-cell death (59). Panicolin exhibited strong anti-inflammatory properties by significantly suppressing the production of IL-6 induced by LPS (60). Baicalein demonstrates anti-inflammatory properties by inhibiting T cell activation and suppressing the thioredoxin system to restrict NF-κB-dependent inflammatory responses (61). Moreover, baicalein exhibits multifaceted effects on glucose metabolism, enhancing glucose uptake and glycolysis while inhibiting hepatocyte gluconeogenesis through modulation of the InsR/IRS-1/PI3K/AKT pathway (62). Simultaneously, it enhances the integrity of the intestinal epithelial barrier via the AhR/IL-22 pathway in ILC3, thereby ameliorating ulcerative colitis (63). The therapeutic efficacy of the active constituents within the herbal formulation GQD for both T2DM and UC has been substantiated.

Ultimately, the affinity between seven key target proteins and active compounds was assessed through molecular docking techniques. Berlambine and Palmatine exhibited promising binding activity to the target, implying their potential relevance to the therapeutic role of GQD in treating T2DM and UC.

It is worth noting that our study also has some limitations. At the outset, our dataset originates from various public databases, each with its own set of inclusion criteria. These distinctions could potentially impact the precision of our findings. Secondly, the sample size in the GEO database is relatively small, potentially contributing to some degree of error. Additionally, variations in algorithms and parameter selections could yield divergent outcomes and interpretations. Hence, although employing various bioinformatics and machine learning approaches, validating the results through clinical trials and animal studies is imperative.

In summary, we delineated potential co-morbid mechanisms between T2DM and UC, primarily implicating pathways such as IL-17, TNF, chemokine, and Toll-like receptor signaling, alongside the involvement of immune-inflammatory pathways and various immune cells like T cells, B cells, and neutrophils. Three distinct machine learning studies identified IGFBP3 as a biomarker for GQD in treating T2DM, while BACE2, EPHB4, and EPHA2 emerged as biomarkers for GQD in UC treatment. Ultimately, our investigation identified Berlambine and Palmatine as key components of GQD, presenting promising therapeutic prospects for managing the concurrent occurrence of T2DM and UC. Additionally, our study clarifies the mechanisms underlying the therapeutic effects of GQD, employing strategies that involve multiple components, targets, and pathways. This highlights its capacity to regulate immune responses and inflammation, with a specific focus on targeting toll-like receptors, IL-17, TNF, MAPK, and PI3K-Akt signaling pathways. The therapeutic strategy involving multiple components, targets, and pathways plays a vital and effective role in enhancing treatment outcomes, mitigating drug resistance, customizing treatment plans, managing complications comprehensively, and minimizing therapeutic side effects. Consequently, this approach significantly benefits patients’ clinical progress and enhances their quality of life.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.

FH: Data curation, Formal analysis, Software, Visualization, Writing – original draft. LX: Data curation, Formal analysis, Software, Visualization, Writing – original draft. ZL: Investigation, Validation, Writing – review & editing. LL: Investigation, Validation, Writing – review & editing. LW: Validation, Writing – review & editing. XW: Validation, Writing – review & editing. XZ: Conceptualization, Funding acquisition, Methodology, Project administration, Supervision, Writing – review & editing. YZ: Conceptualization, Funding acquisition, Methodology, Project administration, Supervision, Writing – review & editing.