Pressure ulcers (PUs), also known as pressure sores, bed sores or decubitus ulcer, are localized injures to the skin and underlying tissue. They typically occur over bony prominences, and are classified into stages (Stage 1 to Stage 4) based on their severity (1, 2). These injuries develop when prolonged pressure is applied to the skin, often in combination with friction and shear forces. PUs are a significant concern in healthcare, particularly for individuals with limited mobility, such as those who are bedridden or use wheelchairs (3). PUs have substantial healthcare and economic implications and are present in all healthcare settings (4). Although most PUs are reasonably preventable (5), approximately 1 to 3 million individuals in the United States develop PUs each year (6), and 60,000 people die each year due to complications from PUs (7). The management costs of PU are a major problem, with a recent study estimated the annual cost in the United States to be in excess of $26.8 billion (8), and in the United Kingdom, it is estimated at £1.4–£2.1 billion per annum (9). Moreover, PUs can significantly diminish overall quality of life due to pain, the need for management procedures, extended hospital stays, and psychosocial burdens (2, 10, 11). Therefore, identifying the risk and protective factors for PUs is crucial for its prevention and management.

In developing countries and low-income households in the United States, individuals face not only a financial burden but also a higher risk of negative effects because proper nutrition or caregiver support may be deficient (12–14). Insufficient dietary habits or malnutrition may play an important role in this increase of PUs. The pathogenesis of PUs is multifactorial and may be related to genetic, environmental, and lifestyle factors. A number of studies have revealed that inadequate nutritional intake is associated with a higher risk of developing PUs (15–17). In particular, dietary patterns characterized by elevated fiber content, notably derived from whole grains, fruits, and vegetables, have demonstrated an association with enhanced glycemic control. The presence of fiber in these diets serves to decelerate the absorption of glucose, thereby mitigating spikes in blood sugar levels. Conversely, the consumption of a diet rich in added sugars and processed foods has been implicated in the elevation of blood glucose levels, potentially fostering insulin resistance. Individuals exhibiting heightened fasting blood sugar levels or impaired glucose tolerance face an augmented susceptibility to the onset of type 2 diabetes (T2DM) (18, 19). T2DM, a persistent disorder marked by compromised regulation of blood glucose, holds the potential to manifest as enduring microvascular and macrovascular complications and accumulating evidence showed that patients with type 2 diabetes mellitus (T2DM) are 1.5 to 2 times more likelihood to develop surgery-related PUs than patients with normal glucose tolerance (20, 21). The previous studies on potential risk factors for PUs are based on observational research, which may be susceptible to issues related to potential residual confounding and reverse causation (22). We now aim to assess the causal association between dietary habits, T2DM, and the likelihood of developing PUs using Mendelian randomization (MR).

Under certain assumptions, MR utilizes genetic variants as instrumental variables (IVs), offer the advantage of controlling for nonheritable confounders and reverse causation (23). To date, there has been no genetic study on the relationship between T2DM, glycemic traits, dietary habits, and PUs. Herein, we performed a two-sample MR study to explore the causal relationship between dietary habits, T2DM and PU in this study.

The following basic assumptions constitute the premise of MR analysis. (1) IVs must be directly associated with the exposures; (2) IVs cannot be directly correlated to the outcome only via exposure but not through other pathways; (3) IVs were independent of any potential confounding factors (Figure 1). The GWAS summary-level data used in this study were issued by the IEU open GWAS project,¹ MAGIC² and FinnGen biobank (FREEZE 9).³ This study was exempt from the approval of the Ethical Review Authority because the data used in this study was public, anonymized, and de-identified.

Based on summary level data from large GWAS, we implemented a two-sample univariable MR study to investigate the causal association between dietary habits and PUs. Employing a bidirectional analytical approach for T2DM, Glycemic traits, and the risk of PUs. We further applied Multivariable MR to eliminate the potential confounding factors, specifically BMI, revealing that T2DM is the independent effect factor on PUs, allowing us to differentiate between upstream and downstream factors in the disease pathway. Our results indicated that genetically predicted T2DM and FG are positively associated with the risk of PUs, while Salad / raw vegetable intake shows a negative association with PU risk. Additionally, we observed that PUs is associated with increased levels of FG and FI. These findings were generally robust in sensitivity analysis, ensuring the reliability of our MR analyses and mitigating potential pleiotropic effects. According to our knowledge, this represents the first MR study evaluating potential causative links between T2DM, glycemic traits, dietary habits, and PUs.These findings provide valuable insights for the prevention and treatment of PUs.

Our findings reveal that T2DM and the elevated levels of FG increase the risk of PUs, this conclusion aligns with the results of numerous studies. A meta-analysis of 15 observational studies, encompassing 19,724 intraoperative PUs in patients conducted in Asia, the Americas, Europe, and Australia from 1989 to 2019, indicated that the incidence of PUs in the T2DM population increased by 50% compared to non-T2DM individuals (OR = 1.52, 95% CI 1.25–1.85) (20). Other research also confirms this finding, with a meta-analysis of six observational studies involving all 2,453 patients. Compared to patients without T2DM or normal glucose levels, individuals with T2DM were more than twice as likely to develop surgical PUs (OR = 2.15, 95% CI: 1.62–2.84) (21). One potential explanation is that T2DM induces peripheral neuropathy, impairs sensory perception, and leads to prolonged insensitivity to compression, tissue necrosis, and nonhealing of affected areas. Peripheral neuropathy, in turn, has also been associated with neuropathic ulcers and diabetic foot ulcers (32–34). Another mechanism is that T2DM and high FG levels have been shown to reduce blood flow to the skin and underlying tissues. Poor circulation can result in decreased oxygen and nutrient delivery to these tissues, making them more vulnerable to damage from pressure and friction. Impaired blood flow also slows down the healing process of PUs once they have formed (35). Additionally, T2DM can cause chronic inflammation and reduced angiogenesis, further hindering the healing processes of PUs. In mice models of T2DM, reducing inflammation by increasing levels of several pro-healing growth factors has been shown to improve wound healing (36–38). Lastly, T2DM can reduce the formation of collagen, a protein essential for skin strength and elasticity. This can affect the skin’s ability to withstand pressure and shear forces, making it more susceptible to injury and increasing the likelihood of developing PUs (39). Moreover, T2DM and a longer duration of hyperglycemia can lead to metabolic imbalances, including altered protein and nutrient metabolism (40). These potential mechanisms can affect the body’s ability to generate new tissue and repair damaged skin. Adequate nutrition is critical for the wound healing of PUs, and individuals with poorly controlled T2DM and FI levels may be at greater risk of malnutrition (41, 42). Our findings also suggest a reciprocal causation between FG and PUs, elevated FG is often associated with insulin resistance, a condition where the body’s cells become less responsive to the effects of insulin and tissue damage and inflammation caused by PUs may trigger a stress response in the body, potentially affecting insulin sensitivity and metabolism (43). Therefore, high levels of FI and FG are closely associated with the metabolic response and disease progression in PUs.

It is worth noting that our study revealed an inverse association between salad/raw vegetable intake and PUs. Consistent with previous studies, the beneficial impact could be attribeted to components found in salad/raw vegetables, which are typically rich in vitamins, minerals, sufficient water, and antioxidants. These components play crucial roles in skin health, digestive health, regular bowel movements, and tissue repair (43–46). Recent evidence emphasizes that plant polyphenolic compounds, which are prevalent in the human diet and present in substances such as curcumin (47), apigenin (48), Ocimum basilicum, and Trifolium pratense extracts (49), confer various health benefits. These compounds are well-recognized for their potent antioxidant, antimicrobial, and anti-inflammatory properties. They neutralize free radicals by inhibiting key signaling pathways, including NF-κB, transforming growth factor-beta (TGF-β), and mitogen-activated protein kinase, while also enhancing the activity of antioxidant enzymes including superoxide dismutase (SOD), peroxidases, and catalase (50). Collectively, these effects support wound healing and skin barrier repair. Additionally, these polyphenolic compounds are crucial in recruiting specific cells to sites of inflammation and accelerating the overall healing process. Adequate nutrient supply can promote healthy skin and reduce the risk of PUs development. Diets with higher vegetable intake are generally more favorable for weight management. Maintaining an appropriate weight can alleviate the pressure on the skin, reducing the likelihood of skin damage. Certain components in vegetables have anti-inflammatory and immune-supporting properties, potentially helping to lower skin inflammation levels and mitigate tissue damage caused by inflammation (51).

The relationship between alcohol intake and the risk of developing PUs is a matter of debate, with varying results from different studies. Several studies have linked alcohol consumption to an increased risk of developing PUs (52, 53). However, other research has found that the consumption of alcohol was not significantly linked to the incidence of PUs (54, 55). Despite applying MR analysis to investigate the potential association between alcohol consumption and PUs, no causal association was shown in the study. Vegetables, abundant in Vitamin C and Quercetin, are commonly recommended as dietary components for the prevention or treatment of PUs (44, 56, 57).

Our study has several strengths and limitations. Firstly, this is the first study to investigate the causal relationship between T2DM, glycemic traits, dietary habits and PUs through a Two-sample MR analysis, which is not affected by confounders and reverse causation compared with observational studies. Additionally, we conducted multivariable MR analyses to disentangle the direct causal impacts of T2DM on PUs. Finally, multiple sensitivity analyses and IV strength evaluations were conducted to ensure the robustness and reliability of the results. However, there are also some limitations. Firstly, MR analysis is based on specific assumptions that cannot be verified. Secondly, the present study primarily involved individuals of European ancestry, which may limit the generalizability of our findings to other populations. Thirdly, while we explored the association between T2DM, salad/raw vegetable intake, FI, FG and PUs from a genetic perspective, the underlying mechanisms remain unclear and warrant further investigation.

This study found that salad/raw vegetabke intake associated with a reduced risk of PUs, while T2DM and FG were associated with an increased risk of PUs. Furthermore, FI and FG may play pivotal roles as downstream factors in PUs. This study also found that various dietary habits including alcoholic drinks per week, alcohol intake frequency, bread intake, cheese intake, water intake, cereal intake, non-oily fish intake, oily fish intake, beef intake, fresh fruit intake, coffee intake, pork intake, tea intake, processed meat intake, poultry intake, and cooked vegetable intake were not associated with PUs, which were robust to different analyses and rigorous pleiotropy testing.