We conducted MR analysis on two large databases, investigating the causal relationship between dietary intake and IBD and its subtypes. Using SNPs associated with the dietary habits of 239 different types of diets as the IVs, our study indicated the differential causal effects of various types of dietary intake on the occurrence of IBD and its subtypes. It also preliminarily demonstrated differences in the effects of different fruits and vegetables on the onset of IBD and its subtypes. The findings indicated that baked goods, dairy products, and processed foods may have pathogenic effects on IBD, while meat intake may not be directly associated with the onset of IBD.
Dietary components and habits have been recently identified as one of the environmental factors promoting IBD [25]. They can induce changes in intestinal inflammation and intestinal permeability by affecting the composition of the gut microbiota and the immune response of the intestinal mucosa [26,27], which is more pronounced in individuals with genetic susceptibility.
Although dedicated research exploring the relationship between staple foods primarily composed of carbohydrates, such as porridge and corn, and the onset of IBD is currently unavailable, excessive intake of saccharides is considered a risk factor for IBD development [28]. Our results suggest that the consumption of porridge may be a protective factor for IBD. This may be attributed to the fact that porridge consumption increases gastrointestinal motility and water content in the stool and also enhances the abundance of beneficial gut bacteria such as Bifidobacteria and Lactobacilli, while reducing the abundance of potentially pathogenic bacteria such as Escherichia coli, Enterococcus, and Clostridium [29].
Fruits, vegetables, and whole grains are the main sources of complex carbohydrates in the human diet, and they are believed to have protective effects on the gut due to their plant cell wall polysaccharide, resistant starch, and dietary fiber content [30,31]. While fermentable fiber can increase fecal volume and promote regular bowel movements, it can also be metabolized by the gut microbiota into short-chain fatty acids (SCFAs) such as butyrate, which is the primary energy source for colonic cells and can effectively inhibit the transcription and expression of inflammatory signaling pathway transcription factor NF-κB and its downstream pro-inflammatory mediators. Butyrate is considered a potent regulator of the intestinal immune system [32], and it also plays an important role in regulating the gut microbiota and protecting the integrity of the intestinal mucosal barrier [33].
Evidence suggests that a low-fiber diet (commonly associated with the Western diet) significantly alters the composition and abundance of the gut microbiota and increases the risk of IBD [26]. A prospective observational study indicated that long-term consumption of high levels of dietary fiber, especially soluble or fermentable fiber from fruits, is associated with a reduced risk of CD [34]. However, the effects of fruits and vegetables on the onset of IBD may vary depending on the specific types and nutritional compositions. Our study suggests that the intake of leeks and carrots is associated with a reduced risk of CD, while the intake of plums, grapes, and watercress is associated with an increased risk of CD. Cherry intake is associated with a reduced risk of IBD, while onion and butternut squash intake is associated with a reduced risk of UC.
The phytochemicals present in vegetables, such as saponins and flavonoids, have been reported to have therapeutic value in the treatment of diseases related to oxidative stress, inflammation, and immune dysfunction [35,36]. They may also influence the composition and structure of the gut microbiota, thereby affecting host metabolism, inflammatory response, or the development of infections [37]. In addition to dietary fiber, the presence of vitamins A and C as antioxidants in fruits can effectively inhibit oxidative stress and inflammation [38]. Active retinoic acid (RA), a metabolite of active vitamin A, has been found to promote the maturation of innate immune cells, regulate the differentiation of adaptive immune cells, and contribute to the regeneration of damaged epithelial barriers during infection. It has a potential protective effect on the maintenance of the intestinal mucosa in IBD [39]. Furthermore, polyphenolic compounds found in cherries, such as anthocyanins and proanthocyanidins, can directly exhibit anti-inflammatory and antioxidant properties in the gut [40]. Interestingly our MR analysis indicated that the intake of grapes rich in resveratrol and anthocyanins as well as plums containing carotenoids and polyphenols may increase the risk of CD, which differs from conclusions drawn from a murine model of colitis induced by dextran sodium sulfate (DSS) [41,42]. We believe this discrepancy may be related to the presence of other bioactive substances in grapes and plums that can potentially alter immune responses or have an impact on the gut microbiota, and further research is needed to explore this aspect.
A recent cohort study utilizing data from the UK Biobank also observed no association between natural fruit juice consumption and the risk of IBD [43]. However, in analyses using genetic IVs, our findings indicated that fruit juice consumption can lower the risk of IBD and CD. Pure vegetable/fruit juice, apart from dietary fiber, does not significantly differ from whole fruits in terms of nutrient intake [44]. However, consuming more pure fruit juice can improve the quality of an individual’s dietary pattern [44]. Therefore, the effects of pure fruit/vegetable juice on IBD may be equivalent to those of whole fruits/vegetables.
Several bioactive components in whole grains, including phenolic compounds, folate, and plant sterols, have well-established anti-inflammatory effects [45]. Some meta-analyses including large prospective studies have shown a close relationship between whole-grain intake and a lower risk of cardiovascular diseases and overall cancer mortality [46]. However, the immunogenic gluten peptides released during the digestion of whole-grain foods may trigger intestinal inflammation, although their role as a causative factor for IBD is currently not well-established [47]. Our study revealed that cereal bars may increase the risk of CD; sweet corn could be a risk factor for IBD; and whole-wheat pasta and baked beans can increase the risk of both IBD and UC. An observational study reported no effect of a gluten-free diet on the risk of CD and UC [48], and our results complement the causal effect of the intake of gluten-containing foods (whole-wheat products, cereal bars, and baked beans) on IBD.
Foods baked with composite flour (a mixture of wheat and non-wheat flours) are an essential component of the daily diet, primarily providing carbohydrates, proteins, dietary fiber, and vitamins [49]. However, the nutritional composition and functional effects of functional baked goods are influenced by various factors such as ingredient proportions and baking methods [50], which contributed to the significant heterogeneity in our conclusions; hence, we can only provide preliminary conclusions.
The research results regarding the impact of dairy products on intestinal inflammation are contradictory. Dairy products may be involved in the etiology of IBD through modulation of the gut microbiota and immune responses [51]. One study demonstrated that consumption of high saturated (milk) fat altered the gut microbiota and increased pro-inflammatory Th1 immune responses and the incidence of colitis in genetically susceptible mice, and that these effects may be mediated by the promotion of hepatic taurine-conjugating bile acid binding capacity by high saturated fat [52]. Saturated fatty acids from dairy products may exacerbate inflammation by influencing the transcription of inflammatory cytokines. Hydrolyzed peptides from casein and whey protein groups can affect endothelial cell function, and substances such as nitric oxide (NO) generated from these peptides can induce inflammatory responses [53]. However, some studies have also indicated that the bioactive peptides and carbohydrates present in fermented dairy products can interact with gut microbiota or immune cells, thereby indicating certain anti-inflammatory properties [54]. A prospective investigation within the European Prospective Investigation into Cancer and Nutrition cohort demonstrated a potential association between milk consumption and reduced risk of CD, while no association was found between the onset of IBD and the consumption of yogurt, cheese, and other dairy products [55]. Our results indicate that cheese consumption is a risk factor for IBD. Blue cheese is a risk factor for UC. However, milk-based pudding is a protective factor for UC.
Systematic reviews of previous studies have indicated an increased risk of IBD associated with high intake of total fat, long-chain polyunsaturated fatty acids (PUFAs), ω-6 fatty acids, saturated fat, and meat. High-fat diets have been shown to directly induce inflammatory responses in intestinal epithelial cells [56], further exacerbating intestinal inflammation by driving dysbiosis [57]. A prospective observational study involving 595 IBD patients investigated the relationship between dietary protein consumption and IBD through a validated food frequency questionnaire (FFQ). The study found that meat and red meat consumption were associated with UC risk, but not with the risk of CD. No significant associations were observed between the consumption of other dietary protein sources, such as fish/shellfish, and the risk of UC or CD [27]. This is different from our findings. Although we examined the causal relationship between the consumption of red meat, including beef and lamb, as well as poultry and the onset of UC, it did not exhibit the statistically significant results observed in observational studies. Therefore, we speculate that the toxic substances produced by microbial metabolism of meat, such as sulfides, amines, and phenols, may play a more significant role in the progression and relapse of UC.
The practice of adding artificial sweeteners, preservatives, emulsifiers, and flavors to food for preservation or enhancement of taste has become quite prevalent. However, their adverse effects on health are evident. An ecological analysis using national-level data revealed a positive association between the consumption of emulsifiers and the incidence of CD [58]. A study utilized three large prospective cohorts to investigate the association between overall consumption of ultra-processed foods as well as specific food categories and the risk of CD and UC events, and the results provided strong epidemiological support for the role of ultra-processed foods in CD development [59]. Our study shows that consumption of ham consistently increases the incidence of CD, UC, and IBD, which may represent a clear pathogenic effect of processed foods on these IBDs. Coffee, as one of the most consumed beverages worldwide, is a complex mixture of compounds rich in caffeine and polyphenols. In small-sample observational studies, coffee consumption has been shown to have a protective effect against the onset of UC [60,61]. Although a previous MR study did not find evidence for an association between coffee consumption and the risk of IBD onset [62], our study suggests that instant coffee may increase the risk of IBD and UC. The use of high salt, high sugar, and other chemically synthesized substances inevitably increases the risk of developing IBD by promoting microbial inflammation, disrupting mucosal barriers, and increasing intestinal permeability [63–65].
In fact, food intake is closely related to dietary habits. Consumers with low sugar intake tend to consume less sugary drinks, fruit juice, cookies, and cakes, and are inclined to eat more vegetables, grains, whole-wheat products, and fish [10]. These differences in dietary habits not only result in variations in nutrient intake but can also influence various aspects of bodily functions. A study by Di Paola et al. demonstrated that individuals following a low-fat, high-fiber diet have a more diverse microbial community and lower pathogen ratios than those following the Western diet, likely due to the lower ratio of complex carbohydrates and dietary fiber [66]. The Mediterranean diet, which is rich in fruits and vegetables, has been found to have beneficial effects in controlling chronic inflammatory diseases. Its widespread attention as a dietary therapy for IBD is due to the abundance of compounds with antioxidant properties, such as vitamin A, C, β-carotene, and flavonoids, although further research is needed to investigate its preventive effects on IBD [67,68]. The polyphenols present in a plant-based diet help alleviate intestinal inflammation in patients with IBD by suppressing the expression of pro-inflammatory cytokines and regulating cellular signaling pathways [47], and by reducing the lipopolysaccharide-induced disturbances in intestinal permeability to restore intestinal barrier integrity [69]. Therefore, substantial changes in dietary patterns are needed to prevent the occurrence of IBD, rather than simply eliminating a specific food from the diet.
Dietary intake as a time-varying exposure may change over time and is often subject to difficult-to-remove confounding factors in observational studies, even in prospective studies. The complex interactions between susceptible genes and environmental exposures are rarely studied in IBD, and these interactions may contribute to the different phenotypes of IBD [70]. Case-control or cohort studies can introduce biases due to differences in recruitment methods, selection of cases and controls, and assessment of exposure factors. Additionally, confounding and missing data during the data analysis process can lead to inappropriate estimations and often result in heterogeneous outcomes. We employed the MR approach to investigate the causal effects of intake of different dietary categories on the disease onset in individuals with genetic susceptibility to IBD to evaluate the findings from a genetic perspective. We performed an LD-based clumping procedure to ensure the independence of IVs and excluded weak IVs to avoid bias.
Our study had several strengths. First, we employed the MR analysis method to examine the relationship between different types of dietary intake and the risk of IBD while controlling for potential confounding factors. The large sample size provided sufficient power to estimate the causal effects of dietary intake on IBD. Second, we investigated a total of 239 different dietary categories. Due to significant variations in dietary patterns among individuals, we expanded the range of dietary categories to obtain more specific conclusions.
However, this study also had several limitations. First, the number of food items in the FFQ tool is limited, and self-reported questionnaires and recall bias may be unavoidable in assessments performed with this tool. Additionally, our study population was predominantly composed of Europeans, and limited data suggest that the impact of environmental exposures on IBD risk may vary by race or gender. Therefore, these conclusions cannot be generalized to a larger population at this time, and further research is needed to explore the impact of food intake on IBD onset among different ethnic groups. Moreover, stratified analysis of variables such as sex could not be conducted due to the use of aggregated data instead of individual-level data. The power of certain correlation conclusions in this study was low, which may have increased the probability of type II statistical errors. Since the ratio estimation method assumes a linear causal relationship, this study cannot exclude the possibility of a non-linear relationship between diet and the onset of IBD. Finally, MR studies inevitably involve individual channeling. However, as long as the SNPs used in this study meet the three assumptions of IVs, the resulting MR conclusions remain valid.