Deciphering the diet-inflammatory bowel disease relationship: knowledge gaps and future perspectives

1. Direct Dietary Effects on the Intestinal Epithelium and Immune System

Dietary fiber increases SCFA production, which supports epithelial proliferation, tight junction stability, mucus secretion, and immune homeostasis [13,14]. Similarly, amino acids generate bioactive metabolites that reinforce barrier function [15]. Conversely, excessive protein intake can be detrimental as toxic metabolites such as ammonia, phenols, and hydrogen sulfide, can impair epithelial function and potentially exacerbate colitis [16,17]. Refined carbohydrates and simple sugars also compromise barrier integrity [18,19]. Experimental data suggest that fructose reduces expression of tight junction proteins (occludin, ZO-1) and antimicrobial peptides [20]. Primary bile acids such as cholic acid, chenodeoxycholic acid, and ursodeoxycholic acid help maintain epithelial integrity and regulate immune responses through activation of bile acid receptors, including farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) [21-23]. High dietary salt intake has been shown to directly modulate host immunity by reducing regulatory T cell populations and promoting pro-inflammatory Th17 (T helper 17) responses [24]. These observations highlight that diet can directly shape epithelial barrier resilience and immune balance, independent of microbial intermediates.

2. Dietary Effects Mediated by Microbiota and Microbial Metabolites

Dietary fiber exerts a protective effect on the gut microbiota by selectively enriching saccharolytic and SCFA-producing bacteria, including Faecalibacterium prausnitzii, Roseburia, and Bifidobacterium, while suppressing the overgrowth of pathobionts and enhancing microbial diversity [25-28]. High-fat diets reshape microbial composition by reducing beneficial taxa such as Akkermansia muciniphila, enriching sulfate-reducing bacteria, and promoting expansion of Bilophila wadsworthia, a pathobiont linked to bile acid-driven inflammation and barrier disruption [29,30]. Dietary modulation of bile acid pools represents another key microbiota-mediated mechanism. Microbial conversion of primary bile acids into secondary bile acids, such as deoxycholic acid and lithocholic acid, can exert detergent-like toxicity, disrupt junctional proteins, induce epithelial apoptosis, and promote inflammation when present in excess [21-23]. In addition, food additives—particularly emulsifiers such as carboxymethylcellulose and polysorbate-80—have been shown in animal models to alter the structure of the microbial community, promote bacterial encroachment into the mucus layer, and induce chronic low-grade inflammation [46]. Excessive intake of refined sugars and simple carbohydrates reduces microbial diversity, decreases SCFA-producing taxa, and promotes the expansion of facultative anaerobes, including members of Proteobacteria [36,37]. Dietary modulation of indole signaling is another microbiota-mediated pathway linking diet to intestinal homeostasis and inflammation. Indoles are produced from dietary tryptophan by gut bacteria (e.g., Lactobacillus, Clostridium, Bacteroides), with plant-based, fiber-rich diets enhancing—and Westernized diets reducing—their production. Microbiota-derived indoles activate the aryl hydrocarbon receptor on epithelial and immune cells, strengthening barrier integrity via tight junction and IL-22–mediated antimicrobial responses while promoting mucosal immune tolerance through regulation of innate lymphoid cells and regulatory T cells [47,48].

Together, these mechanistic insights underscore the biological plausibility of diet as a modulator of intestinal inflammation in IBD. However, translating these pathways into clinically actionable knowledge remains challenging. These challenges directly lead into the key gaps that persist in our understanding of diet-IBD relationships.

1. CD and UC Are Not the Same

Crohn’s disease (CD) and ulcerative colitis (UC) differ in their pathophysiology, anatomical involvement, and interactions with diet [49]. Dietary influences appear more pronounced in CD, where early-life exposures such as low fiber intake and early formula feeding, along with consumption of processed foods and emulsifiers, have been associated with increased disease risk and progression [49-51]. Dietary interventions in CD, including exclusive enteral nutrition (EEN) and the Crohn’s disease exclusion diet (CDED), administered with or without partial enteral nutrition (PEN), have demonstrated efficacy in inducing clinical remission [52-55]. Accordingly, the European Crohn’s and Colitis Organisation (ECCO) recommends EEN as an induction therapy for patients with mild-to-moderate CD [56]. A systematic review of 14 studies involving 564 participants demonstrated that PEN combined with CDED achieved the highest clinical remission rates and superior tolerability compared with PEN alone or EEN [57]. Other solid food-based dietary approaches, such as the Mediterranean diet and symptom-guided or reduced refined carbohydrate diets, have also shown potential benefit, although the supporting evidence is limited by small sample sizes and methodological heterogeneity [57,58]. Reflecting this therapeutic relevance, recent ECCO guidelines emphasize that all patients with CD should have access to specialized dietary advice, particularly during disease flares [56].

In contrast, dietary risk factors and therapeutic effects in UC are less consistent and more heterogeneous [59]. Observational studies have not shown a clear overall association between pro-inflammatory diets and UC risk, with discrepant findings across study designs. The total dietary fiber intake does not appear to be significantly associated with disease risk [60]. Interventional studies suggest that dietary modification may improve symptoms, quality of life, and inflammatory markers—particularly in active disease—but effects on sustained clinical remission remain inconsistent [61,62]. Combined Mediterranean and low-fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (low-FODMAP) diets, with or without PEN, have been associated with reductions in disease activity indices, high-sensitivity C-reactive protein, fecal calprotectin, and favorable modulation of the gut microbiota, alongside improvements in quality of life [63]. Current consensus-based guidance for UC emphasizes reducing saturated fats, red and processed meats, and food additives, while increasing intake of omega-3 fatty acids, tryptophan, pectin, and resistant starch. However, despite encouraging symptomatic benefits, consistent translation into durable clinical remission remains uncertain [62,64,65].

Taken together, the available evidence indicates that although dietary risk factors have been investigated in both CD and UC, findings are more robust and actionable in CD. In CD, diet-based interventions can induce remission and serve as effective primary or adjunctive therapies, whereas in UC, dietary strategies currently function mainly as supportive measures that ameliorate symptoms, inflammatory burden, and quality of life rather than as reliable disease-modifying treatments. These divergent responses highlight the importance of phenotype-specific dietary approaches that reflect the distinct biological and immunological underpinnings of CD and UC.

2. Age-Related Modifiers

Age is a key determinant of dietary exposures and eating behaviors, influencing both nutritional quality and disease susceptibility, and may partly explain age-specific epidemiological patterns observed in IBD [66]. In infancy and early childhood, dietary intake is largely dictated by breastfeeding or formula feeding, followed by caregiver-directed complementary feeding. Adolescence and young adulthood are characterized by greater dietary autonomy, often accompanied by higher consumption of ultra-processed foods, fast foods, and sugar-sweetened beverages—patterns that coincide with the peak incidence of IBD. In contrast, middle-aged adults generally adopt more structured and balanced diets, shaped by occupational demands, family responsibilities, and increasing health awareness. In older adults, dietary diversity often declines due to physiological, medical, and social constraints, including reduced appetite, altered taste and smell, dental issues, polypharmacy, limited mobility, cognitive decline, and social isolation, leading to more monotonous habitual diets.

Ageing is also associated with structural and functional changes in the gastrointestinal tract, including increased intestinal permeability, altered motility, small intestinal bacterial overgrowth, and chronic low-grade inflammation (“inflammaging”), all of which modify diet-microbiota-host interactions [67,68]. Microbial diversity generally declines with age, alongside shifts in key taxa and weakening of protective mechanisms such as gastric acid secretion, bile flow, mucus production, and antimicrobial peptide activity.

From an epidemiological perspective, these patterns may partly account for the high incidence of IBD among young adults, in contrast to the relatively lower incidence observed in elderly populations, despite an overall rise in prevalence attributable to improved survival. Consequently, age groups should not be considered homogeneous in dietary IBD research, and age-specific dietary exposures must be accounted for in risk assessment and intervention design.

3. Sex and Hormonal Differences

Sex-specific hormonal and metabolic profiles modulate nutrient handling, gut physiology, and IBD susceptibility [69,70]. Estrogen and progesterone in women have been shown to enhance epithelial barrier integrity, reduce endoplasmic reticulum stress, and suppress pro-inflammatory cytokine production, effects that are complemented by sex-related differences in gut microbial composition. In contrast, testosterone is associated with distinct microbial signatures and metabolic effects in men and women, reflecting complex hormone–microbiota interactions [71]. Sex differences also extend to energy metabolism and adipose tissue distribution. Women typically exhibit lower basal fat and protein oxidation and differential amino acid metabolism, whereas men accumulate more visceral adiposity and display higher postprandial free fatty acid flux [72]. These metabolic and microbial differences influence epithelial barrier function and immune activation, shaping diet-microbiome interactions relevant to IBD pathogenesis. Incorporating sex-specific biological differences into dietary research and therapeutic strategies is therefore essential for personalized and mechanistically informed IBD care.

4. Host Genetics

Genetic predisposition shapes individual responses to dietary exposures [73,74]. Polygenic risk variants can modify inflammatory responses to specific nutrients [75]. Polygenic risk scores, which integrate the cumulative burden of both risk and protective alleles, help explain why two individuals with similar diets may have divergent outcomes. For example, FUT2 secretor status has been linked to differences in gut microbial composition and mucosal glycosylation, where protective alleles may support a more favorable microbial environment despite exposure to pro-inflammatory diets [76]. Similarly, variants in genes such as HNF4A, which regulates epithelial barrier function, or IL23R, which modulates immune signaling, may reduce inflammatory responses triggered by dietary antigens [77,78]. Thus, while a diet high in processed foods, emulsifiers, or saturated fats may accelerate dysbiosis and mucosal injury in genetically susceptible individuals, those with protective variants may preserve epithelial integrity and immune balance, remaining resilient. Genetic background also interacts with metabolic phenotype to influence the fermentation of dietary nutrients by the gut microbiota [79-81]. This interaction determines not only the efficiency of nutrient utilization but also the spectrum of microbial metabolites produced [82]. Importantly, these metabolic outputs are also influenced by sex-specific hormonal milieu. Such genotype-phenotype-diet interactions may therefore contribute to inter-individual variability in susceptibility to colonic inflammation and disease behavior.

5. Habitual Diet Needs Characterization

The effects of diet on the gut microbiota and intestinal epithelial barrier are inherently transient unless dietary exposures are sustained over time. Consequently, habitual dietary intake represents a critical determinant in both the design and interpretation of dietary intervention studies. The physiological, metabolic, and inflammatory consequences of diet are shaped not only by individual nutrients but also by the habitual combinations in which foods are consumed, as nutrients are rarely ingested in isolation. Long-term dietary patterns, therefore, exert cumulative effects on microbial composition, immune regulation, and epithelial barrier integrity, providing a more ecologically valid reflection of real-world eating behaviors [83,84]. For example, habitual consumption of vegetables alongside red meat may attenuate the pro-inflammatory effects of meat through fiber, polyphenols, and micronutrients that favorably modulate the gut microbiota and immune responses, whereas regular intake of red meat in combination with refined carbohydrates may synergistically promote dysbiosis, impair barrier function, and amplify inflammatory pathways. Accordingly, systematic assessment of habitual dietary patterns allows classification into pro- or anti-inflammatory profiles and offers a more mechanistic and integrative understanding of diet-gut interactions than analyses focused on isolated dietary components. However, it is also important to recognize that habitual diet may also be heterogeneous and shaped by multiple contextual factors, including cultural practices, geographic region, socioeconomic status, religious beliefs, and access to healthcare and nutritional counselling [85]. This variability further extends to food processing techniques, additive exposure, cooking methods, and meal timing. In the context of IBD, this heterogeneity is further compounded by frequent experimentation with exclusion diets, alternative eating patterns, and clinician-recommended modifications, resulting in substantial inter- and intra-individual variability over time. Collectively, these sources of heterogeneity limit comparability across studies and contribute to inconsistent or conflicting findings.

6. Cooking Methods

Cooking and food preparation methods modify nutrient availability and metabolic impact. To illustrate, consider the example of boiled potatoes and fries. Both originate from the same raw ingredient, yet differences in cooking techniques yield distinct biochemical and physiological effects. Boiling potatoes preserves heat-sensitive nutrients and resistant starch, promoting SCFA production, whereas frying generates advanced glycation end products, increases fat content, and may favor pro-inflammatory gut microbiota [86,87]. Thus, even identical raw ingredients can exert markedly different physiological and gut-related effects depending on preparation. Careful consideration and characterization of the mode of food preparation is hence critical when evaluating diet-microbiome interactions, as foods that appear superficially similar may elicit divergent biochemical and physiological effects.

7. Lifestyle

Lifestyle behaviors, including physical activity levels, interact with dietary patterns to influence gut health. Regular physical activity has been linked to increased microbial diversity and the abundance of Bifidobacterium and Lactobacillus [88]. Conversely, a sedentary lifestyle can lead to reduced microbial diversity and an overrepresentation of pro-inflammatory taxa, potentially increasing the risk of IBD. Additionally, eating patterns, including meal timing, frequency, and context, significantly influence gut physiology. Overeating or late-night snacking can disrupt circadian rhythms of the gastrointestinal tract, impair gastric emptying, and alter hormone secretion, including ghrelin and leptin [89,90]. Irregular meal spacing has been associated with altered gut microbiota composition and decreased microbial diversity [91]. Brain-gut interactions further modulate digestive efficiency. Distracted eating, such as watching television or using digital devices, can impair sensory perception, reduce mastication efficiency, and modify postprandial hormonal responses, thereby affecting nutrient absorption and satiety signaling [92-94]. Also, regular consumption of meals outside the home, even when selecting ostensibly “healthy” options, introduces variability in cooking methods, processing, salt, sugar, and additive content, which can influence the gut microbial activity and intestinal barrier integrity.

8. Environmental Contaminants

Dietary exposures are increasingly shaped by environmental contaminants and chemical adulterants. Pollutants, including organic compounds, heavy metals, and pesticides, can accumulate in food, promoting systemic inflammation. The widespread use of pesticides has contributed to intensified food production; however, exposure to specific pesticides has been associated with an elevated risk of IBD [95,96]. While dietary recommendations for IBD often advocate a shift from a Western diet to a Mediterranean dietary pattern, evidence from a randomized controlled trial indicates that transitioning to a Mediterranean diet can be associated with increased exposure to insecticides, organophosphates, and pyrethroids [97]. Thus, even with adoption of a nutritionally favorable dietary pattern, concomitant pesticide exposure may attenuate its health benefits. Food adulteration represents an additional concern; for example, turmeric/curcumin products in Bangladesh have been reported to contain lead, thereby compromising nutritional safety [98]. Chronic exposure to such contaminants can modulate gut health, influence disease susceptibility, and potentially alter disease progression.

9. Drug-Diet Interactions

Pharmacologic therapies in IBD, including corticosteroids, immunosuppressants, biologics, and small molecules, can indirectly influence the gut microbiota and modulate host-microbe interactions with dietary substrates through their effects on immune signaling and epithelial barrier integrity. This interplay generates complex, bidirectional interactions in which specific nutrients may potentiate or attenuate drug effects, while pharmacologic agents may in turn alter the host response to dietary components [99,100].

10. Functional Attributes of Dietary Components

Dietary composition, particularly high intake of sugar, salt, and ultra-processed foods, has been consistently associated with adverse outcomes. However, notable paradoxes challenge simplistic assumptions regarding processed foods. Enteral nutrition therapies, including EEN and PEN, are highly processed formulations yet demonstrate therapeutic benefits, especially in CD. These processed formulations are designed to optimize nutrient composition, reduce dietary antigens, and modulate the gut microbiome in a manner that suppresses inflammation. This contrast indicates that the health impact of processed foods is context-dependent, influenced by nutrient quality, bioactive components, and the physiological goals of the intervention. Additionally, these observations suggest that labelling foods simply as “processed” may be overly reductive. Instead, the functional and compositional attributes, such as macronutrient balance, fiber content, micronutrient adequacy, and absence of harmful additives, determine the net effect on gut health and disease risk.

11. Patient Preferences and Socio-Cultural Impacts

The implementation and effectiveness of dietary interventions in IBD are influenced by patient preferences and socio-cultural factors. Adherence remains the cornerstone of success of dietary interventions and is shaped by a complex interplay of taste preferences, habitual food patterns, socioeconomic status, and cultural or religious beliefs. These determinants not only influence dietary acceptance but also affect the sustainability and real-world applicability of interventions [4,101,102]. Despite a global nutrition transition that has led to partial homogenization of food cultures, distinct regional dietary identities persist. These regional variations present additional challenges to the universal application of dietary strategies. The Mediterranean and CDED require adaptation for vegetarian populations. In contrast, plant-based and anti-inflammatory diets align more closely with Asian dietary traditions but necessitate dietary counselling to ensure adequate protein, iron, and vitamin B₁₂ intake [103,104]. Religion, a fundamental element of culture, further shapes dietary behavior through prescribed food restrictions and fasting practices, thereby influencing nutritional outcomes and intervention feasibility. Therefore, the design of dietary interventions in IBD should incorporate culturally sensitive, economically feasible, and locally tailored frameworks, as these considerations are essential for enhancing patient adherence and ultimately optimizing therapeutic outcomes.

1. Lack of Long-Term Studies

Despite increasing interest in dietary interventions for IBD, there remains a notable paucity of long-term studies evaluating their efficacy, safety, and sustainability. Most existing studies assessing induction of remission have follow-up periods of 4 to 24 weeks, whereas studies evaluating maintenance of remission typically span 1–2 years [58]. While these medium-term studies provide preliminary insights into the potential benefits of specific dietary approaches, they are insufficient to address critical questions regarding sustained effects and long-term feasibility. Dietary interventions represent a continuous exposure that must be maintained over the lifespan to exert meaningful influence on disease trajectory. Short- to medium-term studies cannot fully capture the cumulative impact of diet on relapse rates, nutritional status, gut microbiome composition, or systemic inflammatory processes. Moreover, adherence to dietary interventions is often heterogeneous, yet compliance is infrequently assessed in a systematic manner. Equally important, the outcomes following withdrawal of dietary interventions are poorly reported, leaving the durability of observed benefits uncertain. There is a clear need for well-designed, long-term studies that not only evaluate clinical endpoints but also systematically monitor patient adherence, nutritional adequacy, and quality of life. Incorporating mechanistic analyses, including gut microbiota profiling and metabolomics, will be essential to elucidate the pathways through which dietary exposures modulate disease pathophysiology.

2. Lack of Comparator Diets

In studies assessing dietary interventions for IBD, a major methodological limitation is the lack of a standardized “Western diet” control arm. The Western diet is widely implicated in promoting gut dysbiosis and inflammation. However, when dietary interventions, such as the Mediterranean diet, specific carbohydrate diet, or low-FODMAP diets, are compared directly against each other without this common reference point, it becomes unclear whether observed outcomes reflect true therapeutic benefit, differential efficacy, or simply the absence of harm [105]. In such cases, the statement that “the compared diets were equally effective or equally ineffective” highlights an interpretive gap rather than true equivalence.

3. Limitations of Dietary Assessment Tools

A comprehensive understanding of diet-gut interactions in IBD requires not only the acknowledgment of contextual factors influencing dietary exposures but also the development of precise and multidimensional tools to assess them. Environmental, cultural, socioeconomic, and behavioral determinants shape dietary habits; however, these subtleties are rarely captured by conventional dietary assessment methodologies [106]. Existing instruments, such as food frequency questionnaires and short-term dietary recalls, were originally developed for use in general populations and often fail to adequately reflect the complex, disease-specific dietary behaviors observed in IBD. These self-reported tools are susceptible to recall bias and frequently overlook critical modifiers, including methods of food processing, combinations of food items, portion sizes, meal timing, and temporal variations linked to disease activity or treatment phases [107]. This heterogeneity is amplified by variability in food processing, additive exposure, and nutrient composition. Also, their limited assessment windows restrict the evaluation of long-term dietary patterns and cumulative nutritional exposures. Many studies also inadequately adjust for key confounders such as age, total caloric intake, comorbid conditions, and sex-specific factors. Furthermore, while mechanistic insights into diet-barrier interactions have predominantly emerged from preclinical studies, robust clinical evidence substantiating barrier modulation through dietary interventions in IBD remains scarce.

4. IBD-Specific Sources of Bias

Dietary influences on IBD encompass a broad spectrum of effects, which can differ depending on the stage of disease. It is important to distinguish between factors that contribute to the risk of disease onset and those that affect disease exacerbation or progression. Factors influencing disease onset are those that may predispose an otherwise healthy individual to develop IBD. These include habitual dietary patterns. In contrast, factors affecting disease exacerbation pertain to triggers that influence the course of disease in patients who already have IBD. These may include specific foods, dietary additives, or patterns that provoke inflammation, alter gut microbial activity, or compromise barrier function, leading to flares or symptom worsening. It is therefore important that the diet studies in IBD clearly differentiate these two contexts to guide targeted nutritional strategies for prevention and disease management.

Despite extensive patient-reported data, the specific dietary triggers that precipitate flares in IBD remain incompletely understood. Surveys and studies examining dietary beliefs among patients commonly identify foods such as spicy items, high-fat or fried foods, dairy, red and processed meats, sugary drinks, alcohol, and certain high-fiber foods (including raw vegetables, nuts, seeds, and legumes) as potential exacerbating factors [108]. However, the scientific basis for these associations remains unclear, and in many cases, these attributions reflect patient perceptions rather than rigorously established causal relationships.

Another challenge in elucidating diet-IBD relationships is the influence of disease activity on dietary behavior, which introduces a risk of reverse causality. During disease flares, patients frequently modify or restrict their diet in an effort to alleviate symptoms such as abdominal pain, diarrhea, and bloating [109]. As a result, observed associations between dietary patterns and disease outcomes may reflect symptom-driven dietary changes rather than true causal effects of diet on disease activity. This limitation is particularly relevant in observational studies, where dietary intake is often assessed after disease onset and/or during periods of active inflammation. Furthermore, symptom-related food avoidance may vary between CD and UC, across disease phenotypes, and within the same individual over time, further complicating interpretation of exposure-outcome relationships. Inadequate consideration of disease activity, timing of dietary assessment, and prior dietary modifications may therefore lead to spurious associations or underestimation of beneficial dietary effects, hindering the ability to distinguish habitual dietary patterns from reactive dietary behavior. In addition, under-reporting of dietary intake may be more pronounced among patients with active IBD. Individuals may inadvertently forget, omit, or deliberately under-report foods consumed irregularly or in small quantities. Foods perceived as socially undesirable or “unhealthy” are also more likely to be selectively under-reported. Such differential reporting can introduce systematic bias into dietary assessments. Beyond general nutritional epidemiology challenges, evaluation of diet in IBD is also likely to be affected by medication use (e.g., corticosteroids, biologics), prior surgeries, and psychosocial factors such as anxiety around food. These factors can independently influence appetite, metabolism, and dietary choices, confounding observed associations between diet and outcomes. Failure to account for these IBD-specific biases may obscure true dietary effects.