The gut microbiota comprises of diverse communities of microorganisms, including bacteria, archaea, fungi, and viruses, which collectively perform essential functions in nutrient metabolism, immune modulation, and epithelial protection. In a healthy state, this microbial ecosystem is characterised by a balance between commensal and potentially pathogenic species, with dominant bacterial phyla including Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria. These microorganisms contribute to gut health by fermenting dietary fibres into short-chain fatty acids (SCFAs), regulating mucosal immunity, and reinforcing the integrity of the epithelial barrier.

In IBD, however, a distinct shift in microbial composition, referred to as dysbiosis, has been consistently observed. This dysbiotic state is characterised by a reduction in beneficial bacteria, such as Faecalibacterium prausnitzii and Bifidobacterium (28), and an increase in potentially pro-inflammatory species, including adherent-invasive Escherichia coli and Ruminococcus gnavus (29). The loss of microbial diversity is particularly concerning as it is associated with impaired production of SCFAs, weakened mucosal protection, and heightened immune activation. Additionally, dysbiosis is not only a consequence but also a driver of disease progression, as an altered microbial landscape can influence immune cell differentiation and cytokine production, further promoting chronic inflammation (30, 31). Recent evidence suggests that dysbiosis may precede clinical disease onset, supporting its potential role as an early biomarker of IBD risk (17). Emerging evidence suggests that reduced microbial diversity and enrichment of pro-inflammatory taxa (e.g., Enterobacteriaceae) may serve as early predictors of IBD relapse (32).

Research in animal models and human studies has demonstrated a lasting imbalance in the gut microbiome in IBD (33–39). Reducing bacterial load with broad-spectrum antibiotics decreases the severity of colitis in IL-10 deficient mice (40). Another argument for the role of the microbiota is that CD lesions primarily occur in areas of the intestine with high bacterial populations such as ileum and colon (41).

IBD is characterised by an aberrant activation of both innate and adaptive immune responses. The innate immune system, plays a crucial role in recognising and responding to microbial-associated molecular patterns through pathogen recognition receptors. In healthy individuals, innate immune responses are tightly regulated to prevent excessive inflammation. However, in IBD, innate immune cells, such as macrophages, dendritic cells, and neutrophils exhibit increased production of inflammatory mediators such as TNF-α, IL-1β, and IL-6 (56).

Neutrophils, in particular, are heavily recruited to the inflamed gut mucosa in IBD, where they release reactive oxygen species (ROS) and proteolytic enzymes that contribute to epithelial damage (57). Additionally, macrophages and dendritic cells in IBD patients display an altered cytokine profile, favouring the differentiation of pro-inflammatory T-helper (Th) cell subsets while suppressing regulatory mechanisms that could dampen inflammation (54, 58).

The adaptive immune system, which provides antigen-specific responses, also plays a central role in IBD pathogenesis. In CD, there is an overactivation of Th1 and Th17 cell immune responses, leading to excessive production of interferon-gamma (IFN-γ) and IL-17, both of which amplify inflammatory pathways and can drive tissue damage (59). Conversely, UC is primarily associated with a dysregulated Th2 cell response, characterised by increased secretion of IL-5 and IL-13, which disrupt epithelial barrier integrity and compromise the mucus layer (60).

Another key player in immune regulation is the population of Tregs, which are responsible for maintaining immune tolerance and suppressing excessive inflammation. In IBD, the balance between pro-inflammatory and regulatory immune responses is disrupted, with a reduction of Treg cells and an expansion of effector T cells. This imbalance results in persistent immune activation, prolonged tissue injury, and impaired mucosal healing. Importantly, the interaction between microbiota-derived metabolites and Treg cell differentiation and function is a growing area of research, with SCFAs playing a key role in promoting Treg expansion and function (61–64).

Significant challenges remain in elucidating the complex interplay within the gut microbiota-immune system axis during IBD. Key questions involve understanding precisely how and to what extent the homeostasis between the microbiota, the epithelial barrier, and the host immune system is disrupted (31, 47, 65–67). This includes determining the mechanisms driving the loss of microbial diversity and characterizing the functional consequences of altered microbial metabolite profiles during different disease stages (e.g., remission versus active disease). The inherent complexity arises from the multitude of interacting variables—spanning genetic, microbial, immune, and environmental factors—and their dynamic nature. Addressing these questions necessitates integrative approaches. As discussed further in Chapter 4, systems biology, which combines high-throughput ‘omics’ technologies with computational modelling, provides essential tools to dissect these interactions in both relevant animal models and human studies, paving the way for a more mechanistic understanding of IBD pathogenesis.

While the Western diet as a whole has been implicated in exacerbating IBD, individual dietary components exert specific effects on gut microbiota composition, immune responses, and epithelial integrity. Among the most concerning elements of this diet is the excessive consumption of refined carbohydrates, including sucrose and fructose, found in sugar-sweetened foods and beverages, and processed starches in energy-dense, nutrient-poor products, which contribute to metabolic dysregulation and gut inflammation (71). High-fructose corn syrup, a ubiquitous ingredient in processed foods and beverages, has been shown to increase gut permeability and oxidative stress, further aggravating inflammatory responses (71).

Carbohydrates include monosaccharides, disaccharides, oligosaccharides (typically comprising 3–10 units), and polysaccharides. Monosaccharides and disaccharides—often referred to as sugars—are generally soluble and are commonly consumed in the form of refined carbohydrates such as sucrose, fructose, and starch, found in energy-dense but nutrient-poor processed foods (72). Within the Western dietary pattern, refined sugars and processed grains (e.g. white flour and white bread) stand out for their detrimental impact on gut microbial composition and immune function (73).

The intake of refined sugars, particularly from sugar-sweetened beverages, has been shown to alter the gut microbiota, increasing the Firmicutes/Bacteroidetes ratio and reducing levels of beneficial butyrate-producing bacteria such as Lachnobacterium (74). These changes are linked to increased intestinal permeability and endotoxemia, which in turn promote local and systemic inflammation (75). Khan et al. investigated the effects of a high-sugar diet on colitis in rodent models and demonstrated that excessive intake of simple sugars exacerbated colitis in mice, whether administered before or after disease induction (76). Excessive sugar consumption has also been identified as a risk factor for obesity, type 2 diabetes, and cardiovascular disease (77). Furthermore, high sugar intake has been shown to induce physiological changes in the intestinal epithelium, including increased cell proliferation in crypts (78).

Fats, though an essential component of a balanced diet, can become harmful depending on their type and quantity. Unsaturated fats, often referred to as “healthy fats,” are associated with reduced risk of cardiovascular disease and metabolic syndrome (79, 80). In contrast, saturated and trans fats—prevalent in processed foods—are used to improve shelf life, texture, and flavours (81). These fats have been linked to intestinal dysfunction, including altered enteroendocrine cell activity, increased permeability, and mucosal inflammation (82). These effects contribute to chronic low-grade inflammation, a common feature underlying various NCDs (83).

Animal studies have demonstrated that high-fat diets significantly alter the gut microbiota, increasing the Firmicutes/Bacteroidetes ratio, reducing the antimicrobial function of Paneth cells, and elevating pro-inflammatory cytokines such as IFN-γ, TNF-α, IL-1β, and IL-6. These alterations promote bacterial translocation and systemic endotoxemia (72, 74).

The Western diet is often rich in fats associated with negative health outcomes, including refined seed oils (e.g. sunflower oil, palm oil), coconut oil, and processed foods high in omega-6 polyunsaturated fatty acids (84, 85). When consumed in excess, especially in the context of industrial food processing, these fatty acids may disrupt microbial homeostasis, promote the release of pro-inflammatory mediators, and compromise intestinal barrier integrity. Such alterations have been associated with an increased risk of IBD and colorectal cancer (86–90).

Likewise, diets rich in saturated and trans fats—particularly those derived from processed meats and fried foods—promote a microbial profile that favours pro-inflammatory species, thereby increasing susceptibility to intestinal inflammation (91). The consumption of red and processed meats has also been linked to the generation of harmful microbial metabolites, such as trimethylamine-N-oxide (TMAO), which contribute to both intestinal and systemic inflammation (92, 93).

The presence of food additives and emulsifiers in processed foods further complicates the dietary landscape of IBD. These substances may alter the composition and function of the gut microbiota, promoting the expansion of bacteria with pathogenic potential. In particular, dietary emulsifiers such as carboxymethylcellulose and polysorbate-80 have been shown to increase mucolytic bacterial activity, resulting in erosion of the protective mucus layer that separates the microbiota from the intestinal epithelium (53).

The thinning of this mucus barrier facilitates direct microbial–epithelial interactions, which can activate immune pathways and exacerbate inflammatory responses (66). Additionally, artificial sweeteners, widely used as sugar substitutes, have been implicated in metabolic dysregulation and shifts in microbial composition, potentially contributing to pro-inflammatory states within the gut (94).

Many food products within the Western diet are subjected to industrial processing techniques such as high-temperature cooking and extrusion. During these processing methods, harmful compounds such as advanced glycation end-products and other pro-inflammatory molecules can form through reactions between sugars, proteins, and lipids (95–97). Moreover, the Western diet is rich in UPFs, which typically contain a range of food additives, emulsifiers, preservatives, and synthetic colourings that may disrupt gut microbial balance and contribute to chronic low-grade inflammation (98). Synthetic food colorants, such as azo dyes (e.g. Red 40 and Yellow 6), are among the most commonly used additives in processed foods. Experimental evidence in genetically susceptible mouse models indicates that these compounds may induce colitis-like inflammation. Commensal bacteria, including Bacteroides ovatus and Enterococcus faecalis, have been shown to metabolize these dyes into 1-amino-2-naphthol-6-sulphonate sodium salt, a metabolite associated with colitis development (99).

Similarly, artificial sweeteners such as aspartame and sucralose have been shown to alter gut microbial composition, favouring the proliferation of pro-inflammatory bacterial species. Collectively, these dietary components can impair gut barrier integrity, enabling bacterial translocation and the passage of microbial antigens into the mucosal immune system, thereby exacerbating inflammation and mucosal damage (100).

However, there are challenges in interpreting data regarding the health effects of UPFs. The nutritional composition and quality of UPFs vary widely; for example, both seasoned canned tuna and ice cream are classified as UPFs despite their differing nutritional profiles (101). In a recent prospective cohort study, an association with CD risk was observed only when comparing extreme levels of UPF consumption (102). Furthermore, diets higher in UPF tend to also be high in fat and sugar and low in dietary fibre, making it difficult to determine whether health effects are due to ultra-processing itself or the overall nutritional composition. Although the precise mechanisms by which UPFs influence IBD risk are not yet fully understood, current clinical guidelines recommend that UPFs should be minimized in the diets of individuals with IBD or those at increased risk (103–105). Future studies employing systems biology approaches could help isolate the independent effects of food processing from overall nutrient composition.

Processed and preserved foods prevalent in the Western diet typically contain high levels of salt. However, the effects of this excessive salt intake on the human gut microbiota remain largely unknown (106). Several studies have linked UPFs to excessive salt consumption, which contributes to the development of hypertension and cardiovascular disease (107).

A high-salt diet (HSD) increased the abundance of Bifidobacterium and promoted greater gut permeability, which facilitated the intratumoural localization of Bifidobacterium. This, in turn, enhanced natural killer (NK) cell activity and contributed to tumour regression (108). Wilck et al. (2017) demonstrated that high-salt diets alter the gut microbiota–immune system axis by reducing populations of Lactobacillus spp., which may affect the production of SCFAs. This microbial shift was associated with enhanced activation of pro-inflammatory Th17 cells also limited metabolite availability cause cellular stress and enhance Th17 cell polarization (109, 110). Th17 cells play a pivotal role in IBD by producing pro-inflammatory cytokines such as IL-17A, IL-17F, and IL-22, which drive neutrophil recruitment, epithelial damage, and persistent inflammation (111). Excessive Th17 responses disrupt mucosal homeostasis, contributing to the chronic inflammatory milieu observed in CD and UC.

Similarly, Wu et al., 2013 showed that a modest increase in dietary salt concentration, promote IL-23 expression and enhance Th17 cell differentiation and pathogenic roles both in vitro and in vivo (112). An emerging body of evidence suggests that increased dietary salt intake, as a component of UPFs-rich diets, may contribute to the pathogenesis of IBD by disrupting immune homeostasis. Experimental models of colitis further support the role of high salt in exacerbating intestinal inflammation and promoting other immune-mediated disorders (113).

Conversely, some dietary components have been identified as protective factors in maintaining gut health and reducing IBD risk. Fibre-rich diets, promote the growth of beneficial gut bacteria and enhance the production of SCFAs, which are associated with reduced inflammation and improved gut barrier function (114).

Prebiotic fibres, such as inulin and resistant starch, selectively enhance the growth of commensal bacteria, leading to a more diverse and resilient microbiota. Unlike traditional diets, which support gut homeostasis through a diverse nutrient intake, the Western diet is reduced in key bioactive compounds such as dietary fibre and polyphenols (115).

The low intake of dietary fibre, has significant consequences for gut health, as fibre serves as a substrate for microbial fermentation. This process results in the generation of SCFAs—including butyrate, acetate, and propionate—which play a critical role in maintaining epithelial integrity, modulating immune responses, and supporting mucosal energy metabolism (116).

In addition to fibre, other bioactive dietary components such as polyphenols and omega-3 fatty acids have been recognized for their anti-inflammatory and immunomodulatory properties. Polyphenols, abundant in fruits, vegetables, and green tea, exert strong antioxidant effects and modulate inflammatory signalling pathways (117). Similarly, omega-3 fatty acids—commonly found in oily fish such as salmon and mackerel—have been shown to reduce the production of pro-inflammatory cytokines and enhance epithelial barrier function, offering potential therapeutic benefits for individuals with IBD (43).

The Western diet decreases microbiota diversity and consequently impact the composition of microbial metabolites. With metagenomics, metabolomics studies and development of models in systems biology the impact of diet and impact of individual component is already studied and will be extensively studied in the future (118). This will solidify which component of diet have predominate and harmful impact on intestinal microbiota and could be avoid in diets in the treatments of inflammatory disease such as NCDs and IBD.

High-throughput ‘omics’ technologies, including genomics, transcriptomics, proteomics, metabolomics, and metagenomics, has revolutionized IBD research by enabling integrated analyses of genetic, microbial, and immune dysregulation. Molecular profiling of patient samples has uncovered genetic risk loci, dysregulated pathways, metabolic alterations, and microbial imbalances, moving research beyond reductionist models. However, despite their promise, multi-omics-based systems approaches are rarely translated into clinical practice, primary due to challenges in data standardization, integration, and interpretation (18).

Genome-wide association studies (GWAS) represent a cornerstone of IBD genetics, identifying over 200 genetic loci linked to disease risk, particularly in pathways related to innate immunity, epithelial barrier function, and host-microbe interactions (17). While GWAS have been instrumental in mapping the genetic architecture of IBD, it’s important to note that the identified genetic predisposition explains only a portion of the overall disease variance, underscoring the significant contribution of environmental factors and gene-environment interactions.

Transcriptomic analyses, measuring gene expression levels, have provided critical insights into the molecular pathways perturbed in IBD. Studies analysing mucosal biopsies and circulating immune cells from IBD patients using bulk RNA sequencing have consistently revealed dysregulated pathways related to cytokine signalling, oxidative stress responses, and immune cell differentiation (19). More recently, the application of single-cell RNA sequencing (scRNA-seq) has added another layer of resolution. This powerful technique has allowed researchers to characterize the extensive heterogeneity of immune and stromal cell populations within the inflamed gut mucosa. Such studies have successfully uncovered distinct populations of pro-inflammatory cells, including specific subsets of Th17 cells, activated macrophages, and mucosa-associated invariant T (MAIT) cells, that are enriched or activated in patients with active IBD (19).

Metabolomics, the study of small molecule profiles in biological samples, complements transcriptomic and genomic data by revealing the functional metabolic outputs of the host and associated microbiota. Analyses of faecal, serum, and tissue metabolites from IBD patients have consistently identified significant alterations compared to healthy controls. Commonly observed changes include reduced levels of beneficial microbial-derived SCFAs like butyrate, alterations in bile acid profiles which impact fat digestion and signalling, and elevated markers indicative of increased oxidative stress within the intestinal environment (119). These metabolic shifts are often closely linked to the observed patterns of microbial dysbiosis and the compromised epithelial barrier function characteristic of IBD.

While individual omics technologies provide valuable information about specific molecular layers, a deeper understanding of IBD requires integrating these diverse data types to capture the complex interplay between different biological processes. Beyond single-omics studies, systems biology methodologies aim to integrate multi-layered data to construct predictive models of disease mechanisms and therapeutic responses. Key approaches include statistical integration, network-based analysis, and computational modelling.

Nutritional epidemiology helps identify dietary risk factors and informs prevention strategies. Randomised controlled trials (RCTs) in nutrition are limited by cost, compliance, and long-term adherence. Therefore, prospective cohort studies and case–control designs are essential for assessing associations between dietary patterns and disease outcomes.

Recent large-scale studies, such as the PURE cohort and the Nurses’ Health Study, show that high UPF intake correlates with increased IBD risk, especially CD. UPFs are rich in synthetic additives, refined sugars, and poor in fibre and micronutrients, all of which affect microbiota composition and immune regulation (98).

Conversely, adherence to anti-inflammatory dietary patterns, particularly the Mediterranean diet, is associated with improved outcomes. Rich in polyphenols, fibre, and unsaturated fats, the Mediterranean diet promotes microbial diversity, supports SCFA production, and reduces intestinal inflammation. Butyrate, the most abundant SCFA, exerts anti-inflammatory effects by promoting the differentiation of Tregs in the colon, inhibiting histone deacetylases, and suppressing pro-inflammatory cytokine expression, thereby strengthening mucosal immune tolerance (134). Additionally, specific therapeutic diets such as the specific carbohydrate diet, low fermentable oligo-, di-, monosaccharides and polyols diet, and CD exclusion diet are being explored for their utility in symptom management and disease modulation (135). Recent studies also suggest that partial enteral nutrition combined with targeted dietary interventions, such as an anti-inflammatory diet or a modified CD exclusion diet, can achieve comparable rates of clinical and endoscopic remission to exclusive enteral nutrition in paediatric CD, while offering improved tolerability (136, 137).

The convergence of systems biology with nutritional epidemiology enables the design of personalised dietary interventions tailored to an individual’s microbiome composition, immune profile, and metabolic status. Advances in machine learning and computational modelling further enhance the ability to predict individual responses to specific dietary interventions, paving the way for precision nutrition in IBD care (138). Pilot studies suggest that gut microbiota profiling can predict individual dietary responsiveness, enabling the development of targeted precision nutrition interventions for IBD patients (138, 139).

Emerging evidence highlights the critical importance of early-life nutrition in programming the gut microbiome and immune system. Breastfeeding, maternal fibre intake, and low exposure to emulsifiers during infancy are associated with enhanced microbial diversity and a lower risk of inflammatory diseases, including IBD later in life (140, 141). These findings underscore the need for preventive strategies beginning in early childhood.

Looking forward, the convergence of systems biology with precision nutrition represents a transformative frontier in IBD research and clinical practice. Advances in machine learning and artificial intelligence will enable the development of personalised dietary recommendations based on an individual’s genetic profile, microbiome composition, and immune status. Future research should priorities elucidating the mechanistic links between specific dietary components, microbiota modulation, and immune responses in IBD pathogenesis. In parallel, the identification of reliable, clinically relevant biomarkers capable of predicting dietary responsiveness will be crucial for the personalization of nutritional interventions.

Another crucial area of investigation involves the impact of early-life nutritional exposures, including maternal diet, breastfeeding practices, and early childhood nutrition, on microbiota development, immune system programming, and long-term disease susceptibility. Given the ubiquity of food additives, emulsifiers, and artificial sweeteners in modern diets, their potential role in disrupting gut barrier function and promoting intestinal inflammation demands urgent and focused investigation. Although significant progress has been made in elucidating the complex interactions between diet, microbiota, and immune responses in IBD, numerous critical questions remain unanswered.

Future research must embrace interdisciplinary collaborations, combining expertise across gastroenterology, immunology, microbiology, bioinformatics, and nutritional sciences to develop comprehensive, patient-centred approaches. By leveraging the full potential of systems biology and nutritional epidemiology, the goal is to shift the paradigm of IBD care, from reactive disease management to proactive, personalized prevention, ultimately improving long-term outcomes and quality of life for individuals affected by this complex condition. Establishing causality remains a key challenge, and future progress will require large-scale, well-controlled, longitudinal studies to generate robust, evidence-based dietary guidelines for individuals at risk of, or living with, IBD.