The prevalence of chronic inflammatory diseases affecting mucosal sites such as the intestine and the airways is increasing worldwide (1, 2). Among these, inflammatory bowel disease [IBD, mainly comprising ulcerative colitis (UC) and Crohn’s Disease (CD)] and allergic asthma are the most relevant. Recent findings point toward potential links between these two pathologies, e.g., histamine and mast cell activity and immunoglobulin E (IgE) production, reviewed in Ref. (3). Both diseases have a multifactorial cause, in which environmental factors such as diet and the commensal microbiota are gaining increased attention. In this regard, consumption of the so-called “Westernized” diet is associated with increased risk for IBD (4) and asthma morbidity (5). Westernized diet is characterized by a high content of proteins (derived from fatty domesticated and processed meats), saturated fats, refined grains, sugar, alcohol, salt, and corn-derived fructose syrup, with an associated reduced consumption of fruits and vegetables (4, 6, 7). Research in the last decade has uncovered that changes from a diet rich in fibers and low in fats to a diet low in fibers and high in saturated fats directly contributes to the development of obesity, metabolic syndrome, and cardiovascular diseases (8, 9). Macronutrients (carbohydrates, lipids, and protein) and micronutrients (vitamins and minerals) are required for our body to function and several of these are naturally obtained from our diets and from the resident microbiota. Both patients with IBD and asthma present nutritional problems leading to several complications including anemia, osteoporosis, acute respiratory infections, etc. The link between diet, nutrients and immune responses is embedded in a complex network of signals and has to be considered in the light of other factors including microbial composition, genetic background, and lifestyle, to mention but a few. The advent of high-throughput Next-Generation Sequencing technologies has driven the discovery and dissection of regulatory mechanisms involved in the disease state. In this review, we will focus on the interactions between diets and nutrients associated with Westernized regimes and their impact on the microbiota and immune responses at mucosal interfaces, i.e., the intestines and lungs. We will outline the complex network between nutrients, microbial alterations and abnormal immune responses associated with IBD and asthma.

Table 1 summarizes the impact of dietary factors on host responses. Figure 1 summarizes identified genes associated with IBD and asthma and immune responses. Figure 2 displays the regulatory interaction between diet, mucosal immunity, and commensal microbiota to maintain mucosal homeostasis and the resulting pathology upon loss of balance. Figures 3 and 4 outline the mechanisms targeted by nutrients in the healthy intestine and lung and in the inflamed gut (IBD) and lung (asthma), respectively.

Inflammatory bowel diseases are multifactorial chronic immune-mediated diseases of the gastrointestinal (GI) tract. They often have an early onset and a course which is characterized by intermittent phases of remission and relapses (42, 43). Nearly 2.2 million people in Europe, 1.5 million Americans, and several 100,000 more individuals suffer from IBD. The prevalence and incidence of IBD is increasing worldwide and its growth is not confined to Western Europe or the USA; countries adapting a westernized lifestyle, such as Japan and South Africa, are seeing mounting numbers of affected individuals (2). Patients suffering from IBD present symptoms such as abdominal pain, fever, and diarrhea with blood and/or mucus excretion. Antibiotics, biologics, corticosteroids, and immune modulators are the current treatments of choice for patients with IBD, with the overall goal being inflammation reduction, increase of mucosal healing and symptom relief (16, 44). New treatment strategies include inhibitors targeting leukocyte trafficking (α4β7 integrin, sphingosine-1-phosphate, S1P), cytokine [interleukin (IL)-12p40, IL-23], janus kinase-pathway, inflammasome (NLRP3/IL-1β), to name a few (45, 46). The etiology of IBD is still unknown but the evidence points toward environmental factors, with the microbiota being of particular interest. The microbiota can trigger and/or sustain a tissue damaging immune response in genetically susceptible individuals. Research in the last decade has identified a crucial role for the commensal bacteria in the pathogenesis of IBD. Experimental IBD was not evidenced in animals raised under germ-free (GF) conditions when compared to groups of conventionalized animals (47). Antibiotics have proven beneficial to certain subgroups of patients with CD but not in patients with UC (48) and inflammatory lesions are more frequently located in areas with large bacterial burden, i.e., ileum and colon (49). Alterations in the enteric microbial flora reported in patients with IBD include decreases in Firmicutes and Bacteroidetes and increases in Enterobacteriaceae (e.g., Escherichia coli) (50). A reduction in anti-inflammatory commensals, such as Faecalibacterium prausnitzii has been associated with CD (51). Several pathogenic bacteria are suggested as etiological agents of IBD but to date none has been identified to cause IBD (47). In contrast, pathobionts, i.e., commensal bacteria with potential pathological properties, have been isolated, including strains of adherent and invasive E. coli (AIEC), commonly identified in the mucosa of CD patients (52).

Genome-wide association studies have so far identified over 160 genetic loci in IBD, with 30 loci being specific to CD, 23 loci to UC, and 110 loci are associated with both forms of IBD (53). IBD susceptibility single-nucleotide polymorphisms were identified in genes affecting innate and adaptive immune cell function, bacterial recognition, etc. (Figure 1). Therefore, the role of mononuclear phagocytes including monocytes/macrophages and dendritic cells (DCs) in the development of IBD has been extensively studied. Several mouse models of IBD, including dextran sodium sulfate (DSS)- and 2,4,6-trinitrobenzene sulfonic acid-induced colitis and the TNFΔARE model of Crohn’s-like ileitis, have revealed that lamina propria mononuclear phagocytes have protective as well as pathogenic roles during the disease progression (54–60). Three explanations have been postulated to explain these findings—(1) an inappropriate response to non-harmful commensal bacteria (i.e., NOD2, REL, CARD9); (2) an inefficient clearance of microbes (commensals/pathobionts) leading to chronic immune stimulation (i.e., ATG16L1, IRGM), and (3) a failure to resolve inflammation by maintaining a pro-inflammatory phenotype (i.e., IL-12, IL-18RAP/IL-1R1, IFNGR/IFNAR1) (39) (Figure 1). The intestinal epithelium functions as a barrier between the host and its environment (microbes, non-self-antigens from diet, nutrients, etc.) and consists of highly specialized cells that fulfill this barrier task. Genes associated with epithelial cell function, such as HNF4A, ECM1, CDH1 have a UC correlation (53) (Figure 1). Alterations in barrier integrity associated with IBD include decreased structure of tight-junction (TJ) proteins, which regulate paracellular permeability, impaired mucus production due to loss of goblet cells and an altered production of antimicrobial peptides (61) (Figure 4).

In terms of location, CD can affect any part of the GI tract from the mouth to rectum. However, in the majority of patients with CD the inflammation is localized to the distal ileum and proximal colon (62). The inflammation in CD is patchy and often transmural, which can lead to the development of fibrosis, fistulas, fissures, strictures, etc. A dense infiltration with macrophages and lymphocytes and granuloma formation is a typical feature of the disease. Patients with CD present an imbalanced immune response with high expression of innate pro-inflammatory cytokines, including IL-1β, IL-6, and tumor necrosis factor (TNF)-α and a T helper (Th)1 (IL-12-mediated interferon (IFN)γ) and Th17 (IL-17a) profile resulting in an enhanced and uncontrolled immune response (16, 43, 62) (Figure 4). In contrast to CD, UC is restricted to the mucosa of the colon and is associated with large infiltrates of neutrophils, T and B cells in the lamina propria. Characteristically, the inflammation originates in the rectum extending continuously in a proximal fashion. Crypt abscesses, formed by extravasation of neutrophils through the intestinal epithelium, ulcerations, and goblet cell loss are typical features of UC. Moreover, high levels of innate cytokines, including IL-1β, IL-6, and TNFα, and chemokines, such as CXCL8 and GROα/CXCL1 (neutrophil attractants), as well as an atypical Th2 cytokine profile accompanied by high production of IL-5, IL-10, transforming growth factor beta (TGFβ) and only initially IL-4 production, which is superseded by IL-13 production is associated to patients with UC (62–65) (Figure 4).

Asthma is an increasingly common heterogeneous chronic inflammatory disease, which places substantial burden on patients, their families, and the community (66). Asthma is characterized by airway immune hyper responsiveness to inhaled environmental particles leading to wheezing, breathlessness, chest tightness, and coughing effecting airway function (http://ginasthma.org/). Worldwide the incidence of asthma, is increasing, with an estimated 300 million affected individuals (http://ginasthma.org/). Once thought to be a childhood disease it is now presenting in respiratory clinics as first time adult onset asthma.

Asthma presents with airway inflammation following exposure to insults such as allergens, pollutants, and microbes (67). The primary site of immune induction is initially the lung epithelium, which interacts with the underlying antigen presenting cells such as DCs, inducing an immune response (Figure 4). Alveolar macrophages in the airway lumen act as clearance and immune sampling mechanisms at the interface between the mucosa and the external environment (68). The immune signaling from epithelial cells and macrophages results in secretion of first order cytokines, such as CXCL8, IFNα, IL-1β, IL-33, TGFβ, and thymic stromal lymphopoietin (TSLP), which induce a rapid immune trafficking and a clearance response which subsequently results in second order cytokine secretion by T cells (69). Activated DCs migrate to the lymph nodes and induce T cell activation (70) (Figure 4). The subsequent T cell immune response can result in either an allergenic Th2/eosinophilic IgE-mediated inflammation or an inflammatory Th1/neutrophilic cell influx into the airway. The Th2 allergenic response involves the interaction of DCs, Th2 cells, and IL-4 producing basophils which induce the expansion of type 2 innate lymphoid cells (ILC2) which also produce the Th2 cytokines, IL-5, IL-9, and IL-13, leading to eosinophil and mast cell trafficking to the lung and goblet cell mucus secretion (70) (Figure 4). IL-4 derived from Th2 cells also induces IgE production by B cells. The mixed Th2 and Th1 neutrophilic or Th2 low asthma is induced by toll-like receptor (TLR) activation resulting in IL-1β secretion and activation of inflammatory Th1 and Th17 cells. These cells release IL-17a and IFNγ, which activate neutrophils and macrophages to release TNFα and induce inflammatory signals. The resulting immune infiltrates induces the symptoms of asthma—bronchoconstriction, mucus production, and the resultant tissue remodeling increasing smooth muscle and collagen deposition (71, 72). The subsequent remodeling results in airway wall thickening, compromised lung function and changes in the lung microbiota (41, 73). The mechanisms of asthma have been studied successfully over the decades using murine models, such as the ovalbumin and the house dust mite challenge models (74). While all models have limitations, these studies have led to successful therapy development and understanding of the genetics of asthma (75). Asthma treatment targets immune processes by using inhaled corticosteroids, to reduce inflammation, and bronchodilators to counteract the effects of bronchoconstriction induced by the release of histamine, prostaglandins, interleukins, or leukotrienes.

Several genetic studies have identified asthma susceptibility genes, including IRAK3, SMAD3, ORMDL3, IL-1RL1, IL-13, IL-33, TNFAIP3, and TSLP (76) (Figure 1). Recent studies have highlighted the role of the site of the mutation and allele frequency and the particular site of functionality, such as the asthmatic epithelium, and the epigenetic regulation thereof as being key factors contributing to asthma (77, 78). Studies on DNA methylation, and microRNA modulation of gene expression, are now shedding light on the pathogenesis of this multifactorial disease.

There is increasing evidence that the gut plays a key role in effecting the allergic immune response. Murine models have demonstrated how feeding of gut commensals can reduce allergy symptoms by inducing T regulatory cells (Tregs) which migrate to the lung and reduce the immune response (79, 80). Indeed, antibiotic-mediated disruption of the gut microbiota and mycobiota has been shown to exacerbate allergic asthma symptoms in mice (81, 82). Recently, an elegant study by Arrieta and colleagues found that the relative abundance of the bacterial genera Faecalibacterium, Lachnospiria, Veillonella, and Rothia and Clostridium neonatale are decreased in the gut of children at risk of asthma development (83, 84). These microbes were significantly different between the groups at 3 months of age and the difference decreased as children reached 1 year of age highlighting a colonization window of opportunity and of an appropriate immune education.

Diet has a major impact on human health, whether by affecting the host directly or through changes of the microbial community. The microbial community in the mammalian gut is a complex and dynamic system with a steady state (85), which can be perturbed by many environmental factors, including diet, lifestyle, drugs, thereby changing the host’s physiology (10, 86) (Figure 2). As a response to dietary changes, shifts in the composition of the gut microbiota occur. Especially during early-life events like weaning off and introduction to solid food, the dynamics of colonization are critically involved in educating as well as training the immune system (87). The consumption of a Westernized diet containing excessive amounts of refined and processed foods, red meats, and sugary beverages, accompanied with a low consumption of fibers, fruits, and vegetables, is associated with the increased occurrence of metabolic diseases, such as diabetes and obesity, both of which are associated with systemic low-grade inflammation attributed to endotoxemia (88, 89) (Figure 2B). A healthy gut microbiota maintains a symbiotic relationship within the gut mucosa offering essential functions in metabolism, immunology, and protection of the host (Figure 2A). The commensal microbiota, consisting of up to 1 × 10¹⁴ bacteria, confers colonization resistance against pathogens, which is a key host defense mechanism against enteric infections. Commensal microbes occupy niches and exhaust nutrients thereby limiting the growth of newcomers. Dietary changes, inflammation, and antibiotics can disrupt the commensal microbial community and hence increase the risk of colonization and expansion of incoming pathogens (90). The commensal microbiota is also essential for the elimination of pathogens from the gut. For example, unlike conventional specific pathogen free mice, GF mice are unable to eradicate enteric pathogens such as Citrobacter rodentium from the gut (19). Therefore, the abundance and diversity of microbial members plays a crucial role in fulfilling these functions, i.e., symbiosis, colonization resistance, clearance of pathogens, etc. Decreased microbial diversity or altered composition, e.g., increased Firmicutes to Bacteroidetes ratio, entail various health risks for the host and are generally associated to poor health (91). Feeding high-fat and high sucrose diet to wild-type (WT) mice leads to decreased gut microbiota diversity and an increase in opportunistic pathogens, resulting in a decreased prevalence of specific gut barrier-protective bacteria (92). However, reverting the animals to regular chow food reverses the dietary perturbations thereby confirming the structural resilience of the gut microbiota. Similarly, the human microbiota can rapidly adapt to dietary changes (93, 94). A comparative analysis of vegan, vegetarian, and omnivore diets and the corresponding shifts in microbial communities revealed that a significant increase in β-diversity was present as quickly as 24 h post switch to the animal-based diet (93). These findings suggest that changes in environmental conditions of gut microbiota, e.g., through changes in diet, put selective pressure on various species, which in turn leads to competition for the most adaptable bacteria to survive and replicate (7).

The adipose tissue is an active endocrine and secondary immune organ consisting of adipocytes, immune cells (T cells and macrophages) and connective/nerve tissue which produces hormones including adipokines [such as leptin and resistin (pro-inflammatory) and adiponectin (anti-inflammatory)], cytokines, and chemokines. The adipose tissue in lean individuals is characterized by an anti-inflammatory cytokine and adipokine profile (e.g., IL-4, IL-10, IL-33, adiponectin) produced by M2 macrophages and Tregs, while obese mice present an initial CD8⁺ T cell infiltration followed by macrophages resulting in a pro-inflammatory (Th1/Th17 and M1) profile. M1 macrophages secrete pro-inflammatory cytokines, including TNFα, IL-1β, and IL-6 (95). Although a correlation between obesity and IBD is not confirmed [reviewed in Ref. (96)], the cytokine profile of the adipose tissue in patients with IBD and especially in CD patients, is similar to obese individuals exhibiting increased levels of TNFα, IL-6 and leptin and a reduction in adiponectin (97–100). CD adipocytes express TLRs, display a higher presence of commensal bacteria (Enterococcus faecalis) and an increased translocation of intestinal bacteria resulting in an increased C-reactive protein production (101). These findings indicate that adipocytes participate in the antimicrobial response and represent a barrier to maintain homeostasis and link the adipose tissue with innate immune responses (102). A typical feature of patients with CD is an enlarged mesenteric tissue wrapped around the intestine, so-called “creeping fat.” This fat is usually found adjacent to inflammatory lesions, it correlates with disease activity, is characterized by high infiltration of lymphocytes and macrophages, high levels of peroxisome proliferator-activated receptor γ (PPARγ) and TNFα and fibrosis (103–105). PPARγ is a nuclear receptor that controls the expression of a large number of regulatory genes in lipid metabolism, insulin sensitization, inflammation, and cell proliferation (106, 107) and can inhibit the activation of nuclear factor κB (NFκB), mitogen-activated protein kinase (MAPK), and cyclooxygenase 2 (COX-2) pathways leading to reduction of pro-inflammatory mediators (cytokines and prostaglandins). These findings indicate that mesenteric obesity may play an important role in CD pathogenesis. Contrary to IBD, an association between obesity and asthma, with increased asthma disease severity, has been specifically identified in children. Obesity appears to increase injury in the lungs of asthmatic patients by increasing eosinophil numbers to the airway wall and the systemic production of pro-inflammatory cytokines TNFα, IL-6, IL-1 (5). A recent publication highlighted a pathogenic role for IL-17a produced from ILC3 cells in airways disease in mice with diet-induced obesity. This was accompanied by NLRP3 inflammasome and IL-17a activation in the adipose tissue and the lungs, leading to the identification of a new inflammasome/Th17 mechanism in asthma (108). Similarly to IBD, a reduction in adiponectin levels has also been reported, which can affect the anti-inflammatory immune function in asthma patients (5).

Dietary nutrients shape the intestinal environment by having a crucial impact on intestinal microbial populations and immune responses. To date, epidemiological evidence from observational studies indicate that intake of fiber rich food, such as fruits and vegetables, can protect against IBD and asthma. Conversely, this protective effect has not been confirmed in randomized controlled trials. Recently, the evidence for the airway and gut microbiota in effecting asthma development and induction is mounting. Timing of neonatal exposure to microbes and the diversity of the exposing environment and gut metabolites appear to effect asthma development (83). In a seminal work by Gevers et al., microbial alterations in naïve treated pediatric CD patients were correlated with certain microbes, specific location and effect of antibiotic treatment—findings that can pave the way for new CD diagnostic tools (109). The effect of dietary habits on the early development of these diseases is yet to be discovered. In the next section, we summarize studies covering different dietary patterns and their contribution to disease status. For a more comprehensive review on dietary advice and interventions see recent reviews (27, 110–112).

Recent evidence has identified the existence of a cross talk between the host and the commensal microbiota within the gut. In this dialog, nutrients play an important role either by directly interacting with the host via the epithelium or the intestinal immune system or indirectly, by modulating the composition of the commensal microbiota which in turn will interact with the immune system, and vice versa (Figure 2A). The immune system will react promptly and adapt depending on the microbiota (commensal, pathobionts, and pathogens) and the diet (prebiotics, supplements, or detrimental nutrients). The worldwide increased incidence of IBD and asthma has been hypothesized to be associated with changes in dietary habits, i.e., westernized life style. In the following sections, we will outline several important macro- and micronutrients associated with diets and their effect on immune responses at mucosal sites important in health and in IBD and asthma.

The increasing incidence of IBD and asthma implies a fundamental role for environmental factors. Several lines of evidence have identified the consumption of a diet high in saturated fat and high in sucrose increases a person’s risk for several chronic conditions including IBD and asthma (4, 27). Studies in animal models, human cells and tissues for both conditions have also highlighted the complex interaction between diet, the microbiota and the host response, especially regarding aggravation of inflammatory responses upon consumption of certain triggering nutrients and diets. Dietary ingredients in the western diet are not limited to the ones listed in this review. Apart from the increased consumption of saturated fats and sucrose, there is an increased consumption of food additives including sweeteners, emulsifiers, thickeners, preservatives and food colorings. Some of these have already been associated to asthma and IBD (122, 132, 134) but there is a need for larger epidemiological studies to identify the effect that these products may have on both microbial composition and host responses (e.g., inflammation, metabolism, etc.) in disease development. In an elegant study by Arrieta and colleagues it was shown that changes in the microbiota especially at a young age, can help to identify a window of opportunity for bacteria colonization and an appropriate immune education in asthmatics (83). Future studies aiming to identify whether a similar new widow also exists prior to IBD onset and whether the education of the mucosal immune system can be regulated by specific diet combinations and corresponding microbial alterations are required. Such studies would likely lead to the discovery of new target/regulatory mechanisms for both conditions.

Individuals with IBD and asthma present with a deficiency in certain essential nutrients, e.g., VitD and Iron. The reductionist approach undertaken whereby the effect of one single nutrient has been investigated in animal models, has so far provided major insights into the regulatory mechanisms associated with inflammation and metabolism. In addition, the majority of animal studies and diets, employs standard “high fat” diet containing a nutrient content designed to sustain rodent health and are, therefore, not relevant to a human and patient dietary intake (263). Studies using more complex systems, e.g., humanized mice (consisting of both a human immune system and human microbiota) fed with a humanized diet will provide a deeper mechanistic understanding of the complex diet-microbiota-host network. Integration of various approaches, e.g., genomic, transcriptomic, metabolomics or systems biology, will reveal a clearer picture of the components contributing to the pathology of these chronic inflammatory conditions. Furthermore, the impact of current therapeutic treatments and diets on disease progression and the microbiota are currently lacking, therefore, future studies addressing this question could lead to new beneficial treatment strategies.

DS, MA, and JM wrote the manuscript; SM wrote and edited the manuscript. All authors read and approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.