Diet and Nutrients and Immune

Review
published: 28 July 2017

doi: 10.3389/fimmu.2017.00838
The impact of western Diet and

Nutrients on the Microbiota and
immune Response at Mucosal
interfaces
Donjete Statovci 1, Mònica Aguilera 1, John MacSharry 1,2 and Silvia Melgar 1*
1
APC Microbiome Institute, University College Cork, Cork, Ireland, 2 School of Microbiology, University College Cork,
Cork, Ireland
Recent findings point toward diet having a major impact on human health. Diets can either
affect the gut microbiota resulting in alterations in the host’s physiological responses
or by directly targeting the host response. The microbial community in the mammalian
gut is a complex and dynamic system crucial for the development and maturation of
both systemic and mucosal immune responses. Therefore, the complex interaction
between available nutrients, the microbiota, and the immune system are central regu-
lators in maintaining homeostasis and fighting against invading pathogens at mucosal
sites. Westernized diet, defined as high dietary intake of saturated fats and sucrose
Edited by:
Raquel Hontecillas, and low intake of fiber, represent a growing health risk contributing to the increased
Virginia Tech, United States occurrence of metabolic diseases, e.g., diabetes and obesity in countries adapting a
Reviewed by: westernized lifestyle. Inflammatory bowel diseases (IBD) and asthma are chronic muco-
Mourad Aribi,
University of Tlemcen, Algeria
sal inflammatory conditions of unknown etiology with increasing prevalence worldwide.
Christopher Alan Jolly, These conditions have a multifactorial etiology including genetic factors, environmental
University of Texas at Austin, factors, and dysregulated immune responses. Their increased prevalence cannot solely
United States
be attributed to genetic considerations implying that other factors such as diet can be
*Correspondence:
Silvia Melgar a major contributor. Recent reports indicate that the gut microbiota and modifications
[email protected] thereof, due to a consumption of a diet high in saturated fats and low in fibers, can
trigger factors regulating the development and/or progression of both conditions. While
Specialty section:
This article was submitted to
asthma is a disease of the airways, increasing evidence indicates a link between the gut
Nutritional Immunology, and airways in disease development. Herein, we provide a comprehensive review on the
a section of the journal impact of westernized diet and associated nutrients on immune cell responses and the
Frontiers in Immunology
microbiota and how these can influence the pathology of IBD and asthma.
Received: 31 January 2017
Accepted: 03 July 2017 Keywords: westernized diet, inflammatory bowel disease, asthma, saturated fat, micronutrients, microbiota
Published: 28 July 2017
Citation:
GENERAL INTRODUCTION
Statovci D, Aguilera M, MacSharry J
and Melgar S (2017) The Impact
The prevalence of chronic inflammatory diseases affecting mucosal sites such as the intestine and the
of Western Diet and Nutrients
on the Microbiota and Immune
airways is increasing worldwide (1, 2). Among these, inflammatory bowel disease [IBD, mainly com-
Response at Mucosal Interfaces. prising ulcerative colitis (UC) and Crohn’s Disease (CD)] and allergic asthma are the most relevant.
Front. Immunol. 8:838. Recent findings point toward potential links between these two pathologies, e.g., histamine and mast
doi: 10.3389/fimmu.2017.00838 cell activity and immunoglobulin E (IgE) production, reviewed in Ref. (3). Both diseases have a
Frontiers in Immunology | www.frontiersin.org 1 July 2017 | Volume 8 | Article 838

Statovci et al. Diet and Nutrients, Microbiota, Immunity in IBD/Asthma
multifactorial cause, in which environmental factors such as diet and immune modulators are the current treatments of choice
and the commensal microbiota are gaining increased attention. for patients with IBD, with the overall goal being inflammation
In this regard, consumption of the so-called “Westernized” diet is reduction, increase of mucosal healing and symptom relief
associated with increased risk for IBD (4) and asthma morbidity (16, 44). New treatment strategies include inhibitors targeting
(5). Westernized diet is characterized by a high content of proteins leukocyte trafficking (α4β7 integrin, sphingosine-1-phosphate,
(derived from fatty domesticated and processed meats), saturated S1P), cytokine [interleukin (IL)-12p40, IL-23], janus kinase-
fats, refined grains, sugar, alcohol, salt, and corn-derived fructose pathway, inflammasome (NLRP3/IL-1β), to name a few (45, 46).
syrup, with an associated reduced consumption of fruits and The etiology of IBD is still unknown but the evidence points
vegetables (4, 6, 7). Research in the last decade has uncovered toward environmental factors, with the microbiota being of
that changes from a diet rich in fibers and low in fats to a diet particular interest. The microbiota can trigger and/or sustain a
low in fibers and high in saturated fats directly contributes to the tissue damaging immune response in genetically susceptible indi-
development of obesity, metabolic syndrome, and cardiovascular viduals. Research in the last decade has identified a crucial role for
diseases (8, 9). Macronutrients (carbohydrates, lipids, and protein) the commensal bacteria in the pathogenesis of IBD. Experimental
and micronutrients (vitamins and minerals) are required for our IBD was not evidenced in animals raised under germ-free (GF)
body to function and several of these are naturally obtained from conditions when compared to groups of conventionalized animals
our diets and from the resident microbiota. Both patients with (47). Antibiotics have proven beneficial to certain subgroups of
IBD and asthma present nutritional problems leading to several patients with CD but not in patients with UC (48) and inflamma-
complications including anemia, osteoporosis, acute respiratory tory lesions are more frequently located in areas with large bacte-
infections, etc. The link between diet, nutrients and immune rial burden, i.e., ileum and colon (49). Alterations in the enteric
responses is embedded in a complex network of signals and has microbial flora reported in patients with IBD include decreases in
to be considered in the light of other factors including microbial Firmicutes and Bacteroidetes and increases in Enterobacteriaceae
composition, genetic background, and lifestyle, to mention but a (e.g., Escherichia coli) (50). A reduction in anti-inflammatory
few. The advent of high-throughput Next-Generation Sequencing commensals, such as Faecalibacterium prausnitzii has been asso-
technologies has driven the discovery and dissection of regula- ciated with CD (51). Several pathogenic bacteria are suggested as
tory mechanisms involved in the disease state. In this review, etiological agents of IBD but to date none has been identified to
we will focus on the interactions between diets and nutrients cause IBD (47). In contrast, pathobionts, i.e., commensal bacteria
associated with Westernized regimes and their impact on the with potential pathological properties, have been isolated, includ-
microbiota and immune responses at mucosal interfaces, i.e., ing strains of adherent and invasive E. coli (AIEC), commonly
the intestines and lungs. We will outline the complex network identified in the mucosa of CD patients (52).
between nutrients, microbial alterations and abnormal immune Genome-wide association studies have so far identified over
responses associated with IBD and asthma. 160 genetic loci in IBD, with 30 loci being specific to CD, 23
Table 1 summarizes the impact of dietary factors on host loci to UC, and 110 loci are associated with both forms of IBD
responses. Figure 1 summarizes identified genes associated with (53). IBD susceptibility single-nucleotide polymorphisms were
IBD and asthma and immune responses. Figure 2 displays the identified in genes affecting innate and adaptive immune cell
regulatory interaction between diet, mucosal immunity, and function, bacterial recognition, etc. (Figure 1). Therefore, the role
commensal microbiota to maintain mucosal homeostasis and the of mononuclear phagocytes including monocytes/macrophages
resulting pathology upon loss of balance. Figures 3 and 4 outline and dendritic cells (DCs) in the development of IBD has been
the mechanisms targeted by nutrients in the healthy intestine extensively studied. Several mouse models of IBD, including
and lung and in the inflamed gut (IBD) and lung (asthma), dextran sodium sulfate (DSS)- and 2,4,6-trinitrobenzene sulfonic
respectively. acid-induced colitis and the TNFΔARE model of Crohn’s-like ile-
itis, have revealed that lamina propria mononuclear phagocytes
have protective as well as pathogenic roles during the disease
IBD—GENETICS, IMMUNE RESPONSE, progression (54–60). Three explanations have been postulated
AND MICROBIOTA to explain these findings—(1) an inappropriate response to non-
harmful commensal bacteria (i.e., NOD2, REL, CARD9); (2)
Inflammatory bowel diseases are multifactorial chronic immune- an inefficient clearance of microbes (commensals/pathobionts)
mediated diseases of the gastrointestinal (GI) tract. They often leading to chronic immune stimulation (i.e., ATG16L1, IRGM),
have an early onset and a course which is characterized by intermit- and (3) a failure to resolve inflammation by maintaining a pro-
tent phases of remission and relapses (42, 43). Nearly 2.2 million inflammatory phenotype (i.e., IL-12, IL-18RAP/IL-1R1, IFNGR/
people in Europe, 1.5 million Americans, and several 100,000 more IFNAR1) (39) (Figure 1). The intestinal epithelium functions as
individuals suffer from IBD. The prevalence and incidence of IBD a barrier between the host and its environment (microbes, non-
is increasing worldwide and its growth is not confined to Western self-antigens from diet, nutrients, etc.) and consists of highly
Europe or the USA; countries adapting a westernized lifestyle, specialized cells that fulfill this barrier task. Genes associated
such as Japan and South Africa, are seeing mounting numbers with epithelial cell function, such as HNF4A, ECM1, CDH1 have
of affected individuals (2). Patients suffering from IBD present a UC correlation (53) (Figure 1). Alterations in barrier integrity
symptoms such as abdominal pain, fever, and diarrhea with blood associated with IBD include decreased structure of tight-junction
and/or mucus excretion. Antibiotics, biologics, corticosteroids, (TJ) proteins, which regulate paracellular permeability, impaired

mucus production due to loss of goblet cells and an altered migrate to the lymph nodes and induce T cell activation (70)
production of antimicrobial peptides (61) (Figure 4). (Figure 4). The subsequent T cell immune response can result in
In terms of location, CD can affect any part of the GI tract either an allergenic Th2/eosinophilic IgE-mediated inflammation
from the mouth to rectum. However, in the majority of patients or an inflammatory Th1/neutrophilic cell influx into the airway.
with CD the inflammation is localized to the distal ileum and The Th2 allergenic response involves the interaction of DCs, Th2
proximal colon (62). The inflammation in CD is patchy and often cells, and IL-4 producing basophils which induce the expansion
transmural, which can lead to the development of fibrosis, fistu- of type 2 innate lymphoid cells (ILC2) which also produce the Th2
las, fissures, strictures, etc. A dense infiltration with macrophages cytokines, IL-5, IL-9, and IL-13, leading to eosinophil and mast
and lymphocytes and granuloma formation is a typical feature cell trafficking to the lung and goblet cell mucus secretion (70)
of the disease. Patients with CD present an imbalanced immune (Figure 4). IL-4 derived from Th2 cells also induces IgE produc-
response with high expression of innate pro-inflammatory tion by B cells. The mixed Th2 and Th1 neutrophilic or Th2 low
cytokines, including IL-1β, IL-6, and tumor necrosis factor asthma is induced by toll-like receptor (TLR) activation result-
(TNF)-α and a T helper (Th)1 (IL-12-mediated interferon ing in IL-1β secretion and activation of inflammatory Th1 and
(IFN)γ) and Th17 (IL-17a) profile resulting in an enhanced Th17 cells. These cells release IL-17a and IFNγ, which activate
and uncontrolled immune response (16, 43, 62) (Figure 4). In neutrophils and macrophages to release TNFα and induce inflam-
contrast to CD, UC is restricted to the mucosa of the colon and is matory signals. The resulting immune infiltrates induces the
associated with large infiltrates of neutrophils, T and B cells in the symptoms of asthma—bronchoconstriction, mucus production,
lamina propria. Characteristically, the inflammation originates in and the resultant tissue remodeling increasing smooth muscle
the rectum extending continuously in a proximal fashion. Crypt and collagen deposition (71, 72). The subsequent remodeling
abscesses, formed by extravasation of neutrophils through the results in airway wall thickening, compromised lung function
intestinal epithelium, ulcerations, and goblet cell loss are typical and changes in the lung microbiota (41, 73). The mechanisms
features of UC. Moreover, high levels of innate cytokines, includ- of asthma have been studied successfully over the decades using
ing IL-1β, IL-6, and TNFα, and chemokines, such as CXCL8 and murine models, such as the ovalbumin and the house dust mite
GROα/CXCL1 (neutrophil attractants), as well as an atypical Th2 challenge models (74). While all models have limitations, these
cytokine profile accompanied by high production of IL-5, IL-10, studies have led to successful therapy development and under-
transforming growth factor beta (TGFβ) and only initially IL-4 standing of the genetics of asthma (75). Asthma treatment targets
production, which is superseded by IL-13 production is associ- immune processes by using inhaled corticosteroids, to reduce
ated to patients with UC (62–65) (Figure 4). inflammation, and bronchodilators to counteract the effects of
bronchoconstriction induced by the release of histamine, prosta-
glandins, interleukins, or leukotrienes.
ASTHMA—GENETICS, IMMUNE Several genetic studies have identified asthma susceptibility
RESPONSE, AND MICROBIOTA genes, including IRAK3, SMAD3, ORMDL3, IL-1RL1, IL-13,
IL-33, TNFAIP3, and TSLP (76) (Figure 1). Recent studies
Asthma is an increasingly common heterogeneous chronic inflam- have highlighted the role of the site of the mutation and allele
matory disease, which places substantial burden on patients, their frequency and the particular site of functionality, such as the
families, and the community (66). Asthma is characterized by asthmatic epithelium, and the epigenetic regulation thereof
airway immune hyper responsiveness to inhaled environmental as being key factors contributing to asthma (77, 78). Studies
particles leading to wheezing, breathlessness, chest tightness, on DNA methylation, and microRNA modulation of gene
and coughing effecting airway function (http://ginasthma.org/). expression, are now shedding light on the pathogenesis of this
Worldwide the incidence of asthma, is increasing, with an esti- multifactorial disease.
mated 300 million affected individuals (http://ginasthma.org/). There is increasing evidence that the gut plays a key role in
Once thought to be a childhood disease it is now presenting in effecting the allergic immune response. Murine models have
respiratory clinics as first time adult onset asthma. demonstrated how feeding of gut commensals can reduce
Asthma presents with airway inflammation following expo- allergy symptoms by inducing T regulatory cells (Tregs) which
sure to insults such as allergens, pollutants, and microbes (67). migrate to the lung and reduce the immune response (79, 80).
The primary site of immune induction is initially the lung epithe- Indeed, antibiotic-mediated disruption of the gut microbiota
lium, which interacts with the underlying antigen presenting cells and mycobiota has been shown to exacerbate allergic asthma
such as DCs, inducing an immune response (Figure 4). Alveolar symptoms in mice (81, 82). Recently, an elegant study by Arrieta
macrophages in the airway lumen act as clearance and immune and colleagues found that the relative abundance of the bacterial
sampling mechanisms at the interface between the mucosa and genera Faecalibacterium, Lachnospiria, Veillonella, and Rothia
the external environment (68). The immune signaling from and Clostridium neonatale are decreased in the gut of children
epithelial cells and macrophages results in secretion of first order at risk of asthma development (83, 84). These microbes were
cytokines, such as CXCL8, IFNα, IL-1β, IL-33, TGFβ, and thymic significantly different between the groups at 3 months of age
stromal lymphopoietin (TSLP), which induce a rapid immune and the difference decreased as children reached 1 year of age
trafficking and a clearance response which subsequently results highlighting a colonization window of opportunity and of an
in second order cytokine secretion by T cells (69). Activated DCs appropriate immune education.

Figure 1 | Shared and individual inflammatory bowel disease (IBD) and Asthma susceptibility genes/loci. The outlined genes are grouped according to function. In
green color are the genes associated to asthma, in blue color are the genes associated to ulcerative colitis only, in orange color are the genes associated to Crohn’s
disease only, in purple color are the genes associated to IBD, in black color are the genes associated to asthma and Crohn’s disease or asthma and IBD,
respectively. Adapted from Ref. (37–40). Abbreviations: AK2, adenylate kinase 2; ATG16L1, autophagy related 16 like 1; CARD9, caspase recruitment domain family
member 9; CD14, cluster of differentiation 14; CDH1, cadherin 1; CREM, CAMP responsive element modulator; CTLA4, cytotoxic T-lymphocyte associated protein
4; DENND1B, DENN domain containing 1B; ECM1, extracellular matrix protein 1; FCGR2A, Fc fragment of IgG receptor IIa; FCGR2B, Fc fragment of IgG receptor
IIb; FLG, filaggrin; GNA12, G-protein subunit alpha 12; GSTM1, glutathione S-transferase mu 1; GSTP1, glutathione S-transferase pi 1; GSTT1, glutathione
S-transferase theta 1; HAVCR1, hepatitis A virus cellular receptor 1; HNF4A, hepatocyte nuclear factor 4 alpha; IL-13, interleukin 13; IL-4, interleukin 4; IL-10,
interleukin 10; IL-12B, interleukin 12B; IL-1R1, interleukin 1 receptor type 1; IL-1R2, interleukin 1 receptor type 2; IL23R, interleukin 23 receptor; IL-27, interleukin
27; IL-4R, interleukin 4 receptor; CXCR1, C–X–C motif chemokine receptor 1; CXCR2, C–X–C motif chemokine receptor 2; IRGM, immunity related GTPase M;
LAMB1, laminin subunit beta 1; LRRK2, leucine rich repeat kinase 2; LTA, lymphotoxin alpha; LTC4S, leukotriene C4 synthase; NOD2, nucleotide binding
oligomerization domain containing 2; ORMDL3, ORMDL sphingolipid biosynthesis regulator 3; REL, REL proto-oncogene, NF-κB subunit; SBNO2, strawberry notch
homolog 2; SLC11A1, solute carrier family 11 member 1; SLC22A5, solute carrier family 22 member 5; SMAD3, SMAD Family Member 3; STAT3, signal transducer
and activator of transcription 3; Th, T helper cell; TGFB1, transforming growth factor beta 1; TNF, tumor necrosis factor; TRAF1, TNF receptor associated factor 1;
TYK2, tyrosine kinase 2.
REGULATION OF MICROBIOTA BY DIET and protection of the host (Figure 2A). The commensal micro-
biota, consisting of up to 1 × 1014 bacteria, confers coloniza-
Diet has a major impact on human health, whether by affecting tion resistance against pathogens, which is a key host defense
the host directly or through changes of the microbial community. mechanism against enteric infections. Commensal microbes
The microbial community in the mammalian gut is a complex and occupy niches and exhaust nutrients thereby limiting the growth
dynamic system with a steady state (85), which can be perturbed of newcomers. Dietary changes, inflammation, and antibiotics
by many environmental factors, including diet, lifestyle, drugs, can disrupt the commensal microbial community and hence
thereby changing the host’s physiology (10, 86) (Figure 2). As a increase the risk of colonization and expansion of incoming
response to dietary changes, shifts in the composition of the gut pathogens (90). The commensal microbiota is also essential for
microbiota occur. Especially during early-life events like weaning the elimination of pathogens from the gut. For example, unlike
off and introduction to solid food, the dynamics of colonization conventional specific pathogen free mice, GF mice are unable to
are critically involved in educating as well as training the immune eradicate enteric pathogens such as Citrobacter rodentium from
system (87). The consumption of a Westernized diet containing the gut (19). Therefore, the abundance and diversity of micro-
excessive amounts of refined and processed foods, red meats, bial members plays a crucial role in fulfilling these functions,
and sugary beverages, accompanied with a low consumption i.e., symbiosis, colonization resistance, clearance of pathogens,
of fibers, fruits, and vegetables, is associated with the increased etc. Decreased microbial diversity or altered composition,
occurrence of metabolic diseases, such as diabetes and obesity, e.g., increased Firmicutes to Bacteroidetes ratio, entail various
both of which are associated with systemic low-grade inflamma- health risks for the host and are generally associated to poor health
tion attributed to endotoxemia (88, 89) (Figure 2B). A healthy (91). Feeding high-fat and high sucrose diet to wild-type (WT)
gut microbiota maintains a symbiotic relationship within the gut mice leads to decreased gut microbiota diversity and an increase
mucosa offering essential functions in metabolism, immunology, in opportunistic pathogens, resulting in a decreased prevalence

of specific gut barrier-protective bacteria (92). However, revert- and asthma, with increased asthma disease severity, has been
ing the animals to regular chow food reverses the dietary pertur- specifically identified in children. Obesity appears to increase
bations thereby confirming the structural resilience of the gut injury in the lungs of asthmatic patients by increasing eosino-
microbiota. Similarly, the human microbiota can rapidly adapt phil numbers to the airway wall and the systemic production
to dietary changes (93, 94). A comparative analysis of vegan, of pro-inflammatory cytokines TNFα, IL-6, IL-1 (5). A recent
vegetarian, and omnivore diets and the corresponding shifts publication highlighted a pathogenic role for IL-17a produced
in microbial communities revealed that a significant increase from ILC3 cells in airways disease in mice with diet-induced
in β-diversity was present as quickly as 24 h post switch to the obesity. This was accompanied by NLRP3 inflammasome and
animal-based diet (93). These findings suggest that changes IL-17a activation in the adipose tissue and the lungs, leading to
in environmental conditions of gut microbiota, e.g., through the identification of a new inflammasome/Th17 mechanism in
changes in diet, put selective pressure on various species, which asthma (108). Similarly to IBD, a reduction in adiponectin levels
in turn leads to competition for the most adaptable bacteria to has also been reported, which can affect the anti-inflammatory
survive and replicate (7). immune function in asthma patients (5).
DIETARY PATTERNS IN IBD AND ASTHMA

DIET AND IMMUNE RESPONSES
IN THE ADIPOSE TISSUE Dietary nutrients shape the intestinal environment by having a
crucial impact on intestinal microbial populations and immune
The adipose tissue is an active endocrine and secondary responses. To date, epidemiological evidence from observational
immune organ consisting of adipocytes, immune cells (T cells studies indicate that intake of fiber rich food, such as fruits and
and macrophages) and connective/nerve tissue which produces vegetables, can protect against IBD and asthma. Conversely,
hormones including adipokines [such as leptin and resistin this protective effect has not been confirmed in randomized
(pro-inflammatory) and adiponectin (anti-inflammatory)], controlled trials. Recently, the evidence for the airway and gut
cytokines, and chemokines. The adipose tissue in lean indi- microbiota in effecting asthma development and induction is
viduals is characterized by an anti-inflammatory cytokine and mounting. Timing of neonatal exposure to microbes and the
adipokine profile (e.g., IL-4, IL-10, IL-33, adiponectin) produced diversity of the exposing environment and gut metabolites
by M2 macrophages and Tregs, while obese mice present an appear to effect asthma development (83). In a seminal work by
initial CD8+ T cell infiltration followed by macrophages result- Gevers et al., microbial alterations in naïve treated pediatric CD
ing in a pro-inflammatory (Th1/Th17 and M1) profile. M1 patients were correlated with certain microbes, specific location
macrophages secrete pro-inflammatory cytokines, including and effect of antibiotic treatment—findings that can pave the way
TNFα, IL-1β, and IL-6 (95). Although a correlation between for new CD diagnostic tools (109). The effect of dietary habits on
obesity and IBD is not confirmed [reviewed in Ref. (96)], the the early development of these diseases is yet to be discovered.
cytokine profile of the adipose tissue in patients with IBD and In the next section, we summarize studies covering different
especially in CD patients, is similar to obese individuals exhibit- dietary patterns and their contribution to disease status. For a
ing increased levels of TNFα, IL-6 and leptin and a reduction more comprehensive review on dietary advice and interventions
in adiponectin (97–100). CD adipocytes express TLRs, display see recent reviews (27, 110–112).
a higher presence of commensal bacteria (Enterococcus faecalis)
and an increased translocation of intestinal bacteria resulting in Fat and Sucrose
an increased C-reactive protein production (101). These find- A recent report from the European Prospective Investigation
ings indicate that adipocytes participate in the antimicrobial in Cancer (EPIC) study, did not identify a correlation between
response and represent a barrier to maintain homeostasis and body mass index (a measure of obesity) and IBD morbidity
link the adipose tissue with innate immune responses (102). (113), therefore proposing that a hypercaloric diet per se is not
A typical feature of patients with CD is an enlarged mesenteric enough to trigger the development of IBD. Epidemiological
tissue wrapped around the intestine, so-called “creeping fat.” studies indicate an increased risk of IBD is associated with
This fat is usually found adjacent to inflammatory lesions, it cor- a higher consumption of red and/or processed meat, dietary
relates with disease activity, is characterized by high infiltration fat [especially n-6 polyunsaturated fatty acids (PUFAs)] and
of lymphocytes and macrophages, high levels of peroxisome low levels of vitamin D (VitD) (4, 114, 115). In addition, an
proliferator-activated receptor γ (PPARγ) and TNFα and fibrosis association between disease activity and intake of total fat
(103–105). PPARγ is a nuclear receptor that controls the expres- [trans, saturated, and monounsaturated fatty acids (MUFAs)]
sion of a large number of regulatory genes in lipid metabolism, and a high n-6/n-3 PUFA ratio has been identified in patients
insulin sensitization, inflammation, and cell proliferation (106, with CD (116). Also, a direct correlation of colonic cytokine
107) and can inhibit the activation of nuclear factor κB (NFκB), levels with saturated fatty acids (SFA) was identified in patients
mitogen-activated protein kinase (MAPK), and cyclooxygenase with UC (115). Similarly to IBD, the quality of fatty acids
2 (COX-2) pathways leading to reduction of pro-inflammatory (FAs) appear also to effect the asthma response as trans FAs
mediators (cytokines and prostaglandins). These findings indi- margarine (a trans FA source), n-6 FAs intake, and oleic acid
cate that mesenteric obesity may play an important role in CD intake are associated with increased asthma risk (117, 118). In
pathogenesis. Contrary to IBD, an association between obesity addition to saturated fats, a higher prevalence and preference

Figure 2 | Interaction between diet, microbiota, and immune response at mucosal sites. (A) To keep a healthy state, the local microbiota and mucosal immune
system are in homeostasis at mucosal sites. The microbiota educates and promotes the maturation of the immune system by induction of pro-inflammatory and
anti-inflammatory immune cells, e.g., Th17 (SFB), T regulatory cells (Clostridia spp.), and Th1 (Bacteroides fragilis). Moreover, the immune system surveys microbial
activities (e.g., antigen sampling at the mucosal barrier) and responds in a controlled fashion by producing, e.g., antimicrobial peptides, sIgA to prevent tissue
damage. The integrity of the mucosal barrier is sustained by bacteria-produced metabolites (e.g., SCFA) such as butyrate resulting in high expression of tight-
junction proteins and mucus production, thereby restricting interaction of microbes to the lumen and luminal epitheliums. The diet is involved in all processes,
serving the microbiome with fermentable fibers and the immune system and epithelium with essential nutrients, e.g., vitamins and minerals. (B) During pathological
conditions, such as inflammatory bowel disease and asthma, the homeostasis at the mucosal barrier is disrupted. A westernized diet, i.e., high in SFA, high ω-6/ω-3
ratio, high sucrose and iron (oral iron supplements), and low in fiber promotes inflammation and growth of pathogenic/pathobiont (disease causing) bacteria in the
gut. The microbiota, which is rich in non-beneficial bacteria, favorably induces the maturation of pro-inflammatory immune cells, leading to uncontrolled inflammation
resulting in tissue damage of the mucosal compartment. The damaged mucosa and shifted immune response fail to control the microbiota, which exaggerates the
pathophysiological state. Under certain conditions, bacteria-derived LPS enters the systemic circulation and further stimulates the immune system toward a
pro-inflammatory state. Abbreviations: LPS, lipopolysaccharide; SCFAs, short-chain fatty acids; SFAs, saturated fatty acids; SFB, segmented filamentous bacteria;
sIgA, secretory immunoglobulin A; ω-6/ω-3, omega-6/omega-3 fatty acid ratio; Th, T helper.
for foods with high calories, i.e., from fat and sucrose, has been sucrose, resulted in altered microbiota composition, par-
linked to the worldwide increase in metabolic diseases (119). ticularly in the expansion of and colonization of AIEC and
In IBD, one of the first studies that related sucrose to the devel- reduction in protective bacteria, increased permeability and
opment of CD was published four decades ago (120). More colonic pro-inflammatory mediators (Figure 4), and reduction
recently, the EPIC study uncovered an association between in short-chain fatty acids (SCFA) concentrations and the SCFA
high consumption of sugar and soft drinks accompanied by receptor GPR43, supporting a role of fat and sucrose in exacer-
a low vegetable intake to a higher UC risk (121). Similarly, bating inflammation due to changes in microbial composition
high sugar consumption in sweetened beverages has been (20, 123). Overall, the studies to date indicate that a diet rich in
linked to asthma and dental caries which is also increased saturated fat and high sucrose content presents a risk factor for
in asthmatics (18, 21, 122). Studies in experimental models, IBD and asthma and is associated to inflammation while results
e.g., transgenic CEABAC10 mice fed a diet high in fat and from MUFA-containing diets are contradictory.

Figure 3 | Schematic illustrating the nutrient factors regulating microbial and host responses in the healthy gut and lung. Homeostatic balance at the mucosa due
to a balanced diet rich in fiber allows for regulated interactions between the epithelia and the microbiome. This dialog with the microbiome allows for appropriate
epithelial barrier function, mucus secretion, and underlying immune sensing. In the gut, a balanced microbiome generates SCFAs and dietary long chain FAs and the
fat-soluble vitamins A and D which induce a tolerogenic mucosal immune state locally at the gut but also systemically and particularly in the lung. The gut-derived
SCFAs acetate and propionate enhance DCs, ILC, and macrophage phagocytic function and Tregs balance resulting in the control of lung microbiota and efficient
mucocillary clearance of inhaled microbes and particulates. Lung figure adapted from Ref. (41). Abbreviations: CCR9, C–C motif chemokine receptor 9; DCs,
dendritic cells; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; FAs, fatty acids; GC, goblet cells; GPR, G-protein coupled receptor; ILC, innate lymphoid
cells; α4β7, integrin α4β7; IL-1β, interleukin 1 beta; IL-4, interleukin 4; IL-5, interleukin 5; IL-10, interleukin 10; Fe2+, iron; MΦ, macrophage; NFκB, nuclear factor
kappa-light-chain-enhancer of activated B cells; PPARγ, peroxisome proliferator-activated receptor gamma; RA, retinoic acid; SCFAs, short-chain fatty acids; TGFβ,
transforming growth factor beta; Th, T helper; Tregs, T regulatory cells; TLR4, toll-like receptor 4; VitA, vitamin A; VitD, vitamin D; VDR, vitamin D receptor; healthy
bacteria phyla— , bacteroides; , firmicutes ; , barrier integrity.
Dairy Products effect of raw milk has been speculated to be due to improvement
Dairy products are a major source of SFA present in our diets. in nutrition, prevention of lactose intolerance, or the presence
In a Japanese study, an increased incidence of CD was strongly of “good” bacteria. However, the topic is still debatable and more
correlated to milk protein (124). Furthermore, an increase in studies are needed.
cheese consumption is associated with an increased risk of both
UC and CD (125). In line with these findings, IL-10−/− mice fed a Emulsifiers
saturated milk fat-derived diet resulted in an increased severity of Processed foods have been identified as a risk factor for IBD
colitis associated with a colonic Th1 profile and presence of CD4+ (4, 115) and in 2013, it was hypothesized that the increased
IFN-γ+ cells in the mesenteric lymph nodes (MLNs) as a result incidence in CD was the result of a higher consumption of
of blooming of an opportunistic bacteria Bilophila wadsworthia emulsifiers in processed foods (131). Indeed, using an animal
(126) (Figure 4). Interestingly, WT mice fed milk fat diet and model of colitis (IL-10−/− mice), it was shown that exposure
presenting a blooming of B. wadsworthia did not develop colitis, to two common emulsifiers, carboxymethylcellulose (CMC)
indicating the impact of genetic predisposition on the subsequent and polysorbate-80 (P80), aggravated colitis by increasing gut
inflammatory response. Of note, 20% of patients with UC ben- permeability, reducing mucus thickness, promoting higher
efited from excluding milk and cheese from their diet (127). These penetration of intestinal bacteria, and altered microbial compo-
collected data indicate that dairy products may play a role in IBD sition, particularly by enrichment in Bilophila spp. (Figure 4).
pathology. In contrast to IBD, a decreased asthma risk is associated Exacerbation in obesity/metabolic syndrome was also observed
to milk fat (117, 118). Additionally, it has been reported children in emulsifier-treated TLR5−/− mice (132). Supporting these
who consumed raw milk during childhood show a reduced risk findings, it was shown in vitro that addition of P80 induced a
of developing atopy and/or asthma (128–130). The protective higher translocation of E. coli across M-cells (133) (Figure 4).

More recently, using an ex vivo model of human microbiota NUTRIENTS AND THEIR IMPACT ON
culture which was exposed to CMC and P80 revealed an altered MICROBIOTA AND IMMUNE RESPONSES
gene expression and microbial composition by, e.g., induction
of bioactive flagellin. However, transfer of emulsifier-treated
AT MUCOSAL SITES
microbiota to GF mice resulted in a low-grade inflammation Recent evidence has identified the existence of a cross talk between
and metabolic syndrome features but not colitis (134). The rel- the host and the commensal microbiota within the gut. In this
evance of these findings for the development of the microbiota dialog, nutrients play an important role either by directly interact-
and immune system and in other chronic conditions is yet to ing with the host via the epithelium or the intestinal immune system
be addressed. 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
Fibers, Vegetables, Fruits, and Fish adapt depending on the microbiota (commensal, pathobionts, and
In contrast to dietary fats, diets rich in fish (n-3 PUFAs), fer- pathogens) and the diet (prebiotics, supplements, or detrimental
mentable fibers and vegetables and fruits lower the risk for IBD nutrients). The worldwide increased incidence of IBD and asthma
(4, 115). For example, an inverse correlation of eicosapentaenoic has been hypothesized to be associated with changes in dietary
acid (EPA) and docosapentaenoic acid with colonic cytokine habits, i.e., westernized life style. In the following sections, we will
levels was identified in UC patients (115). Several studies have outline several important macro- and micronutrients associated
suggested that a diet low in refined carbohydrates could be ben- with diets and their effect on immune responses at mucosal sites
eficial in the treatment of CD, reviewed in Ref. (135); however, important in health and in IBD and asthma.
clinical trials are needed for this view to be proven (136, 137).
Findings from a prospective study investigating the long-term
intake of dietary fiber and risk of incidence of CD and UC in
Macronutrients
In this section, we will summarize the impact of the main macro-
women revealed a 40% reduction in risk of developing CD while
nutrients fat, carbohydrates and proteins on immune responses
no association to UC was observed (138). Much of the fiber
and microbiota (Table 1).
intake in this study originated from fruits. The Aryl hydrocarbon
receptor (AhR) was identified as a potential mechanism linking
Fats
the positive effects of fruit-derived fiber. AhR is expressed ubiq-
Under this section, we will outline the impact that saturated-,
uitously in vertebrate cells and mediates the toxicity of xenobiotic
monounsaturated-, and PUFAs have on immune and microbial
molecules by binding to the AhR nuclear translocator and acti-
responses associated with IBD and asthma.
vating dioxin- or xenobiotic-response element sequences (139).
Indole-3-carbinol, a major component of cruciferous vegetables Saturated Fatty Acids
(e.g., broccoli, cabbage, and cauliflower) can activate AhR in the Fatty acids belonging to SFAs and containing 12 or less carbon
intestine (140), inducing maintenance and expansion of intestinal (CX) atoms, include carprylic acid (C8:0), capric acid (C10:0),
intraepithelial lymphocytes (IELs) and IL-22-producing ILCs and lauric acid (C12:0), are found in vegetable oils, cocoa butter,
(141). IELs are T cells expressing αE (CD103)/β7 integrin, local- palm oil. SFAs containing more than 12 carbon atoms include
ized in between epithelial cells and are characterized as either myristic (C14:0), palmitic acid (C16:0), stearic acid (C18:0)
conventional (CD4+ or CD8αβ+TCRαβ+) or unconventional which can be found in lard, butter, beef, pork, chicken fats, eggs,
(TCRγδ+ and CD8αα+TCRαβ+) IELs. IELs have been regarded and vegetable oils (147).
as a first line of defense against infected/damaged epithelial cells Evidence exists that SFA can act as pro-inflammatory media-
and are implicated in the regeneration of the intestinal epithelium tors, e.g., as ligands for TLR4 (148, 149). Potential mechanisms
(142). Indeed, recent studies have demonstrated that IELs play by which SFAs elicit a TLR4-induced inflammatory response
a hitherto underappreciated role in gut epithelial homeostasis have been recently reviewed (12). Briefly, it is proposed that
(143). In addition, aberrant IEL phenotype and lineages are now similar to lipopolysaccharide (LPS), the SFA lauric acid can
evident in pathologies such as celiac disease and enteropathy- trigger TLR4 via CD14/MD2 activation thereby promoting
associated T lymphoma (144). The roles that these differing IELs the expression of the transcription factor NF-κB, which plays
play in sensing and interacting with the gut microbiota in IBD a crucial role in the induction of the pro-inflammatory media-
and other GI conditions warrants further investigation. tors COX2, TNFα, IL-1β, IL-6, CXCL8, IL-12, and IFNγ (150)
In asthma, a high-fiber intake in late pregnant mothers was (Figure 4). Comparably, palmitic acid and stearate can induce
correlated with high serum acetate levels and resulted in lower pro-inflammatory cytokine production from macrophages via
infant GP visits for cough or wheeze (17). In children aged 10–14, degranulation of Ikappa B alpha (IκBα) and phosphorylation of
a dietary intake of fruits, but not vegetables, was negatively related c-Jun N-terminal kinases, MAPKs, and extracellular signal-regu-
to wheeze, while no protective effect was identified in adults (27). lated kinases (ERK). LPS together with palmitate activate reactive
Intake of oily fish, such as salmon, sardines, herring, tuna, oxygen species and the NLRP3 inflammasome leading to IL-1β
and mackerel, which are rich in n-3 FAs, have shown a potential maturation in macrophages (95) (Figure 4). Moreover, a high
benefit in preventing asthma in children and in patients with intake of SFA, i.e., given in western diet, leads to the modification
UC, while no beneficial effect in adults with asthma was reported of the gut microbiota raising the proportion of Gram-negative
(145, 146). bacteria and thereby the natural ligand for TLR4, LPS, as well as

Figure 4 | Schematic illustrating the nutrient factors affecting microbial and host responses in the inflamed gut in inflammatory bowel disease (IBD) and the lung in
Asthma. In both IBD and Asthma genetic susceptibility, microbiota, and dietary changes result in disease development and inflammation. Dysfunctional epithelia
barrier function allows for malabsorption of nutrients, inappropriate immune sampling, and colonization of the gut by pathobionts and subsequent disease
exacerbation. In the lung, environmental triggers stimulate inflammatory and allergic reactions resulting in mucus hypersecretion, epithelia, and tissue remodeling
and resulting compromised of lung function. This microenvironment change allows for microbial changes which allow for increased respiratory infections in asthmatic
patients. Both IBD and asthma pathogenesis is related to reduced microbiota-derived SCFAs, malabsorption of iron and Vitamins and reduced gut-derived SCFA
result in a trend toward an inflammatory sensing of the mucosa associated microbiota. A diet high in SFA increases TLR4 sensing and subsequent inflammatory
reactions to the microbiota resulting in disease progression. This dysregulated mucosal inflammation changes the epithelia barrier function and subsequently alters
the microbiota of both sensitive immune sites displaying the characteristic phenotypes associated with both IBD and asthma. Lung figure adapted from Ref. (41).
Abbreviations: CXCL8, C–X–C Motif Chemokine Ligand 8; DCs, dendritic cells; Emul, emulsifier; GC, goblet cell; HF/HS, high-fat/high sucrose; ILC, innate lymphoid
cells; IL-1β, interleukin 1 beta; IL-6, interleukin 6; IL-12, interleukin 12; Fe2+, iron; LPS, lipopolysaccharide; MΦ, macrophage; MAPK/ERK, mitogen-activated protein
kinase/extracellular signal-regulated kinase; MF, milk fat diet; N, neutrophils; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; PPARγ,
peroxisome proliferator-activated receptor gamma; SFA, saturated fatty acids; SCFAs, short-chain fatty acids; TGFβ, transforming growth factor beta; Th, T helper;
TNF, tumor necrosis factor; TLR4, toll-like receptor 4; VitA, vitamin A; VitD, vitamin D; healthy bacteria phyla— , bacteroides; , firmicutes; , adherent and
invasive Escherichia coli (AIEC); , Bilophila wadsworthia; , other altered bacterial spp; , compromised barrier integrity.
an increase in intestinal permeability, which in itself induces a propria but without the development of obesity or obesity-
state of metabolic endotoxemia (151) (Figure 4). Intake of SFAs associated metabolic features (154). Similarly, Mdr1a−/− mice
can also increase plasma low-density lipoprotein cholesterol by fed a lard-based high-fat diet for 12 weeks led to an exacerbation
inducing the formation of low-density Lipoprotein (LDL) and of spontaneous colitis associated with elongated crypts, loss
by reducing LDL turn-over leading to the generation of oxidized of goblet cells, and infiltration of immune cells. Contrary to
LDL (152). Both oxidized LDL and phospholipids are damage- TNFΔARE mice, Mdr1a−/− mice developed obesity as character-
associated molecular patterns, which are also recognized by TLR4 ized by increased adiposity and presence of foamy macrophages,
and can trigger a CD36–TLR4–TLR6-mediated inflammatory while WT mice did not (155). Rats fed a diet containing capric
response (153). These findings support a pro-inflammatory effect and lauric acid followed by DSS-induced colitis, developed worse
of SFA on the microbiota on innate responses in macrophages. colitis associated with a higher colonic myeloperoxidase activity
To date, mechanistic studies on saturated fats in human IBD and a pro-inflammatory cytokine profile as well as a reduction
are scarce and, therefore, much of our knowledge on SFAs and in goblet cells (156). Overall, these findings indicate that the
intestinal inflammation emanates from studies in experimental type of SFA diet, microbiota status, diet regimen, and/or the
models. TNFΔARE mice fed a palm oil-based high-fat diet for genetic background of the animals determine the development
up to 12 weeks resulted in an initial acceleration of ileitis fol- of intestinal inflammation and obesity, suggesting that different
lowed by worsening of proximal colitis associated with loss of dietary-induced mechanisms regulate these two conditions. In
TJ protein occludin in the distal ileum, endotoxin translocation, asthma, SFA have been shown to effect symptoms and immune
and increased infiltration of DCs and Th17 cells into the lamina activation, e.g., by inducing a neutrophilic inflammation and

suppressing bronchodilator recovery in asthmatic patients (11, role, e.g., it is produced by macrophages and neutrophils as a
27) (Figure 4). response to inflammatory stimuli and (2) a regulatory role, by
inducing immune tolerance, independent of IL-10 or Tregs (167).
Monounsaturated Fatty Acids and Derived Oils n-3 PUFAs are primarily sourced from the human diet, with
Monounsaturated fatty acids, including palmitoleic acid (C16:1) DHA and EPA especially sourced from fish (e.g., salmon) and
and oleic acid (C18:1, OA) are normally found in macadamia ALA from seed oils (e.g., walnut, linseed oil). Several reports
nuts, blue-green algae, olive oil, canola oil, beef tallow, lard, and have highlighted their effect in preventing and/or treatment of
avocado. different inflammatory diseases in animals and humans, includ-
Diets rich in MUFA appear to reduce LDL cholesterol and ing IBD and asthma. n-3 PUFAs can inhibit TLR4 signaling
potentially increase high-density lipoprotein (HDL) cholesterol and the subsequent gene transcription of pro-inflammatory
(157), and palmitoleate treatment of M1 macrophages induce an mediators (168), a process partly mediated via GPR120 (169)
anti-inflammatory M2 profile (158) indicating an anti-inflamma- (Figure 3). n-3 PUFAs can also activate the anti-inflammatory
tory capacity of MUFAs. The specific role of MUFAs in IBD and transcription factor PPAR-γ and inhibit NF-κB (Figure 3) and
asthma remains inconclusive. For example, a prospective study the subsequent pro-inflammatory cytokine production includ-
by de Silva and colleagues showed that a dietary oleic acid was ing TNFα, activity which is highly expressed in the mucosa of
inversely associated with UC development (114), while palmi- patients with IBD and asthma subtypes (13, 170, 171). DHA
toleic and oleic acid treatment of polarized intestinal epithelial can also improve epithelial barrier integrity by increasing the
cells impaired epithelial barrier function (159). MUFA and oleic expression of the TJ proteins occludin and claudin-1 (Figure 3)
acid intake indicated an increased risk of wheeze and non-atopic (172), as the integrity of the epithelium is critical in prevent-
asthma, respectively (160). Extra virgin olive oil, high in MUFAs, ing paracellular translocation of LPS into systemic circulation.
contains highly bioactive components which are present in the PUFA supplementation in particular those related to fish oils can
unsaponifiable fraction (UF). Beneficial effects of UF and olive oil also modulate asthma symptoms (173, 174), with reduction of
were demonstrated in an acute DSS model of colitis and in mice with wheeze, improved pulmonary function and reduced pro-inflam-
C. rodentium induced colitis. Disease amelioration included matory mediators in sputum. However, it should be noted that
alleviation of oxidative stress, reduction of pro-inflammatory many trials are designed to measure different outcomes which
proteins and increased levels of intestinal alkaline phosphatase, can deliver conflicting findings (27, 175). With the evolution in
which can de-phosphorylate bacterial LPS (161–163). In line food technology and modern agriculture in the last 100 years the
with these findings, isolated blood and intestinal T cells from amount of n-6 FAs, e.g., LA present in our food has increased
UC patients treated with UF resulted in a reduction in T cell due to change in animal feed from grass to grains (176, 177).
activation, β7 integrin expression and IFNγ production as well as Therefore, the ratio of n-6/n-3 PUFAs present in the food has
induction of apoptosis (164). Findings from these studies indicate changed from 1:1 to 16:1 in USA/Europe (177) (Figure 2). This
MUFA exert both pro- and anti-inflammatory activities in these ratio has increased dramatically due to food processing, less fish
mucosal conditions. and fiber consumption, and the dietary habits of farm animals. In
line with this, a recent study identified a higher ARA:EPA ratio in
Polyunsaturated Fatty Acids the inflamed mucosa of UC patients, which correlated with the
Polyunsaturated fatty acids are FAs containing more than one severity of the disease (178). No association of n-6/n-3 ratio was
double carbon bonds. Therefore, naturally, they are more prone found in individuals with hay fever or allergic sensitization (179).
to oxidation and oxidized LDL synthesis. Long chain PUFAs The relevance of a lack of n-6/n-3 ratio association to asthma is
are divided in two main groups; omega-3 (n-3) PUFAs includ- still to be uncovered.
ing—alpha-linolenic acid (ALA, C18:2), docosahexaenoic acid
(DHA, C22:6), and EPA (C20:5); and omega-6 (n-6) PUFAs Carbohydrates
including—linoleic acid (LA, C18:3), and arachidonic acid (ARA, Carbohydrates are divided into four groups: monosaccharides,
20:4). LA and ALA are referred to as essential FAs as they are disaccharides, oligosaccharides and polysaccharides. Generally,
the precursors of ARA, EPA, and DHA. DHA and EPA compete monosaccharides and disaccharides are referred to as sugar. In
for the enzymes and products of ARA metabolism whereby they the western diet a large amount of calories are ingested in form
can antagonize the formation of inflammation related eicosanoid of refined carbohydrates, i.e., sucrose, starch, fructose syrup,
mediators (165, 166). etc.—obtained from soft drinks, pastries and desserts, and white
Arachidonic acid is the primary n-6 PUFA found in inflam- bread. This energy-dense but nutrient-poor diet is a risk factor
matory cells and is important for the production of inflammatory for obesity, type 2 diabetes, cardiovascular diseases and more.
eicosanoids. ARA is formed out of LA which is further converted Therefore, the biological plausibility exists that it has impact on
to prostaglandins [e.g., prostaglandin E2 (PGE2), leukotrienes intestinal inflammation and asthma. Moreover, related to the
(LTBD4), and other lipoxygenase or cyclooxygenase products carbohydrates that can be metabolically used by gut microbes, the
(COX1/-2)], the so-called eicosanoids, all of which have pro- and term “microbiota-accessible carbohydrate” has been proposed.
anti-inflammatory in addition to atherogenic and pro-thrombotic The term refers to the ability of microbial carbohydrates to modify
effects (166). PGE2 is one of the key prostaglandins produced in the composition of the microbiota, and dictate the functionality
the intestine where it has dual functions: (1) a pro-inflammatory and metabolic output (180).

Fibers and acetate and propionate to GPR43 also supported the reduc-
Dietary fiber is a plant-based nutrient and a type of carbohy- tion in airway inflammation (17, 23, 194, 195). These microbiota-
drate, which due to its biochemical structures resists digestion mediated effects are also linked to maternal influences of asthma
by intestinal and pancreatic enzymes in the human GI tract. risk, where high serum acetate concentrations, but not propion-
Therefore, the fiber passes through the GI tract relatively intact. ate, in pregnant mothers’ correlate with reduced asthma risk and
Fermentable carbohydrate substrates such as non-starch polysac- are thought to modulate Tregs biology of the fetus (17). These
charides, resistant starch and oligosaccharides serve as important findings clearly point to a crosstalk between the gut and the lung
substrates for the gut microbiota. The microbes located in the via SCFA in asthma and between the microbiota and the intestine
human colon use fermentation to produce SCFAs, lactate and in IBD, indicating that treatments aiming to increase SCFAs and
gas (181). These fermentation products selectively promote the SCFA producing bacteria should be further investigated.
growth of beneficial Bifidobacteria and Lactobacilli and exert
anti-inflammatory (inhibition of NFκB transcription via GPR41) Proteins
and anti-carcinogenic functions (182). Proteins consist of carbon, hydrogen, oxygen, and nitrogen
elements. They are essential nutrients and are involved in virtu-
Short-Chain Fatty Acids. Upon fermentation of dietary fiber, ally all physiological functions. High protein intake, especially
bacterial metabolites such as SCFAs are produced in the colon. animal derived protein, is associated with an increased risk of
SCFA mediates the communication between the commensal CD (196). In asthmatics high ingestion of cured meats is linked
microbiota and the immune system affecting the balance between with worsening of symptoms (24).
pro- and anti-inflammatory responses. The beneficial effects of Carnitine is an amino acid derivative synthesized primar-
butyrate on colonic health are particularly well established (183). ily in the liver and kidneys from lysine and methionine and
Microbial-derived butyrate and to a lesser extent acetate and is involved in lipid metabolism in eukaryotic cells (197). In
propionate, can facilitate the generation of extrathymic Foxp3+ humans, the main source of carnitine is red meat. Humans
Tregs which are crucial for limiting intestinal inflammation with an omnivorous diet following ingestion of l-carnitine,
(17, 184, 185) (Figure 3). Presence of butyrate during human DC presented increased plasma trimethylamine-N-oxide (TMAO)
maturation results in a tolerogenic phenotype, with an increased levels, which was dependent on microbiota mechanisms, when
expression of IL-10 (186, 187), further supporting the regulatory compared to vegans or vegetarians. Elevated plasma levels of
potential of SCFAs (Figure 3). SCFA can signal through the acti- TMAO are positively correlated with an increased risk for major
vation of specific G-protein coupled receptors (GPCRs), GPR41, adverse cardiovascular events (198). However, TMAO has also
GPR43, GPR109, which are particularly expressed in immune protective functions, e.g., by protecting cells from osmotic and
cells, e.g., polymorphonuclear leukocytes, and are suggested to hydrostatic damage, and therefore, is essential for all organisms
participate in immune surveillance of the colonic mucosa affect- (25). A recent study proposed plasma TMAO as a non-invasive
ing the balance between pro- and anti-inflammatory responses biomarker for IBD, as decreased TMAO levels are seen in these
(188). GPR43 is additionally expressed in the colonic epithe- patients (199). The reduced TMAO was likely related to altera-
lium where it can mediate SCFA-regulated effects on epithelial tions in the gut microbiome (the abundance of anaerobes or fac-
barrier and proliferation (Figure 3). Butyrate is also a natural ultative anaerobes) in these patients. TMAO is also an oxidation
ligand for PPARγ, which is expressed in colonic epithelial cells, product of trimethylamine which can be found in seafood, fish,
macrophages and lymphocytes. Colonic PPARγ expression is etc. Consumption of TMAO-containing food, e.g., oily fish can
linked to host–microbe interactions with natural (e.g., SCFA— lead to accumulation of TMAO and protection against asthma
butyrate, conjugated LA) and synthetic (e.g., 5-aminosalicylic in childhood (200). Further studies are necessary to shed a light
acid) PPARγ ligands preventing inflammation in experimental into mechanisms that underlie the association of high intake of
colitis (189). animal protein in these conditions.
A significant decrease in the number of butyrate-producing Other studies have also shown how dietary peptides and amino
bacteria including Eubacterium rectale/Roseburia spp (which acids can modulate intestinal immune functions and influence
belong to Clostridium coccoides) and F. prausnitzii (which belong inflammatory responses. Supplementation with the dipeptide
to Clostridium leptum cluster), both within the Firmicutes phylum alanine-glutamine, led to decreased expression of inflammatory
was revealed in patients with UC and CD (190, 191). In patients mediators and increased expression of mucin 2 (MUC2) promot-
with UC, colonic irrigation with butyrate is able to limit inflam- ing mucosal recovery in the DSS-induced colitis mouse model
mation and in experimental models it ameliorates inflammation (26). Moreover, lower serum tryptophan is associated to active
and modifies microbial composition (183, 192). CD (201). Supplementing tryptophan presented beneficial effects
In the Canadian CHILD study the SCFA acetate was reduced in the DSS-induced porcine IBD model, by inducing T cell apop-
in the feces of infants with atopy and wheeze (83). Feeding a tosis and thereby inhibiting Th1-mediated immune responses
high fiber diet to mice has resulted in gut microbiota alteration and subsequently reducing inflammation (202).
which concomitantly leads to increased serum SCFAs, such as
acetate and propionate, and alleviates allergic asthma symptoms Micronutrients
(Figure 3). These SCFAs induced an enhanced DC and mac- Micronutrients or trace elements are nutrients required by
rophage phagocytosis and reduced Th2 responses in the murine organisms in small quantities to maintain a variety of physi-
lung (17, 23, 193). Furthermore, binding of propionate to GPR41 ological functions and as most of them are essential, they need

to be obtained from the diet. These minerals include iron, cobalt, shift in Th17/Tregs in UC biopsies (216–218). VitA appears to
chromium, copper, iodine, manganese, selenium (Se), zinc (Zn) influence the microbiota, as its deficiency seems to favor a non-
and vitamins include Vitamin A (VitA), vitamin B1 (VitB1), symptomatic reservoir of E. coli-like enteric infections (219, 220).
Vitamin B6 (VitB6), Vitamin B9 (VitB9), VitB12, VitD, and VitK.
Micronutrient deficiencies impair immune function and increase Vitamin D
the severity of disease (203). Micronutrient deficiencies occur in Vitamin D belongs to a group of fat-soluble vitamins which are
more than half of patients with IBD, with CD patients present- essential for bone mineralization and optimal intestinal absorp-
ing more deficiencies than UC patients, with the most common tion of calcium, iron, magnesium, phosphate, and Zn. VitD
being VitB1, VitB6, VitB12, VitD, VitK, iron, folic acid, Se, and Zn regulates the epithelial integrity/barrier function and is involved
(204). This deficiency in vitamins (hypovitaminosis) is thought in the detoxification and protection against infection as well as in
to be the result of malabsorption, altered microbial composition controlling of the commensal microbiota (221, 222).
and impaired host mucosal system. Low dietary intakes of VitA Vitamin D can be obtained from the diet or by dermal synthesis,
and VitC are associated with asthmatics (205). The next section e.g., in the skin where it is produced from 7-dehydrocholesterol
summarizes the most relevant micronutrients in relation to IBD (222). 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] is the active
and asthma pathology. form, which arises from the bloodstream (endocrine action) or
it can be locally produced from circulating 25(OH)D3 within
Vitamins intestinal cells (intracrine, autocrine and paracrine action). VitD
Vitamins can be absorbed from the diet but the gut commensal is ubiquitously expressed in several human tissues including
microbiota play an important role in their production and bio- immune cells, but its expression is higher in intestinal epithelial
availability (206). Indeed, the diet of germ-free mice requires cells (223). VitD deficiency has been associated with a greater dis-
supplementation with dietary VitK and B Vitamins to maintain a ease activity and extended disease duration in patients with IBD
normal function (207). (Figure 4) – why a supplementation of VitD is often required.
Human polymorphisms in the vitamin D receptor (VDR) are
Vitamin A also associated with susceptibility to IBD (224). Vitamin D3 has
Vitamin A is a group of unsaturated organic compounds been linked to beneficial effects in asthma; however, the benefits
including retinol, retinoic acid (RA), and several pro-vitamin A are mainly observed in children or via maternal supplementa-
carotenoids including beta-carotene. They are fat-soluble sub- tion (225). Recent studies have identified that VitD3 appear to
stances obtained from animal food sources. RA is a metabolite modify VEGF function and reduction in airway smooth muscle
of VitA, which is produced by CD103+ DCs and epithelial cells proliferation (226).
and acts as ligand for RA receptors (RARs) and Retinoic-X- The biological actions of 1,25(OH)2D3 are mediated via
Receptor (RXR), transcription factors regulating gene expres- the VDR, which acts as an heterodimer with RXR to acti-
sion. Lymphoid cells express RAR, RXRs and RA, which are vate VitD target genes (222, 227). VDR targeted pathways
known to regulate IgA and mucosal homeostasis (Figure 3). regulating inflammatory responses include TLR and NF-κB
DCs from Gut associated lymphoid tissue (GALT) produce RA signaling, Th17/Tregs response, apoptosis, cell proliferation
to sustain gut tropism and in synergy with GALT-DC-derived and differentiation, barrier function, etc. (Figure 3). The anti-
IL-6 or IL-5, induce IgA production (208) (Figure 3). RA can inflammatory role of 1,25(OH)2D3 is based on the suppressive
also control the presence of RORγ+ ILCs, the formation of effect of NFκB activity, as NFκB-induced pathways are enhanced
lymphoid tissue in the small intestine (209) and appears to be a in VDR−/− mice exposed to bacterial and chemically induced
cofactor in IgA class switch recombination (210). RA can also colitis (228). 1,25(OH)2D3 regulates intestinal barrier trough
induce the gut-homing capacity on T cells by the up-regulation the up-regulation of TJ proteins including occludin, ZO1, clau-
of the integrin α4β7 and the chemokine receptor CCR9 (211) din 2 and E-cadherin (221, 229) (Figure 3). In support of this,
(Figure 3). A diet deficient in VitA can lead to a systemic pro- IL-10−/− mice expressing the human VDR in intestinal epithelial
inflammatory state, due to a lack of homing integrins in MLN cells resulted in a reduced development of spontaneous colitis
activated T- and B-cells, which then go into systemic circulation (230). VitD has been linked to the modulation and control of
instead of migrating back to the gut (212, 213). RA, together the gut commensal microbial composition (Figure 3), since
with TGFβ, promotes naïve CD4+ to become Foxp3+ Tregs and VDR−/− mice present an altered microbiota with more abundance
RA alone has also inhibitory effects on Th17 cell differentiation on Bacteroidetes and Proteobacteria phyla and less abundance on
(Figure 3). Others have also described that VitA can impair the Firmicutes phyla (231). Interestingly, analysis of mice treated
the reprogramming of Tregs into IL-17-producing cells during with 1,25(OH)2D3 revealed an increased C. rodentium load in
intestinal inflammation (214). the colon and spleen doubtless due to the suppression of a Th17
Patients with IBD have been reported to be deficient in VitA response, which is essential for C. rodentium clearance (232). In
(Figure 4). Cytochrome P450 26 B1 (CYP26B1) participates in contrast, following infection with C. rodentium, a diet deficient
the degradation of RA, and homozygous carriers of the CYP26B1 in VitD aggravated barrier function, microbiota composition and
polymorphism rs2241057 have been associated as risk factor of inflammation (233). Correspondingly, mice fed a high-fat and
CD development, linking an elevated catabolic function of RA to VitD deficient diet presented increased ileal antimicrobial pep-
IBD (215). Supplementation of VitA/RA seems to attenuate intes- tides and Helicobacter hepaticus and reductions in TJ proteins,
tinal inflammation in experimental models and even induces a MUC2 expression and abundance of beneficial bacteria such as

Table 1 | Dietary factors and host inflammatory responses at mucosal sites.
Dietary factor Inflammatory/immune response Reference
Intestine Lung
Macronutrients
Fat
High-fat diet Permeability of epithelial barrier ↑ Neutrophil ↑ (10, 11)
TLR4 mRNA ↑
Saturated fatty acids Activation of TLR4↑ (12)
n-3 PUFA, e.g., EPA, DHA PG (series-3) ↑ Maternal supplementation reduced Childhood (13)
LK (series-5) ↑ Asthma (14, 15)
Leukocyte chemotaxis↓ IL-13 cord blood ↓
IL-1β ↓, TNFα ↓ Mucus (murine) ↓
Resolvins, Maresins and Protectins↑ CD45+ inflammatory cell infiltrates (murine) ↓
n-6 PUFA, e.g., ARA, linoleic acid PG (series-2) ↑ Mucus (murine) ↓ (14)
LK (series-4) ↑
SCFA, e.g., butyrate Energy source for colonocytes Allergy ↓ (16, 17)
Barrier function ↑
Peroxisome proliferator-activated receptor γ activation ↑
Carbohydrates
Sucrose Permeability of epithelial barrier ↑ Asthma and dental caries ↑ (18–21)
Fermentable carbohydrates, e.g., fiber Butyrate production ↑ SCFA levels ↑ (22, 23)
DC maturation ↓
TH2 response ↓
Proteins
Animal-derived proteins, e.g., carnitine TMAO synthesis ↑ Asthma exacerbation (cured meats) (24, 25)
Dipeptides, e.g., alanine–glutamine Mucin 2 expression ↑ (26)
Micronutrients
Vitamins
Vitamin A, e.g., RA, β-carrotene Induction of tolerogenic DC and Tregs ↑ (27, 28)
Vitamin D Cathelicidin production Maternal supplementation reduction in airway (27, 29, 30)
Innate defense toward regulatory state ↑ smooth muscle
Ca2+absorption ↑
Vitamin B, e.g., thiamine, folate, Vitamin B9 deficiency—colonic Foxp3 + Tregs ↓ Folate deficiency—asthma exacerbations (31–34)
cobalamine, pyridoxine
Minerals
Iron Incorporated into iron–sulfur clusters, redox cofactors, or used (35, 36)
metalloenzymes
ARA, arachidonic acid; Ca2+, calcium; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; Foxp3, Forkhead-Box-Protein P3; LK, leukotrienes; PG, prostaglandins; RA, retinoic
acid; TLR4, toll-like receptor 4; PUFA, polyunsaturated fatty acid; SCFA, short-chain fatty acid; Tregs, T regulatory cells; CD, cluster of differentiation; DC, dendritic cells;
IL, interleukin; TMAO, trimethylamine-N-oxide; Th, T helper cell.
Akkermansia muciniphila developing insulin resistance and fatty highlight a potential link between the microbiota, glucose, FAs
liver (234). and mucosal alteration leading to intestinal inflammation in
which thiamine may have a key role.
Other Vitamins
Vitamin B1. Vitamin B1, also known as thiamine, is mainly Vitamin B6. Vitamin B6 is a water-soluble vitamin, also known
obtained from whole grains, trout, pork, peas and beans. It has as pyridoxine, which exists in several forms and can be obtained
an important role in the catabolism of sugars and amino acids from fruits, vegetables, grains, fish and meat. The biologically
(235, 236). Thiamine is a component of the pyruvate dehydroge- active form of VitB6, Pyridoxal 5′-phosphate (PLP), is involved
nase that catalyzes the formation of Acetyl CoA in FA synthesis, in the synthesis or metabolism of proteins, lipids and carbohy-
a pathway which is altered in IBD (237). Pediatric IBD patients drates and important in the modulation of immune pathways
presented alterations in cellular transport of thiamine and FAs (236, 239). PLP treatment ameliorated colitis in IL-10−/− mice due
synthesis (e.g., bile acids) (237, 238). Altogether, these findings to a reduction in colonic TNFα, IL-6, IFNγ, COX-2 and nitric oxide

synthase (iNOS) expression and modulation of the chemotactic spp. and Clostridium cluster IV, leading to an increased butyrate
lipid S1P (240). Eubacterium rectale, a dominant non-pathogenic concentration in the gut, without the induction of colitis. Thus,
fecal Gram-positive commensal bacterium has been described as iron supplementation can increase the proportion of beneficial
one of the important bacterial group synthetizing PLP (241). gut microbiota metabolites which may contribute to gut health
in IBD individuals (256).
Vitamin B9. Vitamin B9 is a water-soluble vitamin also known
as folic acid or folate, it can be obtained from vegetables and fruits Other Minerals
and is important in DNA repair and methylation aiding rapid Selenium. Selenium is an essential antioxidant trace min-
cell division and growth during, e.g., infancy and pregnancy. eral which can be obtained from proteins or vegetables and is
Bacteria linked to folate biosynthesis include Bifidobacteria and used in the body to synthetize the amino acid selenocysteine
Lactobacilli groups (207, 242, 243). A deficiency in VitB9 has been (selenoproteins). Large amounts of Se can cause toxicity (257).
more commonly ascribed to CD, especially in patients with ileal The amino acid transporters SLC3A1 and SLC1A4 have been
disease, than in UC patients (244, 245). VitB9 deficiency has also suggested as Se transporters (236) and play a role in intesti-
been associated with a reduction in colonic Foxp3+ Tregs (33). nal epithelial permeability and barrier function. Lower Se
Folate supplementation during pregnancy has been linked to serum levels have been described in children with IBD (258).
an increased risk of infants developing asthma; however, this is A possible therapeutic role for Se has been described, whereby
controversial with conflicting studies providing little clear evi- macrophage derived selenoproteins enhance 15-hydroxypros-
dence (34, 246). taglandine dehydrogenase (15-PGDH) and protects mice from
DSS-induced colitis (259). A potential role for Se in asthma
Vitamin K. Vitamin K is a fat-soluble vitamin required for pathogenesis has been hypothesized; however, data from
synthesis of certain proteins involved in blood coagulation human studies are conflicting. A benefit of Se supplementation
and is linked to calcium pathways and calcification. VitK1 can in animal asthma studies has been identified by regulating Th
be obtained from, e.g., meats, cheeses, and eggs or synthetized cell differentiation (260).
(VitK2) by the microbiota of the colon de novo or from VitK1
(236, 247, 248). VitK deficiency has been associated with both Zinc. Zinc is an important mineral involved in wound repair,
adult and pediatric CD patients (249). A protective role of VitK tissue regeneration, and the immune response. Low serum Zn
was shown in a model of DSS-induced colitis associated with a levels have been reported in children with IBD (258). Zn given
reduction in IL-6 production from B cells (250). orally to CD patients restored intestinal permeability by modu-
lating TJ proteins in both the small intestine and colon (261). Zn
Minerals concentrations have been found to be significantly lower in asth-
Minerals are obtained from the diet, and are essential nutrients matic patients and it is thought to result in reduced antioxidant
needed by organisms for synthesis of common organic molecules. function increasing asthma risk (262).
Accordingly, mineral deficiencies in the westernized diet have a
major impact on host health. The next section summarizes the CONCLUSION AND FUTURE
most relevant minerals in relation to IBD and asthma pathology. PERSPECTIVES
Iron The increasing incidence of IBD and asthma implies a funda-
Anemia is one of the most common extra-intestinal manifesta- mental role for environmental factors. Several lines of evidence
tions of IBD. The deficiency, results from either an absolute state, have identified the consumption of a diet high in saturated fat
i.e., poor dietary intake of iron, reduced iron absorption, and/ and high in sucrose increases a person’s risk for several chronic
or increased blood loss from chronically inflamed intestinal conditions including IBD and asthma (4, 27). Studies in animal
mucosa; and/or functional iron state, i.e., deficiency in VitB12 models, human cells and tissues for both conditions have also
and insufficient availability of iron for incorporation into eryth- highlighted the complex interaction between diet, the micro-
roid precursors despite normal or increased body iron stores biota and the host response, especially regarding aggravation of
(251, 252). It is estimated that up to 80% of patients with IBD inflammatory responses upon consumption of certain trigger-
present with anemia (253). Consequently, oral or i.v. iron supple- ing nutrients and diets. Dietary ingredients in the western diet
mentation is important in treatment of IBD patients. Nonetheless, are not limited to the ones listed in this review. Apart from the
caution is needed as non-absorbed iron can be toxic to intestinal increased consumption of saturated fats and sucrose, there is an
epithelial cells, since it can stimulate growth and virulence of increased consumption of food additives including sweeteners,
bacteria and appears to worsen disease activity in the patients emulsifiers, thickeners, preservatives and food colorings. Some
(178, 254). In support of this data, rats supplemented with iron of these have already been associated to asthma and IBD (122,
and exposed to DSS-induced colitis revealed an increased neu- 132, 134) but there is a need for larger epidemiological stud-
trophil infiltration, TNFα and IL-1 expression and NF-κB acti- ies to identify the effect that these products may have on both
vation – all of which could be prevented by supplementing the microbial composition and host responses (e.g., inflammation,
diet with VitE (dl-alpha-tocopherol acetate) (255). In contrast, metabolism, etc.) in disease development. In an elegant study by
rats with humanized gut microbiota and fed dietary iron sup- Arrieta and colleagues it was shown that changes in the micro-
plementation exhibited an increased abundance of Bacteroides biota especially at a young age, can help to identify a window of

opportunity for bacteria colonization and an appropriate immune metabolomics or systems biology, will reveal a clearer picture of
education in asthmatics (83). Future studies aiming to identify the components contributing to the pathology of these chronic
whether a similar new widow also exists prior to IBD onset inflammatory conditions. Furthermore, the impact of current
and whether the education of the mucosal immune system can therapeutic treatments and diets on disease progression and
be regulated by specific diet combinations and corresponding the microbiota are currently lacking, therefore, future studies
microbial alterations are required. Such studies would likely addressing this question could lead to new beneficial treatment
lead to the discovery of new target/regulatory mechanisms for strategies.
both conditions.
Individuals with IBD and asthma present with a deficiency in AUTHOR CONTRIBUTIONS
certain essential nutrients, e.g., VitD and Iron. The reductionist
approach undertaken whereby the effect of one single nutrient DS, MA, and JM wrote the manuscript; SM wrote and edited the
has been investigated in animal models, has so far provided major manuscript. All authors read and approved the final manuscript.
insights into the regulatory mechanisms associated with inflam-
mation and metabolism. In addition, the majority of animal ACKNOWLEDGMENTS
studies and diets, employs standard “high fat” diet containing a
nutrient content designed to sustain rodent health and are, there- The APC Microbiome Institute and the authors in this publication
fore, not relevant to a human and patient dietary intake (263). receive financial support from Science Foundation Ireland (SFI)
Studies using more complex systems, e.g., humanized mice (con- under Grant Number SFI/12/RC/2273. The authors would like
sisting of both a human immune system and human microbiota) to acknowledge SERVIER INTERNATIONAL for the Servier
fed with a humanized diet will provide a deeper mechanistic medical art illustrations that were used in this review. The authors
understanding of the complex diet-microbiota-host network. want to thanks Dr. Amanda Lohan for proofreading of the
Integration of various approaches, e.g., genomic, transcriptomic, manuscript.
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Diet and Nutrients and Immune

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How does diet impact the gut microbiota and immune system?

How does diet impact the gut microbiota and immune system?

What are some potential links between inflammatory bowel diseases and asthma?

What are some potential links between inflammatory bowel diseases and asthma?

Review

published: 28 July 2017

The impact of western Diet and

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DIETARY PATTERNS IN IBD AND ASTHMA

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Table 1 | Dietary factors and host inflammatory responses at mucosal sites.

Dietary factor Inflammatory/immune response Reference

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