IBD: In Food We Trust

Abstract

Background and Aims:

Both science and patients associate diet with inflammatory bowel disease [IBD]. There is no doubt that links between IBD and diet are numerous, based on both epidemiological studies and experimental studies. However, scientific evidence to support dietary advice is currently lacking, and dietary counselling for IBD patients is often limited in clinical practice to the improvement of nutrient intake. This review aimed to focus on both patient’s beliefs about and molecular mechanisms for crosstalk between nutrients and inflammation.

Methods:

A literature search using PubMed was performed to identify relevant studies on diet and/or nutrients and their role in IBD. Pubmed [from inception to January 20, 2016] was searched using the terms: ‘Crohn’, ‘colitis’,’ intestinal epithelial cells’, and a list of terms relating to diet or numerous specific nutrients. Terms associated with nutrients were individually tested in the context of IBD. Reference lists from studies selected were manually searched to identify further relevant reports. Manuscripts about diet in the context of IBD from basic science, epidemiological studies, or clinical trials were selected and reviewed. Only articles published in English were included.

Results:

Epidemiological studies highlight the key role of diet in IBD development, and many IBD patients report diet as a triggering factor in relapse of disease. In addition, we present research on the impact of nutrients on innate immunity.

Conclusion:

Diet may offer an alternative approach to restoring deficient innate immunity in IBD, and this may be the scientific rationale for providing dietary counselling for IBD patients.

1. Introduction

Links between inflammatory bowel disease [IBD] and diet are numerous, ranging from clinical evidence of frequent multifactorial nutritional deficiencies in IBD patients to efficacy of nutrition therapy either as sole therapy or as adjunctive therapy.¹ Moreover, IBD patients frequently report that specific foods cause aggravation of their symptoms, and recent reports have highlighted the importance of these dietary beliefs from the patient’s perspective.^2,3 However, scientific evidence to support specific dietary advice is currently lacking, and dietary counseling [apart from perhaps in paediatrics] is almost limited in clinical practice to the improvement of nutrient intake in IBD patients, or the avoidance of foods that may precipitate obstructive symptoms in selected patients. Nevertheless, enteral nutrition is a dietary therapy for IBD. In active Crohn’s disease [CD] in children, exclusive enteral nutrition was as effective as corticosteroids in inducing remissions.⁴ In adult patients with CD, exclusive enteral nutrition can lead to mucosal healing and quality of life improvement.⁵

IBD is a complex chronic inflammatory condition, and compelling studies have confirmed the concept that IBD results from an unbalanced relationship within the triad: environment, genes, and innate immunity.⁶ Nutrients seem to be involved in these interactions, and among environmental factors, a Western diet is considered to be a possible trigger for chronic intestinal inflammation, by altering the microbiome and by other mechanisms. Epidemiological observations suggest an association between IBD incidence and dietary patterns.⁷ In an experimental IBD model, exposure to a Western diet induced dysbiosis accompanied by an intestinal barrier dysfunction in mice.⁸ The pathways implicated in the nutrient-driven proinflammatory effects are numerous: nutrients may modulate innate immunity and consequently promote inflammation and influence the microbiota.⁹

This review will focus on interactions between nutrients and innate immunity, and attempt to relate patient’s beliefs to molecular mechanisms.

1.1. Dietary beliefs of IBD patients

IBD patients frequently report that specific food items are able to influence their disease by worsening or alleviating their symptoms.¹⁰ During the last 2 years, studies have investigated associations between diet and IBD patient symptoms.^{2, 3, 10–12} Hou et al. focused on patient-designed diets.¹¹ Indeed, patients have access to numerous non-medical resources for dietary advice, such as IBD support groups or unverified sources on the internet. Hou et al. observed that patient-devised diets are mainly based on food restrictions, and advice from patients’ various sources is highly conflicting.¹¹ Similarly, a French team investigated dietary beliefs and behavior in adult IBD patients and reported that the majority of IBD patients [66%] are avoiding certain foods.³ Patients base their choices mainly on personal experience of symptoms worsening and on their beliefs about a relapse prevention effect by specific food elimination.³ In a similar study performed in the UK, 60% of patients felt they expressed a desire for more dietary advice.²

Consequently, IBD patients are frequently on restricted diets without a scientific rationale.¹³ The most documented example is avoidance of dairy products. Contrary to the belief frequently held by IBD patients, Jowett et al. did not find any association between relapse and increased intake of milk and dairy products.¹⁴ Also, such dietary practice is not taking into account the evidence of links between low dairy products intake and increased nutritional deficiencies. An Italian study using a food questionnaire reported that the diet of IBD patients contained less calcium than that of healthy controls.¹⁵ This might potentially increase the risk of osteoporosis through inadequate dietary calcium intake. In addition, a survey from New Zealand reported that the influence of dairy products on CD symptoms was more influenced by fat content than lactose content.¹⁶ Furthermore, reduced dairy product intake is associated with low vitamin D intake. Vitamin D impact on innate immunity will be discussed later in this review—compelling evidence suggests it has a role in IBD physiopathology. Indeed, vitamin D deficiency correlates with disease activity.¹⁷ In an IBD model, vitamin D protects from colitis through microbiome modifications.¹⁸ More recently, a low level of the vitamin D receptor [VDR] was associated with innate immunity dysfunction: abnormal Paneth cells, impaired autophagy function, and dysbiosis.¹⁹

Another very popular exclusion diet, especially in the USA [0.5% of the US population], is a gluten-free diet [GFD] initiated without a diagnosis of coeliac disease. Herfarth et al. have performed a cross-sectional study on 1647 IBD patients from the Crohn’s & Colitis Foundation of America [CCFA] partners cohort, demonstrating the high prevalence of a GFD [19.1%].¹² Among patients who attempted a GFD, two out of three described an improvement in their gastrointestinal symptoms, and 38% reported fewer or less-severe IBD flares.¹² These observations are yet to be confirmed by appropriate controlled intervention trials. Inflammatory bowel disease patients need dietary advice based on strong scientific rationale to avoid them using unnecessarily restrictive diets that may impair their nutritional status. Richman et al. have recently reviewed the literature in order to provide dietary guidance based on ‘best available evidence’ and have pointed out an urgent need for further evidence.²⁰

1.2. Epidemiological evidence of the role of diet in IBD

It has long been suspected that environment, in particular dietary habits, contributes to the development of IBD [Table 1, Figure 1]. Migration studies have demonstrated the role of dietary patterns, particularly Westernization of diet, in IBD development.²¹ The Western dietary pattern [high fat, high n-6 polyunsaturated fatty acids [PUFAs], high meat, low fruits and vegetables] is associated with an increased IBD risk⁷ and also with exacerbated colitis [red meat,²² dietary fats²³]. In addition, an increased incidence of IBD has been associated with diets high in animal protein.²⁴ In Japan, dietary pattern [fat/protein] was found to be associated with CD risk,⁷ while increased consumption of animal protein has been associated with higher IBD risk in France.²⁵ The Western diet is also characterized by an unbalanced ratio of both types of PUFA [n-3:n-6 ratio]. Linoleic acid [LA, n-6 PUFA] consumption has markedly increased [3-fold throughout the 20th century].²⁶ Recent epidemiological studies have demonstrated the role of dietary intake of mono-unsaturated fatty acids [MUFAs] and PUFAs in ulcerative colitis [UC] development: Higher intake of LA, an n-6 PUFA,²⁷ or higher intake of trans-unsaturated fat²⁸ is associated with an increased risk of UC, whereas oleic acid [n-9 MUFA]²⁹ or n-3 PUFA consumption^{28, 30} is beneficial. The Western diet is associated with a low intake of fruit and vegetables, but a long-term high intake of dietary fibre reduces CD risk.³¹ Western dietary components can affect mucosal immunology by affecting numerous mechanisms (such as gut barrier function, pattern recognition receptors [PRRs] or mucin expression). For example, we previously demonstrated that n-3 PUFAs can downregulate intestinal inflammation through peroxisome proliferator-activated receptor gamma [PPARγ].³² Dimerization of Toll-like receptor-4 [TLR-4], a PRR, can be activated or inhibited according to the fatty acid type.³³

While we mainly discuss changes directly affecting host immunology, diet can also shape the microbiota, leading to a host immunity response. Comparison of the microbiota from rural Burkina Faso children with that of urban European children from Italy demonstrated how diet can profoundly modify the microbiota composition.⁹

1.3. Innate immunity sensors: a target for nutrients?

A family of intracellular danger-sensing molecules called NLRs [NOD-like receptors or nucleotide-binding domain leucine–rich repeat-containing genes] has been implicated in the pathogenesis of IBD. Within this family are the NOD [nucleotide-binding oligomerization domain] and NLRP [pyrin domain containing NLR] subfamilies [Figure 2]. The link between NOD2 mutation and CD has been well established, and it is the most commonly found gene variant associated with CD.³⁴ In addition, alteration of another family of bacterial sensors, the Toll-like receptors [TLRs, Figure 2], is well described in IBD studies. IBD patients also exhibit an abnormal composition and activity of gut microbiota. Interactions between intestinal microbes and food may influence IBD pathogenesis. Compelling studies demonstrate the role of diet in shaping gut microbiota.³⁵ Defective innate immunity could contribute to IBD pathogenesis by enabling a tolerance breakdown to intestinal microbiota in genetically predisposed individuals.

These findings demonstrate innate immunity control of the adaptive immune response and the crucial role of the gene–environment interplay in IBD induction. Until now, this emerging theory has not taken into account the role of diet in IBD development. There is considerable interest in modulating IBD development through dietary therapy in an attempt to rectify innate immunity defects resulting from genetic mutations. Given this, we have investigated how nutrients may affect innate immunity and whether diet modification offers an alternative therapeutic approach.

The mucosal surface of the intestine plays a key role in control of the host immune response by acting as a barrier against bacterial and dietary antigens. In addition, the gut barrier is a first defence mechanism strongly influenced by nutrients. Nevertheless, interactions between nutrients and the gut barrier could represent a review in themselves. We chose to focus our review on the innate immune cell components.

1.4. Dietary habits and innate immunity in chronic diseases

Obesity and diabetes studies have demonstrated that dietary compounds are able to modulate innate immunity components. For example, a high-fat, high-carbohydrate [HFHC] meal induced TLR expression and increased plasma endotoxin concentrations in monocytes from normal-weight subjects.³⁶ Interestingly, orange juice intake with the HFHC meal prevented meal-induced inflammatory stress, including the increase in endotoxin and TLR expression.³⁶ The authors of this study have also investigated the effect of saturated fat [as cream intake] in healthy volunteers, and they found that cream was able to induce TLR-4 expression and lipopolysaccharide [LPS] concentration in mononuclear cells.³⁷ Similarly, splenocytes from mice with high-fat–induced obesity exhibited a 60% higher expression of NOD2 compared with the control group.³⁸ Exacerbation of colitis has been reported in IL-10^-/- mice receiving a high saturated fat diet.²³ The authors of that study demonstrated that the high saturated fat diet modulated the composition of the bile acids, leading to a modified composition of intestinal microbiota and a subsequent perturbation of gut homeostasis.²³ Similarly, a Western diet increased the NOD-2 and TLR-5 mRNA levels in an experimental CD model.⁸ Thus, consumption of a high-fat diet was associated with changes in the gut microbiota and with upregulated PRR expression in murine models. While the influence of a Western diet on gut microbiota has already been established, more research is required in order to identify the underlying mechanisms by which nutrients can modify intestinal microbiota. Nevertheless, a metabolomics study recently reported that intestinal microbiota-derived metabolites can be correlated with CD—that group found a strong correlation between the most abundant bacteria in ileal CD and fatty acids.³⁹

A Western diet is also associated with added ingredients, such as emulsifiers or added sugars. Maltodextrin is a common dietary polysaccharide used as an emulsifier in the Western diet. McDonald et al. have demonstrated its deleterious role in defence mechanisms. Indeed, E. coli adhesion to intestinal epithelial cells (IECs) was improved in the presence of maltodextrins in vitro.⁴⁰ They also observed that consumption of maltodextrins in mice leads to better Salmonella survival and higher mucosal colonization.⁴¹ In a recent study from Chassaing et al., mice received the emulsifiers at a low concentration via drinking water for 12 weeks. The authors found that consumption of emulsifiers leads to a low-grade inflammation and obesity/metabolic syndrome in wild-type mice, while it promoted colitis in IL-10^-/- mice.⁴²

Red meat is also a hallmark of the Western dietary pattern. Its consumption is associated with an increased IBD risk,²⁵ while a diet rich in red meat exacerbates dextran sulfate sodium [DSS]-induced colitis.²² In addition, Erridge (from the UK), who has studied the ability of numerous foodstuffs to induce innate immunity, reported that numerous unspoiled foods can contain TLR-2 or -4 stimulants.^{43, 44}

In conclusion, a Western diet may exacerbate intestinal inflammation through changes in the gut microbiota leading to an upregulation of the TLR- and NOD-pathways. In addition, obese patients have a more severe disease course.⁴⁵ These new and exciting observations directly link diet and obesity to activation of the innate immune system, inflammation, and end organ dysfunction.

2. Effect of specific nutrients on innate immunity compounds [Table 2]

2.1. Fatty acids

Butyrate and propionate are short-chain fatty acids that are produced through the fermentation of dietary fibre by intestinal microbiota. In peptidoglycan [PGN]-treated intestinal epithelial cell line Caco-2, increasing concentration of butyrate enhanced production of the chemokines IL-8 and GRO-α through NF-κB activation.⁴⁶ The authors of that study demonstrated that butyrate enhanced NOD-2 expression by activating histone acetylation in the Nod2 promoter region, thus promoting chemokine secretion.⁴⁶ Interestingly, they have shown that silencing NOD2 and TLR2 significantly inhibited PGN-mediated chemokine production, suggesting that both NOD2 and TLR2 are required for maximal response.⁴⁶ In the bovine mammary gland, short-chain fatty acids such as propionate and hexanoate have demonstrated antimicrobial properties by inhibiting internalization of Staphylococcus aureus and by producing antimicrobial peptides.⁴⁷ In the intestine, the effect of digested and fermented green kiwifruit has been evaluated in intestinal epithelial cell line HT-29, and those authors found that only fermented compounds were able to increase human β-defensin 1 and 2 production⁴⁸; they speculated that this effect was probably mediated by the short-chain fatty acid content of the fermenta, because short-chain fatty acids were able to increase hBD-1 and hBD2 production.⁴⁸ More recently, butyrate treatment was able to restore VDR expression and inhibit inflammation in a colitis model.⁴⁹

3. Short-chain fatty acids are key bacterial products and can target innate immunity through antimicrobial peptide production

Unsaturated fatty acids are essential components of the intestinal inflammatory response. Indeed, they modulate cell membrane composition with a subsequent modification of the activation of receptors. They can also act as signalling molecules, and numerous nuclear receptors are molecular targets of fatty acids: the outcome is altered gene expression.

TLR-4 is a cell-surface receptor and is activated by ligand-induced dimerization. Opposing effects of fatty acids on TLR-4 activation have been demonstrated in vitro: TLR-4 dimerization is facilitated by saturated fatty acids, while unsaturated fatty acids (like docosahexaenoic acid [DHA]) inhibit its dimerization.³³ Inhibition of TLR-4 expression by DHA has been confirmed in IL-1–treated human intestinal microvascular endothelial cells.⁵⁰

Similarly, fish oil supplementation for 21 days led to an enrichment of intestinal mucosa into eicosapentaenoic acid [EPA], DHA, and total [n-3] PUFA [an improved intestinal integrity], but also downregulated mRNA levels of TLR-4 and NOD2 signalling pathways in LPS-treated weaned pigs.⁵¹ In contrast, both n-3 PUFA and n-6 PUFA treatment at 15 µM resulted in an increase in the internalization of the microorganisms by the murine macrophage cell line RAW.⁵²

4. In IBD models, n-3 PUFA can regulate intestinal innate immunity through PRR inhibition

4.1. Amino acids

Glutamine and arginine are non-essential amino acids, but they are considered essential in stress situations, and both demonstrate anti-inflammatory properties in IBD models.^53–63 Glutamine is the preferential substrate for enterocytes, and its effect has been evaluated in numerous experimental models of gut barrier dysfunction. In a neonatal deprivation model, TLR-4 expression was upregulated in separated rats, and from our laboratory we reported the specific effect of alanyl-glutamine supplementation in downregulating its colonic expression.⁶² Similarly, glutamine supplementation decreased TLR-4 mRNA levels in the jejunum and the colon of LPS-treated rats.⁶⁴ Intraperitoneal injection of alanyl-glutamine decreased colon TLR-4 in a DSS colitis model.⁶⁵ No potential mechanisms have yet been demonstrated to explain the effect of glutamine on TLR-4. As TLR-4 activation⁶⁶ involves reactive oxygen species, we hypothesized that the antioxidant properties of glutamine may be responsible for TLR-4 inhibition.

Arginine is a nitric oxide precursor. Supplementation of diets with 0.5–1% L-arginine increased serum levels of arginine and inhibited the TLR-4–Myd88 signalling pathway in Salmonella-infected weaned piglets.⁶⁷ It has been demonstrated that nitric oxide can downregulate TLR-4 gene expression,⁶⁸ and bacterial infection is also associated with inducible nitric oxide synthase [iNOS] overexpression, with subsequent nitric oxide formation as a defence mechanism. Thus, arginine supplementation may decrease TLR-4 expression through the nitric oxide pathway. Treatment with arginine or isoleucine also upregulated secretion of human beta-defensin-1 [hBD1] in the HCT-118 intestinal cell line.⁶⁹ Surprisingly, the authors tested a range of arginine concentrations from 25 to 500 µg/mL, and only the particular concentration of 250 µg/mL of arginine was able to induce hBD1.⁶⁹ Dietary nutrients such as tryptophan are also involved in host–microbiome interactions. Tryptophan is an amino acid and its metabolites regulate intestinal homeostasis. The authors of an elegant study⁷⁰ have investigated the potential action of tryptophan metabolites on resident microbiota, and they describe a novel metabolic pathway whereby Lactobacilli are able to switch their fuel from sugar to tryptophan to produce indoles. Upon aryl hydrocarbon receptor activation by indoles, IL-22 was produced, conferring resistance to Candida albicans in mice. The authors demonstrated that dietary tryptophan affected host–fungal symbiosis via the microbiota.⁷⁰

Fermented milks are a source of bioactive peptides with a beneficial effect on the intestinal mucosa. For example, beta-casomorphin-7, a peptide produced from bovine β-casein, strongly stimulates mucin production in human intestinal mucus-producing cell line HT-29MTX.⁷¹ A French team has evaluated the effect of the total peptide pool from fermented milk in the same cell line, and they found that mucin gene expression [MUC2–4] and production increased.⁷² They then identified the peptide responsible for the biological activity by high-performance liquid chromatography, and the identified peptide was then administrated by gavage in rat pups.⁷² They reported an enhanced number of goblet and Paneth cells along the small intestine, associated with a higher expression of intestinal mucins and antibacterial factors such as lysozyme.⁷²

Therefore, amino acids can target innate immunity by numerous mechanisms: [i] PRR inhibition [glutamine, arginine], [ii] antimicrobial production [arginine, isoleucine], and [iii] by acting on microbiota. Further studies in IBD are required.

4.1. Phytochemicals

Curcumin derived from Curcuma longa is the yellow pigment of curry. It exerted anti-inflammatory properties in experimental models of IBD^73–76 and also in IBD clinical trials.^{77, 78} In rats with 2,4,6-trinitrobenzenesulfonic acid [TNBS]-induced colitis, administration of curcumin at the dose of 100mg/kg inhibited inflammatory mediators [such as myeloperoxidase] and also downregulated colon TLR-4 and Myd88 expression.⁷⁹ Phytochemicals can also inhibit NOD2 activation by interfering with NOD2 dimerization.⁸⁰ This has been reported for curcumin in the colonic epithelial cell line HCT-116.⁸¹In vitro, it has been demonstrated that curcumin is able to counteract the effects of SLC22A4 and IL-10 variants associated with IBD.⁸² A novel mechanism behind the anti-inflammatory effect of curcumin has been described in the lung⁸³ and involves the cell surface receptor Triggering Receptor Expressed on Myeloid cells 1 [TREM-1]. TREM is expressed on macrophages and dendritic cells [DCs] and is believed to be an amplifier of the TLR-induced inflammatory response. Curcumin at 10 µM inhibited TREM-1 expression and mRNA levels in primary mice macrophages and prevented the binding of NF-κB to TREM-1 promoter.⁸³ The authors confirmed the downregulation of TREM-1 by curcumin at 200mg/kg in the lung from septic mice.⁸³ Very recently, Lang et al. have reported in an international multicenter prospective double-blind study that 53.8% of patients receiving 0.3g per day of a 95% pure curcumin compound added to 4 g of maintenance mesalamine achieved a clinical remission in patients with mild-to-moderate ulcerative colitis compared with none in the control group at the end of a 1-month study.⁷⁸

It has also been demonstrated that a derivative of ginger, 1-dehydro-10-gingerdione, acts on TLR-4 expression in macrophages.⁸⁴ 1-dehydro-10-gingerdione at from 10 to 100 µM inhibited LPS binding to myeloid differentiation 2 [MD2], a TLR-4 co-receptor, and also downregulated both TLR-4–mediated expression of NF-κB and activating protein-1 in LPS-treated murine macrophage cell line RAW264.7.⁸⁴

Phytochemicals can interfere with TLR4 dimerization [Figure 2]. For example, garlic extract downregulated NF-κB activity, with a subsequent decreased expression of iNOS and COX-2 by inhibiting TLR-4 dimerization in LPS-treated RAW264.7 cells.⁸⁵ The same team described a similar mechanism with cinnamaldehyde, a cinnamon extract.⁸⁶ Similarly, resveratrol, a polyphenol from grapes, also inhibited the TLR-4 signalling pathway in the same cell line RAW264.7 in response to LPS.⁸⁷

Epigallocatechin-3-gallate [EGCG] is a green tea polyphenol and it has been demonstrated to exert anti-inflammatory effects in IBD models.^{80, 88} A cell surface receptor called 67kDa Laminin Receptor [67LR] is considered to be a polyphenol-sensing molecule, and it has been recently identified as a regulator of proliferation and adhesion in normal intestinal epithelial cells.⁸⁹ Epigallocatechin-3-gallate is able to downregulate the inflammatory response in immune cells,^{90, 91} and it inhibited the TLR-signalling pathway through 67LR in LPS-treated DCs.⁹¹ Similar effects on the TLR-2 signalling pathway have been found in PGN-treated macrophages.⁹⁰

Effects of flavonoids on inflammasome have been described for other organs, but their effects on intestinal inflammation have not yet been documented. Inhibition of NLRP1 inflammasome by EGCG at 0.1 to 10 µM has been reported in human metastatic melanoma cells.⁹² The effects of quercetin and its derivative rutin have been evaluated in rats with fructose-induced renal injury, and both blocked NLRP3 inflammasome activation.⁹³ Very recently, it has been reported that resveratrol inhibited NLRP1 and NLRP3 inflammasome in LPS-treated human macrophages.⁹⁴

Phytochemicals are able to downregulate Janus-kinase pathways. In mesenchymal stromal cells, treatment with EGCG at 30 µM downregulated STAT3 phosphorylation.⁹⁵ Malvidin, a red wine polyphenol, inhibited NF-κB activation through the JNK MAPK pathway in LPS-stimulated RAW 264.7 macrophages.⁹⁶ Resveratrol, a polyphenolic compound found in red wine, downregulated nitric oxide production and chemokine secretion by blocking JAK/STAT-1 IFNγ-treated macrophages.⁹⁷ Treatment with curcumin at 50mg/kg/D ameliorated the inflammatory score in mice with DSS-induced colitis by targeting the STAT3 pathway.⁹⁸

5. Phytochemicals can target innate immunity, and their main documented action is their inhibitory effect on TLR-4

5.1. Vitamins

Vitamin D influences innate immunity,⁹⁹ and Ananthakrishnan et al. have recently reported that higher predicted plasma levels of 25[OH]D significantly reduce the risk of incident CD and non-significantly reduce the risk of UC in women.¹⁰⁰ Similarly, vitamin D metabolism is dependent on sun exposure, and a French team has recently found an association between high residential sun exposure with a decreased risk of incident CD in a prospective French cohort.¹⁰¹ In human peripheral blood mononuclear cells exposed to M. tuberculosis, antimicrobial peptide cathelicidin was upregulated 16-fold by 25[OH]D at 100nM, while TLR-2 and TLR-4 expression were downregulated.¹⁰² A recent study highlighted the link between its receptor signalling and a key component of innate immunity: intestinal autophagy.⁴⁹ They found that a low intestinal epithelial VDR alters intestinal autophagy [reduces ATG16L1 expression and impairs antimicrobial function of Paneth cells].⁴⁹ The authors were able to restore VDR signalling by a dietary approach. Indeed, butyrate administration can restore intestinal VDR expression, leading to colitis inhibition.⁴⁹

6. Vitamin D deficiencies are very common in IBD patients and may partly contribute to an altered innate immunity response through reduced antimicrobial peptide production by Paneth dysfunction or PRR upregulation

Retinoic acid is a vitamin A derivative that plays a crucial role in maintaining immune homestasis, and it has recently been highlighted that retinoic acid also regulates the homeostasis of pre-DC–derived DC subsets.¹⁰³

6.1. Probiotics

The main single dietary approach to influencing IBD development is the use of probiotics. A recent case–control study demonstrated that more IBD patients than controls use probiotics to manage their health. There is considerable variability among probiotic strains, and not all probiotics will be beneficial for IBD management. Compelling studies have demonstrated the inhibitory effect of probiotics on TLR signalling pathways in vitro in intestinal epithelial cells and DCs.^104–106 While a strain of Lactobacillus exerts beneficial effects in experimental necrotizing enterocolitis through modulation of TLR-4 and NF-κB,¹⁰⁷ a different strain acts through TLR2 in a radiation injury model.¹⁰⁸ In addition, production of defensins was also upregulated in vitro in response to probiotic treatment.¹⁰⁵ Another strain of probiotic, Bifidobacterium breve, was able to reduce susceptibility to colitis in Nod1^-/- and Nod2^-/- mice.¹⁰⁹ While probiotic studies have been promising in experimental models of IBD, clinical trials have failed to prove their efficacy for postoperative prophylaxis.^{110, 111} Nevertheless, the last systematic review from the Cochrane database studies suggests that VSL#3 appears more effective than placebo for maintenance of remission in chronic pouchitis and prevention of pouchitis.¹¹² The dietary targets of innate immunity are illustrated in Figure 2.

6.2. Starch

Dietary starch is able to modulate intestinal inflammation in numerous IBD models. Resistant starch–fed IL-10^-/- mice exhibited a lower cytokine secretion [IL-6, CXCL1] than control diet–fed mice.¹¹³ Interestingly, resistant starch can counterbalance the deleterious effect of red meat consumption in mice with DSS-induced colitis.²² Dietary starch also protects against colitis-associated colorectal cancer in rats by reducing tumor multiplicity and adenocarcinoma formation through intestinal microbiota changes.¹¹⁴

6.3. FODMAPs

FODMAPs are food items that are rich in fermentable oligo-, di- and monosacharides, and polyols. Low FODMAP diet has been proposed to limit functional symptom in irritable bowel syndrome patients.¹¹⁵ FODMAPs are also able to target innate immunity compounds [Figure 2].

Inulin is a polysaccharide, and treatment with inulin at 1mg/mL increased phagocytosis in phorbol myristate acetate [PMA]-stimulated macrophages; this effect was inhibited by using a blocking antibody specific to TLR4.¹¹⁶ Similarly, levan treatment at 10 µg/mL induced production of IL-12 p40 and TNF-α by macrophage cell lines in vitro through the TLR4 pathway.¹¹⁷ Treatment with beta-1,4-mannobiose induced TNF-α and IL-6 secretion in RAW 264.7 macrophages, and this effect was abrogated by inhibiting TLR4.¹¹⁸ Nevertheless, the same study reported that beta-1,4-mannobiose was able to reduce the inflammatory process in endotoxemic mice.¹¹⁸ In contrast, an apple oligolactan was able to downregulate TLR4 levels in mice with colitis-associated colon cancer and in LPS-treated intestinal cell line HT-29.¹¹⁹ Honey is able to stimulate cytokine production in macrophages and human monocytes.^{120, 121} The TLR4 signalling pathway mediated the pro-inflammatory effect of honey. Both studies considered that there may be factors other than TLR4 stimulants [such as LPS] that may explain this effect.^{120, 121}

Interestingly, all the FODMAPs cited above are also considered as prebiotics, meaning that they should confer benefits upon host well-being and health. In a randomized, double-blind, placebo-controlled trial, active CD patients received 15 g of fructo-oligosaccharides for 4 weeks, but there was no significant benefit in clinical response.¹²² In UC patients, 12 g/day of oligofructose-enriched inulin for 2 weeks was associated with a reduced fecal calprotectin.¹²³

7. Combination treatment studies

Most of the studies presented above use a single nutrient, but a combination of individual nutrients may be better. For example, we have previously shown that only the combination of both amino acids [glutamine and arginine] was able to decrease TNF-α production in CD intestinal biopsies; use of a single amino acid was not effective.⁵⁹ Similarly, the combination of EPA and resveratrol had a stronger anti-inflammatory effect than either of these molecules separately in LPS-treated macrophages.¹²⁴ We also reported that rats with TNBS-induced colitis had a lower inflammatory score when they received a combination of fish oil with conventional treatment 5-aminosalicylic acid [5-ASA] than when they received a higher dose of 5-ASA alone.¹²⁵

8. The interest of a multidisciplinary team

Inflammatory bowel disease patients often question their gastroenterologists about diet, and they believe that diet can influence their disease course.^{2, 3} While studies have highlighted that IBD patients have a strong interest in diet, their nutritional knowledge is mainly limited to unofficial sources such as lay websites.^{11, 13, 126} A multidisciplinary team including gastroenterologists, dietitians and nutritionists is mandatory for providing relevant dietary advice and adequate expert clinical dietitian support for IBD patients. A review about the existing dietary guidelines is available,¹²⁷ but individualized dietetic intervention should be encouraged, because it may enable patient-tailored dietary advice based on current therapy and the natural history of the disease. Indeed, dietary intake is dependent on gender, age and disease course,¹²⁶ and a one-size-fits-all approach is unwise, especially in the face of a paucity of data. Individualized dietetic advice may also limit the use of inappropriate patient-devised exclusion diets¹³ and the subsequent accentuating of nutrient deficiencies or even potential eating disorders [Table 3]. Instead, it will contribute to improving their quality of life. Some dietary restriction, such as low lactose, may be suitable for patients suffering from active inflammation.

This will require much work and clinical research, and these studies are challenging to perform. Indeed, large prospective controlled clinical trials are required for providing accurate dietary recommendations to patients. Many of the current recommendations are empiric. A specific opportunity might be to conduct interventional studies in patients undergoing resection and anastomosis due to complications of CD—such patients most closely replicate evolution of the disease with histological recurrence, endoscopic recurrence, clinical recurrence, complications and surgery. A further opportunity is to study patients with UC who are in remission to determine whether adjunctive dietary intervention [in addition to pharmacological therapy] in a randomized controlled study may provide benefits in terms of maintenance of remission.

However, as previously mentioned, restriction of dairy products is frequent in IBD patients.^{15, 128} This may contribute to calcium deficiency. Appointment with a dietitian may clarify why the patient is limiting his/her dairy intake. In the case of lactose malabsorption or dairy fear, the dietitian can suggest alternative sources of calcium other than from a dairy source according to individual patient taste or dietary lifestyle, for example, calcium-rich water or calcium-enriched orange juice. Since the effects of dairy products on symptoms are linked to their fat content,¹⁶ low fat cheese can be advised. Calcium supplementation can also be proposed.

While red meat and processed meat intake are associated with potential relapse,^{14, 25} iron deficiency is frequent in IBD patients.¹²⁶ At first, IBD patients often consume protein and total fat to excess,¹²⁶ and the dietitian can translate nutritional dietary guidelines into practical advice to the IBD patients to limit their meat, especially red meat consumption; meat alternatives may be an option. A personalized menu adapted to individual IBD patient taste, individual nutritional needs, and disease course can be programmed and regularly revised as required.

9. Conclusions

Nutrients are very involved in the innate immunity processes implicated in IBD pathogenesis, and the evidence presented here provides a rationale for pushing clinical research forward on this topic. Patients and physicians need to overcome the common ‘if it hurts, don’t do it’ method of guiding diet and reach a more evidence-based nutritional counselling practice.

Funding

No specific funding has been received—this study is part of our routine work.

Conflict of Interest

None.

Author Contributions

Rachel Marion-Letellier: literature search, figures, writing; Guillaume Savoye: literature search, writing; Subrata Ghosh: literature search, writing.

References

Author notes