by Mallory Little and David Suskind MD
Inflammatory bowel disease (IBD) is an immune-mediated inflammatory disorder of the gastrointestinal tract. It is divided into two main types based upon characteristic disease phenotypes: Ulcerative Colitis (UC) and Crohn’s Disease (CD). While the etiology has not been fully elucidated, IBD is felt to be an immune dysregulation where the immune system is attacking the intestines in response to the fecal microbiome. As of 2015, about 3 million adults in the United States suffer from IBD. This is an increase from approximately 2 million adults in 1999, emphasizing the environmental impact of this disorder.1 Despite the impact of environment, our current IBD paradigm emphasizes the immunologic side of the IBD paradigm with a lesser emphasis on the fecal microbiome or mucosal barrier function.2
The primary focus of therapy for inflammatory bowel disease has been to suppress the immune system’s ability to instigate an inflammatory reaction. While these therapies can be effective, they do not work for every patient and can be associated with significant side effects and cost. Healthcare cost in IBD patients is about 4 times more than in non-IBD patients. This cost differential comes from hospitalizations, outpatient care, and pharmaceutical drugs.3 Given incomplete efficacy of medication therapy as well as a continuing rise of healthcare cost, a new focus on the environmental impact of disease has emerged with a focus on diets. Dietary manipulation affects the IBD paradigm from a unique mechanism than that of our current medication therapies. Its primary impact is on the fecal microbiome and mucosal integrity with subsequent anti-inflammatory effects.
The impact of diet has best been shown with exclusive enteral nutrition where it is utilized as first line therapy in pediatric Crohn’s disease. Many whole foods diets have been reported to be efficacious as well but with less rigorous study. These diets are an area of intense research given the potential to improve patient outcomes and decrease overall cost of healthcare. There have been multiple dietary regimes noted to have benefit in IBD, but the best studied to date is the Specific Carbohydrate Diet (SCD). The SCD was created in 1924 to treat celiac disease,4 and was then later used for the treatment of IBD.5 The SCD eliminates all grains, sugars except for honey, and all milk products except for hard cheeses as well as yogurt fermented for 24 hours. The presumed mechanism of action of the SCD is to improve the associated dysbiosis as well as mucosal integrity in IBD by eliminating specific foods.
Initial studies have shown promising results. Both clinical remission and normalization of inflammatory markers were noted after 3 months of the diet without addition of medication therapy in 7 pediatric patients with CD.6 Another study in pediatric CD showed clinical and mucosal improvement after 12 weeks, with further improvement after 52 weeks.7 A case series in 50 adult IBD patients following the SCD noted 91.3% of patients felt the diet was effective for controlling flares, and 92.1% rated the diet as effective for maintaining remission.8 In addition, an online survey of 417 IBD patients found that the majority of patients on the SCD felt that it helped them achieve remission.9 A case series of 26 pediatric Crohn’s or UC patients who followed the SCD had associated improvement in their Pediatric Crohn's Disease activity index (PCDAI) and Pediatric Ulcerative Colitis Activity Index (PUCAI), respectively.10 Finally, in a prospective study of the SCD in active pediatric IBD, the mean PCDAI decreased from 28.1±8.8 to 4.6±10.3 at 12 weeks for CD, while the mean PUCAI decreased from 28.3 ± 23.1 to 6.7 ± 11.6 at 12 weeks. Dietary therapy was ineffective for 2 patients while 2 individuals were unable to maintain the diet. Mean C-reactive protein decreased from 24.1 ± 22.3 to 7.1 ± 0.4 mg/L at 12 weeks in the Seattle Cohort (nl < 8.0 mg/L) and decreased from 20.7 ± 10.9 to 4.8 ± 4.5 mg/L at 12 weeks in the Atlanta Cohort (nl < 4.9 mg/L). Stool microbiome analysis showed a distinctive dysbiosis for each individual in most pre-diet microbiomes with significant changes in microbial composition after dietary change.11
To understand the potential mechanism of action by diet, and specifically the SCD has on IBD, it is important to understand the impact of the specific components of the diet on the different aspects on the IBD paradigm: the fecal microbiome, mucosal integrity and the immune system. As an elimination diet designed to limit exposure of specific foods, patients on the SCD become more reliant on other foods for nutritional completeness. Therefore, the effects of the diet may be related to elimination of specific foods as well as increase in other foods. We will further examine the effects of each food group on the gut microbiome, mucosal integrity and inflammation in the context of diets effect in IBD.
Impact of food elimination on IBD
The success of the SCD is likely a result of foods that are eliminated. The main foods eliminated are grains, sugars - besides honey, as well as milk products aside from hard cheeses and yogurt fermented for 24 hours. Although this elimination is broad, there is some limited data on the effects of specific food items on clinical and inflammatory components in IBD. Both basic and clinical research show potential adverse effects of these eliminated foods.
Some improvement has been shown in patients by eliminating milk and most milk products, which is assumed to be due to the exclusion of lactose. Therefore, the milk products that are allowed on the SCD have low amounts of lactose, including hard cheeses and yogurt fermented longer than 24 hours. However, clinical research has shown inconclusive evidence linking lactose to IBD.12 This is likely related to the difficulty in separating the negative effects of potential lactose-intolerance from any inflammation that is caused by other components of milk, such as the various casein proteins.13 This is especially true for CD patients with small bowel disease who are more likely to have lactose malabsorption than patients with CD of the colon, or UC.14 In animal models, rats fed lactose experience diarrhea, disrupted colonic epithelial cells, and disrupted mucosal integrity – all symptoms of IBD.15 These negative gut health effects may be due to the consumption of lactose causing an overgrowth of Lactobacillus spp, a bacterial genus often touted for its probiotic health benefits. In fact, a higher abundance of Lactobacillus in biopsy specimens from patients with active IBD has been noted.16 However, multiple species of Lactobacillus have been shown to alleviate colitis in an animal model (PMID: 28752563). Whether there is a causative effect of Lactobacillus on the inflammation in IBD is unknown, but perhaps the positive health effects of this bacterial genus are overshadowed by its overabundance – which is detrimental to IBD patients. Conversely, lactose has been shown in other disease states to have an anti-inflammatory effect, specifically in the diet of infants with milk allergy. The mechanism is felt to be an increase of anti-inflammatory short-chain fatty acids (SCFAs), which help ameliorate inflammation in the gut.17 Allergy to milk is often caused by allergy to the milk protein casein, which has been shown to worsen UC.18 As mentioned previously, caseins are a group of proteins found in milk which exist in several types, most notably β-casein. Two subtypes of β-casein, A1 and A2, have been shown to have differing effects on gastrointestinal health, and production of these subtypes depends on the genetic makeup of the individual cow. Interestingly, A1 β-casein metabolizes into β-casomorphin-7 (BCM-7), which has been shown to cause symptoms similar to lactose intolerance. In a clinical trial, consumption of A1 β-casein increased inflammatory biomarkers, decreased anti-inflammatory SCFAs, and increased gastrointestinal symptoms (27039383). These effects were partially attributed to the activation of the Th2 immune response, a pathway which incidentally gets dysregulated in IBD. Therefore, milk contains several components which can cause similar health effects harmful to patients with IBD, making it difficult to attribute these to a specific compound. Luckily, you can purchase milk which only contains A2 β-casein, making it possible for an individual with IBD to determine if it works for them.
Foods in the dairy category which are allowed on the SCD are hard cheese and yogurt fermented greater than 24 hours. These are covered in the Allowed foods section of this paper.
While the current fad of the health industry is to exclude gluten from grain-containing products, all grains are banned from the SCD, whether they contain gluten or not. Fad or not, following a gluten-free diet has been successful for IBD patients in reducing clinical symptoms (PMID: 24865778). The bad press around gluten has incidentally obscured the fact that grains contain other compounds aside from gluten which have been shown to cause negative health effects. Additionally, gluten-free products often contain harmful additives to replace the gluten, which have been shown to cause their own array of IBD-specific negative health effects (see Additives). Therefore, dieticians have been unable to narrow down the grains category into specific IBD-safe foods. However, this is not to say that gluten is safe for patients with IBD. Gluten was originally excluded from the celiac diet due to its ability to cause a gastrointestinal immune reaction in patients with celiac disease. Additionally, one causal factor of IBD is a dysregulated immune response similar to what occurs in celiac patients. This is one explanation for why adapting the celiac diet for IBD patients into the SCD has achieved success. Clinically, gluten sensitivity has been shown to commonly co-occur with IBD, resulting in flares (PMID: 29216767). This same clinical study had another important finding – that gluten sensitivity is more likely to occur during flares and decreases as the intestines heal. Therefore, a patient with IBD may be able to slowly reintroduce gluten-containing foods as their gastrointestinal health improves. It is important to note however that gluten and its component gliadin have been found to cause intestinal cells to release zonulin, a protein that disrupts the integrity of the intestinal barrier. 21 Therefore, one must be careful about overconsumption of gluten, because this can trigger an IBD flare. In addition to gluten, wheat and other grains contain lectins such as wheat germ agglutinin (WGA), whose primary purpose is to protect the plants from insects and other pests. WGA and other lectins have been shown to resist digestion and attach to mammalian cells, enabling them to cause a wide variety of health effects (PMID: 23482055). WGA in particular has been shown to increase the production of pro-inflammatory cytokines and cross the intestinal barrier, thereby impairing the intestinal epithelial layer,21 as well as causing an immune response. In fact, patients with CD exhibit higher levels of antibodies specific to WGA compared to patients with other intestinal disorders, indicating that patients with CD are particularly vulnerable to this lectin (PMID: 23482055). Another harmful component of wheat is the class of proteins called amylase/trypsin inhibitors, which have incidentally also been found in legumes (see Vegetables section). Amylase and trypsin are digestive enzymes, and in addition to interfering with this process, amylase/trypsin inhibitors activate the innate immune system of the intestinal mucosa, causing intestinal inflammation via TLR4 activation with increased production of pro-inflammatory cytokines.22 Wheat and other grains also contain the anti-nutrients phytic acid and oxalate, which have been shown to disrupt mineral absorption. Patients with IBD want all the nutrition they can get, so it is important to avoid these anti-nutrients23. That being said, a goal of the SCD is to enable the patient to slowly add foods over time as they are able to tolerate them. Therefore, oats and white rice are the first foods suggested in the grains category to test for sensitivity. Oats are often contaminated with wheat and other grains, but are gluten-free themselves, so it is important to purchase high quality oats to avoid the negative health effects from these other grains. White rice – in addition to brown rice and wild rice – is gluten-free, making this food a good starting point. As white rice has had the bran removed, it has the added bonus of being low in phytic acid and oxalate.
The composition of the gut microbiome is heavily implicated in intestinal health. Gut microbiome dysbiosis is a major factor contributing to IBD, and patients with IBD have been shown to have markedly different microbiome composition and function compared to healthy individuals (28743984). Whether beneficial or detrimental, these microbes feed on complex carbohydrates known as prebiotics. Historically, there have been two schools of thought concerning consumption of carbohydrates and gut health in patients with IBD: either eat carbohydrates which act as prebiotics to support the growth of beneficial bacteria, or completely abstain from all fermentable sugars to avoid growth of harmful bacteria. This is called Gibson’s Conundrum, and is reinforced by evidence supporting both options (22518336). For example, prebiotics support the production of the SCFAs acetate, propionate, and butyrate, which are anti-inflammatory, can prevent diarrhea, and inhibit the growth of pathogenic bacteria such as species within the Clostridium genus (25822014). Conversely, prebiotics have not been shown to help patients with IBD in clinical trials, and in fact can lead to excessive fermentation and intestinal permeability.5 (25227297) For example, fructans, a class of fermentable complex carbohydrates found in agave, artichoke, asparagus, garlic, and onion, significantly worsened IBD symptoms in a clinical trial (28525543). In fact, clinical studies have shown a connection between consumption of sugar and increased IBD symptoms, in that patients in one trial experienced a reduction in symptoms for as long as they maintained a low carbohydrate diet (PMID: 8858747). A recent meta-analysis of 6 other clinical trials involving consumption of carbohydrates by patients with IBD support this conclusion that a diet low in complex carbohydrates ameliorates IBD symptoms. The SCD attempts to resolve this conundrum by allowing the consumption of monosaccharides in the form of honey and fruit and disallowing all other fermentable carbohydrates.
As the only natural sweetener currently allowed on the SCD is honey (covered in the Allowed Foods section), there is a need for alternatives. The next natural source of sugar that patients try once their symptoms are in remission is maple syrup. Unfortunately, no research has been done examining the effect of maple syrup on IBD. However, extensive research has been done on the polyphenols found in maple syrup. For example, maple syrup contains quebecol, a polyphenol with anti-inflammatory activity.24 Numerous other polyphenols in maple syrup have been shown to decrease NO production, therefore reducing inflammation.25 However, maple syrup contains inulin, a type of fructan, which as previously described can exacerbate symptoms of IBD (28525543). Numerous other studies have found beneficial effects for patients with IBD attributed to inulin consumption, and so patients with quiescent IBD are advised to weigh the risks and benefits when deciding whether to try maple syrup.
All artificial sweeteners are disallowed on the SCD. Splenda (sucralose) has been shown to cause the overgrowth of Escherichia coli and other taxa within the pathogen-heavy phylum Proteobacteria, and dysregulate levels of total aerobic bacteria.27 In addition to sucralose, aspartame and saccharin have also been shown to cause gut dysbiosis, which is a risk factor for IBD.28 Saccharin is derived from coal tar, and extensive epidemiological studies have linked saccharin consumption with IBD incidence.30 Saccharin has also been found to be carcinogenic in the bladders of animal models31, and therefore was banned in the United States in 1981. While saccharin is now legal in the United States32, it is still recommended to be avoided. Another class of artificial sweeteners are the sugar alcohols, such as sorbitol, mannitol, and xylitol. Sugar alcohols, while mildly absorptive in the small intestine, act as prebiotics in the large intestine. This can lead to gastrointestinal distress when consumed in excess as has been shown by a systematic review of both healthy individuals and patients with IBS (28710145). However, when research is specific to the consumption of individual sugar alcohols, beneficial effects on gastrointestinal health have been observed. For example, sorbitol is used as an alternative for sugar in a lot of low-calorie foods and exists naturally in many fruits, and did not exacerbate IBD symptoms when compared to fructans in a clinical trial.29 Xylitol, most notably found in gum labeled as sugar-free, has been shown to shift the fecal microbiome to a healthier profile, increase SCFA production, and protect against pathogen infection in several studies (30721958). Therefore, more research needs to be conducted on the effects of sugar alcohols on IBD to determine their consumptive capacity.
Mucilaginous foods are non-starch polysaccharides, a type of complex carbohydrate. Some rich sources of mucilage are agar agar, aloe, cassava, chia seeds, figs, flax seeds, natto, okra, plantain, psyllium, and slippery elm. These foods contain intermediate fermentable fiber which retains water when exposed. When ingested, mucilaginous foods form a gel coating in the intestines (27696378, 27314323). The fermentability of this gel leads to increased microbiota growth, production of SCFAs, and increased volume of stool. Due to these interactions with the intestines, some research has been conducted examining the effects of mucilaginous foods on patients with IBD. Most notably, psyllium fiber (Plantago spp.) has been examined due to its traditional therapeutic use as a laxative. In one randomized clinical trial, patients with UC in active remission took mesalamine, psyllium fiber, or both. While one patient in the psyllium fiber and 2 patients in the psyllium fiber plus mesalamine group had to be withdrawn due to constipation and flatulence, patients in all 3 groups experienced no significant difference in recurrence rate, implying that psyllium fiber was as effective as mesalamine (10022641). In another placebo-controlled trial, patients with UC in active remission experienced a higher rate of improvement in gastrointestinal symptoms with psyllium fiber supplementation than placebo (1654592). Similar results were obtained from an animal model of colitis fed psyllium fiber, including healed colon damage and reduced inflammation (29185927). Another animal model of colitis fed psyllium fiber experienced ameliorated intestinal damage and reduced inflammation, as well as increased production of SCFAs (12421838).
What about the effects of some lesser known dietary sources of mucilage? While the majority of mucilage comes from the outer seed coat of several foods, mucilage is also found in marine sources of food such as seaweeds and red algae. Similar to mucilage from seeds, the mucilaginous portions of seaweeds and red algae are fermented by gut bacteria leading to multiple effects. For example, consumption of Laminaria, Saccharina, and Palmaria palmata increases the production of SCFAs, and the consumption of Laminaria, Saccharina, and Porphyridium has been shown to affect goblet cells in the gut leading to increased production of mucus (26828501). While no clinical trials have been conducted specifically focusing on the interactions between marine mucilage and IBD, in general the production of SCFAs is beneficial due to their subsequent enhancement of intestinal epithelial cells barrier ability whereas increased mucus is controversial (30096921). For example, the additive carrageenan is extracted from the mucilaginous polysaccharide portion of red algae, and has been used to induce colitis in animal models (27092122).
While the research points to beneficial effects from psyllium fiber as well as other mucilaginous foods, it would be pertinent to avoid them during flares to avoid overgrowth of bacteria and their accompanying negative side effects. When determining whether to add mucilaginous foods to the diet of a patient with IBD, it is important to weigh the benefits of increased SCFA production to the potential negative side effects, such as bloating and excessive gas production.
Additives can make seemingly innocuous foods harmful for patients with IBD. A simple way to avoid additives is to change your diet to completely unprocessed and homemade foods, but this can be time consuming and not always feasible for patients. Luckily, store-bought food can be a great addition to the SCD if labels are read with a discerning eye. One category of additive to avoid is emulsifiers, which help stabilize high-fat containing foods by creating a blend of the fatty and aqueous ingredients (http://www.emulsifiers.org/ViewDocument.asp?ItemId=11&). For example, emulsifiers such as the plant-based carboxymethyl cellulose (cellulose gum) and synthetically-derived polysorbate-80 fed to mice reduce their microbial diversity and simultaneously increase proportions of the pro-inflammatory phylum Proteobacteria, which includes pathogenic species.40 Emulsifiers directly cause intestinal inflammation by disrupting the gut barrier and enabling bacteria to cross.41 Another common emulsifier is glycerol monolaurate, which is derived from coconut and has also been shown to cause gut microbial dysbiosis. Specifically, glycerol monolaurate decreased levels of the anti-inflammatory bacteria Akkermansia muciniphila and increased levels of the pathogen Escherichia coli, as well as increased levels of pro-inflammatory cytokines in serum of mice42. Another emulsifier of note is carrageenan, which is derived from red seaweed. Carrageenan is a common additive because it is both an emulsifier and a thickener. However, carrageenan is so detrimental to gut health that it is used to induce colitis in animal models. A possible mechanism for how carrageenan causes IBD is through its role as a lysosomal disrupter, which causes macrophage dysregulation and the creation of colonic ulcers.43
Another class of additives are nanoparticles. Nanoparticles are synthetic compounds added to food to enhance color and act as anticaking agents. Nanoparticles also absorb into food when food comes into contact with packaging materials. Studies have shown that nanoparticles such as titanium dioxide, silicon dioxide, and silver both cross and disrupt the mucus layer in the intestine, making it easier for microbes to translocate and cause inflammation.44 Nanoparticles also upregulate pro-inflammatory cascades triggered by their uptake into macrophages, causing intestinal epithelial disruption and higher levels of the nanoparticles themselves in the blood of patients with IBD.45 It is important to note that ingredients lists aren’t required to include nanoparticles, so it is best to limit your intake of packaged food as much as possible.
Nitrites and nitrates are added to food such as processed meats to act as antimicrobial preservatives as well as to improve color, and nitrates are naturally found in vegetables as well.46 The scientific consensus concerning the effects of dietary nitrites/nitrates on human health is still evolving, with limited studies specific to IBD. This is due in part to the difficulty in separating the effects of dietary nitrates/nitrites from endogenous nitrites and their metabolites. Under normal conditions, nitric oxide synthases (NOSs) use L-arginine to produce nitrite, which metabolizes into nitric oxide by host mechanisms as well as intestinal bacteria (24494186). Humans also consume nitrates in the form of leafy vegetables, which are then converted to nitrites by salivary bacteria. These salivary bacteria also convert nitrates produced from nitric oxide from the NOS pathway to nitrites. As mentioned previously, the nitrites are converted into nitric oxide, which acts as a signaling molecule responsible for a range of functions. Gastrointestinal health-relevant nitric oxide functions include killing bacteria, fungi, and viruses, and nitrites have been found to preserve the mucus layer as well as restore epithelial cell integrity in the gut.47 However, during IBD, nitric oxide is produced in higher amounts than in healthy intestines, and causes inflammation as well as is used as a marker of inflammation along with nitrites (16265127, 28842625). The higher counts of nitric oxide are due to increased activation of NOS from pro-inflammatory cytokines (16265127). Therefore, one would conclude that patients with IBD should avoid consumption of nitrates and nitrites to limit the production of nitric oxide. However, dietary nitrate and nitrite has been found to improve wound healing, reduce colonic inflammation, and prevent decreased mucus thickness in a mouse model of IBD (24494186). A similar IBD animal study found that dietary nitrite reduced colonic biomarkers of inflammation (20399279). The carcinogenic potential of nitrosamine byproducts of excessive nitrite and nitrate intake should also be considered when determining if nitrates and nitrites are safe for consumption, particularly since patients with IBD are more susceptible to gastrointestinal cancers. The conversation around the carcinogenic potential of nitrites and nitrates began in the 1960s when a number of animal and human studies were published concluding their causation of stomach cancer. However, further epidemiological research has concluded that dietary intake of nitrates and nitrites are not causative of stomach cancer, and therefore do not need to be avoided for this reason (22889895). Therefore, the current state of research surrounding nitrates and nitrites suggests that dietary intake of these added and naturally existing compounds need not be avoided by patients with IBD, and in fact are considered beneficial to gut health. More research needs to be conducted in an IBD-context before final conclusions can be reached.
Impact of Foods allowed on the SCD
Just as an unhealthy diet can shift the gut microbiota towards a pro-inflammatory and pathogenic composition, a healthy, balanced diet can shift the gut microbiota to a more beneficial enterotype. While the SCD is primarily an elimination diet, it is equally important to ensure that patients get adequate nutrition. Indeed, more than 50% of patients with IBD have micronutrient deficiencies (26418823). Included is the latest evidence for the benefits of foods allowed on the SCD.
Malnutrition is a common issue for patients with IBD, with protein-energy malnutrition a particular area of concern (23602613). Therefore, consumption of meat is a great way to maintain a healthy weight for patients with IBD. In addition to protein, fish contains many other healthful components for the management of the disease. For example, fish are rich in poly-unsaturated fatty acids such as omega-3 fatty acids, which have been shown to increase bacteria responsible for producing SCFAs (the Lachnospiraceae family).50 SCFAs are anti-inflammatory molecules which have been shown to reduce IBD symptoms in a mouse model.51 In addition to enhancing the production of SCFAs, a diet rich in fish oil reduced the pro-inflammatory types of fatty acids (omega-6 fatty acids) in the colons of mice.52 Therefore, consumption of fish is a great way to maintain the desired balance of a higher concentration of omega-3 fatty acids over omega-6 fatty acids, which has been shown to reduce the incidence of IBD as well as other chronic diseases.53 Also, salmon in particular have been shown to contain anti-inflammatory bioactive peptides which helped ameliorate IBD in male rats.54 It should also be noted that fermented fish is rich in Lactobacillus plantarum AN1, which has been shown to reduce clinical symptoms of IBD in mice.55
Another type of meat is poultry, which is high in the amino acid tryptophan. In addition to being a dietary sleep aid, tryptophan is an important component of the aryl hydrocarbon receptor (AhR) transcription factor.56 Patients with IBD have been shown to have low levels of AhR, but when AhR is activated it helped reduce levels of pro-inflammatory cytokines.57 Therefore, a diet rich in tryptophan supports the function of AhR.
While all types of meat are allowed on the SCD, some literature indicates meat consumption increases risk for IBD. An epidemiological study surveying 67,581 French women found that meat consumption increases the risk of IBD.58 The most evidence for negative health effects that examines the effect of meat on IBD comes from red meat. A colitic mouse model given a diet of red meat resulted in an increase in IBD when compared to mice fed resistant starch.59 Red meat contains high concentrations of pro-inflammatory omega-6 fatty acids, in particular linoleic acid, which has been shown to be associated with increased risk of UC.60 Red meat also contains high levels of sulfur amino acids, which support bacterial species which ferment these amino acids into hydrogen sulfide (H2S).61 High concentrations of H2S in the gut impairs the metabolism of SCFAs as well as impairs mucosal integrity.62 Conversely, consumption of SCFAs can reduce the mucosal damage done by H2S, so a diet with lean meat and fish predominant over red meat is encouraged.63 Keep in mind that processed, smoked, and canned meats are illegal on the SCD due to their possible additives. Overall, the benefits of meat consumption have been judged to outweigh the risks and so is encouraged on the SCD. In fact, an unpublished study found that adherence to the SCD with low animal protein did not help patients reduce their IBD symptoms.
Epidemiological64 and dietary studies65 have shown vegetables to be beneficial for IBD. While most vegetables are allowed on the SCD, it is encouraged to only eat cooked vegetables during a flare. Raw vegetables have higher fiber content, which can cause an overgrowth of bacteria and therefore aggravate IBD. However, the fiber in vegetables has also been shown to be beneficial for IBD. For example, diets high in fiber have been shown to support the growth of the beneficial Prevotella genus, which has been linked to increased SCFA production.66 A diet rich in SCFAs was shown to reduce IBD symptoms in a mouse model.51
In addition to the beneficial effects of SCFAs, vegetables contain other compounds which may ameliorate IBD symptoms. Cruciferous vegetables are members of the Brassicaceae family and are rich in glucosinolates. Glucosinolates breakdown into isothiocyanates, which have been shown to be anti-inflammatory through the activation of the transcription factor Nrf2.67 In addition to Nrf2, cruciferous vegetables have been shown to activate the AhR transcription factor, which is downregulated in patients with IBD and is important for intestinal barrier integrity. 68,69
Vegetables are also high in polyphenols, which act as antioxidants. Polyphenols have a wide range of benefits for patients with IBD, such as reduction of inflammation, upregulation of antioxidant pathways, and improved intestinal barrier function.70 Polyphenols have also been shown to support the growth of bacteria involved in the intestinal lining, SCFA production, as well as to decrease the amount of pro-inflammatory, pathogenic bacterial species.27
While legumes are allowed on the SCD, they might cause some difficulties for IBD patients. Legumes contain amylase/trypsin inhibitors71, which help protect the plants from microbial insult. However, in humans, amylase/trypsin inhibitors have been shown to activate toll-like receptors (TLRs), which results in an increase of pro-inflammatory cytokines.72 It should be noted that tomatoes also contain trypsin inhibitors (19582234). Therefore, one should exercise caution when supplementing their diet with these foods.
Fresh and frozen fruits are a great way to eat a tasty snack while consuming healthy fibers and sugars. In fact, consumption of fruit might help ameliorate IBD symptoms. An epidemiological study of 170,776 women examining the effects of various sources of fiber found the greatest association between intake of fruit-derived fiber and lowered risk for CD.73 In addition to fiber, a recent review found that extracts of a wide variety of fruits such as prunes, pomegranates, cranberries, and blueberries were shown to decrease the production of pro-inflammatory cytokines.74 Also, mice fed black raspberry extract experienced reduced clinical symptoms of UC.75 One possible reason for the beneficial effects of fruits and their extracts on IBD are their high concentrations of polyphenols. One study examined the polyphenols procyanidin B(1), procyanidin B(2), and phloretin and found them to reduce pro-inflammatory signaling pathways.76 Another study examined a wider variety of polyphenols and found that they reduce levels of pro-inflammatory cytokines, suppress pro-inflammatory cellular signaling mechanisms, and act as antioxidants.77 Polyphenols have also been shown to activate toll-like receptors (TLRs), which are dysregulated in IBD. In this study, polyphenols activated the TLRs to exert anti-inflammatory effects.78 Therefore, consumption of fruit is beneficial for patients with IBD through a variety of mechanisms.
While most added sweeteners aren’t allowed on the SCD, honey is a tasty exception. Honey is a safe, simple sugar in that it consists only of monosaccharides.96 Since honey doesn’t contain complex carbohydrates, there is no risk for bacterial overgrowth and its associated IBD effects.96 Honey is rich in polyphenols, with Manuka honey having the highest concentration.98 The beneficial effects of polyphenols on IBD have been explored earlier in this article. In addition to its polyphenolic capacity, honey also contains antioxidant flavonoids and vitamin B3.99 Antioxidants from Manuka honey were found to help reduce UC in rats.100 However, the monosaccharides in honey derive from its concentrations of fructose which can cause malabsorption if too much is consumed, especially in individuals with faulty fructose transporter expression.97 Therefore, honey should be used in moderation. Overall, when consumed within reason, honey is a great choice for patients looking to add sweetness to their diets, with Manuka honey recommended in particular.
All nuts are allowed on the SCD. While no epidemiological dietary studies specific to the effects of nuts on IBD have been done, one study found that a diet rich in nuts as well as fish, olive oil, grains, fruits, and vegetables reduced the risk of IBD in children.79 Also, dietary supplementation of nuts was found to decrease inflammatory biomarkers and the pro-inflammatory cytokines in a survey of 5013 participants free from diabetes.80 These effects may be because nuts are rich in omega-3 fatty acids81, whose benefits have been discussed in the sections above. Notably, one study used PUFAs derived from nuts and found this resulted in a decrease in pro-inflammatory signaling pathways and cytokines, as well as cell adhesion molecules.82 In fact, therapeutics targeting cell adhesion molecules have been approved for treatment of IBD, so dietary sources of these effects are encouraged (21180606).
Another beneficial component of nuts is their high concentration of polyphenols. In particular, the proanthocyanidins in pistachios were found to inhibit a pro-inflammatory cell signaling pathway in intestinal epithelial cells.83 Peanuts (while technically legumes) contain resveratrol, which is the same polyphenol found in red wine responsible for its antioxidant effects.84 In fact, resveratrol supplementation was found to decrease UC in mice.85 Nuts contain many other beneficial polyphenols in addition to the ones listed here, so one should make them a staple of their diet in order to take advantage of their benefits for IBD symptoms.
Spices are a good way of getting creative in the kitchen while increasing the benefits of the SCD for IBD. One notable spice is turmeric, which is rich in the antioxidant, anti-inflammatory compound curcumin. Curcumin inhibits IBD, possibly through suppression of TLRs and pro-inflammatory signaling pathways.86 Another spice, onion powder, is rich in quercetin, which has been shown to reduce clinical symptoms of IBD in a colitic animal model through the upregulation of the potent antioxidant, glutathione.87 In addition, tamarind, saffron, fenugreek, ginger, and garlic have been shown to be beneficial for treating IBD, through antioxidant- and inflammatory signaling pathway-mediated mechanisms.84 The anti-inflammatory capabilities of a wide variety of spices not described here have been extensively studied elsewhere.86
Aged cheese and yogurt
While the majority of dairy products are eliminated from the SCD diet, a few notable exceptions are allowed. For example, cheese aged past 30 days is allowed on the SCD because most to all lactose has been depleted via bacterial fermentation. The interaction between lactose and IBD is discussed in depth in the Dairy section. Therefore, most cheeses are allowed, except for some of the soft variety such as cottage cheese. Consumption of cheese has many health benefits, including an increase in SCFAs and a decrease in the pro-inflammatory metabolite trimethylamine N-oxide (TMAO).19,20 While one case-control study examining the diets of patients with IBD found an association between cheese and Crohn’s disease, no clinical studies specific to the impact of cheese on IBD have been conducted, signifying more research needs to be done (20818813).
A unique part of the SCD is the inclusion of homemade yogurt. Instructions for making SCD-compliant yogurt can be found on the Breaking the Vicious Cycle website (http://btvc.webfactional.com/legal/detail/homemade-yogurt/). In comparison to store-bought yogurt, homemade yogurt contains higher counts and quality of beneficial bacteria, lower amounts of lactose, and lower complex carbohydrates. In fact, dietary inclusion of yogurt has been reported to improve symptoms of IBD (22923336). This may be due to the anti-inflammatory effects of probiotics from yogurt, which act by decreasing levels of pro-inflammatory cytokines in patients with IBD.89 In addition, the probiotics in yogurt can outcompete yeast, which is beneficial because yeast has been shown to exacerbate IBD symptoms in a patient dietary study.90 Also, the probiotics in yogurt have been shown to inhibit microbial injury and increase the health of the intestinal epithelia.91 Therefore, while the majority of the SCD is focused on eliminating bacterial growth in the intestines, the inclusion of homemade yogurt allows the controlled addition of probiotics beneficial to patients with IBD.
While not exactly a food, vitamin D supplementation is an important part of the SCD. This is because patients with IBD are more likely to be vitamin D-deficient.92 While vitamin D is important to a large number of cellular processes, it is hypothesized that vitamin D affects IBD via an immunological mechanism. For example, vitamin D upregulates healthy T cells (Th2) while downregulating disease-pathway T cells (Th1/Th17).94 Vitamin D is also implicated in health gut barrier function through its interactions with the vitamin D receptor and regulation of tight junction proteins necessary to gut epithelial health.95 In fact, supplementation of 2000 IUs of vitamin D resulted in fewer patients with elevated pro-inflammatory markers and cytokines in a pediatric IBD study.93 Therefore, whether it’s through supplementation or enjoying the sunshine, make sure you get a healthy dose of vitamin D!
A healthy, balanced diet is necessary to ensure patients with IBD get adequate nutrition while avoiding triggering foods. While the mechanisms of IBD pathology are complicated, the diet of IBD patients need not be so. With its origins in the celiac diet, the SCD is constantly evolving as more research emerges to better serve patients with IBD.
1. Prevention CfDCa. Inflammatory Bowel Disease. 2018; https://www.cdc.gov/ibd/data-statistics.htm.
2. Vindigni SM, Zisman TL, Suskind DL, Damman CJ. The intestinal microbiome, barrier function, and immune system in inflammatory bowel disease: a tripartite pathophysiological circuit with implications for new therapeutic directions. Therap Adv Gastroenterol. 2016;9(4):606-625.
3. Bahler C, Vavricka SR, Schoepfer AM, Brungger B, Reich O. Trends in prevalence, mortality, health care utilization and health care costs of Swiss IBD patients: a claims data based study of the years 2010, 2012 and 2014. BMC Gastroenterol. 2017;17(1):138.
4. Haas SV, Haas MP. The treatment of celiac disease with the specific carbohydrate diet; report on 191 additional cases. Am J Gastroenterol. 1955;23(4):344-360.
5. Dixon LJ, Kabi A, Nickerson KP, McDonald C. Combinatorial effects of diet and genetics on inflammatory bowel disease pathogenesis. Inflamm Bowel Dis. 2015;21(4):912-922.
6. Suskind DL, Wahbeh G, Gregory N, Vendettuoli H, Christie D. Nutritional therapy in pediatric Crohn disease: the specific carbohydrate diet. J Pediatr Gastroenterol Nutr. 2014;58(1):87-91.
7. Cohen SA, Gold BD, Oliva S, et al. Clinical and mucosal improvement with specific carbohydrate diet in pediatric Crohn disease. J Pediatr Gastroenterol Nutr. 2014;59(4):516-521.
8. Kakodkar S, Farooqui AJ, Mikolaitis SL, Mutlu EA. The Specific Carbohydrate Diet for Inflammatory Bowel Disease: A Case Series. J Acad Nutr Diet. 2015;115(8):1226-1232.
9. Suskind DL, Wahbeh G, Cohen SA, et al. Patients Perceive Clinical Benefit with the Specific Carbohydrate Diet for Inflammatory Bowel Disease. Dig Dis Sci. 2016;61(11):3255-3260.
10. Obih C, Wahbeh G, Lee D, et al. Specific carbohydrate diet for pediatric inflammatory bowel disease in clinical practice within an academic IBD center. Nutrition. 2016;32(4):418-425.
11. Suskind DL, Cohen SA, Brittnacher MJ, et al. Clinical and Fecal Microbial Changes With Diet Therapy in Active Inflammatory Bowel Disease. J Clin Gastroenterol. 2018;52(2):155-163.
12. Szilagyi A, Galiatsatos P, Xue X. Systematic review and meta-analysis of lactose digestion, its impact on intolerance and nutritional effects of dairy food restriction in inflammatory bowel diseases. Nutr J. 2016;15(1):67.
13. Szilagyi A. Adaptation to Lactose in Lactase Non Persistent People: Effects on Intolerance and the Relationship between Dairy Food Consumption and Evalution of Diseases. Nutrients. 2015;7(8):6751-6779.
14. Mishkin S. Dairy sensitivity, lactose malabsorption, and elimination diets in inflammatory bowel disease. Am J Clin Nutr. 1997;65(2):564-567.
15. Galvez J, Sanchez de Medina F, Jimenez J, et al. Effect of quercitrin on lactose-induced chronic diarrhoea in rats. Planta Med. 1995;61(4):302-306.
16. Wang W, Chen L, Zhou R, et al. Increased proportions of Bifidobacterium and the Lactobacillus group and loss of butyrate-producing bacteria in inflammatory bowel disease. J Clin Microbiol. 2014;52(2):398-406.
17. Francavilla R, Calasso M, Calace L, et al. Effect of lactose on gut microbiota and metabolome of infants with cow's milk allergy. Pediatr Allergy Immunol. 2012;23(5):420-427.
18. Judaki A, Hafeziahmadi M, Yousefi A, et al. Evaluation of dairy allergy among ulcerative colitis patients. Bioinformation. 2014;10(11):693-696.
19. Zheng H, Yde CC, Clausen MR, et al. Metabolomics investigation to shed light on cheese as a possible piece in the French paradox puzzle. J Agric Food Chem. 2015;63(10):2830-2839.
20. Wang Z, Zhao Y. Gut microbiota derived metabolites in cardiovascular health and disease. Protein Cell. 2018.
21. de Punder K, Pruimboom L. The dietary intake of wheat and other cereal grains and their role in inflammation. Nutrients. 2013;5(3):771-787.
22. Junker Y, Zeissig S, Kim SJ, et al. Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J Exp Med. 2012;209(13):2395-2408.
23. Lee D, Albenberg L, Compher C, et al. Diet in the pathogenesis and treatment of inflammatory bowel diseases. Gastroenterology. 2015;148(6):1087-1106.
24. Cardinal S, Azelmat J, Grenier D, Voyer N. Anti-inflammatory properties of quebecol and its derivatives. Bioorg Med Chem Lett. 2016;26(2):440-444.
25. Liu Y, Rose KN, DaSilva NA, Johnson SL, Seeram NP. Isolation, Identification, and Biological Evaluation of Phenolic Compounds from a Traditional North American Confectionery, Maple Sugar. J Agric Food Chem. 2017;65(21):4289-4295.
26. Sun J, Ma H, Seeram NP, Rowley DC. Detection of Inulin, a Prebiotic Polysaccharide, in Maple Syrup. J Agric Food Chem. 2016;64(38):7142-7147.
27. Valdes AM, Walter J, Segal E, Spector TD. Role of the gut microbiota in nutrition and health. BMJ. 2018;361:k2179.
28. Nettleton JE, Reimer RA, Shearer J. Reshaping the gut microbiota: Impact of low calorie sweeteners and the link to insulin resistance? Physiol Behav. 2016;164(Pt B):488-493.
29. Cox SR, Prince AC, Myers CE, et al. Fermentable Carbohydrates [FODMAPs] Exacerbate Functional Gastrointestinal Symptoms in Patients With Inflammatory Bowel Disease: A Randomised, Double-blind, Placebo-controlled, Cross-over, Re-challenge Trial. J Crohns Colitis. 2017;11(12):1420-1429.
30. Qin X. Etiology of inflammatory bowel disease: a unified hypothesis. World J Gastroenterol. 2012;18(15):1708-1722.
31. Reuber MD. Carcinogenicity of saccharin. Environ Health Perspect. 1978;25:173-200.
32. Touyz LZ. Saccharin deemed "not hazardous" in United States and abroad. Curr Oncol. 2011;18(5):213-214.
33. Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol. 2010;28:573-621.
34. Galvez J, Rodriguez-Cabezas ME, Zarzuelo A. Effects of dietary fiber on inflammatory bowel disease. Mol Nutr Food Res. 2005;49(6):601-608.
36. Xu Q, Yajima T, Li W, Saito K, Ohshima Y, Yoshikai Y. Levan (beta-2, 6-fructan), a major fraction of fermented soybean mucilage, displays immunostimulating properties via Toll-like receptor 4 signalling: induction of interleukin-12 production and suppression of T-helper type 2 response and immunoglobulin E production. Clin Exp Allergy. 2006;36(1):94-101.
40. Chassaing B, Koren O, Goodrich JK, et al. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature. 2015;519(7541):92-96.
41. Roberts CL, Keita AV, Duncan SH, et al. Translocation of Crohn's disease Escherichia coli across M-cells: contrasting effects of soluble plant fibres and emulsifiers. Gut. 2010;59(10):1331-1339.
42. Jiang Z, Zhao M, Zhang H, Li Y, Liu M, Feng F. Antimicrobial Emulsifier-Glycerol Monolaurate Induces Metabolic Syndrome, Gut Microbiota Dysbiosis, and Systemic Low-Grade Inflammation in Low-Fat Diet Fed Mice. Mol Nutr Food Res. 2018;62(3).
43. Tobacman JK. Review of harmful gastrointestinal effects of carrageenan in animal experiments. Environ Health Perspect. 2001;109(10):983-994.
44. Gillois K, Leveque M, Theodorou V, Robert H, Mercier-Bonin M. Mucus: An Underestimated Gut Target for Environmental Pollutants and Food Additives. Microorganisms. 2018;6(2).
45. Ruiz PA, Moron B, Becker HM, et al. Titanium dioxide nanoparticles exacerbate DSS-induced colitis: role of the NLRP3 inflammasome. Gut. 2017;66(7):1216-1224.
46. Dahle HK. Nitrite as a food additive. NIPH Ann. 1979;2(2):17-24.
47. Jadert C, Phillipson M, Holm L, Lundberg JO, Borniquel S. Preventive and therapeutic effects of nitrite supplementation in experimental inflammatory bowel disease. Redox Biol. 2014;2:73-81.
48. Balmus IM, Ciobica A, Trifan A, Stanciu C. The implications of oxidative stress and antioxidant therapies in Inflammatory Bowel Disease: Clinical aspects and animal models. Saudi J Gastroenterol. 2016;22(1):3-17.
49. Song P, Wu L, Guan W. Dietary Nitrates, Nitrites, and Nitrosamines Intake and the Risk of Gastric Cancer: A Meta-Analysis. Nutrients. 2015;7(12):9872-9895.
50. Costantini L, Molinari R, Farinon B, Merendino N. Impact of Omega-3 Fatty Acids on the Gut Microbiota. Int J Mol Sci. 2017;18(12).
51. Maslowski KM, Vieira AT, Ng A, et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature. 2009;461(7268):1282-1286.
52. Bosco N, Brahmbhatt V, Oliveira M, et al. Effects of increase in fish oil intake on intestinal eicosanoids and inflammation in a mouse model of colitis. Lipids Health Dis. 2013;12:81.
53. Wall R, Ross RP, Fitzgerald GF, Stanton C. Fatty acids from fish: the anti-inflammatory potential of long-chain omega-3 fatty acids. Nutr Rev. 2010;68(5):280-289.
54. Grimstad T, Bjorndal B, Cacabelos D, et al. A salmon peptide diet alleviates experimental colitis as compared with fish oil. J Nutr Sci. 2013;2:e2.
55. Yokota Y, Shikano A, Kuda T, Takei M, Takahashi H, Kimura B. Lactobacillus plantarum AN1 cells increase caecal L. reuteri in an ICR mouse model of dextran sodium sulphate-induced inflammatory bowel disease. Int Immunopharmacol. 2018;56:119-127.
56. Abegunde AT, Muhammad BH, Bhatti O, Ali T. Environmental risk factors for inflammatory bowel diseases: Evidence based literature review. World J Gastroenterol. 2016;22(27):6296-6317.
57. Monteleone I, MacDonald TT, Pallone F, Monteleone G. The aryl hydrocarbon receptor in inflammatory bowel disease: linking the environment to disease pathogenesis. Curr Opin Gastroenterol. 2012;28(4):310-313.
58. Jantchou P, Morois S, Clavel-Chapelon F, Boutron-Ruault MC, Carbonnel F. Animal protein intake and risk of inflammatory bowel disease: The E3N prospective study. Am J Gastroenterol. 2010;105(10):2195-2201.
59. Le Leu RK, Young GP, Hu Y, Winter J, Conlon MA. Dietary red meat aggravates dextran sulfate sodium-induced colitis in mice whereas resistant starch attenuates inflammation. Dig Dis Sci. 2013;58(12):3475-3482.
60. Investigators IBDiES, Tjonneland A, Overvad K, et al. Linoleic acid, a dietary n-6 polyunsaturated fatty acid, and the aetiology of ulcerative colitis: a nested case-control study within a European prospective cohort study. Gut. 2009;58(12):1606-1611.
61. Magee EA, Richardson CJ, Hughes R, Cummings JH. Contribution of dietary protein to sulfide production in the large intestine: an in vitro and a controlled feeding study in humans. Am J Clin Nutr. 2000;72(6):1488-1494.
62. Pitcher MC, Cummings JH. Hydrogen sulphide: a bacterial toxin in ulcerative colitis? Gut. 1996;39(1):1-4.
63. Christl SU, Eisner HD, Dusel G, Kasper H, Scheppach W. Antagonistic effects of sulfide and butyrate on proliferation of colonic mucosa: a potential role for these agents in the pathogenesis of ulcerative colitis. Dig Dis Sci. 1996;41(12):2477-2481.
64. Amre DK, D'Souza S, Morgan K, et al. Imbalances in dietary consumption of fatty acids, vegetables, and fruits are associated with risk for Crohn's disease in children. Am J Gastroenterol. 2007;102(9):2016-2025.
65. Chiba M, Abe T, Tsuda H, et al. Lifestyle-related disease in Crohn's disease: relapse prevention by a semi-vegetarian diet. World J Gastroenterol. 2010;16(20):2484-2495.
66. Dolan KT, Chang EB. Diet, gut microbes, and the pathogenesis of inflammatory bowel diseases. Mol Nutr Food Res. 2017;61(1).
67. Sturm C, Wagner AE. Brassica-Derived Plant Bioactives as Modulators of Chemopreventive and Inflammatory Signaling Pathways. Int J Mol Sci. 2017;18(9).
68. Durchschein F, Petritsch W, Hammer HF. Diet therapy for inflammatory bowel diseases: The established and the new. World J Gastroenterol. 2016;22(7):2179-2194.
69. Metidji A, Omenetti S, Crotta S, et al. The Environmental Sensor AHR Protects from Inflammatory Damage by Maintaining Intestinal Stem Cell Homeostasis and Barrier Integrity. Immunity. 2018;49(2):353-362 e355.
70. Kaulmann A, Bohn T. Bioactivity of Polyphenols: Preventive and Adjuvant Strategies toward Reducing Inflammatory Bowel Diseases-Promises, Perspectives, and Pitfalls. Oxid Med Cell Longev. 2016;2016:9346470.
71. Mojica L, de Mejia EG. Characterization and Comparison of Protein and Peptide Profiles and their Biological Activities of Improved Common Bean Cultivars (Phaseolus vulgaris L.) from Mexico and Brazil. Plant Foods Hum Nutr. 2015;70(2):105-112.
72. Lu Y, Li X, Liu S, Zhang Y, Zhang D. Toll-like Receptors and Inflammatory Bowel Disease. Front Immunol. 2018;9:72.
73. Ananthakrishnan AN, Khalili H, Konijeti GG, et al. A prospective study of long-term intake of dietary fiber and risk of Crohn's disease and ulcerative colitis. Gastroenterology. 2013;145(5):970-977.
74. Mijan MA, Lim BO. Diets, functional foods, and nutraceuticals as alternative therapies for inflammatory bowel disease: Present status and future trends. World J Gastroenterol. 2018;24(25):2673-2685.
75. Montrose DC, Horelik NA, Madigan JP, et al. Anti-inflammatory effects of freeze-dried black raspberry powder in ulcerative colitis. Carcinogenesis. 2011;32(3):343-350.
76. Jung M, Triebel S, Anke T, Richling E, Erkel G. Influence of apple polyphenols on inflammatory gene expression. Mol Nutr Food Res. 2009;53(10):1263-1280.
77. Hamzehlou S, P RA, M MF. Requirement of a Blocking Step in Affinity Purification of Polyclonal Antibodies. Int J Mol Cell Med. 2015;4(3):196-198.
78. Nasef NA, Mehta S, Murray P, Marlow G, Ferguson LR. Anti-inflammatory activity of fruit fractions in vitro, mediated through toll-like receptor 4 and 2 in the context of inflammatory bowel disease. Nutrients. 2014;6(11):5265-5279.
79. D'Souza S, Levy E, Mack D, et al. Dietary patterns and risk for Crohn's disease in children. Inflamm Bowel Dis. 2008;14(3):367-373.
80. Yu Z, Malik VS, Keum N, et al. Associations between nut consumption and inflammatory biomarkers. Am J Clin Nutr. 2016;104(3):722-728.
81. Tian T, Wang Z, Zhang J. Pathomechanisms of Oxidative Stress in Inflammatory Bowel Disease and Potential Antioxidant Therapies. Oxid Med Cell Longev. 2017;2017:4535194.
82. Zhao G, Etherton TD, Martin KR, et al. Anti-inflammatory effects of polyunsaturated fatty acids in THP-1 cells. Biochem Biophys Res Commun. 2005;336(3):909-917.
83. Gentile C, Perrone A, Attanzio A, Tesoriere L, Livrea MA. Sicilian pistachio (Pistacia vera L.) nut inhibits expression and release of inflammatory mediators and reverts the increase of paracellular permeability in IL-1beta-exposed human intestinal epithelial cells. Eur J Nutr. 2015;54(5):811-821.
84. Saxena A, Kaur K, Hegde S, Kalekhan FM, Baliga MS, Fayad R. Dietary agents and phytochemicals in the prevention and treatment of experimental ulcerative colitis. J Tradit Complement Med. 2014;4(4):203-217.
85. Yao J, Wang JY, Liu L, et al. Anti-oxidant effects of resveratrol on mice with DSS-induced ulcerative colitis. Arch Med Res. 2010;41(4):288-294.
86. Kunnumakkara AB, Sailo BL, Banik K, et al. Chronic diseases, inflammation, and spices: how are they linked? J Transl Med. 2018;16(1):14.
87. Dodda D, Chhajed R, Mishra J. Protective effect of quercetin against acetic acid induced inflammatory bowel disease (IBD) like symptoms in rats: possible morphological and biochemical alterations. Pharmacol Rep. 2014;66(1):169-173.
89. Lorea Baroja M, Kirjavainen PV, Hekmat S, Reid G. Anti-inflammatory effects of probiotic yogurt in inflammatory bowel disease patients. Clin Exp Immunol. 2007;149(3):470-479.
90. Barclay GR, McKenzie H, Pennington J, Parratt D, Pennington CR. The effect of dietary yeast on the activity of stable chronic Crohn's disease. Scand J Gastroenterol. 1992;27(3):196-200.
91. Wen L, Duffy A. Factors Influencing the Gut Microbiota, Inflammation, and Type 2 Diabetes. J Nutr. 2017;147(7):1468S-1475S.
92. Pappa HM, Gordon CM, Saslowsky TM, et al. Vitamin D status in children and young adults with inflammatory bowel disease. Pediatrics. 2006;118(5):1950-1961.
93. Pappa HM, Mitchell PD, Jiang H, et al. Maintenance of optimal vitamin D status in children and adolescents with inflammatory bowel disease: a randomized clinical trial comparing two regimens. J Clin Endocrinol Metab. 2014;99(9):3408-3417.
94. Reich KM, Fedorak RN, Madsen K, Kroeker KI. Vitamin D improves inflammatory bowel disease outcomes: basic science and clinical review. World J Gastroenterol. 2014;20(17):4934-4947.
95. Meeker S, Seamons A, Maggio-Price L, Paik J. Protective links between vitamin D, inflammatory bowel disease and colon cancer. World J Gastroenterol. 2016;22(3):933-948.
96. Aleksandrova K, Romero-Mosquera B, Hernandez V. Diet, Gut Microbiome and Epigenetics: Emerging Links with Inflammatory Bowel Diseases and Prospects for Management and Prevention. Nutrients. 2017;9(9).
97. Knight-Sepulveda K, Kais S, Santaolalla R, Abreu MT. Diet and Inflammatory Bowel Disease. Gastroenterol Hepatol (N Y). 2015;11(8):511-520.
98. Schneider M, Coyle S, Warnock M, Gow I, Fyfe L. Anti-microbial activity and composition of manuka and portobello honey. Phytother Res. 2013;27(8):1162-1168.
99. Chua LS, Rahaman NL, Adnan NA, Eddie Tan TT. Antioxidant Activity of Three Honey Samples in relation with Their Biochemical Components. J Anal Methods Chem. 2013;2013:313798.
100. Medhi B, Prakash A, Avti PK, Saikia UN, Pandhi P, Khanduja KL. Effect of Manuka honey and sulfasalazine in combination to promote antioxidant defense system in experimentally induced ulcerative colitis model in rats. Indian J Exp Biol. 2008;46(8):583-590.