Crohn’s disease (CD), an inflammatory bowel disease (IBD) subtype, is a chronic transmural intestinal inflammatory disorder with an unknown etiology.¹ The occurrence of CD relates to genetic, immunological, and environmental factors.¹ Current clinical guidelines recommend nutritional support therapy essential for improving a patient’s nutritional status and drug response. Nutritional support therapy also reduces the need for surgery and postoperative complications, simultaneously.^2-4 Moreover, in high risk prevalence of intestinal infections, such as tuberculosis and infectious enterocolitis, nutritional support therapy is a safe treatment option especially in the biologic era.⁵ For pediatric CD, nutritional support therapy is even more important. Appropriate nutritional support therapy improves clinical indicators and helps children grow and develop better, in addition to being similar or possibly better than glucocorticoid therapy in terms of clinical remission and mucosal healing.⁶

Exclusive enteral nutrition (EEN) and partial enteral nutrition (PEN) are the most common nutritional therapies. A current study on EEN, the result showed that inducing clinical response across different phenotypes of CD was treated by EEN.⁷ Advances in nutriology include more CD-related nutritional therapies, such as the Crohn’s disease exclusion diet (CDED), specific carbohydrate diet, Crohn’s disease treatment-with-eating diet, the Mediterranean diet and low fermentable oligo-, di-, mono-saccharides, and polyols diet (low-FODMAP diet) (Table 1). Similar to medical treatment of CD, nutritional therapy consists of induction and maintenance of remission.^8,9 EEN or CDED are recommended to induce remission and are usually administered for 6 to 8 weeks (at least 4 weeks and up to 12 weeks), depending on the patient’s needs.¹⁰ Regrettably, low compliance is unavoidable with EEN.¹¹ After inducing remission, patients with CD gradually switch to diets to maintain remission and prevent the cascade of pro-inflammatory CD events.¹² During the maintenance phase, more diet choices are available. However, a free diet is not a reasonable recommendation for these patients.

Table 1 . Comparison of the Characteristics of Different Therapies.

Therapies	Features	Shortness	Clinical studies*	References
CDED	The most clinically documented; exclusion and inclusion	Inexperienced in clinical application	7	14-20
SCD	Exclusion diet just for carbohydrate	Unable to control the diet out of carbohydrate	8	21-28
CD-TREAT	An individualized anti-inflammatory diet	Complex to screen inflammation-related foods	1	29
Low-FODMAP diet	Low carbohydrate diet	Complex and difficult to teach and to learn	4	30-33
Mediterranean diet	Low in saturated fat and high in vegetable oils	A little difficulty implementing	7	22,34-39

CDED, Crohn’s disease exclusion diet; SCD, sspecific carbohydrate diet; CD-TREAT, Crohn’s disease treatment-with-eating diet; low-FODMAP diet, low fermentable oligo-, di-, mono-saccharides, and polyols diet..

*One study might contain two or more different therapies.

CDED is a supportive nutritional CD treatment. Unlike PEN, CDED is a standardized diet that excludes some dietary items.¹³ CDED aims to reduce exposure to items that may negatively affect the gut microbiota, intestinal barrier, and intestinal immunity, thereby maintaining intestinal homeostasis.¹³ CDED achieves its therapeutic purposes by reducing CD activity and recurrence. This article reviews the structure, mechanisms, research findings, and applications of CDED.

Exclusion and inclusion principles are used to adjust the composition of a patient’s diet every 6 weeks (Fig. 1).¹³ Diets with high sugar, fat, gluten, maltodextrin, and emulsifiers are restricted or avoided; meanwhile, high-quality protein, vitamin D, and foods rich in complex carbohydrates are consumed in appropriate quantities.^10,13 The goal of CDED is to gradually improve the patient’s nutritional status. The example of CDED dietary schedule was included in a previous review.¹³

Figure 1. Schematic diagram of Crohn’s disease exclusion diet in each phase. PEN, partial enteral nutrition.

The first phase involves strict control and commences at the beginning of 6 weeks of nutritional therapy. Inflammation-promoting foods that are high in sugar and fat are excluded. During this period, food tolerance and intolerance should be assessed. The initial phase also appropriately restricts consumption of vegetables and fruits so as to limit dietary fiber intake.¹³ For example, 150 to 200 g of chicken breast, two eggs, two potatoes, one apple, and two bananas could be considered as a plan of whole-day-meal. A complete, liquid formula should deliver 50% of caloric intake, simultaneously.¹⁴

The second phase is the transitional phase and begins after the initial 6 weeks. To improve meal quality and flexibility, additional dietary elements like gluten, red meat, fish oil, and beans are permitted. After the 6-week intervention period, we expect to see some relief from CD symptoms. At this phase, a higher-fiber diet that includes vegetables and fruits is generally allowed.¹³ Moreover, the number of food products in the first phase could be increased, and enteral nutritional powder could be reduced to 25% of daily caloric.¹⁴

The third phase is the maintenance phase and begins 12 weeks after the initiation of nutritional treatment. Foods that are not allowed during the initial phases can be accommodated using intermittent and controlled consumption. This phase does not have a stipulated duration and is rather meant as a sustainable and long-term healthy diet.¹³

The efficacy of CDED is attributed to its exclusion and inclusion characteristics, combining the advantages of various nutritional therapies. Some previous studies and epidemiological surveys demonstrated that high-sugar, high-fat, and low-fiber Western diets are related to IBD etiology.^40,41 Dietary elements associated with IBD have been confirmed using animal models.^42-46 We make speculations as following according to recent studies and the results can be generalized as interactions between the diet, gut microbiota, and immune system.⁴⁷ Hence, CDED necessitates excluding dietary components harmful to patients with CD, and including beneficial diets (Fig. 2).

Figure 2. Evolving role of diet in the pathogenesis and treatment in Crohn’s disease.

1. Sugar

A high-sugar diet, including saccharose- and fructose-rich diets,⁴⁸ is positively correlated with IBD incidence and severity. However, the association between carbohydrate intake and IBD is not reported.⁴⁹ In animal studies, mice fed a high-sugar diet showed pro-inflammatory changes in the colon consistent with CD: increased intestinal permeability and increased levels of serum lipopolysaccharides, a bacterial endotoxin and driver of inflammation, leading to altered gut microbiota and thus an increased risk of developing CD.⁵⁰ In population studies, high-sugar beverages may aggravate IBD,^51,52 particularly in the context of a low-fiber diet.⁵³ Sugar consumption should be limited even during remission as it exacerbates gastrointestinal symptoms in quiescent patients with IBD.³⁰ High-sugar diets may not increase the levels of inflammation markers but may change the abundance of microbes in feces.³¹ In contrast, low-sugar diets quench IBD.^32,33 Additionally, patients with CD do not need to worry about hypoglycemia after reducing their sugar intake because glucose metabolism changes to prevent hypoglycemia and compensates for carbohydrate malabsorption.⁵⁴

2. Fat and bile acids

There are four types of fats: saturated, monounsaturated fatty acids, polyunsaturated fatty acids, and trans fats.⁴⁷ A meta-analysis of 19 studies⁵⁵ revealed that excess total fat and polyunsaturated fatty acids intake are associated with CD. Furthermore, the high-fat diet affected treatment efficacy.⁵⁶ Li et al.⁴³ found that by feeding mice a high-fat diet for 4 weeks, the levels of triglycerides, cholesterol and free fatty acids in plasma and colonic mucosa were significantly higher, along with more pro-inflammatory cytokines produced by the intestinal mucosa and a significant increase in the permeability of the mucosal barrier, which aggravated oxidative stress in the mucosa and thus rapidly drove the development of intestinal inflammation. The damaging effect of free fatty acids on the intestine is referred to as intestinal lipotoxicity⁵⁷ and evident even during early disease stages.⁵⁸ On the contrary, consumption of low-fat diets may decrease fecal inflammatory markers and bacterial abundance in patients with CD.⁵⁹

Bile acids are soluble products resulting from the catabolism of highly insoluble cholesterol and are involved in the digestion and absorption of lipids in the small intestine.⁶⁰ Damage to the terminal ileum may result in malabsorption of bile acids⁶¹ and affect the hepatic and intestinal circulation of bile acids. Bile acid metabolites interact with intestinal epithelium and immune cells, leading to an inflammatory environment in IBD.⁶² Thus, imbalances in bile acid metabolism can directly affect intestinal inflammation or indirectly cause damage to the intestinal mucosa by affecting lipid metabolism.

3. Dietary fiber

Dietary fiber is not a single substance which includes all carbohydrates neither digested nor absorbed in the small intestine that have a degree of polymerization often or more monomeric units.⁶³ Daily intake of fiber-rich foods, such as vegetables and fruits, is necessary to meet daily dietary fiber requirements.⁶⁴ A 26-year retrospective cohort study,⁶⁵ including approximately 200,000 people, showed that long-term dietary fiber intake decreased the risk of CD.¹⁴ Hence, increasing dietary fiber intake could reduce the risk of CD. This advice also applies to patients with CD. Yang et al.⁴⁴ fed dietary fiber to mice with colitis and found that dietary fiber reduced weight loss, diarrhea and fecal bleeding, and also slowed the release of serum tumor necrosis factor-α. Short-chain fatty acids are thought to play an important role in this process. Short-chain fatty acids are metabolites of dietary fiber that are broken down by gut microbiota in the intestine,⁶⁶ and they reduce intestinal barrier defects and inflammation levels in mice with colitis.⁶⁷ Thus, higher dietary fiber or short-chain fatty acids intake may prevent colitis.⁶⁶ Furthermore, dietary fiber plays an important role in maintaining intestinal homeostasis by altering the intestinal microbiota and metabolites,⁶⁸ whereas lack of dietary fiber alters the characteristics of the metabolome of the intestinal microbiota, causing a deviation in the intestinal immune response to inflammation, disruption of the integrity of the intestinal mucosal barrier, and making the intestinal mucosa more susceptible to colitis induction, as well as making individuals more susceptible to intestinal pathogens.^68-70 Of note, dietary fiber increases mechanical irritation to the intestine.⁷¹ This is why dietary fiber intake should be avoiding during the early phases of disease activation. After the patient’s symptoms improve, the dietary fiber intake can be increased.

4. Protein and vitamin D

Several clinical and animal studies focused on the association between protein and vitamin D and CD. The correlation between protein and CD presented different results in animal experiments. A study by Vidal-Lletjós et al.⁷² found that moderate protein diet feeding accelerated intestinal inflammation regression, reduced intestinal mucosal permeability and increased intestinal epithelial repair, but superabundant protein diet demonstrated increased intestinal mucosal inflammation. In a French population survey, high protein intake is associated with an increased risk of incident CD among middle-aged women.⁷³ A review by Fabisiak et al.⁷⁴ showed that patients with IBD usually have lower levels of fat-soluble vitamins. Thus, the supplementation of them should be considered. In patients with IBD, vitamin D is thought to be involved in processes such as immune cell differentiation, gut microbiota regulation, gene transcription and maintenance of intestinal barrier integrity.⁷⁵ Vitamin D may prevent the development of IBD through its effects on barrier function and gut microbiota homeostasis and may also improve disease progression through anti-inflammatory immune responses.⁷⁶

The restriction or supplementation of sugar, fat, dietary fiber, protein, and vitamin D are critical to the nutritional management for CD patients. Sugar and fat significantly promote the incidence and exacerbation of colitis. Thus, high-sugar, high-fat diets must be strictly limited in the first even till the third stage of CDED. Signs of intestinal inflammation and ulcers will gradually heal in response to pharmacological and lifestyle interventions. Therefore, dietary fiber and an appropriate amount of high-quality protein can be added during the second, transitional stage. After that, and as symptoms continue to improve, the CDED can gradually incorporate more foods and maintaining remission status.

CDED was first reported in 2014. Sigall-Boneh et al.¹⁵ designed a single-center retrospective study of 47 subjects (13 adults and 34 children). After the 6-week CDED period, response and remission rates were 78.7% and 70.2%, respectively. Subsequently, clinical studies involving CDED have been developed to induce disease remission, aiding medical response and accelerating disease remission (Table 2). Fortunately, the researchers did not observe CDED-related complications.

Table 2 . Summary of Clinical Studies of CDED.

Author (year)	Total of participants	Study design	Primary results
Sigall-Boneh et al. (2014)15	47 (13 adults and 34 children)	40 patients in CDED plus PEN; 7 patients in CDED alone	27 of 40 patients in CDED plus PEN group obtained remission, and 6 of 7 patients using CDED alone obtained remission.
Yanai et al. (2021)16	44 (44 adults)	20 patients in CDED plus PEN; 24 patients in CDED alone	25 patients (13 patients in CDED plus PEN, 12 patients in CDED alone) achieved clinical remission at wk 6; 14 patients (8 patients in CDED plus PEN, 6 patients in CDED alone) were in endoscopic remission at wk 24.
Levine et al. (2019)17	74 (74 children)	40 patients in CDED plus PEN; 34 patients in EEN	97.5% of patients tolerated CDED plus PEN whereas EEN was tolerated by 73.6% of patients; both diets were effective in inducing remission by wk 6, while CDED plus PEN induced sustained remission in a significantly higher proportion of patients than EEN.
Niseteo et al. (2021)18	61 (61 children)	41 patients in EEN; 20 patients in CDED plus PEN	Patients in CDED plus PEN had comparable efficacy to EEN, and it led to better weight gain.
Szczubełek et al. (2021)14	32 (32 adults)	All patients in CDED	Clinical remission was obtained in 76.7% patients after 6 wk and in 82.1% after 12 wk.
Sigall Boneh et al. (2017)19	21 (11 adults and 10 children)	12 patients in CDED plus PEN; 4 patients in CDED alone; 5 patients in modified EEN plus CDED	13 of 21 patients with failing biological therapy obtained clinical remission.
Sigall Boneh et al. (2021)20	73 (73 children)	34 patients in EEN; 39 patients in CDED	82% of patients in the CDED group and 85% of patients in the EEN group had a rapid response or remission on the diet at wk 3; remission at wk 3 increased odds of remission by wk 6.
Matuszczyk et al. (2022)77	48 (48 children)	All patients in CDED	16 of 29 patients who were not in clinical remission at baseline achieved clinical remission.

CDED, Crohn’s disease exclusion diet; PEN, partial enteral nutrition; EEN, exclusive enteral nutrition..

The most common outcome of CDED is the introduction of disease remission. Therefore, a multicenter, open-label, pilot, randomized, CDED-based trial was conducted.¹⁶ In this study, 44 adults with CD were randomly divided into CDED plus PEN and CDED groups. No difference in clinical remission at week 6, in addition to clinical and endoscopic remissions at week 24, was observed. Moreover, these results agree with the findings of another prospective study,¹⁵ which showed no significant difference in the therapeutic effect between CDED with and without PEN. Two other studies^17,18 showed similarities in sample size and design scheme: the participants were divided into the EEN and CDED plus PEN groups. Although both studies showed that these two diet interventions effectively induced disease remission, the CDED plus PEN group overcame more disadvantages than by the EEN group. Moreover, the CDED plus PEN group had better compliance and had continuous remission and weight gain. Szczubełek et al.¹⁴ verified these results and showed that 76.7% at week 6 and 82.1% at week 12 of 32 patients with CD achieved clinical remission. Patients in the aforementioned studies effectively avoided the inflammatory stimulus caused by diet, which delayed disease progression during CDED.

Regarding improved medical responses, Sigall Boneh et al.¹⁹ designed and completed the first study, where nutritional therapy, including CDED, EEN, and PEN, was used to treat 21 patients (11 adults and 10 children) with CD, who experienced a loss of response to biologics. After 6 weeks, the Harvey-Bradshaw Index and C-reactive protein levels had significantly decreased. Treatment modalities with other mechanisms of action are essential when anti-tumor necrosis factor treatment fails; hence, CDED functions as a bridge in such situation. Meanwhile, no adverse events were recorded in the clinical trial.

In addition to re-inducing the efficacy of biologics in patients who experienced a loss of response, CDED benefitted patients whose biologics remained effective. Sigall Boneh et al.²⁰ demonstrated that CDED accelerated the process of response and remission. A multicenter randomized trial²⁰ demonstrated that CDED accelerated the process of response and remission. A multicenter randomized trial²⁰ involving 73 pediatric patients with CD who were treated using short-term CDED or EEN was conducted. At week 3 of the diet, >80% of the patients in the CDED group had a rapid clinical remission and experienced a decrease in their C-reactive protein levels. Further multivariate analysis showed that remission at week 3 might increase the probability of remission at week 6. Based on this phenomenon, therefore, early response was proposed as a treatment guide.⁷⁸ Hence, for patients experiencing severe symptoms at the beginning with rapid progression, dietary intervention with medical treatments should be initiated as soon as possible.

A recent study⁷⁹ dug into metabolomic changes showing that CDED-induced remission was associated with significant changes in IBD-associated metabolites in pediatric CD. Notably, immune status differs between children and adults.⁸⁰ Therefore, for these populations, nutritional management and needs are different.⁸¹ Current studies^15,19 have not independently explored CDED; however, clinical efficacy has been observed at week 6 in both adults and children. Patients treated with CDED had higher compliance than those treated with EEN or PEN. Meanwhile, CDED is more feasible, as its principles are more straightforward than those of specific carbohydrate diet or the low-FODMAP diet.

1. CDED candidates

In adult and pediatric patients with CD, nutritional treatment, mainly EEN, plays a crucial role in comprehensive therapy.⁸² Compared with EEN, specific carbohydrate diet, and low-FODMAP diet, CDED is easy to execute and has good compliance and long-term efficacy.^10,83 Hence, children and adults with CD are advised to try to introduce adjuvant CDED as early as possible after excluding enteral nutrition-related contraindications, such as severe functional bowel disturbances, gastrointestinal obstruction, gastrointestinal tract bleeding, severe malabsorption, and short life expectancy.⁸⁴ For patients who fail biological therapy or seek a rapid response and remission, current evidence supports the initiation of CDED.^19,20 Before initiation, exhaustive details on CDED should be acquired, and the ability to distinguish ailments during the three phases of CDED is paramount. Considering the importance and criticality of nutritional therapy for pediatric CD, juveniles should be treated under their parents’ supervision.

2. Monotherapy or combination therapy

No guidelines or consensus statements are available instructing physicians to use CDED as a cure for CD. Currently, doctors who treat patients with IBD, based on their experiences, mainly refer to case reports and case series.^85,86 According to the Montreal classification of CD, Crohn’s Disease Activity Index, and the Harvey-Bradshaw Index, patients with mild/moderate disease without structuring, penetrating, perianal disease, or extraintestinal manifestations might be initially treated using CDED monotherapy. In addition, individuals who are overly concerned about the side effects of biologics or corticosteroids could be intervened using CDED monotherapy. Importantly, the CDED requires extremely high compliance. Patients in the following situations are suggested to be treated with combination therapy: (1) patients with severe disease or more than one complication; (2) patients with no Improvement during periodic evaluations; and (3) patients who are not candidates for monotherapy for any reason.

3. Handling complications

Although so far, no serious adverse events or treatment-related adverse events about CDED have been reported, malnutrition and micronutrient deficiencies have been noticed.⁸⁷ Thus, a patient’s nutritional status micronutrient levels should be closely monitored, especially in long-term CDED, to allow for early intervention and avoidance of complications.

4. Evaluation

Similar to evaluating the effects of medical treatments, patients need to be continually assessed, whether or not they are being treated with CDED. Those treated with CDED can be reassessed every 6 weeks depending on phase (more frequently during strict control and transition phases and appropriate reduction during maintenance). These evaluations need to include clinical manifestations, laboratory examinations, endoscopy, Crohn’s Disease Activity Index, Harvey-Bradshaw Index, measures of compliance, and noting of any complications or adverse events.¹ The therapeutic duration of CDED phases could also be extended for patients who present with issues during these evaluations.

5. Integrated case management

As CD is a lifelong condition that necessitates continuous treatment, integrated case management is critically important. Because underlying dietary components were harmful to CD patients, nutritionists should be intimately involved in care planning for these patients.¹³ The significance of a nutritionist has been established in a previous clinical practice.⁸⁸

Advances in medical therapies and nutritional treatments allow patients with CD to increasingly achieve. CDED is a relatively simple and nutritional supportive treatment that, when properly executed, will serve as an effective adjuvant treatment for patients with CD.

This work was supported by the National Natural Science Foundation of China (No. 82170599).

No potential conflict of interest relevant to this article was reported.