Introduction

Elemental diets (EDs) have been used for more than 50 years for various conditions and illnesses. Whereas polymeric diets contain whole proteins and oligomeric diets contain short peptides, the nitrogen content of EDs typically consists of free amino acids [1]. The lipid content of EDs consists of medium chain triglycerides, which passively diffuse into the portal system, with or without additional long-chain triglycerides. The carbohydrate content of the elemental diets generally consists of monosaccharides (dextrose, glucose, or maltose) or easily digestible saccharide polymers, such as maltodextrins. EDs are complete nutritional sources and contain the daily requirements of vitamins and minerals.

The production and mixing processes of ED formulas continue to be highly complex and necessitate involvement of specialized food engineering laboratories. EDs are devoid of allergens and can be largely absorbed without active digestion, allowing for rapid absorption and high nutritional efficacy. As such, EDs have favorable characteristics to be effective for several gastrointestinal (GI) and systemic diseases, particularly those driven by atopy, indigestion, and malabsorption. They further possess anti-inflammatory and mucosal healing properties that contribute to their utility in inflammatory conditions. Given their high absorbability index, EDs generate little fecal bulk, which provides additional benefit in severe diarrhea, high output ostomies, and gastrointestinal fistulae. (Fig. 1) Many of these GI diseases have limited therapeutic options, particularly when first-line therapies are unsuccessful, a gap which elemental nutrition therapy may be able to fill as an adjunct or stand-alone therapeutic and nutritional intervention.

Fig. 1
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Mechanistic pathways through which elemental diets exert their beneficial effects

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In addition to its utility in the management of GI diseases, ED has been shown to have potential use in the management of non-GI atopic illnesses such as perennial asthma and inflammatory illnesses such as rheumatoid arthritis [2, 3]. ED can be of particular benefit in the pre-, peri-, and post-operative management of patients undergoing pancreaticoduodenectomy, gastrectomy, ileal resection, or colectomy in the management of malignancy or inflammatory bowel disease [4,5,6,7].

The main barriers to the widespread use of EDs include poor palatability, high out-of-pocket cost, and lack of provider awareness. While numerous studies have investigated the application of EDs in various diseases, these valuable insights remain scattered across the literature, posing a challenge in accessing this information. The aim of this review is to provide a comprehensive elucidation of formulation variability, mechanisms of action, clinical applications, and tolerability of elemental diet as a therapeutic modality in GI disorders.

Methods

In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews (PRISMA-ScR) [8], we systematically searched three electronic databases: MEDLINE, PubMed, and the Cochrane Database for Systematic Reviews and Cochrane Central Register for Controlled Trials for relevant articles from inception until September 2023. The search strategy was designed to identify all studies evaluating the effect of ED in treating various GI diseases. Study designs included randomized controlled trials (RCTs), systematic reviews, case–control studies, cohort studies, cross-sectional studies, case series, and case reports. The exclusion criteria included studies involving animal subjects, non-English literature, conference abstracts and review articles and editorials. For indications where a systematic review or meta-analysis has already been completed, the results of these reviews were preferentially discussed. Further details regarding the search strategy, eligibility criteria, reviewing process, and study selection flow diagram are described in the supplementary material.

Results

The initial database search yielded a total of 1243 articles. After removing 583 duplicates, 660 records remained for screening. Among these, 51 studies met the inclusion criteria and were included in the review and presented based on disease state (Supplementary Fig. 1).

Eosinophilic Esophagitis (EoE)

EDs have been used in the management of EoE in pediatric patients since the description of the disease, with the first report on efficacy being published in 1995 by Kelly et al. [9]. (Table 1) In this study 10 proton pump inhibitor (PPI)-refractory children with EoE (6 also failed fundoplication) underwent a minimum of 6 weeks of exclusive ED. All subjects showed symptomatic response (80% resolution and 20% improvement of symptoms) along with endoscopic and histologic improvement. Subsequent studies in pediatric cohorts assessing exclusive ED therapy reproduced high rates of response ranging from 75 to 95%. A recent meta-analysis determined the pooled efficacy of ED in EoE to be 91% (95% CI 85%-96%) [10].

Table 1 Studies assessing the effect of exclusive elemental diet in eosinophilic esophagitis and eosinophilic gastroenteritis
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Two prospective studies have investigated the efficacy of exclusive ED in adult EoE [11, 12]. Peterson et al. assessed the efficacy of 4 weeks of ED (2 weeks if their response was complete at week 2 endoscopy) on 29 adult patients with EoE. All patients underwent at least 8 weeks of PPI therapy prior to baseline endoscopy. Compliance was poor as 11 subjects (38%) could not tolerate the elemental diet (Elecare). Of the remaining 18 subjects, one had complete response (< 2 eos/hpf) at 2 weeks and the rest completed 4 weeks of ED. Presence of endoscopic furrows and exudates significantly dropped from 78 and 56% to 17% and 6%, respectively (p < 0.01). However, the reduction in the rate of strictures (39% vs 28%) was not statistically significant (p = 0.21). Overall, there was a fivefold decrease in tissue eosinophil count (54 to 10 eos/hpf, p < 0.01). Of 18 subjects, 9 (50%) had complete histologic response (< 5 eos/hpf), 2 (12%) had near complete response (< 6–10 eos/hpf), 4 had partial histologic response (> 10 eos/hpf but > 50% drop in eosinophil count), and 1 (6%) failed (only 18% drop in eosinophil count at 4 weeks). Eight subjects were steroid refractory with 50% complete response similar to non-steroid refractory cases. Mast cell counts also significantly dropped from 32 to 14/hpf (p < 0.01). Six subjects underwent repeat endoscopy after introduction of solid food which showed recurrence of eosinophils but not mast cells.

Warners et al. prospectively assessed 34 adults with EoE. Only 17 subjects were able to finish 4 weeks of ED therapy (50% drop-out rate) mostly due to unpalatability. Of 17 patients, 16 (94%) showed complete (n = 12) or partial histologic response (n = 4). Peak tissue eosinophil count dropped from 40 to 9/hpf, while mast cell counts were unchanged (10 to 7/hpf, p = 0.82). Significant improvement in the number of patients with severe/moderate eczema was observed (76% vs 30%, p = 0.01). Significant endoscopic improvement was observed as the mean endoscopic reference score dropped from 7 to 3 after the diet (p < 0.01). Fifteen patients (88%) became completely asymptomatic [12]. Peripheral eosinophil counts, IgE levels, interleukin (IL)-5, IL-13, and thymic stromal lymphopoietin significantly decreased after diet. Disease recurrence was seen in all six subjects who underwent follow-up endoscopy at 6 months after reintroducing all food groups.

In the clinical guidelines by the American Gastroenterological Association and the Joint Task Force on Allergy-Immunology Practice Parameters, ED was described to have the highest response rate across treatment interventions, receiving a conditional recommendation for use in EoE [13] with moderate quality of evidence. The conditional recommendation cited the difficulty of adherence and high cost as areas of concern. Overall, exclusive elemental diets appear to be highly effective in induction of remission in EOE; however, a strategy needs to be adopted for maintenance of remission following completion of the diet. Further studies are needed to elucidate which maintenance therapy (e.g., food elimination diet, partial ED, topical/systemic immunomodulators, or monoclonal antibodies) is superior in this setting.

Eosinophilic Gastritis/Gastroenteritis (EGID)

Gonsalves et al. assessed the efficacy of ED in 15 cases of eosinophilic gastritis and gastroenteritis in a prospective, single-arm trial. Of 15 subjects, 14 had failed at least one standard of care treatment, including PPIs, steroids, immunosuppressive therapy, or elimination diets. All 15 subjects had complete histologic remission (< 30 eos/hpf) in both the stomach and duodenum after 6 weeks of ED [14]. Average eosinophil count dropped from 50 to 11 eos/hpf in the stomach and from 49 to 16 in the duodenum (p < 0.01). An average weight loss of 5.9% was observed. Furthermore, all patients had improvements in molecular disease activity, endoscopic signs, and symptoms, including pain and fatigue. Thirteen patients who pursued regular food reintroduction experienced disease relapse. Microbiome analysis showed increased abundance of Firmicutes, Porphyromonadaceae, and Veillonellaceae and decreased Bacteroidetes, Ruminococcaceae, and Bacteroidaceae.

Of the 18 patients who initially started the diet, two (10.5%) withdrew due to inability adhere to exclusive diet and one patient was withdrawn after developing hyponatremia in the context of having renal insufficiency, multiple diuretics, and ingesting less than the recommended amount of the formula and an excess of free water.

Similar to EOE, EGID appears to be highly responsive to exclusive ED. To decrease the chance of recurrence after the diet, patients may require to be on a maintenance therapy, such as food elimination diets, partial ED, or immunosuppressive therapy.

Inflammatory Bowel Disease (IBD)

Nutrition and dietary interventions are critical steps in the management of IBD patients with and without undernutrition. Exclusive enteral nutrition (EEN) with intake of liquid elemental, semi-elemental, or polymeric formulas for 6–8 weeks has been shown to be effective in Crohn’s disease (CD). In children and adolescents, EEN is recommended as first-line therapy [15] for induction of remission. ED is of particular interest in patients with active disease as a stand-alone or adjunct to induction therapy.

A 2018 Cochrane systematic review [16] of 11 trials showed that ED has similar rate of induction of remission in CD (63.8%) as compared to non-elemental diet enteral feeds (62.5%, p = 0.83, n = 378) with no difference in adverse events (Relative risk 1.01, 95% CI 0.62–1.65, n = 323).

A 3 to 6 weeks of ED appear to be effective in inducing clinical, endoscopic, and histologic remission in CD. (Table 2) Effect of ED in ulcerative colitis (UC) is only assessed in one small study in 1989 where 24 mild to severe UC patients were randomized to an ED (n = 12) or a blended normal diet (n = 12) for two weeks. Five patients withdrew from the study due to taste, but significant clinical improvement was noticed in both groups. The role of ED in management of UC remains to be elucidated. Of note, the ED used in this trial contained 70–90% short-chain peptide and 10–30% free amino acids which underlines the variability in definition “elemental diet” especially in older studies which needs to be taken into consideration when assessing the efficacy of Eds (Supplementary Table 1). Fat composition of elemental diet is also important as high large-chain triglyceride content has been linked to lower efficacy of ED in CD [17].

Table 2 Studies assessing the effect of exclusive elemental diet in inflammatory bowel disease
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Notably, owing to known poor oral tolerance and palatability, in the majority of the studies exclusive ED was delivered via tube feeding (Table 2). Where ED was given orally, rates of intolerance in pediatric [18] and adult [19] patients are reported up to 36% and 41%, respectively.

While several studies [20,21,22] have assessed the addition of elemental diet to regular food, the efficacy of exclusive ED for maintenance of remission in IBD is not yet evaluated.

Overall, ED appears to be highly effective in inducing remission in adult and pediatric CD. Upon induction of remission, an appropriate maintenance of remission strategy should be adopted.

Small Intestinal Bacterial Overgrowth/Intestinal Methanogen Overgrowth

While antibiotics are the mainstay of treatment for small intestinal bacterial overgrowth (SIBO) and intestinal methanogen overgrowth (IMO), their overall efficacy is limited at 50% or less [23, 24]. Elemental diet provides an alternative option to treat patients who are refractory, cannot tolerate antibiotics, or prefer a non-antibiotic treatment approach. [20]Pimentel et al. conducted a retrospective study on patients with irritable bowel syndrome (IBS) and hydrogen-predominant SIBO (based on abnormal lactulose hydrogen breath testing). Subjects took 14 days of ED (Vivonex Plus, Nestle) and if breath test remained abnormal, they were encouraged to take the diet for an additional 7 days. Of 124 included subjects, 93 had complete records or could tolerate the diet for analysis. Normalization of breath test was observed in 80% after 14 days and another 5% normalized with an extension to 21 days. Significant clinical improvement in symptoms (66%) was noticed among 28 patients who normalized their breath and had clinical data available [25]. Rezaie et al. evaluated an oral palatable ED (Mbiota Elemental) in a prospective clinical trial on 30 subjects with IMO and/or SIBO. All patients were able to tolerate 14 days of exclusive ED and a significant drop in maximum methane levels (41 ± 35 to 12 ± 15 ppm, p < 0.001) and peak hydrogen rise (43 ± 42 to 12 ± 11 ppm, p < 0.001) were observed. Complete normalization of breath test was seen in 100%, 58%, and 75% in SIBO (n = 6), IMO (n = 12), and IMO/SIBO (n = 12), respectively. No serious or severe adverse effects were observed [26].

Overall, ED appears to be effective in treatment of IMO or SIBO. However, studies with longer period of follow-up are needed to assess the response durability and the role of maintenance strategies.

Celiac Disease and Dermatitis Herpetiformis

We identified three studies describing the efficacy of the ED in dermatitis herpetiformis and celiac disease, 1 in celiac disease, and 3 in refractory celiac disease. Kadunce et al. conducted a trial on 8 adult patients with dermatitis herpetiformis on dapsone, 6 of whom were given an exclusive ED (Vivonex TEN) plus 30 g of gluten for 2 weeks followed by the ED alone for 2 weeks, while 2 subjects were given the dietary intervention in reverse order [27]. Subjects started regular diet one month prior to the trial. Dapsone was discontinued three days before the study start date. All patients underwent fluoroscopic small bowel biopsies at days 0, 14, and 28. Following the 2-week ED plus gluten phase, 100% of patients (7/7) demonstrated histologic worsening of their celiac disease and after only 2 weeks on the exclusive ED period, 100% (6/6) demonstrated histologic improvement. Interestingly, 6 out of 8 subjects experienced improvement of their rash during the ED with gluten exposure phase, with all 8 experiencing improvement by the end of the study [27]. Two older studies published in 1981 and 1986 described mixed results in the intestinal histologic response of 7 patients with celiac disease and dermatitis herpetiformis after a trial of elemental diet despite significant improvement in their skin lesions, although these studies were limited by having used Crosby-Kugler capsules to obtain the small bowel biopsies [28, 29]. As opposed to endoscopy, this technique utilizes an orally ingested tube to obtain small bowel biopsies without direct visualization [30].

In a study on presumable celiac disease diagnosed by Crosby-Kugler capsule and clinical symptoms, 4 weeks of exclusive elemental diet (n = 4, Vivonex) achieved similar clinical improvement as gluten-free diet (n = 4). Modest histologic improvement was noticed in both groups [31].

The three studies describing the role of ED in refractory celiac included a prospective study of ED (E028) for four weeks on 10 patients with Type 1 refractory celiac disease despite strict gluten-free diet. One patient dropped out and 6/9 patients demonstrated clinical improvement, while 8/9 demonstrated histologic improvement and decreased IL-15 [32]. Otherwise, 2 case reports were identified, one with symptomatic and histologic improvement of a middle-aged woman on the ED with the patient electing to extend the ED to 10 weeks, later returning to a GFD and remaining asymptomatic [33]. The other described a patient with steroid refractory CD who showed no significant clinical or histologic response to 6 weeks of ED, necessitating a change in treatment and eventually responding to infliximab [34].

Overall, limited data suggest a potential role for ED in treatment of refractory celiac disease type 1 and dermatitis herpetiformis; however, the role of ED in non-refractory Celiac disease requires further evaluation.

Acute Pancreatitis

A limited number of studies were found describing the use of ED in acute pancreatitis. Endo et al. conducted a retrospective cohort study using a national database, identifying patients with acute pancreatitis who received enteral tube feeding within 3 days of admission [35]. There was no significant difference observed for in-hospital mortality, hospital-free days, total health-care costs, and sepsis development between those who received an elemental diet (Elental, n = 382) and those who received non-elemental enteral nutrition (n = 566) [35]. On the other hand, Voitk et al. assessed six patients with complicated severe acute pancreatitis unable to tolerate regular diet and unsuitable for parenteral nutrition. Five of the 6 patients experienced clinical improvement, weight gain, and eventual recovery, while one patient initially improved but later succumbed to a hemorrhagic complication of severe pancreatitis [36].

Overall, current data do not show a clear advantage of ED over other enteral feeding formulas in the treatment of patients with acute pancreatitis. Prospective controlled trials are needed the effect of ED in acute pancreatitis.

Chronic Pancreatitis

Two studies have described the benefit of supplementing with 300–1200 kCal of ED in chronic pancreatitis. A prospective cohort including 596 patients with chronic pancreatitis and chronic pain found clinical improvement in response to partial ED supplementation with a decrease in abdominal pain from 52.9 to 20.0 mm on the visual analog scale after 12 weeks (p < 0.001), with an associated improvement in nutritional indices [37]. Another prospective cohort included 17 chronic pancreatitis patients with chronic pain, finding that partial ED supplementation resulted in complete pain resolution in 59% of patients and pain improvement in 29% [38].

Overall, supplemental ED appears promising in improving pain in patients with chronic pancreatitis. Larger studies are needed to assess the magnitude and durability of response.

Intestinal Lymphangiectasia

Intestinal lymphangiectasia is an acquired or congenital disease complicated with protein losing enteropathy at varying severity [39]. While total parenteral therapy, steroids, and MCT oils have been used for treatment of intestinal lymphangiectasia, one retrospective study and one case report have assessed the role of ED. Aoyagi et al. retrospectively assessed four patients on ED (Elental) for 4–6 weeks and response (increased serum total protein) was seen 3/4 patients. Both patients with objective enteric protein loss normalized [39]. In 2001, Kuroiwa et al. described a patient with octreotide-responsive intestinal lymphangiectasia who did not experience clinical or laboratory improvement with ED, although the duration of the ED trial was not reported [40].

Very limited data exist on the role ED in treatment of intestinal lymphangiectasia. Further prospective trails are needed.

Bile Acid Diarrhea

Two studies investigated the role of the ED in bile acid diarrhea. In 1977, Nelson et al. assessed six patients with bile acid diarrhea secondary to ileal resection who received ED for 8–15 days, and they showed a reduction in their fecal bile acid excretion with marked improvement in their diarrhea and reduction in stool frequency, volume, and urgency [41]. In 1979, Russell et al. reported three patients with non-surgical, Crohn’s-related ileal malabsorption and bile acid diarrhea with marked reduction of fecal bile acid output, and improvement in their stool frequency and consistency during 2–3 weeks of treatment with ED [42]. Of note, neither of these studies ruled out SIBO as a common cause of bile acid malabsorption which is also responsive to ED [43].

Larger prospective trials with up-to-date diagnostic evaluations are needed to assess the role of EDs in bile acid diarrhea.

Risk of Aspiration Associated with Percutaneous Endoscopic Gastrostomy (PEG)

Two publications examined the role of ED in preventing aspiration, both by Horiuchi et al., in 2013 and 2019. In the 2013 publication, consecutive bedridden PEG patients received either ED (n = 60) or standard liquid diets (n = 67). None of those receiving the ED experienced aspiration or aspiration pneumonia, while those receiving the standard liquid diet developed aspiration in 11.9% (p < 0.01) and aspiration pneumonia in 7.5% (p = 0.03) [44]. In their subsequent study, 19 patients were randomized to ED or standard liquid diets with subsequent crossover. Rates of gastric emptying were significantly faster with the ED compared to the standard liquid diet [44]. In 2019, a similar study recruiting 18 consecutive bedridden PEG patients who received the ED, showed one episode (5.6%) of aspiration from the trachea and no episodes of aspiration pneumonia [45].

Overall, ED shows promise in decreasing aspiration events in patients with PEG. Larger studies are needed to assess the magnitude and durability of response.

Prevention of Chemoradiation-Induced Oral Mucositis

Approximately 20–40% of patients with solid tumors undergoing chemotherapy develop mucositis [46]. No trials investigating an exclusive ED were identified, although numerous trials investigated the role of partial ED. A systematic review and meta-analysis by Tanaka et al. in 2022 included 9 studies (6 RCTs and 3 observational studies) and found that partial ED supplementation significantly reduces oral mucositis (grade 2–4) associated with chemotherapy/radiotherapy (OR 0.25, 95 CI 0.10–0.61) [46].

Overall, current data supports supplemental ED in prevention of chemoradiation-induced oral mucositis.

Other Published Uses Outside the Scope of this Review

Multiple other uses for the elemental diet were evident in our search, although they were outside the scope of our review. These included reducing GI bleeding in burn victims [47], severe asthma, severe eczema, Cronkhite–Canada syndrome, orofacial granulomatosis, rheumatoid arthritis, chylothorax, and chylous ascites [2, 3, 48,49,50]. There are also several publications regarding the utility of ED in the perioperative setting for multiple surgeries, including gastrectomy, colectomy, short bowel syndrome, and pancreaticoduodenectomy [5, 6, 51]. No studies were identified to be investigating the benefit of ED in adult food allergies, metabolic syndrome, lactose intolerance, sucrose intolerance, or non-celiac gluten intolerance.

Discussion

EDs have broad applications as stand-alone or adjunct therapy across several GI diseases, many of which have otherwise limited treatment options. The mechanisms by which EDs benefit patients are multifold and vary depending on the underlying disease pathogenesis:

  1. 1.

    Allergen-free content: As the protein content of an ED is completely hydrolyzed, it is intrinsically allergen free. This imparts a distinct benefit in the treatment of allergen-driven diseases, including EoE and EGID, celiac disease, and food allergies. Lack of food allergens minimizes the mucosal immune response with potential benefit in IBD.

  2. 2.

    Bypass of digestion: EDs require minimal to no digestion and as such are readily absorbable in the proximal small intestine. This allows it to bypass exocrine pancreatic insufficiency, biliary pathology, and enzymatic deficiencies, such as lactase and sucrase/isomaltase deficiency.

  3. 3.

    Decreased GI exocrine stimulation: The hydrolyzed protein and minimal fat content modulate the luminal stimulation of gastrointestinal hormones and pancreatobiliary secretions. There is evidence [52] that the ED is a weaker stimulus of pancreatic secretions compared to a regular diet, potentially contributing to its alleviation of pain associated with chronic pancreatitis.

  4. 4.

    Optimal nutritional value: ED is a complete diet that provides all necessary macronutrients and micronutrients with an adjustable daily caloric target which effectively addresses undernutrition, malnutrition, and their associated morbidities.

  5. 5.

    Low-fat content: While high-fat diets are proinflammatory, ED is a low-fat diet, further contributing to its anti-inflammatory effect [53]. Furthermore, MCTs possess several beneficial effects, including anti-inflammatory properties [54].

  6. 6.

    Low fecal bulk: The minimal non-absorbable content and high absorption rate of EDs are associated with a decrease in fecal stream which may benefit certain diseases, such as CD and fistulae [55]. Interestingly, total parenteral therapy has not been associated with remission of IBD, emphasizing that low fecal bulk is not a critical pathway for benefits seen with ED [56].

  7. 7.

    Modulation of the gut microbiome: ED has been shown to be an effective treatment for small intestinal bacterial overgrowth, likely as a result of the extensive proximal absorption of nutrients with minimal residual luminal nutrients in the distal small bowel and colon, directly inhibiting bacterial growth. The diet further [14, 57] influences the composition of the gut flora which itself has been suggested to contribute to the beneficial effects of the diet.

  8. 8.

    Free amino acid content: The free amino acid content of EDs play an important role in mediating their beneficial impact. Glutamine is essential for the growth of rapidly dividing cells, such as epithelial cells. Glutamine supplementation in isolation has been shown to heal and prevent mucosal damage in disease states with impaired mucosal turnover, such as in patients receiving chemotherapy and radiotherapy [58]. It has been shown to improve tight junction protein expression [59] and intestinal permeability in various disease states, including IBS [60], severe burns [61], and IBD [62]. It is also the precursor of glutathione [63], which is a major endogenous antioxidant that protects against apoptosis and cellular stresses. Histidine possesses antioxidant and anti-inflammatory properties [64] that have the potential to positively impact gastrointestinal tract health. While there are no human studies investigating histidine, a rodent model of colitis showed [65] that histidine inhibited NF-κB activation and downregulated downstream proinflammatory cytokine production. Similar to glutamine, arginine stimulates cellular pathways [66] that enhance mucosal cell proliferation, cytoprotection, and recovery. Arginine plays a particularly important role as a precursor for nitric oxide, a vasodilator, and key regulator of intestinal motility through relaxing intestinal smooth muscle cells. Finally, proline, threonine, and serine [67] are critical to the intestinal mucosal barrier as they form mucin glycoproteins.

  9. 9.

    Food additive-free content: True EDs are devoid of food additives including emulsifiers, artificial sweeteners, food colorants, and nanoparticles which have been implicated in pathogenesis of various diseases, including IBD and IBS [68].

While ED can provide 100% of daily nutrition requirements [69], it should be noted that conventional formulas to calculate daily basal metabolic rate likely overestimate the required daily calories during exclusive ED consumption. Active digestion accounts for 10% of daily energy expenditure which significantly reduces with exclusive ED. In addition, unlike non-elemental diets, EDs are optimally absorbed and a higher digestibility coefficient leads to higher calorie harvest [70].

Our findings show that the main limiting factor in implementing an ED is patient intolerance due to taste with study withdrawal rates up to 41%. In pediatric population, this has generally been mitigated by enteral tube feeding, a strategy which is not typically feasible in adult and adolescent subjects especially in outpatient settings. Hence, development of organoleptically acceptable elemental formulations is key to increase the compliance and tolerance rates of patients. Similarly, this can pave the way to use elemental diets for maintenance of remission of relevant GI disorders rather than induction of remission phase. Barriers of cost and access are also notable, particularly as nutritional therapies are often not covered by insurance providers with high out-of-pocket costs. Patient advocacy efforts to increase patient access and insurance coverage are critical.

Avoidant/restrictive food intake disorders with aversion to certain foods based on their sensory characteristics, or a fear of the consequences of eating, or a lack of interest in eating can be seen pediatric and even adult patients suffering from chronic diseases. In the presence of such disorders, caution should be exerted in initiation of strict or restrictive diets or dietary formulations. A multidisciplinary approach remains the ideal approach to care for these patients [71].

Our study has several limitations. Typically, blinding is a challenge in diet trials which can affect the estimation of therapeutic effect. Definition of EDs in terms of fat, carbohydrate and even small peptide content had variability among the studies. The interpretation of the results of included studies should take into account the constitution of each elemental diet (Supplementary Table).

In conclusion, despite cost and palatability barriers, elemental diet offers a potentially highly efficacious intervention with minor side effects in various inflammatory and non-inflammatory GI disorders. Future studies should focus on ameliorating barriers of use and improving the optimal micro- and macronutrient content of elemental diets.