ECCO’24 Nutritional Highlights: What is New in Enteral Nutrition, the Microbiome and Dietary Supplements?

In February 2024, Nutritional Therapy for IBD attended the 19^th Congress of ECCO (ECCO’24) in Stockholm, Sweden. Discover what emerging evidence says about next-generation enteral nutrition therapy, the role of microbial markers in monitoring IBD, and the lights and shadows of dietary supplements (Part 2). 

Current Science on The Role of Enteral Nutrition in the Management of IBD

Exclusive enteral nutrition (EEN) is a well-researched diet for active Crohn’s disease, with more robust evidence in children than adults. This liquid diet, excluding all food and drink, may also be an effective therapy in pregnant women with CD and malnourished patients before undergoing elective surgery for Crohn’s disease to optimize nutritional status and reduce post-operative complications.^1-6 Dr Vaios Svolos, a dietitian investigating the CD-TREAT diet at the University of Glasgow, updated the mechanisms of action behind EEN. EEN shares characteristics with other dietary approaches, such as food-based diets low in carbohydrates that aim to suppress gut microbes, gut rest, and total parenteral nutrition, which have been shown to reduce Crohn’s disease activity. 

Potential mechanisms explaining why patients respond to EEN include a decline in protective gut bacterial species and metabolites,⁷ a reduction of fecal calprotectin,⁸ a decreased immune cells-mediated stress,⁹ and changes in the intestinal epithelium,¹⁰ while the hypothesized reduction of additives and preservatives as a mechanism of EEN action upon reducing CD inflammation is not proven, especially considering the paradoxical high amount of such non-nutritive food ingredients in EEN feeds.¹¹

The efficacy of EEN could also be explained by its effects on increasing circulating effector and memory CD8+ T cell populations, which are likely a result of a depletion of gut bacteria secondary to EEN. These changes were documented irrespective of background immunomodulator use and persisted in children with CD who achieved a decrease in fecal calprotectin. 

While EEN is an effective induction treatment for CD, it is difficult for patients to follow (i.e., poor palatability and interference with social activities) and the gut inflammation comes back within just 17 days of food reintroduction.⁸ Dr. Konstantinos Gerasimidis, dietitian and professor of Clinical Nutrition at the University of Glasgow, updated different approaches for using enteral nutrition to overcome the current limitations of EEN (next-generation enteral nutrition therapies):

1. Partial enteral nutrition (PEN) combined with Crohn’s Disease Exclusion Diet for induction of remission in CD led to 75% of children in corticosteroid-free remission and showed a good tolerance compared to children given EEN alone.¹²

2. PEN after EEN induction for maintaining remission: a dose-response effect has been observed, with the optimal dose for clinical remission being when PEN monotherapy covers at least 35% of daily energy requirements (better response when more than 50% of daily energy requirements are covered with PEN).¹³

3. EEN around the time of surgery to prevent and optimize post-operative outcomes (perioperative optimization with EEN or maintenance enteral nutrition): EEN is associated with reduced systemic inflammation, operative times, length of stay, and post-operative complications such as stoma formation. In some patients with strictures or complications of CD, EEN can reduce the need for surgery.^14,15 The OCEaN study (Optimisation before Crohn’s surgery using Exclusive enteral Nutrition) will explore whether pre-operative EEN is more clinically and cost-effective than the usual diet in patients undergoing surgery for CD.

4. EEN/PEN for increasing biologics’ efficacy to induce clinical remission: preliminary findings from the Biologics and Partial Enteral Nutrition in Crohn’s Disease Study (BIOPIC) presented by Bernadette White and colleagues from the University of Glasgow showed equivalence in clinical efficacy between PEN (providing 50% of daily energy needs) and adalimumab (experimental group) compared to adalimumab monotherapy (control group). In addition, PEN was well tolerated, and patients receiving PEN and adalimumab achieved a higher decrease in faecal calprotectin (< 100 mg/kg) and a similar reduction of C-reactive protein compared to patients receiving adalimumab only. These findings open the role of enteral nutrition combined with biologics to optimize primary response to biologics or when biologics fail.

5. EEN in complicated CD: EEN therapy can relieve inflammatory bowel stricture in CD by increasing the luminal area, favoring perianal fistula closure, and resolving the intra-abdominal abscess. It is also associated with an improvement of inflammatory, nutritional, and radiologic parameters^16,17

Advancing to Predict Which Patients Following Nutritional Therapy Will Achieve Remission

While EEN and CDED combined with PEN are effective in inducing remission in mild-to-moderate CD, some patients still do not achieve remission. Mohammed Ghiboub, Johan E. Van Limbergen at Amsterdam University Medical Centers, and colleagues found microbiota-derived tryptophan metabolites, namely serotonin/kynurenine and 5-OH-tryptophan/kynurenine ratios, show a potential value for predicting which pediatric patients with CD will achieve clinical remission to CDED + PEN and EEN, respectively.

The reduction of fecal calprotectin during EEN is lost rapidly after food re-introduction in children with Crohn’s disease (CD)⁸. iPENS is a large multicentre, prospective study, run across 11 pediatric hospitals in the UK and led by Prof Gerasimidis (University of Glasgow, UK) and Prof Russell (Royal Hospital for Children and Young People, Edinburgh, UK) aiming to identify dietary and microbial triggers of gut inflammation in children with CD.

In a pilot analysis of the first 30 patients who completed the study, Gkikas et al. identified diet-related microbial metabolites that might predict the rebound of fecal calprotectin following EEN completion in children with CD. The ratio of the concentration of fecal branched-chain fatty acids over butyrate was positively correlated with the increase of fecal calprotectin over food reintroduction. Furthermore, the average daily intake of cereal products was lower in children who experienced a fecal calprotectin increase of over 250 μg/g at 21 days after food reintroduction versus those with fecal calprotectin below 250 μg/g.

In another pilot analysis from the iPENS study, Gkikas et al. explored mechanisms that can explain the efficacy of EEN and parameters that can differentiate patients whose fecal calprotectin normalizes against those who still have high levels of fecal calprotectin at EEN completion. Looking at data from 84 patients who clinically responded to EEN, higher fecal pH and lower total microbial load were observed in patients with fecal calprotectin below 250 μg/g against those with levels above 250 μg/g. Machine learning analysis using microbial, clinical, and anthropometric variables predicted normalization of calprotectin with 71% accuracy with higher fecal pH, BMI z-scores, and lower total microbial load being the most influential parameters.

Further analysis is required to confirm those findings once recruitment is complete (n=116), with the iPENS study having the potential to identify what triggers gut inflammation and help answer one of the most frequently asked questions by patients with CD; “What should I eat to control my disease”?

Ultra-Processed Foods as a Trigger for IBD

Ultra-processed foods (UPFs) have been associated with a higher risk of IBD, especially Crohn’s disease (CD), and IBD-related surgery.^18,19 João Sabino from the KU Leuven highlighted that although following a diet free of emulsifiers is accompanied by a decrease in UPFs,²⁰ it is not a “patient-friendly” diet due to restrictive food choices, negative impact on social life (e.g., restaurant visits), and high time-consuming reading of food labels and cooking.

Chen Sarbagili, clinical dietitian and researcher at Wolfson Medical Center in Israel, shared a validated processed foods frequency questionnaire for studying the association between UPF consumption and IBD development.²¹ When it comes to the role of UPFs and the gut microbiota, not all emulsifiers have the same impact on the microbiome. While soy lecithin and mono- and diglycerides have no significant effect on the human microbiota, carrageenans, carboxymethylcellulose, and polysorbate 80 have the most negative impact on the gut microbiota.²² In contrast, organoid-derived epithelial monolayers from patients with CD revealed that emulsifier carrageenan does not directly alter intestinal permeability.²³

While awaiting further quality studies on the role of food processing in maintaining IBD remission and active disease, Sarbagili stated that the exclusion of UPFs and dietary emulsifiers makes sense for preventing IBD development and for treatment for active CD and UC. However, it is paradoxical that EEN fits with the definition of UPF and is rich in emulsifiers and thickeners with a negative impact on intestinal inflammation but overall is effective for active CD^24,25

Ongoing studies are investigating the impact of isolated emulsifiers on the intestinal permeability of healthy volunteers. The FOod Additives on the Mucosal barrier (FOAM) study is a double-blind pilot randomized controlled trial that aims to investigate the effect of five different emulsifiers (polysorbate 80, carboxymethyl cellulose, carrageenan, soy lecithin, and native rice starch) on systemic and intestinal inflammation, intestinal permeability, and the gut microbiome. 

Preliminary findings presented by Sabino showed that after 6 weeks following an emulsifier-free diet, any of the five studied emulsifiers affected faecal calprotectin. The fecal short-chain fatty acid acetic acid increased at week 2, and both acetic and propionic acid increased at week 6 compared to baseline only for the placebo group. While only carrageenan altered intestinal permeability at week 6−as measured by an increased levels of lipopolysaccharide-binding protein−, none of the other tested emulsifiers altered the levels of faecal short-chain fatty acids in healthy individuals.²⁶

Sabino highlighted that while patients are interested in treating IBD with diet, the reality is that restrictive diets low in food additives and UPFs are difficult to follow and maintain (diet paradox). One way to improve this situation, according to Sabino, is to improve UPFs manufactured by the food industry instead of restricting them, which will allow a shift towards “good/neutral” food additives. The first step is testing emulsifiers’ impact on intestinal permeability before their commercialization in foods, similar to what is currently done in toxicology analysis.

Beyond Diet: Lifestyle and Microbiome May Help Predict IBD Risk, Progression, and Remission

Subrata Ghosh, Deputy Director at APC Microbiome Ireland, summarized epidemiological and mechanistic evidence linking other lifestyle factors beyond diet that can affect IBD course, including stress, living in affluent areas, physical activity, obesity, smoking, air pollution, alcohol, cannabis, and sleep. It is worth noting that individuals with high genetic risk and adopting a healthy lifestyle had a 50% reduction in the risk of developing CD or UC.²⁷

The impact of lifestyle on IBD risk could be explained through their effect on the gut microbiome, which is emerging as a potential target for patients with IBD who do not respond to existing treatments.²⁸ 

In the poster findings from S. Taboada-López et al., a novel faecal microbial signature, in combination with faecal calprotectin, was identified for the monitoring of endoscopic activity in Crohn’s disease. This signature exhibited higher performance compared to faecal calprotectin alone. This identification holds significant potential to optimise endoscopic allocation strategies, thereby improving clinical decision support systems in the management of Crohn’s disease. These findings suggest that the use of faecal microbial biomarkers could offer a patient-centric alternative to identify and reduce unnecessary colonoscopies in IBD activity assessment.

Sigall-Boneh and colleagues found that the baseline gut microbiota composition can predict biochemical remission (fecal calprotectin below 250 mcg/g) at week 12 after the Crohn’s Disease Exclusion Diet (CDED) in adults with mild-to-moderate CD. These findings suggest the potential of gut microbiota as a tool to predict the subset of patients that will benefit from long-term CDED.

Dietary Supplements for IBD Patients

The use of dietary supplements is common among patients with IBD, in particular probiotics, prebiotics, omega-3 fatty acids, vitamins and minerals.²⁹ Prof Gerasimidis updated the lights and shadows of dietary supplements in IBD based on conclusions of recent clinical guidelines and systematic reviews. When it comes to supplements bearing nutritional value, omega-3 and omega-6 fatty acids have little or no effect on the prevention or treatment of IBD.³⁰ 

Correction of micronutrient deficiencies is essential as they can affect the need for drugs, surgery, and emergency department utilization, thus increasing complications, length of hospital stay, and costs. Dr Emma Halmos, a senior research dietitian at Monash University in Australia, highlighted that it is necessary to pay particular attention to vitamin D, vitamin B₁₂, folate, zinc, iron, calcium, and magnesium.^31-35 While vitamin D levels are lower in active CD and UC and associated with mucosal inflammation and healing, it is too early to make generalized recommendations for patients with IBD and patients with IBD should ask their healthcare professional for personalized advice based on their baseline vitamin D levels, health status and potential interactions with drugs.³⁶

The available evidence does not support the use of probiotics neither for treatment of CD, neither for treatment for active disease nor for prevention of relapse.³⁷ In patients with UC, limited evidence suggests that combining standard treatment with probiotics might help achieve remission in active UC patients,³⁸ while probiotics have no efficacy in the maintenance of remission.³⁹ In addition, probiotics may be effective in preventing pouchitis after ileal pouch-anal anastomosis.⁴⁰

Soluble fiber psyllium has shown comparable benefits to mesalamine in UC with remission, while it is mostly ineffective in patients in active UC.⁴¹ Prebiotics should not be recommended in CD, neither in active disease nor for maintenance of remission, and no recommendations can be made for the role of prebiotics in pouchitis.²⁴

While 3 daily grams of curcumin have shown efficacy for inducing response and remission in active UC patients,^42,43 independent confirmation of findings is needed before being too optimistic. Also, turmeric supplements can cause liver harm, especially highly bioavailable formulations (e.g., turmeric combined with piperine).⁴⁴  

In case you missed the first part of the ECCO Highlights

Further reading:

1. Andrew Lamb C, Kennedy NA, Raine T, et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut. 2019; 68(Suppl 3):s1-s106. doi: 10.1136/gutjnl-2019-318484.
2. van Rheenen PF, Aloi M, Assa A, et al. The medical management of paediatric Crohn’s disease: an ECCO-ESPGHAN guideline update. J Crohn’s Colitis. 2021; 15(2):171-194. doi: 10.1093/ecco-jcc/jjaa161. 
3. Godny L, Svolos V, Williams AJ, et al. Multidisciplinary perinatal care in IBD. J Crohns Colitis. 2023; 17(5):663-680. doi: 10.1093/ecco-jcc/jjac189.
4. Lomer MCE, Wilson B, Wall CL. British Dietetic Association consensus guidelines on the nutritional assessment and dietary management of patients with inflammatory bowel disease. J Hum Nutr Diet. 2023; 36(1):336-377. doi: 10.1111/jhn.13054.
5. Bischoff SC, Bager P, Escher J, et al. ESPEN guideline on clinical nutrition in inflammatory bowel disease. Clin Nutr. 2023; 42(3):352-379. doi: 10.1016/j.clnu.2022.12.004.
6. Hashash JG, Elkins J, Lewis JD, et al. AGA clinical practice update on diet and nutritional therapies in patients with inflammatory bowel disease: expert review. Gastroenterology. 2024; 166(3):521-532. doi: 10.1053/j.gastro.2023.11.303.
7. Gerasimidis K, Bertz M, Hanske L, et al. Decline in presumptively protective gut bacterial species and metabolites are paradoxically associated with disease improvement in pediatric Crohn’s disease during enteral nutrition. Inflamm Bowel Dis. 2014; 20(5):861-71. doi: 10.1097/MIB.0000000000000023.
8. Logan M, Clark CM, Zeeshan Ijaz U, et al. The reduction of faecal calprotectin during exclusive enteral nutrition is lost rapidly after food re-introduction. Aliment Pharmacol Ther. 2019; 50(6):664-674. doi: 10.1111/apt.15425.
9. Geesala R, Zhang K, Lin YM, et al. Exclusive enteral nutrition alleviates Th17-mediated inflammation via eliminating mechanical stress-induced Th17-polarizing cytokines in Crohn’s-like colitis. Inflamm Bowel Dis. 2024; 30(3):429-440. doi: 10.1093/ibd/izad158.
10. Yamamoto T, Nakahigashi M, Saniabadi AR, et al. Impacts of long-term enteral nutrition on clinical and endoscopic disease activities and mucosal cytokines during remission in patients with Crohn’s disease: a prospective study. Inflamm Bowel Dis. 2007; 13(12):1493-501. doi: 10.1002/ibd.20238.
11. Logan M, Gkikas K, Svolos V, et al. Analysis of 61 exclusive enteral nutrition formulas used in the management of active Crohn’s disease-new insights into dietary disease triggers. Aliment Pharmacol Ther. 2020; 51(10):935-947. doi: 10.1111/apt.15695.
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15. Gordon-Dixon A, Hampal R, Miah A, et al. Does exclusive enteral nutrition reduce the rate of stoma formation in patients requiring ileocolic resection for Crohn’s disease? A single center experience. Clin Nutr ESPEN. 2021; 44:282-286. doi: 10.1016/j.clnesp.2021.05.030.
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18. Narula N, Chang NH, Mohammad D, et al. Food processing and risk of inflammatory bowel disease: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2023; 21(10):2483-2495.e1. doi: 10.1016/j.cgh.2023.01.012.
19. Chen J, Wellens J, Kalla R, et al. Intake of ultra-processed foods is associated with an increased risk of Crohn’s disease: a cross-sectional and prospective analysis of 187 154 participants in the UK Biobank. J Crohns Colitis. 2023; 17(4):535-552. doi: 10.1093/ecco-jcc/jjac167.
20. J Wellens, M Luppens, S Hoekx, et al (2024). Acceptability, feasibility, and adherence of an emulsifier-free diet in healthy volunteers. Journal of Crohn’s and Colitis, 18(Supplement_1), i1555-i1556, https://doi.org/10.1093/ecco-jcc/jjad212.0965.
21. Sarbagili-Shabat C, Zelber-Sagi S, Fliss Isakov N, et al. Development and validation of processed foods questionnaire (PFQ) in adult inflammatory bowel diseases patients. Eur J Clin Nutr. 2020; 74(12):1653-1660. doi: 10.1038/s41430-020-0632-5.
22. Naimi S, Viennois E, Gewirtz AT, et al. Direct impact of commonly used dietary emulsifiers on human gut microbiota. Microbiome. 2021; 9(1):66. doi: 10.1186/s40168-020-00996-6.
23. E Vissers, K Arnauts, L Giorio, et al (2024). Dietary emulsifier  κ-carrageenan does not directly affect intestinal permeability in organoid-derived epithelial monolayers from patients with Crohn’s disease. Journal of Crohn’s and Colitis, 18(Supplement_1), i395-i396, https://doi.org/10.1093/ecco-jcc/jjad212.0241. 
24. Bischoff SC, Bager P, Escher J, et al. ESPEN guideline on Clinical Nutrition in inflammatory bowel disease. Clin Nutr. 2023; 42(3):352-379. doi: 10.1016/j.clnu.2022.12.004.
25. Halmos EP, Godny L, Vanderstappen J, et al. Role of diet in prevention versus treatment of Crohn’s disease and ulcerative colitis. Frontline Gastroenterology. 2024; 15:247-257. doi: 10.1136/flgastro-2023-102417.
26. J Wellens, J Vanderstappen, S Hoekx, et al (2024). FOod Additives on the Mucosal barrier study (FOAM): Effect of five emulsifiers on inflammation, intestinal permeability, and the microbiome: preliminary results. Journal of Crohn’s and Colitis, 18(Supplement_1), i235-i237, https://doi.org/10.1093/ecco-jcc/jjad212.0126.  
27. Sun Y, Yuan S, Chen X, et al. The contribution of genetic risk and lifestyle factors in the development of adult-onset inflammatory bowel disease: a prospective cohort study. Am J Gastroenterol. 2023; 118(3):511-522. doi: 10.14309/ajg.0000000000002180.
28. Bethlehem L, Manuela Estevinho M, Grinspan A, et al. Microbiota therapeutics for inflammatory bowel disease: the way forward. Lancet Gastroenterol Hepatol. 2024; 9(5):476-486. doi: 10.1016/S2468-1253(23)00441-7.
29. Gerasimidis K, McGrogan P, Hassan K, et al. Dietary modifications, nutritional supplements and alternative medicine in paediatric patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2008; 27(2):155-165. doi: 10.1111/j.1365-2036.2007.03552.x.
30. Ajabnoor SM, Thorpe G, Abdelhamid A, et al. Long-term effects of increasing omega-3, omega-6 and total polyunsaturated fats on inflammatory bowel disease and markers of inflammation: a systematic review and meta-analysis of randomized controlled trials. Eur J Nutr. 2021; 60(5):2293-2316. doi: 10.1007/s00394-020-02413-y.
31. Lytvyak E, Sutton RT, Dieleman LA, et al. Management of inflammatory bowel disease patients with clinical care pathways reduces emergency department utilization. Crohns Colitis 360. 2020; 2(4):otaa080. doi: 10.1093/crocol/otaa080.
32. Dignass AU, Gasche C, Bettenworth D, et al. European consensus on the diagnosis and management of iron deficiency and aneamia in inflammatory bowel disease. J Crohns Colitis. 2015; 9(3):211-222. doi: 10.1093/ecco-jcc/jju009.
33. Kilby K, Mathias H, Boisvenue L, et al. Micronutrient absorption and related outcomes in people with inflammatory bowel disease: a review. Nutrients. 2019; 11(6):1388. doi: 10.3390/nu11061388.
34. Fletcher J, Cooper SC, Ghosh S, et al. The role of vitamin D in inflammatory bowel disease: mechanism to management. Nutrients. 2019; 11(5):1019. doi: 10.3390/nu11051019.
35. Vaghari-Tabari M, Jafari-Gharabaghlou D, Sadeghsoltani F, et al. Zinc and selenium in inflammatory bowel disease: trace elements with key roles? Biol Trace Elem Res. 2021; 199(9):3190-3204. doi: 10.1007/s12011-020-02444-w.
36. Guo Y, Zhang T, Wang Y, et al. Effects of oral vitamin D supplementation on inflammatory bowel disease: a systematic review and meta-analysis. Food Funct. 2021; 12(17):7588-7606. doi: 10.1039/d1fo00613d. 
37. Lorentz A, Müller L. Probiotics in the treatment of inflammatory bowel disease in adulthood: a systematic review. J Gastrointestin Liver Dis. 2022; 31(1):74-84. doi: 10.15403/jgld-3936.
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39. Iheozor-Ejiofor Z, Kaur L, Gordon M, et al. Probiotics for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2020; 3(3):CD007443. doi: 10.1002/14651858.CD007443.pub3.
40. Hany Emile S, Horesh N, Freund MR, et al. A systematic review and meta-analysis of randomized clinical trials on the prevention and treatment of pouchitis after ileoanal pouch anastomosis. J Gastrointest Surg. 2023; 27(11):2650-2660. doi: 10.1007/s11605-023-05841-3.
41. Wedlake L, Slack N, Andreyev HJN, et al. Fiber in the treatment and maintenance of inflammatory bowel disease: a systematic review of randomized controlled trials. Inflamm Bowel Dis. 2024; 20(3):576-586. doi: 10.1097/01.MIB.0000437984.92565.31.
42. Ben-Horin S, Salomon N, Karampekos G, et al. Curcumin-QingDai combination for patients with active ulcerative colitis: a randomized, double-blinded, placebo-controlled trial. Clin Gastroenterol Hepatol. 2024; 22(2):347-356. doi: 10.1016/j.cgh.2023.05.023.
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