Microbiome and diet are partners in CD pathogenesis and treatment
Johan Van Limbergen
Crohn’s Disease (CD) is increasing in incidence worldwide . In spite of increased use of immune suppression, which has markedly changed the need for in-hospital care, paediatric CD remains associated with considerable morbidity as well as increased mortality [2, 3]. The onset of disease in childhood and adolescence often interferes with growth and development, both physically and psychologically. In a subset of patients, the progressive nature of disease may be associated with a fibrotic phenotype that does not respond adequately to the currently available immune suppressive medications, yet use of these medications is still associated with increased risk of myelosuppression, opportunistic infections, immune-mediated phenomena and malignancy [2, 4–6].
In paediatric CD, dietary therapy by means of exclusive enteral nutrition (EEN) has long been a mainstay of induction treatment . In adult CD, EEN is receiving renewed attention due to its ability to reduce peri-operative morbidity . For EEN to be successful, a liquid formula diet needs to be taken for 6–8 weeks, while avoiding all other oral intake. Earlier studies in adult CD showed superiority of oral steroids mainly due to problems of compliance with dietary instructions . In more recent paediatric studies, EEN has been shown to be superior to oral corticosteroids in induction of remission, with no medical side-effects, and these results have solidified the position of EEN as a first-line treatment in paediatric CD [7, 10–12]. The few paediatric studies of partial enteral nutrition (PEN) without restriction of additional oral diet intake have consistently shown a markedly reduced rate of remission, highlighting the disease-propagating characteristics of some components of a regular Western diet [13–16].
The successful application of dietary modification suggests a key role for diet in the development and propagation of inflammation. In the search for a more palatable and sustainable dietary strategy, two recent paediatric publications in Gastroenterology have studied different approaches to dietary modification, and the associated microbiome changes, with a view to elucidating impacts on both pathogenetic mechanisms and clinical remission.
In the first Gastroenterology paper, by the group of Konstantinos Gerasimidis from the University of Glasgow and his clinical collaborators Richard Russell and Richard Hansen from the Royal Hospital for Children in Glasgow, the authors built on their previous findings that EEN most likely works by changing the gut microbiome composition and its metabolic activity [17–20]. These EEN effects include changes in microbial diversity and microbial community structures, as well as changes in the production and metabolism of short- and long-chain fatty acids and amino acids . Using the current understanding of the mechanism of EEN action and its known food and nutritional composition, the same research team aimed to develop new effective dietary therapies that are more acceptable and tolerable for patients: a new dietary therapy that works as well as EEN but does not involve stopping all normal food would be more acceptable to most patients with CD . The research team has recently developed a food-based diet using everyday foods (also known as CD-TREAT). The concept behind CD-TREAT is to achieve the same gut microbiome changes with normal foods as are seen in treatment with EEN.
In their Gastroenterology paper, Konstantinos Gerasimidis and his team showed that CD-TREAT changes the gut microbiome composition and function in healthy people in a similar way to EEN . In a carefully designed trial, they randomised 25 healthy adults to receive EEN or CD-TREAT for 7 days, followed first by a 14-day washout period and then by cross-over to the alternate diet. The healthy adult participants reported that CD-TREAT was easier to comply with and more satiating than EEN, producing less desire to eat between meals. The microbiome composition, faecal pH, short-chain fatty acids, total sulphide, faecal bacterial load and faecal metabolome significantly changed in the same direction for both regimens. In a different part of the same study, transgenic rats with gut inflammation received EEN, CD-TREAT or standard chow for 4 weeks. CD-TREAT and EEN both led to similar changes in bacterial load, short-chain fatty acids, microbiome structure and tissue expression of inflammatory cytokine proteins. Most importantly, both were similarly effective in reducing the gut inflammation seen in these rats. As a last experiment, the same team tested CD-TREAT in children with active CD. In a pilot trial in five children with CD, CD-TREAT diet, prepared and delivered free to the patients, improved their blood and gut inflammatory markers. Among the five children receiving CD-TREAT, four (80%) had a clinical response and three (60%) entered remission. Stool markers of inflammation dropped by 55% while on CD-TREAT. Konstantinos Gerasimidis and his clinical colleagues are optimistic that the clinical effect of CD-TREAT will be replicated in larger multicentre studies and will compare well with other mainstream drug therapies. They have recently received ~$1.1 million from The Leona and Harry Helmsley Charitable Trust to extend recruitment to a larger population and explore the mechanisms of action of CD-TREAT and EEN using state-of-the-art multiomics applications.
The second Gastroenterology paper, by Levine et al., reported on the results of the Crohn’s Disease Exclusion Diet randomised controlled trial (CDED-RCT) . CDED is a whole-food diet coupled with PEN, designed to reduce dietary exposure to components which may negatively affect the microbiome (dysbiosis), intestinal barrier and intestinal immunity [16, 23]. Previously, uncontrolled case series had shown clinical benefit, including in CD patients with secondary loss of response to anti-TNF therapy [24, 25]. In the CDED-RCT, the tolerability of CDED coupled with PEN and its efficacy in inducing and sustaining remission were compared head-to-head with EEN. In this multinational RCT (conducted in Israel and Canada), CDED+PEN was shown to be better tolerated than EEN in mild-to-moderate paediatric CD, with comparable rates of clinical remission (>75%) and a significant and similar decrease in inflammation (assessed using C-reactive protein and calprotectin) by week 6. Both CDED+PEN and EEN showed an expansion of Firmicutes and a reduction in Proteobacteria by week 6. These changes were sustained in CDED+PEN until week 12 (the CDED group continued with phase 2 of CDED + 25% of calories from enteral nutrition). The EEN group, which was allowed to return partially to normal diet (but also continuing 25% of calories from enteral nutrition), showed an increase in calprotectin from week 6 to week 12 accompanied by a return of some of the microbiome features of active disease (e.g. Proteobacteria).
The EEN group experienced a drop in sustained remission rate (56%), whereas the CDED+PEN group maintained remission (87%): maintenance of remission and normal CRP remission at week 12 were significantly better in the CDED+PEN treated group. These data support the hypothesis that the exclusion of components found in the regular Western diet is required to maintain remission, as the CDED phase 2 group continued to exclude regular food. Re-exposure to food in the EEN group induced rebound in inflammation and led to decreased sustained remission, in spite of continuing with 25% of calories from enteral nutrition.
Taken together, these studies [17, 22] show the promise of diet in achieving microbiome modification. CD-TREAT trial results are eagerly awaited. The CDED+PEN has already been shown to induce and sustain clinical remission and presents a strong alternative (which is better tolerated and sustainable) to EEN . Data presented by Rotem Sigall Boneh at ECCO 2019 showed that a dietary-responsive phenotype can already be determined as early as week 3 . Both early in the disease course and later on, when immune suppression strategies require adjustment, the identification of a clinical phenotype that is diet-responsive will help optimise treatment for our patients.
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