Fecal transplantation for ulcerative colitis from diet conditioned donors followed by dietary intervention results in favorable gut microbial profile compared to fecal transplantation alone.

BACKGROUND AND AIMS: Several fecal microbial transplantation (FMT) approaches for ulcerative colitis (UC) have been investigated with conflicting results. We have recently published the clinical outcomes from the CRAFT-UC Trial using FMT with the UC Exclusion Diet (UCED), compared with FMT alone. Here we aimed to compare the two FMT strategies in terms of microbial profile and function. METHODS: Subjects recruited to the CRAFT-UC study with available pre- and post-intervention fecal samples were included. Donors received diet conditioning for 14 days based on the UCED principles. Group-1 received single FMT by colonoscopy (Day 1) and enemas (Days 2 and 14) without donors' dietary conditioning (N=11). Group-2 received FMT but with donors' dietary pre-conditioning and UCED for the patients (N=10). Fecal samples were assessed by DNA shotgun metagenomic sequencing. RESULTS: Following diet conditioning, donors had depletion in metabolic pathways involved in sulfur-containing amino acids biosynthesis. Only Group-2 showed significant shifts towards the donors' microbial composition (ADONIS: R2=0.15, p=0.008) and significant increased Eubacterium_sp_AF228LB post-intervention (ß-coefficient 2.66, 95%CI 2.1-3.3, q<0.05) which was inversely correlated with fecal calprotectin (rho=-0.52, p=0.035). Moreover, pathways involved in gut inflammation and barrier function including branched chain amino acids were enriched post intervention in Group-2 and were significantly inversely correlated with fecal calprotectin. CONCLUSION: FMT from diet conditioned donors followed by the UCED led to microbial alterations associated with favorable microbial profile which correlated with decreased fecal calprotectin. Our findings support further exploration of additive benefit of dietary intervention for both donors and patients undergoing FMT as a potential treatment of UC.

Role of diet in prevention versus treatment of Crohn's disease and ulcerative colitis.

Diet is a modifiable risk factor for disease course and data over the past decade have emerged to indicate its role in Crohn's disease (CD) and ulcerative colitis (UC). However, literature is riddled with misinterpretation of data, often leading to unexpected or conflicting results. The key understanding is that causative factors in disease development do not always proceed to an opportunity to change disease course, once established. Here, we discuss the data on dietary influences in three distinct disease states for CD and UC-predisease, active disease and quiescent disease. We appraise the literature for how our dietary recommendations should be shaped to prevent disease development and if or how that differs for CD and UC induction therapy and maintenance therapy. In UC, principles of healthy eating are likely to play a role in all states of disease. Conversely, data linking dietary factors to CD prevention and treatment are paradoxical with the highest quality evidence for CD treatment being exclusive enteral nutrition, a lactose, gluten and fibre-free diet comprising solely of ultraprocessed food-all dietary factors that are not associated or inversely associated with CD prevention. High-quality evidence from dietary trials is much awaited to expand our understanding and ultimately lead our dietary recommendations for targeted patient populations.

The Crohn's Disease Exclusion Diet: A Comprehensive Review of Evidence, Implementation Strategies, Practical Guidance, and Future Directions.

Dietary therapy is increasingly recognized for the management of Crohn's disease (CD) over recent years, including the use of exclusive enteral nutrition (EEN) as first-line therapy for pediatric CD according to current guidelines. The Crohn's disease exclusion diet (CDED) is a whole-food diet designed to reduce exposure to dietary components that are potentially pro-inflammatory, mediated by negative effects on the gut microbiota, immune response, and the intestinal barrier. The CDED has emerged as a valid alternative to EEN with cumulative evidence, including randomized controlled trials, supporting use for induction of remission and possibly maintenance in children and adults. We gathered a group of multidisciplinary experts, including pediatric and adult gastroenterologists, inflammatory bowel diseases (IBD) expert dietitians, and a psychologist to discuss the evidence, identify gaps, and provide insights into improving the use of CDED based on a comprehensive review of CDED literature and professional experience. This article reviews the management of CDED in both children and adults, long-term aspects of CDED, indications and contraindications, selecting the best candidates, identifying challenges with CDED, globalization, the role of the multidisciplinary team, especially of dietitian, and future directions. We concluded that CDED is an established dietary therapy that could serve as an alternative to EEN in many pediatric and adult cases, especially with mild to moderate disease. In severe disease, complicated phenotypes, or with extraintestinal involvement, CDED should be considered on a case-by-case basis, according to physician and dietitians' discretion. More studies are warranted to assess the efficacy of CDED in different scenarios.

The Crohn's disease exclusion diet (CDED) has emerged as an alternative to exclusive enteral nutrition for the treatment of pediatric Crohn's disease. In this review, we summarize data on efficacy and challenges and identify research priorities, clinical gaps, and opportunities.

Gaseous metabolites as therapeutic targets in ulcerative colitis.

Diet therapies are currently under-utilised in optimising clinical outcomes for patients with active ulcerative colitis (UC). Furthermore, existing dietary therapies are framed by poorly defined mechanistic targets to warrant its success. There is good evidence to suggest that microbial production of gaseous metabolites, hydrogen sulfide (H2S) and nitric oxide (NO) are implicated in the development of mucosal inflammation in UC. On a cellular level, exposure of the colonic epithelium to excessive concentrations of these gases are shown to promote functional defects described in UC. Hence, targeting bacterial production of these gases could provide an opportunity to formulate new dietary therapies in UC. Despite the paucity of evidence, there is epidemiological and clinical data to support the concept of reducing mucosal inflammation in UC via dietary strategies that reduce H2S. Several dietary components, namely sulphur-containing amino acids and inorganic sulphur have been shown to be influential in enhancing colonic H2S production. More recent data suggests increasing the supply of readily fermentable fibre as an effective strategy for H2S reduction. Conversely, very little is known regarding how diet alters microbial production of NO. Hence, the current evidence suggest that a whole diet approach is needed. Finally, biomarkers for assessing changes in microbial gaseous metabolites in response to dietary interventions are very much required. In conclusion, this review identifies a great need for high quality randomised-controlled trials to demonstrate the efficacy of a sulphide-reducing dietary therapy for patients with active UC.

Use of Faecal Transplantation with a Novel Diet for Mild to Moderate Active Ulcerative Colitis: The CRAFT UC Randomised Controlled Trial.

BACKGROUND: We evaluated whether integration of novel diets for donors and patients, in addition to faecal transplantation [FT], could increase FT remission rate in refractory ulcerative colitis [UC]. METHODS: This was a blinded, randomised, controlled trial in adults with active UC, defined by a simple clinical colitis activity index [SCCAI] of ≥5 and ≤11 and endoscopic Mayo score 2-3, refractory to medication. Group 1 received free diet and single donor standard FT by colonoscopy on Day 1and rectal enemas on Days 2 and 14 without dietary conditioning of the donor. Group 2 received FT as above but with dietary pre-conditioning of the donor for 14 days and a UC Exclusion Diet [UCED] for the patients. Group 3 received the UCED alone. The primary endpoint was Week 8 clinical steroid-free remission, defined as SCCAI <3. RESULTS: Of 96 planned patients, 62 were enrolled. Remission Week 8 Group 1 was 2/17 [11.8%], Group 2 was 4/19 [21.1%], Group 3 was 6/15 [40%] [non-significant]. Endoscopic remission Group 1 was 2/17 [12%], Group 2 was 3/19 [16%], Group 3 was 4/15 [27%] [Group 1 vs 3 p = 0.38]. Mucosal healing [Mayo 0] was achieved only in Group 3 [3/15, 20%] vs 0/36 FT patients [p = 0.022]. Exacerbation of disease occurred in 3/17 [17.6%] of Group 1, 4/19 [21.1%] of Group 2, and 1/15 [6.7%] of Group 3 [Group 2 vs 3, p = 0.35]. CONCLUSIONS: UCED alone appeared to achieve higher clinical remission and mucosal healing than single donor FT with or without diet. The study was stopped for futility by a safety monitoring board.

A Novel UC Exclusion Diet and Antibiotics for Treatment of Mild to Moderate Pediatric Ulcerative Colitis: A Prospective Open-Label Pilot Study.

BACKGROUND: As the microbiome plays an important role in instigating inflammation in ulcerative colitis (UC), strategies targeting the microbiome may offer an alternative therapeutic approach. The goal of the pilot trial was to evaluate the potential efficacy and feasibility of a novel UC exclusion diet (UCED) for clinical remission, as well as the potential of sequential antibiotics for diet-refractory patients to achieve remission without steroids. METHODS: This was a prospective, single-arm, multicenter, open-label pilot study in patients aged 8-19, with pediatric UC activity index (PUCAI) scores >10 on stable maintenance therapy. Patients failing to enter remission (PUCAI < 10) on the diet could receive a 14-day course of amoxycillin, metronidazole and doxycycline (AMD), and were re-assessed on day 21. The primary endpoint was intention-to-treat (ITT) remission at week 6, with UCED as the only intervention. RESULTS: Twenty-four UCED treatment courses were given to 23 eligible children (mean age: 15.3 ± 2.9 years). The median PUCAI decreased from 35 (30-40) at baseline to 12.5 (5-30) at week 6 (p = 0.001). Clinical remission with UCED alone was achieved in 9/24 (37.5%). The median fecal calprotectin declined from 818 (630.0-1880.0) µg/g at baseline to 592.0 (140.7-1555.0) µg/g at week 6 (p > 0.05). Eight patients received treatment with antibiotics after failing on the diet; 4/8 (50.0%) subsequently entered remission 3 weeks later. CONCLUSION: The UCED appears to be effective and feasible for the induction of remission in children with mild to moderate UC. The sequential use of UCED followed by antibiotic therapy needs to be evaluated as a microbiome-targeted, steroid-sparing strategy.

Moderate-to-severe Endoscopic Inflammation is Frequent After Clinical Remission in Pediatric Ulcerative Colitis.

OBJECTIVES: Pediatric ulcerative colitis (UC) is characterized by low sustained remission rates and frequent extension of disease even if clinical remission is obtained with therapy. Moderate-to-severe endoscopic activity is a risk factor for relapse while prospective evidence regarding early mucosal healing or persistence of inflammation after remission in children is not available. Our aim was to evaluate if significant inflammation is common after clinical remission and could explain the high relapse rate in pediatric UC. METHODS: Pediatric UC patients with clinical remission, defined as pediatric UC activity index (PUCAI) scores <10, were prospectively assessed for mucosal healing by endoscopy 3 to 5 months after remission was documented. Mayo score was assessed for each segment by a blinded adult gastroenterologist using central reading. Symptomatic patients before sigmoidoscopy were excluded. Sustained remission was assessed retrospectively at 18 months follow-up. RESULTS: Forty-two children were screened, 28 children in continuous clinical remission at time of sigmoidoscopy were included. Mayo 0 was present in 12/28 (42.86%), Mayo 1 in 2/28 (7.1%) and Mayo 2 to 3 in 14/28 (50.0%) endoscopies. Among 23 patients with follow-up through 18 months, remission was sustained in 6/12 (50.0%) with Mayo score 0 to 1 versus 2/11 (18.18%) of patients with Mayo 2 and 3. CONCLUSIONS: Over 50% of children assessed for mucosal healing 3 to 5 months after clinical remission is obtained, have endoscopic disease, primarily moderate-to-severe Mayo 2 to 3 inflammation, which was associated with lower sustained remission.

Development and validation of processed foods questionnaire (PFQ) in adult inflammatory bowel diseases patients.

BACKGROUND: Processed foods have been implicated in the pathogenesis of inflammatory bowel diseases (IBD). Our goal was to develop a validated processed foods frequency questionnaire (PFQ) and assess its reliability and validity. METHODS: We recruited adult IBD patients to fill-in a PFQ in this prospective single-center study. Food intake was categorized into three groups of processed food levels: unprocessed, processed, and ultra-processed. Reliability was assessed by comparing the PFQ results of each patient at 2 time points. Validity was assessed by comparing the PFQ results to a 3-7 day food diary (FD), and by comparing urine sodium as a biomarker for the high intake of sodium that is mostly present in processed food. RESULTS: Eighty-six IBD patients were enrolled. Good test-retest reliability was indicated by intraclass correlation of 0.75-0.88 for the different food processing levels. Validity was fair-to-strong as assessed by correlations for different levels of processed food intake between FDs and PFQ, ranging between 0.43 and 0.64 (Pearsonr, P < 0.001), and further supported by higher mean urine sodium levels in patients with high processed foods consumption compared with low consumption (104.57 ± 53.26 vs. 78.62 ± 39.08 mmol/L, respectively, P = 0.022). Agreement between PFQ and the FD in categorizing patients to high and low processed food consumption groups was fair (Kappa 0.23-0.35). CONCLUSIONS: The PFQ is a reliable and valid tool for the assessment of processed foods consumption in IBD patients and can be utilized for studying the association between processed food consumption and IBD etiopathogenesis.

Differences in Outcomes Over Time With Exclusive Enteral Nutrition Compared With Steroids in Children With Mild to Moderate Crohn's Disease: Results From the GROWTH CD Study.

BACKGROUND: Exclusive enteral nutrition [EEN] and corticosteroids [CS] induce similar rates of remission in mild to moderate paediatric Crohn's disease [CD], but differ with regard to mucosal healing. Our goal was to evaluate if EEN at diagnosis was superior to CS for improving long-term outcomes. METHODS: We prospectively followed newly diagnosed children aged < 17 years, with mild to moderate CD at baseline, for 2 years in the GROWTH CD study. Patients were evaluated at baseline and at 8, 12, 78, and 104 weeks. Remission, relapses, complications [fibrostenotic disease, penetrating disease, and active perianal disease] and growth were recorded throughout the study. A propensity score analysis was performed. RESULTS: A total of 147 children [mean age 12.9 ± 3.2 years], treated by EEN [n = 60] or CS [n = 87] were included. New complications developed in 13.7% of CS [12/87] versus 11.6% of EEN [7/60], p = 0.29. Remission was achieved in 41/87 [47%] in CS and 38/60 [63%] EEN, p = 0.036. Median time to relapse did not differ [14.4 ± 1 months with CS, 16.05 ± 1.1 EEN, p = 0.28]. Mean height Z scores decreased from Week 0 to Week 78 with CS [-0.34 ± 1.1 to -0.51 ± 1.2, p = 0.01], but not with EEN [-0.32 ± 1.1 to -0.22 ± 0.9, p = 0.56]. In a propensity score analysis, EEN was superior to CS for inducing remission [p = 0.05] and trended to superiority for height Z score [p = 0.055]. CONCLUSIONS: Use of EEN was associated with higher remission rates and a trend toward better growth but with similar relapse and complication rates in new-onset mild to moderate paediatric CD.

Dietary Therapy With the Crohn's Disease Exclusion Diet is a Successful Strategy for Induction of Remission in Children and Adults Failing Biological Therapy.

BACKGROUND: Loss of response [LoR] to biologics in Crohn's disease [CD] is a significant clinical problem. Dietary therapy as a treatment strategy in this setting has not been previously reported. We report the use of dietary strategies using enteral nutrition coupled with the Crohn's Disease Exclusion Diet [CDED] for LoR to infliximab or adalimumab as a single-centre experience. METHODS: Patients with LoR to a biologic despite dose escalation or combination therapy were treated with partial enteral nutrition [PEN] by a polymeric formula and the CDED for 12 weeks. Paediatric patients with severe flares received 14 days of exclusive enteral nutrition followed by PEN + CDED as above. All patients were seen at weeks 6 and 12 for follow up. Current and prior treatment, Harvey Bradshaw Index [HBI], C-reactive protein [CRP] and albumin were recorded. Remission was defined as HBI <5 at week 6. RESULTS: Twenty-one patients, mean age 22.1 ± 8.9 years [11 adults and ten children] met study criteria. Seventeen patients [81%] had used combination therapy, and 10/21 [47.6%] had failed a second biologic. Seven patients had a prior intestinal resection. Dose escalation had failed in 13/21 [62%] patients. Clinical remission by physician's global assessment and HBI after 6 weeks was obtained in 13/21 [61.9%]. Mean HBI decreased from 9.4 ± 4.2 to 2.6 ± 3.8 [p < 0.001], mean CRP decreased from 2.8 ± 3.4 to 0.7 ± 0.5 [p = 0.005] and mean albumin increased from 3.5 ± 0.6 to 3.8 ± 0.5 [p = 0.06]. CONCLUSION: Dietary treatment combining PEN with the CDED may be a useful salvage regimen for patients failing biological therapy despite dose escalation.

Nutritional therapy in inflammatory bowel disease.

PURPOSE OF REVIEW: An increasing body of evidence has linked diet to inflammatory bowel diseases (IBD), both Crohn's disease and ulcerative colitis. Most of our current knowledge pertains to the link between diet and Crohn's disease. Exclusive enteral nutrition and partial enteral nutrition are the best known dietary intervention for the induction of remission and maintenance of remission in Crohn's disease both in children and in adults, but the mechanism whereby these interventions may cause or maintain remission and mucosal healing has remained elusive. RECENT FINDINGS: Recent studies have shed light on the possible mechanisms of response to dietary intervention. Epidemiological and rodent model studies over the last year have supplied us with several dietary candidates for an effect of diet on inflammation and disease pathogenesis. Others have shed insight into the effect of diet on dysbiosis and the microbiota. An elimination diet based on some of these candidates has shown clinical efficacy, and bridged the knowledge obtained from rodent models to a human intervention. SUMMARY: These studies may allow better understanding of the pathogenesis of IBD and provide new tools to treat these difficult diseases. Elimination diets based on the identification of deleterious dietary components may pave the way for an improved control of the disease in the future. VIDEO ABSTRACT: http://links.lww.com/COG/A10.