Y-ECCO Literature Review: Beatriz Gros

Given that dietary intake has the capacity to induce rapid microbial changes, Kedia et al. sought to explore the role of diet combined with FMT in UC, hypothesising that such an approach might enhance the success of FMT by favouring a microbiota composition with increased anti-inflammatory capacity.

Methods and key findings

The FMT-AID trial (ISRCTN15475780) was an open-label randomised controlled trial conducted to evaluate the effectiveness of FMT combined with an anti-inflammatory diet in adult patients with mild-moderate [Simple Clinical Colitis Activity Index (SCCAI) 3–9], endoscopically active [Ulcerative Colitis Endoscopic Index of Severity (UCEIS) >1] UC on stable therapy. The FMT-AID group, who received seven weekly sessions of FMT (with no antibiotic or bowel preparation prior to FMT), was compared to an optimised standard medical therapy (SMT) group, who continued on their baseline medication with dose optimisation [dose increase of oral 5-aminosalicylic acid (5-ASA) and/or addition of topical 5-ASA or topical steroids]. FMT was performed via colonoscopy using stools obtained from healthy donors residing in rural areas. Patients receiving FMT were also instructed to adhere to an anti-inflammatory diet, which emphasised the avoidance of gluten-based grains, dairy products, processed and red meat, food additives and refined sugars, with an increase in fresh fruits and vegetables and fermented foods.

The primary outcome measures were deep remission [a combination of clinical (SCCAI ≤2) and endoscopic remission (UCEIS ≤1)] and clinical response (SCCAI reduction of ≥3) at week 8. The maintenance phase primary outcome measures were deep remission and steroid-free clinical remission at week 48.

A total of 66 patients (n=35 FMT-AID and n=31 SMT) were included in the analysis. Baseline characteristics, including the baseline dietary macro- and micronutrients, were comparable between groups, except for a lower intake of wheat and insoluble fibre in the FMT-AID group. The trial met its primary outcomes, demonstrating that deep remission at week 8 was significantly higher in the FMT-AID group (36.4% vs 8.7% in the SMT group, p=0.03), as was clinical response at week 8 (65.7% vs 35.5% in the SMT group, p=0.01). Endoscopic response and clinical remission were also superior in the FMT-AID group, although the difference in endoscopic remission did not reach significance. Due to the pandemic, many biomarkers were not available, especially in the SMT group (n=10), for which biomarker outcomes did not show a statistically significant difference. Nonetheless, the number of patients with faecal calprotectin <50 µg/g at week 8 was high in both arms: 85% (17/20) in the FMT-AID group and 60% (6/10) in the SMT group.

Regarding the maintenance phase, 23 FMT-AID and 11 SMT patients entered maintenance. There was a significantly higher rate of deep remission in the FMT-AID group compared to the SMT group (25% vs 0%, p=0.007), while steroid-free clinical remission did not differ significantly. The authors identified mild UC, compared to moderate UC, as a factor associated with higher likelihood of FMT-AID success in inducing remission at week 8. Finally, adverse events were similar in both groups, with no severe adverse events reported.

Clinical implications

This is the first FMT trial conducted in Asia, demonstrating impact of microbial modulation in an Indian population. A further novel aspect was the inclusion of an optimised standard medical therapy arm as a comparator instead of placebo, mimicking real-world clinical practice. In addition, stool samples were obtained from rural donors, which is important in the context of recent work demonstrating that healthy individuals in rural areas tend to have a more diverse microbiome than those in urban areas [8], which may be associated with better outcomes.

The study encountered several difficulties as it was conducted just before the COVID-19 pandemic. Consequently, patient recruitment had to be curtailed: while the initially estimated sample size was 105, only 66 patients were finally enrolled. Additionally, some patients did not have their anticipated seven sessions of FMT or missed follow-up visits – although patients were continued on the anti-inflammatory diet. Missing data for some blood and stool samples at designated time points may have influenced the lack of differences observed in certain comparisons, such as those concerning biochemical outcome measures.

This trial has several implications. First, the approach described offers the benefit of being cost-effective compared to other therapies currently licensed for UC, which is particularly important for IBD clinicians in resource-limited areas. Furthermore, it emphasises the importance of diet in maintaining remission, an area that warrants further exploration.

Conclusions

FMT from rural donors in combination with an anti-inflammatory diet was more effective than optimisation of standard medical therapy in inducing clinical and deep remission in patients with mild to moderate UC. Moreover, deep remission was consistently higher in the FMT-AID arm at 48 weeks, suggesting that the anti-inflammatory diet plays a significant role in this particular context.

References

1. Agrawal M, Sabino J, Frias-Gomes C, et al. Early life exposures and the risk of inflammatory bowel disease: Systematic review and meta-analyses. EClinicalMedicine 2021; 36. doi:10.1016/j.eclinm.2021.100884.
2. Piovani D, Danese S, Peyrin-Biroulet L, Nikolopoulos GK, Lytras T, Bonovas S. Environmental risk factors for inflammatory bowel diseases: An umbrella review of meta-analyses. Gastroenterology 2019;157:647–59.e4. doi:10.1053/j.gastro.2019.04.016.
3. Wastyk HC, Fragiadakis GK, Perelman D, et al. Gut-microbiota-targeted diets modulate human immune status. Cell 2021;184:4137–53.e14. doi:10.1016/j.cell.2021.06.019.
4. Bancil AS, Sandall AM, Rossi M, Chassaing B, Lindsay JO, Whelan K. Food additive emulsifiers and their impact on gut microbiome, permeability, and inflammation: Mechanistic insights in inflammatory bowel disease. J. Crohn’s Colitis 2021:15:1068–79. doi:10.1093/ecco-jcc/jjaa254.
5. Raine T, Bonovas S, Burisch J, et al. ECCO guidelines on therapeutics in ulcerative colitis: Medical treatment. J Crohn’s Colitis 2022;16:2–17. doi:10.1093/ecco-jcc/jjab178.
6. Limketkai BN, Godoy-Brewer G, Parian AM, et al. Dietary interventions for the treatment of inflammatory bowel diseases: An updated systematic review and meta-analysis. Clin Gastroenterol Hepatol 2022. doi:10.1016/j.cgh.2022.11.026. Online ahead of print.
7. El Hage Chehade N, Ghoneim S, Shah S, et al. Efficacy of fecal microbiota transplantation in the treatment of active ulcerative colitis: A systematic review and meta-analysis of double-blind randomized controlled trials. Inflamm Bowel Dis 2023;29:808–17. doi:10.1093/ibd/izac135.
8. Das B, Ghosh TS, Kedia S, et al. Analysis of the gut microbiome of rural and urban healthy Indians living in sea level and high altitude areas. Sci Rep 2018;8:10104. doi:10.1038/s41598-018-28550-3.>

Beatriz Gros - Short Biography

Beatriz Gros works as a Senior Clinical Fellow at the Western General Hospital in Edinburgh (United Kingdom) and as a Consultant Gastroenterologist in Reina Sofía University Hospital in Cordoba (Spain). Beatriz has a specific interest in environmental factors associated with development of IBD and predictors for disease flares and has been working with Professor Charlie Lees to better understand these factors in the PREdiCCt study. She is also involved in medical #SoMe (social media) education on both Instagram and Twitter and is the owner and content creator of the educational website www.ibd-eii.com.