Faecal microbiota transplantation with anti-inflammatory diet (FMT-AID) followed by anti-inflammatory diet alone is effective in inducing and maintaining remission over 1 year in mild to moderate ulcerative colitis: a randomised controlled trial
Kedia S, Virmani S, Vuyyuru SK, et al.
Gut 2022;71:2401–13. doi: 10.1136/gutjnl-2022-327811.
Microbiota are known to play a role in the pathogenesis of both Ulcerative Colitis (UC) and Crohn’s Disease (CD). Various lifestyle factors, including rural living, absence of antibiotic exposure and larger family size, have been associated with greater microbial diversity and lower risk for development of IBD [1, 2]. Conversely, dietary patterns and constituent elements of the diet have been linked to dysbiosis and increased risk of IBD [3, 4]. Despite these associations, the causal relationship between microbiota disturbance and IBD pathogenesis/disease flares remains unclear.
Current therapeutic strategies for IBD primarily focus on targeting the dysregulated immune response. However, these approaches have limitations, including a “ceiling effect” of current treatments and a high risk of relapse following withdrawal of therapy [5]. Consequently, there has been a growing interest in exploring alternative interventions, including through modulation of the gut microbiota or manipulation of dietary factors. Most of the evidence for such therapeutic approaches has focused on CD, including with the use of exclusive enteral nutrition [6]. In UC, microbiota modification has been attempted by faecal microbiota transplantation (FMT) in cohort studies and in randomised controlled trials. However, heterogeneous protocols, methods, donors, doses and intervals of FMT have all likely contributed to the conflicting evidence base for FMT in UC. Notably, however, a recent meta-analysis has suggested an overall clinical and endoscopic benefit of FMT, at least in the short term, in the treatment of UC [7].
Biomarkers for the prediction of disease onset and disease course in Ulcerative Colitis (UC) represent an ongoing and important area of unmet need. However, discovery and validation of such biomarkers has been complicated by the wide heterogeneity in disease presentation and variability in disease course [1]. Despite many initial biomarker discovery efforts in UC focusing on biopsy-based approaches, it has increasingly been recognised that non-invasive blood-based biomarkers would likely have more clinical utility, including because of their ease of collection and high rates of patient acceptance [2, 3].
Previous studies have discovered a novel autoantibody against integrin αvβ6 (anti-αvβ6) in the serum of UC patients, with strong discriminative ability for diagnosis of UC. Integrin αvβ6 plays a critical role in maintaining epithelial barrier integrity and suppressing epithelial inflammation [4–7].
Intestinal barrier healing is superior to endoscopic and histologic remission for predicting major adverse outcomes in Inflammatory Bowel Disease: The Prospective ERIca Trial
Mucosal healing (MH) in both Crohn's Disease (CD) and Ulcerative Colitis (UC) has been recognised as an important treatment target for many years. Indeed, the 2021 update of the Selecting Therapeutic Targets (STRIDE) consensus reaffirmed MH as the top priority among long-term treatment objectives [1]. Nonetheless, it is important to note that endoscopic inflammation may not always mirror the histological picture. Histological healing is an emerging endpoint in IBD. This is particularly true in UC, in which it represents a deeper level of recovery with some early evidence for correlation with better long-term outcomes; for CD, however, findings have been more controversial [2, 3]. Despite the increasing focus on histology, histological scoring systems are complex, with only two validated ones, both in the setting of UC, i.e. there is no validated scoring system in the context of CD.
The management of Crohn’s Disease (CD) is dependent on many factors, including disease activity, site of involvement and the need to tailor treatment for each individual patient [1]. Moreover, features such as obstruction, fistulation, strictures and abscesses can all add to the complexity of CD management. While surgery has played a large role in the management of these patients, it is by no means a cure and the risk of relapse and repeat surgeries remains high [2, 3]. Accordingly, there continues to be a large unmet need for the development of novel medications that target distinct mechanisms of action in order to provide symptomatic and endoscopic control for patients with active disease. In parallel with this need to develop new medications, there has been an increasing desire for fast-acting medications, and movement towards oral administration, which may help both to reduce costs for hospitals and patients and to enhance aspects that are important to patients, such as quality of life and work productivity [4, 5].
Submucosal injection of the RNA nucleotide GUT-1 in active ulcerative colitis patients: A randomized, double-blind, placebo-controlled phase 2a induction trial.
Atreya R, Kuhbacher T, Waldner M, et al.
J Crohns Colitis 2023. doi: 10.1093/ecco-jcc/jjad162. Online ahead of print.
Despite an increasing number of therapeutic options for Ulcerative Colitis (UC), many patients still have disease which progresses over time, and there has been renewed interest in and improved understanding of the chronic fibrosis and remodelling that occurs in UC [1–3]. In particular, there has been a growing appreciation of both the importance of the extracellular matrix (ECM) for remodelling in UC and the potential to target the ECM with new therapeutic agents [4]. One such target is carbohydrate sulphotransferase 15 (CHST15). This is a type II transmembrane Golgi protein that biosynthesises highly sulphated disaccharide units (E-units) of chondroitin sulphate, which binds to various functional proteins and pathogenic microorganisms. Targeting this molecule in mouse models has previously been shown to offer promising signals for ameliorating colitis [5]. Based on this promising pre-clinical data, blockade of CHST15 has emerged as a potentially promising therapeutic target, and such blockade can be achieved by a silencing RNA oligonucleotide molecule called GUT-1 (previously called STNM01). A prior phase I clinical trial demonstrated the safety of GUT-1 in patients with Crohn’s Disease [6]. Accordingly, Atreya and colleagues now sought to evaluate the safety, as well as the efficacy and mode of action, of GUT-1 in patients with UC as part of a phase IIa placebo-controlled, clinical trial.
Patients will often ask, “What causes Inflammatory Bowel Disease?” Frustratingly, we remain unable to answer this seemingly simple question, beyond the often-quoted paradigm that unknown environmental factors trigger inflammation in genetically susceptible individuals. Although our understanding of the immune response in IBD has reached phenomenally detailed levels of resolution, the nature and identity of the initial environmental triggers of IBD have continued to remain a mystery. The strong relationship between socioeconomic development and IBD incidence is tantalising evidence of a definable environmental toxin and various substances such as processed food additives have recently been highlighted as potential suspects [1]. However, searching for the causative agent is like looking for a needle in a haystack as the candidate list includes literally every small molecule in existence!
Higher intra-abdominal visceral adipose tissue mass is associated with lower rates of clinical and endoscopic remission in patients with inflammatory bowel diseases initiating biologic therapy: Results of the Constellation Study
Despite an expanding therapeutic arsenal, a considerable proportion of patients with Crohn's Disease (CD) and Ulcerative Colitis (UC) fail to achieve or sustain therapeutic responses [1, 2]. Mechanisms contributing to this failure, particularly with respect to biologic therapy, are only partially understood [3]. Uncovering the mechanisms behind loss of response may help to enhance the efficacy of existing treatment options or to develop alternative options for the future.
Some investigations have noted an association between obesity, high intra-abdominal visceral adipose tissue (IA-VAT) mass and unfavourable outcomes in individuals with Inflammatory Bowel Disease (IBD). However, these observations have been constrained by their methodology and have to date focused only on patients having treatment with anti-tumour necrosis factor alpha (anti-TNF-α) agents [4–6], limiting their scope.
The Constellation Study by Yarur and colleagues aimed to investigate the relationship between IA-VAT in patients with IBD and the response to biologic drugs with multiple different mechanisms of action.
The SONIC trial yielded seminal findings showing that the combination of infliximab and azathioprine is more effective than either treatment alone for the maintenance of remission in patients with Crohn’s Disease (CD) [1]. In recent years, despite the availability of an increasing number of biologics and small molecules to treat CD, a ceiling of therapeutic efficacy has been reached [2]. Therefore, there has been a resurgence of interest in whether this therapeutic ceiling “effect” can be overcome with new treatment combinations. In the EXPLORER study, the efficacy and safety of triple combination therapy was assessed using two biologics with different modes of action in association with methotrexate for the treatment of CD.
Increased versus conventional adalimumab dose intervals for patients with Crohn’s disease in stable remission (LADI): a pragmatic, open-label, non-inferiority, randomised controlled trial
van Linschoten RCA, Jansen FM, Pauwels RWM, et al.
Adalimumab is an effective and safe treatment for Crohn’s Disease (CD). However, both patients and healthcare professionals may wish to mitigate medication exposure due to potential safety and economic concerns in the long term. Since a high relapse rate follows drug discontinuation, treatment de-escalation without actually stopping the medication may allow for decreasing drug exposure while maintaining efficacy. In two observational studies, de-escalation from a 2-week to a 3-week adalimumab dosing interval was successful in most of the patients, though reversal to a 2-week dosing interval was required in about 30% due to insufficient disease control [1, 2]. The Lengthening Adalimumab Dosing Interval (LADI) study is a pragmatic, open-label, multicentre, non-inferiority, parallel, randomised controlled trial conducted in the Netherlands and specifically designed to address this knowledge gap [3].
Withdrawal of immunomodulators or TNF antagonists in patients with inflammatory bowel diseases in remission on combination therapy: A systematic review and meta-analysis
Combination therapy with anti-TNF inhibitors (ATI) and immunomodulator (IMM) therapy remains an efficacious treatment strategy for disease control in moderate to severe Inflammatory Bowel Disease (IBD). This conclusion was largely based on the findings of landmark trials, SONIC and UC SUCCESS, which showed combination therapy to be far superior to monotherapy in achieving durable clinical and endoscopic remission in IBD [1, 2].
However, combination treatment with ATI and IMM can lead to increased risk of infection and malignancy. Whilst withdrawal of combination treatment once the patient is in disease remission can reduce the risk of treatment-related complications as well as the cost to health services, there remains a risk of relapse of previously controlled disease. At present there is no consensus amongst global clinical guidelines as to the appropriate duration of use of combination therapy. Thus, clinicians often find decisions related to withdrawal of treatment quite challenging.
