Crohn’s disease (CD) is a chronic, immune-mediated inflammatory condition of the gastrointestinal tract. Its etiology is multifactorial, with current hypotheses proposing that CD arises from an aberrant immune response to the intestinal microbiota in genetically susceptible individuals. Over the past decades, numerous studies have reported alterations in the gut microbiome of CD patients, consistently raising the question of whether these changes are a cause or consequence of disease. Recent evidence now suggests that such microbial alterations may in fact precede disease onset, as compellingly demonstrated in a large cohort of Canadian first-degree relatives of CD patients. Researchers from the Crohn’s and Colitis Canada – Genetic, Environmental, Microbial project assembled a substantial dataset of fecal 16S rRNA gene sequencing and developed a machine-learning-based microbiome risk score that could accurately predict the development of CD up to five years before clinical diagnosis.
Despite this growing recognition of the microbiome’s potential role in disease initiation, CD patients are still typically treated with medications that dampen or modulate an excessive or aberrant immune response. As recently emphasized in a commentary in Gastroenterology, even though the etiologic triad of inflammatory bowel disease (i.e., genetics, environment, and the immune system), is well established, all current approved therapies target the immune system. Now that our understanding of the microbiome has expanded considerably, there is an opportunity to leverage this knowledge; not necessarily to replace immune-directed therapies, but to enhance their effectiveness.
Immune-directed treatments include anti–tumor necrosis factor-alpha (anti-TNFα) antibodies such as infliximab and adalimumab, the anti-integrin antibody vedolizumab, which targets the α4β7 integrin, and ustekinumab, which binds the p40 subunit shared by interleukin (IL)-12 and IL-23. These therapies often induce shifts in the gut microbial composition, as documented in several prospective studies over the past years. In particular, anti-TNFα agents have been extensively studied in relation to the microbiome, with several investigations tracking fecal microbial profiles before, during, and after treatment. These studies frequently compare patients who achieve clinical remission with those who do not, highlighting differences in microbial dynamics. Notably, as early as six years ago, Aden and colleagues demonstrated that the efficacy of anti-TNFα therapy is associated with the metabolic functions of the gut microbiota, suggesting a potential role for microbial activity in modulating treatment response.
Despite the availability of advanced biologic therapies, treatment response rates in CD remain suboptimal. Approximately 40% of patients either fail to respond or lose responsiveness over time, underscoring the urgent need for reliable biomarkers to guide therapeutic decisions. This challenge was recently addressed in an epigenome-wide association study conducted by researchers from Amsterdam University Medical Center and John Radcliffe Hospital in Oxford. The study provided evidence for the potential of DNA methylation profiling as a tool for predicting response to vedolizumab and ustekinumab, but not adalimumab, offering a promising avenue for personalized medicine in CD. Notably, the investigators applied machine learning techniques in a highly refined manner, further illustrating the growing role of computational methods in translational biomedical research. At the same time, this work highlights a parallel gap in the microbiome field, where similarly robust predictive models remain underdeveloped.
Given the central role of the gut microbiome in both disease pathogenesis and treatment response, computational approaches should also be applied to predict therapeutic outcomes based on patients’ microbial profiles. While several studies have compared fecal microbiota between responders and non-responders, predictive modeling has been limited. Notably, Sanchis-Artero and colleagues conducted a receiver operating characteristic (ROC) curve analysis using the ratio of Faecalibacterium prausnitzii to Escherichia coli, achieving an area under the curve (AUC) of 0.87. This result highlights the potential of species-specific microbial markers as predictive tools. However, it also underscores the opportunity to explore more comprehensive approaches, whether by incorporating additional taxa or leveraging full microbiome profiles, to enhance predictive accuracy and support personalized treatment strategies in CD. Other research groups are exploring the role of specific fecal microbial signatures with a high capacity to discriminate responders and nonresponders to anti-TNF treatment and determine patients with CD who will have post-surgical recurrence, which occurs in 65-90% of patients in the first year after surgery.
This research gap becomes even more apparent in light of the first-ever ECCO Consensus on Dietary Management of Inflammatory Bowel Disease. First presented at ECCO’25, this landmark document on diet and nutrition in IBD involves, among others, diet recommendations for induction and maintenance, extending far beyond nutritional support. For the first time, dietitians and gastroenterologists jointly offer evidence-based recommendations that position dietary interventions, such as an all-formula diet or exclusive enteral nutrition (EEN), as central components of clinical care. Notably, in a related ECCO post, the lead author of the consensus, IBD dietitian Vaios Svolos, emphasized that “current understanding attributes EEN’s efficacy primarily to the suppression of gut microbiome activity“. This perspective not only affirms the microbiome’s role in CD pathogenesis but also underscores its active involvement in mediating treatment response, whether through biologics or diet. In line with these findings, emerging studies are showing that nutritional therapies affect the efficacy of immune therapies, suggesting that modifications of environmental factors such as the microbiome offer great potential in CD, as proven to be successful in other gastrointestinal diseases, such as the role of fecal microbiota transfers and defined bacteria consortia for managing Clostridioides difficile infection. Together, these insights strengthen the rationale for applying computational approaches to patient-specific microbial profiles in order to predict therapeutic outcomes and guide individualized treatment strategies, encompassing both pharmacologic and dietary modalities. Emerging studies highlight the momentum of using microbial signatures as a non-invasive tool that improves the patients’ quality of life, saves healthcare system costs and gains time in patient improvement.
References
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