DAY 1 - Advances in Understanding and Managing IBD: Global Trends, Genetic Insights, and Emerging Therapies

Ashwin Ananthakrishnan, MD, MPH, from Massachusetts General Hospital in Boston, Massachusetts described the increasing global incidence of IBD from 1980 to 2010. It is predicted that the rate of increase will likely slow and stabilize at around 1.5% prevalence in western countries, and that high population countries with low prevalence will contribute more to the overall global IBD burden. He described a “silver wave,” with older adults expected to comprise a larger fraction of IBD cases. Contributing risk factors include greater antibiotic exposure, particularly in infancy when the microbiome is most vulnerable, smoking, and diet. Macro and micronutrients, the method of food processing, and the use of emulsifiers and food additives are thought to contribute to gut inflammation. Stress and depressive symptoms are also associated with incident IBD and the increased risk of relapse. BMI increases risk and physical activity is protective. The next decade will bring new studies into the underlying mechanisms linking risk factors to IBD incidence, including changes in microbiome diversity, short-chain fatty acid production, antimicrobial peptide production, and mucous secretion. Research is also focusing on environmental exposures to pesticides and microplastics as causal factors, and multi-omic methods are being applied to quantify the effects of exposure. It is also clear that impact assessments must be personalized, as not everyone exposed to risk factors have the same gut response. Dr. Ananthakrishnan also described the concept of asymptomatic “pre-IBD” with markers of disease present years before symptoms occur. The field is in a phase where IBD morbidity is reduced but treatment costs are substantial, with a shift from hospitalization and surgery to treatment as the main source of the cost of care. Multi-pronged strategies are needed to further reduce costs, including earlier treatment to prevent damage, increased awareness, development of noninvasive monitoring tools, and better matching of patients to treatments to move away from sequential paradigms. He concluded with a call for a global IBD agenda with priorities based on regional epidemiology: prevention and tracking in low prevalence regions; research and ensuring access in regions with increasing incidence; and patient and provider education in high prevalence regions.

Judy H. Cho, MD, from the Icahn School of Medicine at Mount Sinai in New York, New York, reviewed the various protein altering gene variants and cellular factors that underlie the biology of IBD. She described that IBD is likely driven by networks of protein-altering gene variants that drive changes in the immune response, and affected genes may be distinct or  overlap across different populations globally. For example, variants in CSF2RB are more significant in Asians but LACC1 variants are seen in both Asians and African Americans. Identification of blood based protein markers based on gene variants may lead to the development of rapid tests. Dr. Cho also described a role for epigenetic memory after the gut is exposed to stress, with transcription factors recruited faster upon exposure to a second challenge. She highlighted the importance of spatial transcriptomics for looking at clusters of gene expression within a tissue section, with changes in the tissue driven by gene and cell factors, similar to wound healing, with characteristics of innate immune deficiency involving epithelial cells.

Harry Sokol, Prof., from St. Antoine Hospital in Paris, France, described the emerging understanding that IBD involves the activation of GI immune system toward gut microbiota in genetically susceptible hosts and under the influence of environmental factors. Early life events affect the first host-microbiome interactions, with an impact on immune system imprinting and miseducation of the immune system. Studies in animal models and in humans demonstrated that changing the microbiome with FMT impacts disease severity, and that FMT from patients with IBD exacerbates colitis in mice. Altered gut microbiota is seen in IBD patients vs. healthy subjects at the level of the gut bacterial and fungi microbiomes, with decreased diversity of the microbiome, particularly during active disease. Studies have shown that microbiome changes occur years before the diagnosis of IBD, making it a potential diagnostic tool as well as a therapeutic strategy. There are limitations to eliminating “bad” bacteria with antibiotics or phages, so the field has focused on enriching or stimulating the “good” bacteria using FMT, probiotics, and postbiotics. FMT has been shown to improve UC, and there is less data in CD. However, it is impossible to standardize FMT: up to 50% of microbiota genes have an unknown function, and up to 90% of metabolites are unknown. Understanding the underlying MOA of FMT efficacy is complex. Bacterial “consortia” have been developed that either use bacteria that work synergistically like a simplified microbiome or individual bacteria with additive effects. VE202 is under clinical development and includes 17 strains to boost regulatory T cells. Another approach is to select a single strain that is highly effective; F. prausnitzii has been shown to effect epithelial cells and reprogram immunoregulation reprogramming and is currently in phase 2 trials in patients with postoperative CD. Postbiotics are factors produced by microbes, such as short-chain fatty acids and tryptophan metabolites, which are thought to have a protective effect. Dr. Sokol concluded by calling for IBD therapies and therapeutic strategies that target both inflammation and the microbiome. The IMPACT-Crohn study examined a strategy that first targets inflammation with corticosteroids followed by FMT once the initial flare is controlled. The pilot study showed that this approach prolonged the time to next flare. The timing of the FMT could be modified to optimize the effectiveness.

Marla C. Dubinsky, MD from the Ichan School of Medicine in New York, New York, discussed the burden of IBD monitoring and the need to improve current practice paradigms. Currently, monitoring is based on patient reported symptoms, which is a reactive approach. She said, “By the time we do anything a lot of damage has already occurred.” Dr. Dubinsky suggested that passive monitoring to identify patients who may be asymptomatic but have objective markers of disease activity and should be managed before the disease progresses. Unfortunately, IBD symptoms and objective measures of disease do not correlate in many patients. Each stage of IBD requires a different monitoring approach. At the time of diagnosis, it is important to establish benchmarks for biomarkers and set patient expectations about what to expect with monitoring during the induction phase. She also recommended incorporating a treat-to-target approach by establishing a change in an objective outcome, not just symptoms. During maintenance, adherence to monitoring can decrease if patients are asymptomatic, and they should be reminded that biomarkers can show active inflammation before symptoms arise and can lead to relapse and complications. The STORI trial found that markers of disease relapse showed up 6 months prior to symptom development, and the CALM study demonstrated that symptom monitoring alone led to delays in treatment escalation. Dr. Dubinsky also suggested new directions for monitoring in IBD, including intestinal ultrasound to detect active inflammation and measure bowel wall thickness. She noted that for many patients “seeing is believing” and they may be empowered to take proactive measures to improve the markers on ultrasound. She also described passive monitoring approaches to identify patients at risk or currently flaring to intercept and avoid progressive damage and complications. Digital collection of HR, HR variability, activity, oxygen saturation, and sleep data could help predict flares. Sweat biosensing of protein markers such as cytokines, CRP, TNFα, and calprotectin may help detect flares and avoid the need for fecal collection as a major barrier to monitoring. Ultimately, passive monitoring should help prevent disease progression in at-risk individuals by identifying and treating them early.

David T. Rubin, MD, from the University of Chicago in Illinois discussed the various IBD treatment paradigms and where the field is moving in the future. Through the years, the field has adopted various treatment paradigms to optimize IBD outcomes, including sequential, step-up, treat-to-target, precision, and combination approaches. The optimal outcomes in IBD are unrestricted and high quality of life, sustained control of bowel inflammation, unencumbered personal and professional functioning, and healthcare that is affordable. In the “desperation era” of IBD therapy, treatment relied on empiricism and symptom management only, and early surgical approaches overreached. Sequential monotherapy emerged with the introduction of medications, however, the “fail first” approach leads to complications and delayed treatment. Infliximab was a treatment revolution in IBD that taught the field about biologic therapies and inflammatory burdens, active disease vs. remission, the systemic risks of TNF inhibition, and that mucosal healing was possible. The era of step-up strategies still required patients to try medications in sequence, but with little evidence of the best order. One approach was “top-down,” using the most effective treatments first, and combination therapy, which improved longer-term outcomes and showed that earlier treatment reduces remission and loss of response. Surgery first is also considered a “top-down” strategy to achieve disease control with a definitive approach, with prolonged remission and a better quality of life (PROFILE study). As surgery has advanced and become safer, it has become a good approach for some patients. More recently, there has been a proliferation of advanced therapies and more head-to-head trials in CD and UC, but there is a need for more active comparator studies and more creative study designs that are independent of industry goals. The treat-to-target approach adjusts therapies until the patient reaches a defined goal, but the ultimate goal is quality of life, which means that there may be some residual disease that is acceptable. Treat-to-target trials have been done in CD only, including CALM, STARTDUST, and REACT-2, and more needs to be done to optimize sequencing and combining therapies with different mechanisms of action, as well as timing. The VERDICT study in UC is still underway. Today, the field is in the combination therapy era, usually for nonresponse, and the main considerations are mechanism of action, synergy, and durability. Cost and drug interactions are also important considerations. The Sonic, Explore, Success, and Vega studies demonstrated the benefits of combination therapy. The Duet, Explore 2, and ExiGEM studies are ongoing. Biomarker-driven precision medicine for IBD is elusive and in its early stages. A Phase 2 study of anti-TL1A monoclonal antibody for UC shows improvement in clinical remission and endoscopic endpoints. Future directions include transmural healing, disease modifying anti-inflammatory drugs (DMAIDs), disease clearance as an endpoint, the concept of functional remission, and a focus on overlooked endpoints such as mental health, sexual health, and quality of life. A recent consensus statement on the global research agenda in IBD laid out priorities, including improving existing medications, investigating new mechanisms of action, de-escalation strategies, microbiome based strategies, dietary strategies, and the removal of emulsifiers from medications to reduce the inflammatory response (Solitano et al. Nat Rev Gastroenterol Hepatol. 2025)