Trending Topics in Gastroenterology | GastroAGI

Ultraprocessed Grains Increase IBD Risk: AJG | June 2026

• This large prospective PURE study evaluated the relationship between ultraprocessed grain consumption and the future development of inflammatory bowel disease across 124,590 participants from 21 countries. • Ultraprocessed grains include heavily refined grain products that often contain additives, emulsifiers, preservatives, flavour enhancers, and other industrial ingredients. • Higher consumption of ultraprocessed grains was associated with a significantly increased risk of developing IBD. • Individuals consuming ≥19 g/day of ultraprocessed grains had nearly double the risk of IBD compared with those consuming less than 9 g/day. • The association remained significant after adjustment for major confounders, including age, sex, smoking, dietary habits, and physical activity. • The findings support growing evidence linking Westernised dietary patterns and food processing to intestinal inflammation. • In contrast, consumption of fresh bread and rice was associated with a lower risk of developing IBD. • The study also confirmed a broader dietary signal: higher overall intake of ultraprocessed foods was strongly associated with future IBD development. • Participants consuming five or more servings of ultraprocessed foods daily had almost a fourfold higher risk of IBD compared with those consuming less than one serving per day. • Several biological mechanisms may explain the findings, including: Alteration of gut microbiota Increased intestinal permeability Disruption of the mucus barrier Exposure to food additives and emulsifiers Enhanced mucosal immune activation • The study adds further support to the hypothesis that environmental and dietary factors contribute substantially to the rising global incidence of IBD. • Although observational, the prospective design and multinational nature of the PURE cohort strengthen the validity of the findings. • The study cannot identify which specific component of ultraprocessed grains is responsible for the increased risk, and further mechanistic research is needed. • From a clinical perspective, dietary counselling aimed at reducing ultraprocessed food consumption may become an increasingly important component of IBD prevention strategies. Bottom line: Higher consumption of ultraprocessed grains is associated with a significantly increased risk of developing IBD, while less processed staple foods, such as fresh bread and rice, appear to be associated with lower risk. The findings reinforce the importance of minimising ultraprocessed foods as part of a gut-healthy dietary pattern

HLA-DRB1*01:03 Identifies a Severe IBD Phenotype : Lancet Gastroenterol Hepatol | June 2026

Introduction: Inflammatory bowel disease (IBD) exhibits marked heterogeneity in disease behavior, progression, and treatment response. Identifying genetic markers associated with aggressive disease could facilitate earlier risk stratification and personalized therapeutic strategies. Among genetic factors, the HLA-DRB1*01:03 allele has long been linked to severe ulcerative colitis, but its broader impact across the spectrum of IBD has remained incompletely understood. Problem Statement: Although HLA-DRB1*01:03 is recognized as a susceptibility allele in ulcerative colitis, it is unclear whether this genetic variant influences long-term disease severity, surgical risk, treatment requirements, and adverse outcomes across both ulcerative colitis and Crohn’s disease. A comprehensive evaluation of its genotype–phenotype associations could help identify patients at risk for a more aggressive disease course. Summary: This large genotype–phenotype association study involving more than 43,000 patients with IBD provides compelling evidence that HLA-DRB101:03 is a marker of severe disease across both ulcerative colitis and Crohn’s disease. Carriers of this allele demonstrated higher rates of major adverse outcomes, including colectomy in ulcerative colitis, colonic resection in Crohn’s disease, and perianal disease in both conditions. Importantly, the genetic association extended beyond disease occurrence to disease trajectory, with carriers developing complications earlier and requiring advanced therapies sooner than non-carriers. The study also showed that HLA-DRB101:03 was associated with an increased likelihood of advanced therapy failure, suggesting a potentially more treatment-resistant disease phenotype. Notably, the allele was linked to younger-onset ulcerative colitis and distinct disease characteristics in Crohn’s disease, further supporting its role in shaping disease behavior. These findings position HLA-DRB101:03 as one of the strongest genetic markers currently associated with adverse IBD outcomes. From a clinical perspective, genetic identification of HLA-DRB101:03 carriers could eventually support precision medicine approaches by identifying patients who may benefit from closer monitoring, earlier introduction of advanced therapies, and proactive management strategies. Although further validation and cost-effectiveness analyses are required before routine implementation, this study represents an important step toward genotype-guided risk stratification in IBD.

Ustekinumab and Anti-TNFs Show Comparable Efficacy After Vedolizumab Failure : GETAID | June 2026

Introduction: Vedolizumab has become a widely used first-line advanced therapy for ulcerative colitis (UC) because of its favorable efficacy and safety profile. However, a substantial proportion of patients experience primary nonresponse or secondary loss of response, creating a growing need for evidence to guide treatment selection after vedolizumab failure. Despite the increasing use of vedolizumab as an initial biologic, data comparing subsequent therapeutic options remain limited. Problem Statement: The optimal second-line advanced therapy following vedolizumab failure is not well established. Clinicians frequently choose between anti-TNF agents and ustekinumab, but comparative real-world evidence regarding effectiveness, treatment durability, and safety is scarce. Identifying the most appropriate strategy is particularly important in patients with differing disease severity and risk profiles. Summary: This multicenter GETAID study evaluated real-world outcomes of infliximab, subcutaneous anti-TNF agents, and ustekinumab as second-line therapies after vedolizumab failure in patients with UC. The investigators found that all three treatment strategies achieved similar rates of steroid-free clinical remission and demonstrated comparable treatment persistence during follow-up. These findings suggest that both anti-TNF therapy and ustekinumab remain effective options after vedolizumab failure and support a flexible, individualized treatment approach. An important observation was that patients receiving corticosteroids at treatment initiation were less likely to achieve remission, highlighting baseline disease severity as a key determinant of outcome. While efficacy was broadly comparable across treatment groups, meaningful differences emerged in safety. Ustekinumab was associated with fewer adverse events and fewer treatment discontinuations related to toxicity, suggesting a more favorable tolerability profile. In contrast, infliximab remained an effective option, particularly for patients requiring rapid disease control in the setting of high inflammatory burden. These results provide valuable real-world guidance for treatment sequencing in UC and suggest that therapeutic selection after vedolizumab failure should be driven by individual patient characteristics, disease activity, comorbidity burden, and safety considerations. Overall, the study supports ustekinumab as an attractive option for patients in whom long-term safety is a major priority, while confirming that anti-TNF therapy remains a highly relevant and effective therapeutic strategy.

Metastatic Crohn’s Disease Often Precedes Intestinal Diagnosis : Gut | June 2026

Introduction: Metastatic Crohn’s disease (MCD), also referred to as cutaneous or genital Crohn’s disease, is a rare extraintestinal manifestation characterized by granulomatous skin inflammation occurring at sites separate from the gastrointestinal tract. Because of its rarity and heterogeneous presentation, MCD is frequently underrecognized and may lead to significant diagnostic delays. Current knowledge regarding its epidemiology, clinical characteristics, and optimal management remains limited, largely due to the absence of large prospective studies. Problem Statement: The rarity of MCD and the predominance of case reports and small case series have hindered the development of standardized diagnostic and therapeutic approaches. Clinicians often face uncertainty regarding recognition of disease patterns, identification of at-risk patients, and selection of effective treatment strategies. Summary: This systematic review represents one of the most comprehensive evaluations of metastatic Crohn’s disease to date, compiling data from over 600 reported patients. The analysis demonstrated that MCD predominantly affects younger individuals and is more common in women. Genital erythema and edema emerged as the hallmark clinical manifestations, with disease frequently involving the genitalia, perineum, and groin. Importantly, one of the most clinically relevant findings was that approximately one-third of patients developed MCD before receiving a diagnosis of luminal or perianal Crohn’s disease. This observation highlights the importance of considering Crohn’s disease in the differential diagnosis of unexplained granulomatous genital or cutaneous lesions, even in the absence of gastrointestinal symptoms. The review also identified associations with colonic Crohn’s disease and perianal involvement, suggesting a distinct disease phenotype. Ulceration appeared to be a marker of more severe and extensive disease. Therapeutic approaches varied widely and included topical therapies, systemic immunosuppressive agents, biologic therapies, and surgical interventions, reflecting the lack of evidence-based treatment guidelines. Anti-TNF agents were the most frequently reported advanced therapy. Overall, the findings underscore the need for increased clinical awareness, standardized reporting, and prospective studies to establish effective diagnostic pathways and treatment algorithms for this challenging manifestation of Crohn’s disease.

Darvadstrocel in Complex Perianal Crohn’s Disease: Gastroenterology | June 2026

• Darvadstrocel is an allogeneic adipose-derived mesenchymal stem cell therapy designed to promote fistula healing through anti-inflammatory and immunomodulatory mechanisms. It is administered locally into conditioned fistula tracts after curettage and closure of the internal opening. • Darvadstrocel previously generated considerable enthusiasm after the original ADMIRE-CD trial demonstrated significantly higher remission rates compared with placebo, leading to regulatory approval in Europe and Japan. • The phase 3 ADMIRE CD II trial was designed as a larger confirmatory study involving patients from Europe, Israel, and North America with treatment-refractory complex perianal Crohn’s fistulas. • A total of 568 patients were randomized to receive darvadstrocel or placebo following standard surgical conditioning of the fistula. • The primary endpoint was combined remission at week 24, defined as closure of all treated external openings together with absence of significant collections on MRI. • The study failed to meet its primary endpoint. Combined remission occurred in 48.8% of darvadstrocel-treated patients compared with 46.3% of placebo-treated patients, showing no statistically significant difference. • Clinical remission, time to remission, and other secondary efficacy outcomes were also similar between treatment groups. • Safety findings were reassuring, with no new safety concerns identified and adverse event rates similar between darvadstrocel and placebo. • The negative result contrasts with the earlier ADMIRE-CD trial and raises important questions regarding the reproducibility of stem-cell–based therapies for fistulizing Crohn’s disease. • These findings challenge the current role of darvadstrocel and suggest that future research may need to focus on alternative cell-based therapies, extracellular vesicles, or more targeted immunoregulatory approaches. Bottom line: Despite promising results from the original ADMIRE-CD trial, the larger phase 3 ADMIRE CD II study failed to demonstrate superiority of darvadstrocel over placebo for complex perianal Crohn’s fistulas, casting doubt on the clinical benefit of stem-cell therapy in this setting.

Inflammaging and Sarcopenia: Nutrients | June 2026

• Inflammaging and sarcopenia are two interconnected hallmarks of aging that contribute to frailty, disability, metabolic dysfunction, loss of independence, and reduced quality of life. • Inflammaging refers to chronic low-grade systemic inflammation that develops with aging, even in the absence of overt infection or disease. • Sarcopenia is characterized by progressive loss of muscle mass, strength, and physical performance, and is increasingly recognized as a major determinant of healthy aging. • The relationship is bidirectional: chronic inflammation accelerates muscle breakdown, while loss of muscle mass further promotes inflammation and metabolic dysfunction. • Several common biological pathways link inflammaging and sarcopenia, including: NF-κB activation Mitochondrial dysfunction Oxidative stress Impaired AMPK–mTOR signaling Reduced cellular stress resilience • Regular physical activity remains the most consistently effective intervention for preserving muscle function and reducing age-related inflammatory burden. • Exercise improves mitochondrial function, insulin sensitivity, anabolic signaling, antioxidant defenses, and immune regulation. • A growing body of evidence supports the role of bioactive dietary compounds in modulating aging-related pathways. • Important bioactive compounds discussed include: Polyphenols Flavonoids Carotenoids Omega-3 fatty acids • These compounds appear to influence several key pathways involved in healthy aging, including NF-κB, Nrf2, AMPK, mitochondrial metabolism, and redox homeostasis. • Anti-inflammatory dietary patterns, particularly Mediterranean-style diets, are associated with better muscle strength, physical performance, and lower inflammatory burden. • The review introduces a geroscience framework, emphasizing that interventions should target fundamental biological aging mechanisms rather than individual diseases alone. • A key concept is hormesis, whereby mild biological stress from exercise or certain nutritional compounds activates adaptive cellular defense mechanisms that improve resilience. • Current evidence suggests that exercise and nutritional bioactives often converge on similar molecular pathways, potentially producing complementary benefits. • However, the authors caution that true biological synergy has not yet been conclusively demonstrated in humans. • Significant challenges remain regarding optimal dosing, bioavailability, duration of intervention, patient selection, and long-term clinical outcomes. • Future studies should focus on integrated lifestyle approaches rather than evaluating exercise and nutrition as isolated interventions. Bottom line: Inflammaging and sarcopenia are closely linked drivers of biological aging. Regular exercise, healthy dietary patterns, and selected bioactive compounds target many of the same molecular pathways and represent promising non-pharmacological strategies to preserve muscle function, metabolic health, and healthy aging.

Managing C. difficile Infection in Patients With IBD: Gastroenterology | May 2026

• Clostridioides difficile infection (CDI) remains one of the most important triggers of disease flares, hospitalization, treatment failure, colectomy, and mortality in patients with inflammatory bowel disease. • Every patient with IBD presenting with new or worsening diarrhea should be evaluated for CDI, particularly those with colonic disease, ileal pouches, or end ileostomies. • Symptoms alone cannot reliably distinguish CDI from an IBD flare, making stool testing essential. • The AGA recommends a multistep toxin-based diagnostic algorithm rather than PCR alone, because asymptomatic C. difficile colonization is common in IBD. • A positive PCR without toxin detection may represent colonization rather than active infection and should be interpreted cautiously. • Fidaxomicin is now the preferred first-line treatment for initial CDI in IBD because it reduces recurrence and preserves gut microbiota. • Oral vancomycin remains an acceptable alternative when fidaxomicin is unavailable or cost-prohibitive. • Metronidazole should no longer be used for CDI treatment in patients with IBD. • Patients with severe colitis, systemic toxicity, marked leukocytosis, hemodynamic instability, or suspected sepsis should be strongly considered for hospitalization. • One of the most important practice changes is that IBD therapy should not routinely be stopped during CDI. • Biologics, immunomodulators, and small molecules should generally be continued when clinically indicated. • Corticosteroids may also be initiated or continued when there is concern for concurrent moderate-to-severe IBD activity. • If symptoms fail to improve within 48–72 hours of CDI treatment, clinicians should evaluate for: Active IBD flare Cytomegalovirus infection Alternative causes of colitis • Endoscopic assessment should be considered when uncertainty persists. • For recurrent CDI, microbiome restoration therapies have moved to the forefront of management. • Patients with IBD who experience at least one recurrence of CDI should be offered microbiome-based therapy, including: FDA-approved fecal microbiota products Fecal microbiota transplantation (where available) • Emerging microbiome therapies demonstrate high efficacy and acceptable safety even in patients receiving immunosuppressive therapy. • Probiotics are not recommended for either primary or secondary prevention of CDI in IBD. • Oral vancomycin prophylaxis may be considered in selected high-risk patients with prior CDI who require systemic antibiotics. • The update emphasizes that successful management requires simultaneous treatment of both CDI and underlying IBD rather than viewing them as competing diagnoses. Bottom line: The major messages of the AGA 2026 update are: use fidaxomicin first-line, continue necessary IBD therapy during CDI, avoid probiotics, use toxin-based testing strategies, and strongly consider microbiome-based therapies after the first recurrence of CDI.

Darvadstrocel Misses Primary Endpoint in Complex Perianal Crohn’s Disease : CGH | Jun 2026

Introduction: Complex perianal fistulas represent one of the most debilitating manifestations of Crohn’s disease, often causing chronic pain, drainage, recurrent infections, and substantial impairment in quality of life. Despite advances in biologic therapy, fistula healing remains difficult to achieve and sustain. Darvadstrocel, an allogeneic adipose-derived mesenchymal stem cell therapy, generated considerable enthusiasm following the positive ADMIRE-CD trial, which demonstrated improved fistula healing in selected patients with refractory disease. Problem Statement: Although earlier studies supported the efficacy of darvadstrocel, its performance in a broader international population and contemporary treatment setting remained uncertain. Confirmation of benefit in a larger phase 3 trial was necessary before establishing its role in routine management of complex perianal Crohn’s disease. Summary: The ADMIRE CD II trial evaluated the efficacy and safety of darvadstrocel in patients with complex perianal Crohn’s disease across Europe, Israel, and North America. All participants underwent standardized surgical preparation, including fistula curettage and closure of the internal opening, before receiving either darvadstrocel or placebo. Contrary to expectations generated by the earlier ADMIRE-CD study, darvadstrocel did not demonstrate superiority over placebo for the primary endpoint of combined remission at 24 weeks. Clinical remission rates and time to remission were also comparable between the treatment groups, indicating no meaningful therapeutic advantage. Importantly, the study confirmed a favorable safety profile, with adverse events occurring at similar rates in both groups and no new safety concerns identified. These findings represent a significant setback for stem cell-based therapy in complex perianal Crohn’s disease and highlight the challenges of translating promising early results into consistent benefits across broader patient populations. While darvadstrocel remains biologically attractive and well tolerated, the negative results of ADMIRE CD II raise important questions regarding patient selection, treatment timing, fistula characteristics, and trial design. Future research will be needed to identify subgroups most likely to benefit and to refine regenerative approaches for fistula healing in Crohn’s disease.

Anti–IL-10 Autoantibodies Define a New Subgroup of IBD: NEJM | June 2026

• This landmark study identifies neutralizing autoantibodies against interleukin-10 (IL-10) as a previously underrecognized mechanism driving inflammatory bowel disease. • IL-10 is a critical anti-inflammatory cytokine that maintains intestinal immune tolerance. Genetic defects in the IL-10 pathway are already known to cause severe early-onset IBD. • The investigators found neutralizing anti–IL-10 autoantibodies in 3.5% of patients with IBD, but in none of the healthy controls, suggesting a disease-specific phenomenon. • Anti–IL-10 autoantibodies were detected across Crohn’s disease, ulcerative colitis, and IBD-unclassified populations. • Functional studies confirmed that these antibodies are not merely biomarkers; they actively block IL-10 signaling and create a pro-inflammatory immune environment. • Patients with anti–IL-10 antibodies demonstrated exaggerated production of key inflammatory cytokines, including: * IL-23 * IL-1β * TNF * IL-6 • The most striking finding was the exceptionally strong association with HLA-DRB1*01:03, already recognized as the strongest genetic risk factor for ulcerative colitis. • More than 80% of anti–IL-10-positive patients carried HLA-DRB1*01:03, providing a mechanistic explanation for one of the strongest known HLA associations in IBD. • The association was remarkably strong, with odds ratios ranging from approximately 25 to 50 across independent cohorts. • Anti–IL-10 autoantibodies persisted over many years in most affected patients, suggesting a stable and durable immunological phenotype. • The study introduces the concept that some patients with IBD may have an acquired “phenocopy” of genetic IL-10 signaling defects. • This finding expands the role of B-cell–mediated autoimmunity in IBD pathogenesis, an area previously overshadowed by T-cell and innate immune mechanisms. • The discovery opens the possibility of a new precision-medicine subgroup of IBD defined by immune dysfunction rather than conventional clinical phenotype. • Potential future therapeutic approaches could include: * B-cell depletion (anti-CD20, anti-CD19) * Plasma cell targeting (anti-CD38) * Fc receptor blockade * Plasma exchange * Future antigen-specific immune therapies • Screening for anti–IL-10 antibodies may eventually become clinically relevant in patients with severe, refractory, extensive, or atypical IBD. • Further studies are needed to determine whether anti–IL-10 positivity predicts disease severity, colectomy risk, biologic response, or extraintestinal manifestations. Bottom line: Neutralizing anti–IL-10 autoantibodies are present in approximately 1 in 30 patients with IBD and are strongly linked to HLA-DRB1*01:03. This discovery identifies a biologically distinct autoimmune subtype of IBD and provides a potential mechanistic explanation for one of the strongest genetic risk factors in ulcerative colitis.

AI Reads Pediatric IBD Biopsies: Cellular and Molecular Gastro and Hepato | June 2026

• Histopathology remains a cornerstone for diagnosing pediatric inflammatory bowel disease, but differentiating Crohn’s disease from ulcerative colitis can be challenging, especially in young children. • This study evaluated whether artificial intelligence could automatically identify key histological features from routine endoscopic biopsy whole-slide images. • Researchers developed three computer vision models using convolutional neural networks and multiple-instance learning, a technique particularly useful when precise lesion-level annotation is unavailable. • The first model differentiated normal versus abnormal tissue with excellent performance, achieving an AUC of 0.91. • The second model identified active inflammation, achieving an AUC of 0.92. • The third model detected chronic architectural distortion, achieving an AUC of 0.93. • Overall model performance was strong despite using a weakly supervised learning approach, suggesting that meaningful pathological signals are present within routine whole-slide images. • The study demonstrates that AI can recognize inflammatory and structural patterns typically assessed by gastrointestinal pathologists. • Importantly, the models were developed from real-world pediatric endoscopic biopsy specimens rather than highly curated research datasets. • The findings support the concept that AI could function as a pathology decision-support tool rather than replacing pathologists. • Potential future applications include: Automated screening of biopsy slides Standardization of histological interpretation Reduction of interobserver variability Faster reporting workflows Objective disease activity assessment • For pediatric IBD, where early diagnosis can significantly influence treatment selection and long-term outcomes, such tools may become increasingly valuable. • The study does not yet provide direct Crohn’s disease versus ulcerative colitis classification, but establishes the foundation for future disease-specific diagnostic algorithms. • Larger multicenter validation studies and integration with clinical, endoscopic, and molecular data will be required before routine clinical implementation. Bottom line: This study demonstrates that artificial intelligence can accurately identify abnormal tissue, active inflammation, and chronic architectural changes in pediatric IBD biopsy slides, highlighting the growing role of computer vision as a diagnostic support tool in gastrointestinal pathology.