The gut microbiota profoundly shapes intestinal immunity through the production of small-molecule metabolites; yet in inflammatory bowel diseases (IBD), where the microbial metabolome is substantially altered, the identities and immunological functions of most disease-associated metabolites remain unknown. Here, we integrate untargeted fecal metabolomics from two independent IBD patient cohorts with gnotobiotic mouse metabolomic data to identify N-acyl putrescines as a class of microbiome-associated metabolites consistently enriched in both Crohn's disease (CD) and ulcerative colitis (UC). Among these, N-oleoylputrescine (NOP) induces potent and selective transcriptional responses in bone marrow-derived dendritic cells (BMDCs) and colonic organoids, establishing it as the primary immunomodulatory candidate in this metabolite class. Enterocloster species harboring nonribosomal peptide synthetase (NRPS) biosynthetic gene clusters produce NOP via conjugation of oleic acid with putrescine, confirmed by isotope-tracing in vitro and germ-free mouse mono-colonization in vivo. NOP suppresses five core IBD-associated inflammatory pathways in mouse dendritic cells and human monocytes, reduces gene signatures of histologic inflammation and IBD therapy non-response, and ameliorates colitis in four murine models. NOP dampens NF-κB activation and iNOS expression in myeloid cells and suppresses type 1 immune responses through a T cell-intrinsic mechanism. The enrichment of NOP in IBD despite its anti-inflammatory activity supports a holobiont defense hypothesis: that the gut microbiota mounts a compensatory metabolic response to intestinal inflammation that may contribute to the restoration of organismal homeostasis.

The success of inflammatory bowel disease (IBD) clinical trials is strongly influenced by study design and disease-specific operational challenges. Over the past decade, however, IBD clinical trials face slow enrolment, poor retention, accumulating costs and limited representativeness. Trials are further constrained by protocol and operational complexity, financial pressures and regulatory requirements. Carefully selected and optimised trial designs may address the inherent challenges of IBD research and should take into account the patient profiles under investigation, mode of action and speed of onset of effect of the investigational product, among other factors. This narrative review discusses four key study design strategies for IBD clinical trials, including treat-through maintenance, responder re-randomisation, Master Protocol approaches (basket, umbrella and platform trials) and Bayesian methodologies. Treat-through maintenance designs are effective at evaluating sustained efficacy and real-world durability, whereas responder re-randomisation approaches are widely used in drug registration programmes to distinguish induction and maintenance effects for regulator clarity. Master Protocol designs may improve efficiency and reduce placebo exposure, while trials using Bayesian methodologies can strengthen interpretation of efficacy and safety outcomes, particularly in early-phase or complex studies. Key considerations within protocols include the use of co-primary endpoints, selection of secondary/exploratory endpoints, control group design and integrating digital health technologies, among others. Strategic application of innovative methodologies can improve trial delivery and enhance data robustness and interpretability, thus supporting more efficient development of effective therapies for patients with IBD.

Fatigue is a common symptom in patients with inflammatory bowel disease (IBD). However, the prevalence is underestimated because it is not intentionally assessed during routine medical evaluation. Our study aimed to evaluate the prevalence and factors associated with fatigue in patients with IBD. A cross-sectional study was conducted in patients with ulcerative colitis and Crohn disease. We evaluated fatigue using the validated IBD questionnaire; a score of ≥1 in both sections was considered indicative of fatigue, and the severity increased with a higher score. A total of 109 patients were included in the study. Fatigue was reported in 102 (94%) patients, affecting 95% of men and 92% of women. The prevalence was 97% in Crohn disease and 92% in ulcerative colitis patients. Fatigue is more common in patients with active diseases, anemia, and those who are overweight or obese. Depression, hypoalbuminemia, and active disease were significantly associated with greater severity of fatigue; however, depression was the only independent predictor (β = 16.094, p = .018). Nine out of 10 patients present some degree of fatigue, regardless of demographic characteristics, and depression is closely related to its severity.

Ulcerative Colitis (UC)-associated diarrhea is a debilitating symptom of persistent intestinal inflammation that significantly reduces a patient's quality of life. Epithelial ion transport failure, tight junction remodeling, dysregulated mucus secretion, immunological overactivation, gut microbiota dysbiosis, and mitochondrial oxidative stress all interact intimately to cause its pathogenesis. While cytokine-mediated suppression of ENaC, NHE3 (Na+/H+ exchanger 3), DRA (SLC26A3), and PAT1 (SLC26A6) significantly reduces fluid and electrolyte absorption, chronic inflammation promotes "claudin switching" and tight junction breakdown, increasing paracellular permeability. Mucosal barrier failure is sustained and inflammatory cascades are intensified by concurrent deregulation of the NF-κB, JAK/STAT, and PXR signaling pathways. Recent findings highlight the critical role of immune-microbiota crosstalk and reactive oxygen species formed from mitochondria in sustaining this pathogenic cycle. Recent developments in biologics, targeted small molecules, colon-specific hydrogels, and nanomedicine offer potential approaches for site-specific drug delivery, immunologic control, and epithelial barrier restoration, in addition to traditional pharmacotherapies. This review highlights future options for tailored, multi-targeted therapies. It provides a framework for mechanism-guided management of UC-associated diarrhea by synthesizing existing mechanistic insights and translational therapeutic advancements.