Inflammatory bowel diseases (IBDs), encompassing Crohn’s disease and ulcerative colitis, are complex chronic disorders characterized by an intricate interplay between genetic predisposition, immune dysregulation, gut microbiota alterations, and environmental exposures. This review aims to synthesize recent advances in IBD pathogenesis, exploring key mechanisms and potential avenues for prevention and personalized therapy. A comprehensive literature search was conducted across major bibliographic databases, selecting the most recent and impactful studies on IBD pathogenesis. The review integrates findings from multi-omics analyses, single-cell transcriptomics, and longitudinal cohort studies, focusing on immune regulation, gut microbiota dynamics, and environmental factors influencing disease onset and progression. Immune dysregulation, including macrophage polarization (M1 vs. M2) and Th17 activation, emerges as a cornerstone of IBD pathogenesis. Dysbiosis, as a result of reduced alpha and beta diversity and overgrowth of harmful taxa, is one of the main contributing factors in causing inflammation in IBD. Environmental factors, including air and water pollutants, maternal smoking, and antibiotic exposure during pregnancy and infancy, significantly modulate IBD risk through epigenetic and microbiota-mediated mechanisms. While recent advances have supported the development of new therapeutic strategies, deeply understanding the complex dynamics of IBD pathogenesis remains challenging. Future efforts should aim to reduce the burden of disease with precise, personalized treatments and lower the incidence of IBD through early-life prevention and targeted interventions addressing modifiable risk factors.

Inflammatory bowel diseases (IBD) and microscopic colitis are chronic immune-mediated inflammatory disorders that affect the gastroenterological tract and arise from a complex interaction between the host’s genetic risk factors, environmental factors, and gut microbiota dysbiosis. The precise mechanistic pathways interlinking the intestinal mucosa homeostasis, the immunological tolerance, and the gut microbiota are still crucial topics for research. We decided to deeply analyze the role of bile acids in these complex interactions and their metabolism in the modulation of gut microbiota, and thus intestinal mucosa inflammation. Recent metabolomics studies revealed a significant defect in bile acid metabolism in IBD patients, with an increase in primary bile acids and a reduction in secondary bile acids. In this review, we explore the evidence linking bile acid metabolites with the immunological pathways involved in IBD pathogenesis, including apoptosis and inflammasome activation. Furthermore, we summarize the principal etiopathogenetic mechanisms of different types of bile acid-induced diarrhea (BAD) and its main novel diagnostic approaches. Finally, we discuss the role of bile acid in current and possible future state-of-the-art therapeutic strategies for both IBD and BAD.

Background: Ustekinumab (UST) is an interleukin-12/interleukin-23 receptor antagonist approved for the treatment of Crohn’s disease (CD). Only limited real-life data on the long-term outcomes of CD patients treated with UST are available. This study assessed UST’s long-term effectiveness and safety in a large population-based cohort of moderate to severe CD patients. Methods: This was a multicenter, retrospective, observational cohort study that included both naïve and biologic-experienced patients treated with UST who achieved clinical remission or clinical response after at least one year of treatment. Clinical activity was scored according to the Harvey–Bradshaw Index (HBI). The primary endpoints were the maintenance or achievement of clinical remission after a further 12-month period of treatment, defined as an HBI of ≤5, and safety. Other endpoints included steroid-free remission, mucosal healing (MH), steroid discontinuation, and the need for treatment optimization during the follow-up. Results: Out of 562 CD patients, after an overall 24-month follow-up, clinical remission was present in 450 (80.0%) patients, and at 12 months, clinical remission was observed in 417/437 (95.4%) patients; 33/125 (26.4%) showed clinical response at 12 months (p = 0.000). A total of 38/103 (36.9%) patients achieved MH. Only 2.1% (12/562), 3% (17/562), and 1.1% (6/562) of patients required surgery, optimization, and re-induction, respectively. Adverse events occurred in eight patients (1.42%). According to a multivariate analysis, the only predictor of long-term remission was the presence of remission at the 12-month follow-up (p = 0.000). Conclusions: Long-term treatment with UST presents good efficacy and safety profiles in CD patients, especially for patients who achieve remission after one year.