Perianal fistulizing Crohn’s disease (pfCD) represents one of the most challenging manifestations of CD, often associated with severe phenotypes, refractory luminal inflammation, and a substantial reduction in quality of life. Its pathogenesis is multifactorial and incompletely understood, involving genetic susceptibility, epithelial and stromal dysfunction, and microbiome-related mechanisms. Diagnosis and monitoring rely on advanced imaging, while management requires coordinated medical–surgical strategies. Significant unmet needs persist regarding standardized treatment targets, optimal imaging follow-up, and personalized therapeutic pathways. In this review, we aim to summarise and provide a comprehensive overview of the most recent evidence across pathogenesis, diagnosis, classification systems, and therapeutic approaches in pfCD. We highlight key advances in understanding epithelial–mesenchymal transition, immune–microbiome interactions, and genetic determinants of disease behaviour. Improvements in diagnostic modalities—including MRI-based scores, ultrasound technologies, volumetric assessment, and AI-enhanced imaging—are discussed alongside modern classification systems such as TOPClass. Evidence guiding medical therapy, seton management, and surgical decision-making is reviewed, emphasising integrated, goal-oriented care. Despite substantial progress, pfCD remains a difficult-to-treat condition with persistent gaps in early diagnosis, objective monitoring, and individualized management. Emerging imaging technologies, standardized treatment targets, and structured classification frameworks offer promising strategies to overcome current limitations and improve long-term outcomes.

Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn’s disease (CD), are consistently associated with alterations in gut microbial communities, although the extent and characteristics of these alterations vary across studies, supporting a potential role of the microbiota in disease pathogenesis and therapeutic modulation. We conducted a systematic review to synthesize current evidence on microbiota alterations in IBD and the clinical application of fecal microbiota transplantation (FMT). A total of 118 studies were included (76 focused on microbiota profiling and 42 evaluated FMT as therapy). Across heterogeneous study designs and microbial characterization methods, reduced microbial diversity was the most consistently reported alteration, generally more pronounced in CD than in UC. Depletion of Faecalibacterium prausnitzii—a key butyrate producer with anti-inflammatory properties—was commonly reported, often accompanied by functional impairment in short-chain fatty acid production. Microbial patterns were frequently associated with mucosal inflammation and varied across disease phenotypes; these patterns have been increasingly explored as predictors of treatment response and relapse, although mechanistic interpretation remains limited and causal relationships are difficult to establish. Evidence from randomized controlled trials suggests potential efficacy of FMT in UC, particularly with intensive or repeated protocols, whereas data in CD remain limited and heterogeneous, with signals of benefit often appearing transient. FMT was generally well tolerated, but long-term safety data remain scarce. Emerging multi-omic approaches are reshaping the field by integrating taxonomic and functional insights, with potential implications for risk stratification, diagnosis, prognosis, and therapeutic optimization. Further standardized, longitudinal, and mechanistically oriented studies are required to translate microbiome research into clinically actionable strategies in IBD.