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Immune checkpoint inhibitors (ICIs) have transformed the treatment of several malignancies, but their efficacy and gastrointestinal (GI) immune-related adverse events (irAEs) vary considerably among patients. Growing evidence suggests that the gut microbiota and intestinal barrier integrity are associated with both therapeutic response and toxicity, although their causal contribution and clinical utility remain incompletely defined. Dysbiosis may disrupt epithelial homeostasis, increase intestinal permeability, and promote mucosal immune activation, potentially influencing antitumor immunity and susceptibility to ICI-induced colitis. Current biomarkers of intestinal permeability are limited by their indirect nature, lack of standardization, or poor spatial resolution. Probe-based confocal laser endomicroscopy (pCLE) enables real-time, in vivo visualization of epithelial abnormalities associated with barrier dysfunction, including fluorescein leakage, epithelial gaps, and cell shedding. In parallel, dietary and microbiota-directed interventions are being investigated as potential strategies to modulate intestinal homeostasis during ICI therapy, although evidence for their clinical benefit and effects on intestinal barrier integrity remains limited. This review summarizes current evidence linking the gut microbiota, intestinal barrier dysfunction, and cancer immunotherapy and discusses the potential role of pCLE as a candidate functional imaging tool in ICI-treated patients. We highlight current knowledge gaps and propose a translational framework integrating pCLE with microbiome profiling, circulating biomarkers, histopathology, and clinical outcomes to determine whether this approach can improve patient stratification and the early identification and monitoring of GI toxicity.