Proton pump inhibitors (PPIs) are among the most widely used drugs in clinical practice. Although generally effective and well tolerated, their widespread and frequently prolonged use has raised concerns about both gastrointestinal and systemic adverse effects. Some of these effects may be directly or indirectly mediated by proton-pump-inhibitor-induced alterations of the gut microbiota. Proton pump inhibitors can reshape gastrointestinal microbial communities through multiple mechanisms, including gastric acid suppression, impaired barrier function, and modulation of the immune and metabolic pathways. The resulting dysbiosis promotes oral-to-gut microbial translocation, reduces microbial diversity, and favors the expansion of potentially pathogenic taxa. These alterations have been associated with several gastrointestinal disorders such as small intestinal bacterial overgrowth, enteric infections, and disturbances of the gut–liver axis, while emerging evidence suggests broader implications for carcinogenesis and the response to immune checkpoint inhibitors. In this context, microbiota-modulating interventions, including probiotics, may provide clinical benefits; however, the current evidence remains limited and inconsistent, precluding their routine use. By integrating mechanistic and clinical evidence, this review aims to clarify the role of the gut microbiota in proton-pump-inhibitor-related adverse effects and to assess the potential of microbiota-targeted strategies to mitigate their clinical consequences.

Colorectal cancer (CRC) remains a major global health burden, and early detection through population-based screening programs significantly reduces both incidence and mortality. Although gut microbiome-based biomarkers have emerged as promising non-invasive tools for CRC detection, limited evidence is available regarding patient acceptance and compliance with microbiome-based screening studies, factors that may influence their future implementation in clinical practice. We conducted a preliminary analysis of an ongoing multicenter, prospective observational study designed to develop a gut microbiome-based diagnostic tool for CRC and advanced colorectal adenomas in fecal immunochemical test (FIT)-positive individuals. The primary objective of this preliminary analysis was to evaluate patient acceptance and compliance with participation in a microbiome-based study within an organized CRC screening setting. Secondary objectives included describing the clinical, endoscopic, and histopathological characteristics of the enrolled cohort. FIT-positive individuals referred for screening colonoscopy at participating Italian centers were screened for eligibility, underwent colonoscopy, and were invited to provide a stool sample for microbiome analysis. A total of 315 individuals were screened, of whom 212 (67%) were enrolled. Among eligible patients, 90% agreed to enroll after receiving study information. Overall, 200 (94%) of enrolled individuals completed the required study activities, including stool sample collection and colonoscopy, indicating high compliance with study procedures. Colonoscopy was performed in 209 patients (99% of enrolled patients). CRC was detected in 7 patients (3%), and advanced colorectal adenomas in 39 (18%), while 86 (41%) colonoscopies were negative. The positive predictive value of FIT was 3.35% for CRC and 18.66% for advanced adenomas. In our preliminary analysis, patient acceptance and compliance with microbiome-based sampling were high among FIT-positive individuals undergoing CRC screening. These findings support the feasibility of conducting microbiome-based studies within organized screening programs. Analyses aimed at developing and validating the microbiome-based diagnostic tool are currently ongoing and are beyond the scope of the present report.