Incremental Diagnostic Value of Fecal Microbial Biomarkers Added to Quantitative Fecal Immunochemical Testing for Colorectal Neoplasia: A Systematic Review

Background: Quantitative fecal immunochemical testing (qFIT) is established for colorectal cancer (CRC) screening but has substantially lower sensitivity for advanced adenomas. Fecal microbial biomarkers may complement qFIT either as sensitivity-oriented add-on tests or as specificity-oriented triage tests, but these strategies address different clinical objectives. Methods: We conducted a PRISMA 2020-reported systematic review of primary studies in adults that directly compared a fecal microbial biomarker plus qFIT with qFIT alone for CRC, advanced adenoma, or advanced colorectal neoplasia (ACN), using colonoscopy with histopathology as the reference standard. Two reviewers independently screened records and extracted data. Risk of bias was assessed using QUADAS-2, with PROBAST principles applied to model-development concerns. Because test architecture, endpoints, thresholds, marker panels, validation stage, geography, and potential cohort overlap precluded a common clinically interpretable estimand, meta-analysis was not undertaken. Results: The search identified 980 records. After 310 pre-screen removals, 670 records were screened and 525 were excluded; 145 reports were sought for retrieval, 116 were not retrieved, 29 were assessed for eligibility, 16 were excluded, and 13 reports were included (12 full-text articles and one 2026 multicenter conference abstract). Sensitivity-oriented add-on strategies generally increased lesion detection, particularly for advanced adenoma: absolute sensitivity gains included 23.1 percentage points in Wong et al., 40.7 points in Liang et al. 2020, and 31.7 points in the asymptomatic cohort of Liang et al. 2021. In the prospective Asia-Pacific multicenter study, M3 plus FIT increased ACN sensitivity by 10.0 percentage points (95% CI 6.3–13.7; p<0.001), with combined specificity of 85.3% (95% CI 83.7–86.9). In specificity-oriented triage, Malagón et al. 2023 increased advanced-neoplasia specificity from 97.8% to 98.2% while sensitivity decreased from 21.8% to 17.5%. Overall risk of bias was high in 11 of 13 reports. Conclusions: Available evidence indicates that fecal microbial biomarkers may add diagnostic value to qFIT, particularly for detecting advanced adenomas missed by qFIT. The magnitude of incremental benefit remains uncertain because most reports were at high risk of bias and differed substantially in test architecture, thresholds, populations, assays, and validation stage. Prospective external validation of prespecified algorithms with complete paired classification data is required before routine clinical implementation.