S1612 Comparative Impact of Low-Dose Aspirin Alone vs Aspirin Plus Rifaximin on Colorectal Cancer Risk in Ulcerative Colitis With Dysplasia

Introduction: Ulcerative colitis (UC), an inflammatory bowel disease of the colon and rectum, affects about 5 million people worldwide. While the general population has a 10-year cumulative risk of colorectal carcinoma (CRC) of ∼0.44%, patients with ulcerative colitis with dysplasia have up to a 39-fold increase in risk. Aspirin has been shown to have efficacy in the chemoprevention of CRC; rifaximin, an antibacterial agent previously used in refractory UC, also has anti-CRC properties. This study seeks to investigate potential synergistic efficacy of these 2 drugs against CRC risk in patients with UC with dysplasia. Methods: We performed a retrospective cohort study using anonymized records from the TriNetX platform, comprising over 170 million patients across 145 healthcare organizations in 18 countries. We compared the 5-year CRC incidence in UC patients with dysplasia and refractory disease treated with 1) daily 81-mg aspirin alone or 2) daily 81-mg aspirin plus intermittent rifaximin (200–550 mg for 7–14 days, ≥3 cycles). Results: In the daily aspirin alone cohort (N = 1,869), 24 patients (1.28%) developed CRC, compared to 11 patients (0.54%) in the daily aspirin plus rifaximin cohort (N = 1,855). This represents a significant increase in CRC incidence for the aspirin-only group (P = 0.017). Patients taking aspirin alone had a 2.382-fold higher risk of CRC compared to those on combination therapy (95% CI, 1.14–4.97). Similarly, the odds of developing CRC were elevated in the aspirin-only group (OR, 2.4). Conclusion: This study demonstrates that adding rifaximin to low-dose aspirin therapy was associated with more than a 2-fold reduction in CRC risk. These findings suggest a synergistic effect between the 2 drugs. Aspirin acts through COX-2 inhibition, mitigating chronic inflammation and slowing dysplasia progression. Rifaximin significantly and concentration-dependently reduces cell proliferation and migration, downregulates VEGF secretion, nitric oxide release, and the expression of VEGFR-2, MMP-2, and MMP-9. Additionally, rifaximin inhibits phosphorylation of Akt, mTOR, and p38MAPK, and suppresses HIF-1α, p70S6K, and NF-κB signaling. It activates the pregnane X receptor (PXR), inhibiting pro-angiogenic pathways, and may help restore microbial homeostasis while suppressing pro-carcinogenic metabolites. Together, these complementary mechanisms may reduce inflammatory and microbial drivers of colitis-associated tumorigenesis, and therefore, warrant further exploration.