P0188Circulating Trimethylamine N-Oxide (TMAO) Is Associated With Fibrostenotic Complications of Crohn’s Disease

Abstract Background Trimethylamine N-oxide (TMAO) originates from dietary nutrients—including choline, phosphatidylcholine, and L-carnitine—that reach the gut. The gut microbiota convert these precursors into trimethylamine (TMA), which is then transported to the liver and oxidized to TMAO before entering the systemic circulation. Elevated levels of TMAO are an established risk factor for cardiovascular events1, and more recently have been linked to fibrosis in the kidneys and heart2. However, the association of TMAO with Crohn’s disease (CD) related fibrosis remains unexplored. Methods To investigate the association between TMAO and fibrotic complications in inflammatory bowel disease (IBD), using untargeted liquid chromatography and mass spectrometry, we measured plasma TMAO levels in blood samples collected from patients with UC and CD, and non-IBD controls. Medical records of CD patients were searched for clinical data and evidence of fibrostenotic complications, defined as any mention of stricture in imaging or endoscopy reports, or history of ileocecal resection, stricturoplasty, or endoscopic dilatation. Results TMAO plasma levels were analysed in 591 patients (267 CD, 144 UC, and 180 controls). Details of demographics and clinical characteristics are reported in Table 1. Circulating TMAO levels were significantly higher in patients with CD compared to patients with UC and non-IBD controls, suggesting a disease-specific association between TMAO and CD (Fig. A). Disease activity, defined as Harvey Bradshaw ≥4 or a Total Mayo Score ≥3, was associated with higher levels of TMAO in CD but not in UC (Fig. B). Importantly, in CD, TMAO levels were significantly higher in patients with fibrotic complications, irrespective of whether the complications occurred before (Fig. C) or after (Fig. D) sample collection, supporting that TMAO is increased in patients prone to fibrosis independently of disease “stage” and of the dysbiosis secondary to intestinal resection. Furthermore, TMAO’s concentration remained elevated in the years following surgery for stricturing disease to a level similar to that before resection (Fig. F). Additionally, TMAO was significantly lower in patients with perianal CD compared to patients with no perianal involvement (P = 0.02), and instead similar between patients on biologics and those not (P = 0.22). In multivariable regression analysis, TMAO was significantly associated with a history of fibrotic complications after accounting for potential confounders such as sex (male/female), race (white/non white), smoking (active/non-active), use of biologics, and perianal disease (Fig. E). Conclusion TMAO is associated with fibrostenotic CD, warranting further studies to clarify its causal role and potential value as a biomarker. References: 1. Tang et al. NEJM 2013 2. Jang et al. Mol Med 2024 Conflict of interest: Dr. Parigi, Tommaso Lorenzo: No conflict of interest Krevlin, Zoe: I have no conflicts of interest to disclose. De Santis, Stefania: Nothing to declare Nguyen, Vu: No conflict of interest Thamma, Kavitha: No conflict of interest Campiglia, Pietro: No conflict of interest Sommella, Eduardo Maria: No conflict of interest Cominelli, Fabio: No conflict of interest Pizarro, Theresa: None.