Impact of Chronic Constipation and Subtypes on Serum Trimethylamine-N-oxide Levels and Their Reduction with Treatment: Multicenter Observational Study

BACKGROUND: Chronic constipation (CC) is associated with increased cardiovascular events, and trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, has been recently shown to correlate with this risk. We examined how constipation status affects serum TMAO and how treatment modifies it. METHODS: This prospective observational study (July 2023-September 2024), conducted at three Japanese centers. Healthy controls (HCs) were recruited during health checkups, and patients with CC recruited from outpatient clinics. Serum TMAO was measured using liquid chromatography-tandem mass spectrometry at baseline and at 4 and 12 weeks after treatment with magnesium oxide (MgO) or elobixibat. CC was classified as normal transit constipation (NTC) or slow-transit constipation (STC) by colonic transit time. RESULTS: Overall, 72 HCs and 165 patients with CC (NTC, n = 110; STC, n = 55) were included. Mean serum TMAO levels were 1.8 [± 1.1] µM and 9.0 [± 8.1] µM in the HC and CC groups, respectively (p<0.01). Serum TMAO levels were significantly higher in the STC group than in the NTC group (p<0.01). Constipation treatment reduced serum TMAO levels to 5.5 ± 7.6 µM (n = 165, p<0.01) at 4weeks and 4.5 ± 7.6 µM (n = 165, p<0.01) at 12 weeks. Elobixibat lowered serum TMAO at 4 and 12 weeks in both NTC and STC. Conversely, MgO lowered TMAO only at 12 weeks in NTC and did not affect STC. CONCLUSIONS: Constipation status, particularly STC, is associated with elevated serum TMAO levels. MgO or elobixibat significantly reduced serum TMAO, with a greater reduction observed with elobixibat.