Gut microbiota-derived metabolite trimethylamine N-oxide in major adverse cardiovascular events: Mechanisms, risk assessment, and therapeutic strategies

Table 1 Evidence on interventions for trimethylamine N-oxide modification

Ref.	Intervention	Mechanism	Sample type	Duration	Population	Results
Specific diets and foods
Argyridou et al[191], 2021	Vegan	Reduces dietary precursors	Plasma	8 weeks	Overweight patients over 18 years of age with untreated HbA1c ≥ 5.7% and ≤ 8%	TMAO decrease
Diao et al[211], 2024	DASH	GM remodeling and concurrent lowering LPS	Plasma	12 weeks	Overweight and obese, ages 20-55 years	TMAO decrease; Firmicutes/Bacteroidetes ratio decrease
Hernández-Alonso et al[190], 2017	Pistachios (57 g/day)	Modulation of GM related metabolism chronic pistachio intake	Urinary	15 days	BMI ≤ 35 kg/m2 and glucose levels between 100 and 125 mg/dL, ages 25-65 years	TMAO decrease
Haas et al[214], 2022	Red wine 250 mL/day	Redox homeostasis	Plasma	3 weeks	CAD, average age 60 years	TMAO (ns)
Thomas et al[192], 2022	Consume three eggs per day (400 mg/day)	Dietary choline (phosphatidylcholine), influences GM-dependent TMA generation	Plasma	4 weeks	MetS, ages 35-70 years	TMAO (-); antioxidants increase
Angiletta et al[188], 2018	Cocoa drink (28 g) and green tea (1.2 g)	Nutritionally relevant flavonol doses could reduce TMAO production	Plasma	5 days	Obesity and risk of insulin resistance, ages 25-55 years	TMAO (-)
Bergeron et al[222], 2016	CHO and resistant starches	GM remodeling and CHO diet-GM interaction influence TMAO production, not simply precursor intake	Plasma	56 days	Men > 20 years and postmenopausal women, BMI ≥ 20 and ≤ 35 kg/m2	TMAO increase
Prebiotics
Baugh et al[189], 2018	Inulin 10 g/day added to a standardized diet	Modulate GM and thereby reduce microbial TMA production	Plasma	6 weeks	Sedentary overweight/obese adults elevated risk for T2DM	TMAO (ns); TMA moieties (ns)
Probiotics
Malik et al[216], 2018	Lactobacillus plantarum 299v (20 billion CFU once daily)	Changes in GM derived metabolites (not TMAO)	Plasma	6 weeks	History of stable CAD, age 40-75 years	TMAO (-); propionate increase; acetate decrease; Lactobacillus in stool increase; endothelial function increase
Spasova et al[215], 2024	Lactobacillus plantarum GLP3 (1 × 109 CFU)	GM modulation (increase in Lactobacillus spp.) with plausible contribution from prebiotic and polyphenol	Plasma	12 weeks	History of CAD, age 58.5 ± 8.16 years	TMAO decrease
Tripolt et al[217], 2015	Lactobacillus casei Shirota (6.5 × 109 CFU 3 ×/day)	GM modulation could alter microbial TMA-formation	Plasma	12 weeks	MetS, age 52 ± 11 years	TMAO (ns)
Awoyemi et al[224], 2021	Saccharomyces boulardii 250 mg capsules twice daily and rifaximin 550 mg orally twice daily	GM modulation affects composition and function reducing microbial-linked metabolites (TMAO)	Plasma	3 months	HFrEF and NYHA functional class II or III, average age 60 years	TMAO (-)
Other interventions
Smits et al[200], 2018	Vegan donor FMT (autologous)	GM replacement strategy to reduce GM conversion of choline/carnitine to TMA	Plasma	2 weeks	MetS, no history of CVD, aged 21-69 years	TMAO decrease
Bestavashvili et al[187], 2023	IHHE (total 15 sessions)	Hypoxic conditioning antioxidant/anti-inflammatory signaling and improving gut-liver axis	Stool and plasma	3 weeks	MetS, age 29-74 years	TMAO (ns)

DASH: Dietary Approaches to Stop Hypertension; CHO: Carbohydrate; CFU: Colony forming unit; FMT: Fecal microbiota transplantation; IHHE: Intermittent hypoxia-hyperoxia exposure; GM: Gut microbiome; LPS: Lipopolysaccharide; TMA: Trimethylamine; TMAO: Trimethylamine N-oxide; HbA1c: Glycated hemoglobin; BMI: Body mass index; CAD: Coronary artery disease; MetS: Metabolic syndrome; T2DM: Type 2 diabetes mellitus; HFrEF: Heart failure with reduced ejection fraction; NYHA: New York Heart Association; CVD: Cardiovascular diseases; ns: Not significant.