Microbiota γ‐Butyrobetaine Is Associated With Increased Risk of Major Adverse Limb Events in People With Lower Extremity Arterial Disease Undergoing Endovascular Therapy

Aug 18, 2025Journal of the American Heart Association

Higher Levels of Gut Microbe Chemical γ-Butyrobetaine Linked to Greater Risk of Serious Limb Problems in People with Leg Artery Disease Having Endovascular Treatment

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Abstract

In a study of 395 patients with peripheral artery disease, 22.5% experienced major adverse limb events.

Serum γ-butyrobetaine was significantly associated with major adverse limb events, with a hazard ratio of 1.93.
The study indicated that higher levels of γ-butyrobetaine could predict an increased risk of lower-limb revascularization and amputation.
In contrast, no significant association was found between trimethylamine-oxide (TMAO) levels and the risk of major adverse limb events.
Patients were followed for an average of 1.5 years, and other factors were adjusted for in the analysis.

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BACKGROUND: Peripheral artery disease (PAD), a significant contributor to both acute and chronic illnesses, indicates a grave prognosis, but it is often unrecognized and receives inadequate treatment. γ-Butyrobetaine, formed during gut microbial metabolism of L-carnitine, acts as a proatherogenic intermediate in the production of trimethylamine-oxide (TMAO). While TMAO has been linked to a heightened risk of cardiovascular mortality of individuals with PAD, the impact of γ-butyrobetaine remains unclear. The objective of this study was to examine the prognostic value of serum γ-butyrobetaine for patients with PAD. N

METHODS: We prospectively enrolled 395 patients with symptomatic PAD. Comprehensive medical histories, encompassing demographic and medication data, were collected, and serum biochemistry data, including TMAO and γ-butyrobetaine, were obtained. These patients, with a mean age of 72.2 years (61% men), were followed for an average of 1.5 years. They were categorized into 2 groups: 165 patients with intermittent claudication and 230 patients with critical limb-threatening ischemia. The primary outcome studied was major adverse limb events (MALE), which included lower-limb revascularization and amputation. MALE developed in 89 (22.5%) patients. Following adjustment for confounding factors in the multivariate Cox proportional hazards model, γ-butyrobetaine was significantly associated with MALE (hazard ratio, 1.93 [95% CI, 1.35-2.76]). By contrast, TMAO did not show a significant association with the risk of MALE.

CONCLUSIONS: While both TMAO and γ-butyrobetaine were linked to increased major adverse cardiovascular events in patients with PAD, only γ-butyrobetaine was associated with an elevated risk of MALE.

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Microbiota γ‐Butyrobetaine Is Associated With Increased Risk of Major Adverse Limb Events in People With Lower Extremity Arterial Disease Undergoing Endovascular Therapy

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