New research reveals how intermittent fasting alters gut bacteria to boost levels of a key metabolite, reducing the risk of deadly blood clots and heart attacks. Could fasting be the key to a healthier heart?
Study: Intermittent fasting inhibits platelet activation and thrombosis through the intestinal metabolite indole-3-propionate. Image Credit: Shutterstock AI Generator / Shutterstock.com
A recent study published in the journal Life Metabolism determines the effect of intermittent fasting (IF) on platelet activation.
What causes cardiovascular disease?
Cardiovascular disease (CVD) is responsible for over 20 million deaths annually, most of which are due to heart attacks or strokes caused by blocked arteries. Risk factors for CVDs include atherosclerosis, high blood cholesterol fractions, and increased blood glucose levels. Each of these risk factors increases platelet aggregation, which subsequently worsens the risk of arterial thrombosis and CVD.
Despite the widespread availability of antiplatelet drugs, heart attacks caused by platelet-triggered coronary vessel clots persist in many patients taking these medications.
Lifestyle choices to mitigate CVD risk include following certain dietary patterns, such as IF, which can involve reducing energy intake by 60% two days a week or on alternate days. IF has been reported to reduce adverse outcomes in patients with diabetes, high cholesterol levels, cancer, Alzheimer’s disease, and aging-related deterioration in health.
Intermittent fasting improves cardiovascular health by reducing blood pressure, cholesterol, and insulin resistance. The current study investigated the effect of IF on the gut microbiota and their metabolites, which may impact platelet-related processes.
About the study
The current study included coronary artery disease (CAD) patients treated with aspirin who were randomly assigned to either the IF or ad libitum (AL) groups. The IF group was advised to fast every second day and consume an AL diet on alternating days. Platelets were isolated from blood samples collected before and after the 10-day experiment.
In vivo studies were also conducted with mice with the apolipoprotein E (ApoE) gene randomly assigned to the AL or IF groups. The IF group was not offered food every second day during the fasting period.
IF reduces platelet activation and thrombosis risk
IF was found to inhibit both platelet activation and thrombus formation in humans and mice.
Spectrometric assessment of the gut microbiota identified high levels of orotate and indole-3-propionic acid (IPA) in the IF group. Since orotate did not affect platelet activation, IPA was further investigated.
In vivo and in vitro experiments demonstrated that IPA treatment inhibits platelet activation and time to thrombin formation, which is comparable to the antithrombotic efficacy of 5 mg/kg of clopidogrel, a commonly prescribed antithrombotic drug. In fact, the combination treatment of IPA and clopidogrel had a synergistic effect on preventing the formation of thrombi.
Platelet activation was reduced in patients with coronary atherosclerosis or CAD following ten days of IF as compared to AL or unrestricted feeding. Platelet aggregation was inversely correlated with blood IPA levels, further supporting the role of IPA in platelet inhibition.
IPA binds to the platelet pregnane X receptor (PXR), which subsequently inhibits downstream platelet-activating pathways like the Src/Lyn/Syk pathway that prevent thrombus formation. Blocking Src, Syk, phosphoinositide phospholipase C (PLCγ), protein kinase C (PKC), and calcium channels led to a significant rise in IPA-induced platelet aggregation, which confirms the role of PXR-related signaling pathways in IPA's ability to suppress platelet activation.
The role of the gut microbiota
IPA is primarily produced by the Clostridium sporogenes, a gram-positive gastrointestinal (GI) bacterium. Mice treated with C. sporogenes exhibited higher IPA levels in their GI systems, plasma, and platelets, which correlated with a significantly lower platelet aggregation ratio and prolonged thrombus time as compared to control-treated mice.
IF was found to increase gastrointestinal levels of C. sporogenes. Comparatively, antibiotic treatment led to increased platelet aggregation in IF mice.
IPA derived from C. sporogenes may mediate the beneficial effects of IF through inhibiting platelet activation and thrombus formation.”
Conclusions
IF likely reduces platelet activation and arterial clot formation, thus indicating that this dietary pattern improves cardiovascular health by altering gut microflora, which leads to higher serum IPA levels. This activity was mediated by IPA-PXR binding, which led to downstream effects that suppressed platelet activation.
Taken together, the study findings indicate that IF has the potential to treat patients with coronary atherosclerosis by suppressing platelet activation and clot formation within their coronary arteries. Nevertheless, additional clinical studies are needed to validate these findings and inferences.
Journal reference:
- Qi, Z., Zhou, L., Dai, S., et al. (2025). Intermittent fasting inhibits platelet activation and thrombosis through the intestinal metabolite indole-3-propionate. Life Metabolism. doi:10.1093/lifemeta/loaf002.