# Lachnospiraceae‐Derived Extracellular Vesicles Mediate the Cardioprotective Effects of Barley Leaf in Myocardial Infarction by Improving Intestinal Stem Cell Function

## TL;DR

Barley leaf protects the heart after a heart attack by improving gut health through Lachnospiraceae bacteria-derived extracellular vesicles.

## Contribution

The study identifies Lachnospiraceae-derived extracellular vesicles as mediators of barley leaf's cardioprotective effects via modulation of gut stem cell function.

## Key findings

- Barley leaf supplementation improves cardiac function and reduces adverse remodelling after myocardial infarction.
- Lachnospiraceae-derived extracellular vesicles enhance gut barrier function and protect the heart through estrogen-like metabolites.
- Supplementing with live Lachnospiraceae, but not heat-inactivated, reduces myocardial injury in mice.

## Abstract

Ischaemic cardiovascular diseases, particularly myocardial infarction (MI), remain the leading causes of morbidity and mortality worldwide. Targeting extracellular vesicles (EVs) from the gut microbiota by diet may provide opportunities to improve cardiovascular health. Barley leaf (BL) has a long history of use in Traditional Chinese medicine and has been found to beneficially influence the gut microbial composition. Herein, we used a murine model of MI to explore the mechanistic role of gut bacteria‐derived EVs in the cardioprotective effects of BL. Dietary supplementation of BL remarkably improved cardiac function and ameliorated adverse remodelling in experimental MI. The cardioprotective effects of BL were linked to enhanced gut epithelial barrier and suppressed transfer of bacterial‐derived lipopolysaccharide. Moreover, BL alleviated MI‐induced gut microbial dysbiosis, with an enrichment of Lachnospiraceae. Gut microbiota depletion by antibiotic treatment abolished the cardioprotective effects of BL. Furthermore, mice receiving microbiota from BL‐fed mice had better cardiac outcomes after MI compared to mice receiving microbiota from mice without BL supplementation. Notably, we identified that BL increased the abundance of Lachnospiraceae_NK4A136_group, a commensal member of the family Lachnospiraceae. Supplementing antibiotic‐treated mice with live but not heat‐inactivated Lachnospiraceae ameliorated myocardial injury and cardiac remodelling in MI mice. We isolated EVs from Lachnospiraceae and demonstrated that Lachnospiraceae‐derived EVs (L‐EVs) achieved desirable biosafety, stability and colonic retention effects following oral administration. Mechanistically, estrogen‐like metabolites from L‐EVs modulated the estrogen receptor alpha (ERα)‐solute carrier family 6 member 14 (Slc6a14)‐Hippo signalling pathway to promote intestinal stem cell function and ultimately protected against MI‐induced adverse remodelling. Our study thus provides novel insights into the role of the microbiota–gut–heart axis in the pathophysiology of MI and underscores the great potential of gut bacteria‐derived EVs to reduce pathological outcomes after MI through improving gut health.