Daily oral administration of probiotics engineered to constantly secrete short-chain fatty acids effectively prevents myocardial injury from subsequent ischemic heart disease.

AIM: Given the extremely limited regeneration potential of the heart, one of the most effective strategies to reduce the prevalence and mortality of coronary artery disease is prevention. Short-chain fatty acids (SCFAs), which are by-products of beneficial probiotics, have been reported to possess cardioprotective effects. Despite their beneficial roles, delivering SCFAs and maintaining their effective concentration in plasma present major challenges. Therefore, in the present study, we aimed to devise a strategy to prevent coronary heart disease effectively by using engineered probiotics to continuously release SCFAs in vivo. METHODS AND RESULTS: We engineered a novel probiotic cocktail, EcN_TL, from the commercially available Escherichia coli Nissle 1917 strain to continuously secrete SCFAs by introducing the propionate and butyrate biosynthetic pathways. Oral administration of EcN_TL enhanced and maintained an effective concentration of SCFAs in the plasma. As a preventative strategy, we observed that daily intake of EcN_TL for 14 days prior to ischemia-reperfusion injury significantly reduced myocardial injury and improved cardiac performance compared to EcN administration. We uncovered that EcN_TL's protective mechanisms included reducing neutrophil infiltration into the infarct site and promoting the polarization of wound-healing macrophages. We further revealed that SCFAs at plasma concentration protected cardiomyocytes from inflammation by suppressing the NF-κB activation pathway. CONCLUSIONS: These data provide strong evidence to support the use of SCFA-secreting probiotics to prevent coronary heart disease. Since SCFAs also play a key role in other metabolic diseases, EcN_TL can potentially be used to treat a variety of other diseases.

The Gut-Heart Axis: Updated Review for The Roles of Microbiome in Cardiovascular Health.

Cardiovascular diseases (CVDs), including coronary artery disease, stroke, heart failure, and hypertension, are the global leading causes of death, accounting for more than 30% of deaths worldwide. Although the risk factors of CVDs have been well understood and various treatment and preventive measures have been established, the mortality rate and the financial burden of CVDs are expected to grow exponentially over time due to the changes in lifestyles and increasing life expectancies of the present generation. Recent advancements in metagenomics and metabolomics analysis have identified gut microbiome and its associated metabolites as potential risk factors for CVDs, suggesting the possibility of developing more effective novel therapeutic strategies against CVD. In addition, increasing evidence has demonstrated the alterations in the ratio of Firmicutes to Bacteroidetes and the imbalance of microbial-dependent metabolites, including short-chain fatty acids and trimethylamine N-oxide, play a crucial role in the pathogenesis of CVD. However, the exact mechanism of action remains undefined to this day. In this review, we focus on the compositional changes in the gut microbiome and its related metabolites in various CVDs. Moreover, the potential treatment and preventive strategies targeting the gut microbiome and its metabolites are discussed.

Core-Shell Droplet-Based Angiogenic Patches for the Treatment of Ischemic Diseases: Ultrafast Processability, Physical Tunability, and Controlled Delivery of an Angiogenic Cocktail.

The patch-based delivery system has been a promising therapeutic approach for treating various vascular diseases. However, conventional methods face several challenges, including labor-intensive and time-consuming processes associated with patch fabrication or factor incorporation, inadequate physical properties, and uncontrolled release of factors. These limitations restrict the potential applications in clinical settings. To overcome these issues, we propose a novel core-shell-shaped droplet patch system called an angiogenic patch (AP). Our system offers several distinct advantages over conventional patches. It enables a rapid and straightforward fabrication process utilizing only two biodegradable ingredients [alginate and ε-poly(l-lysine)], ensuring minimal toxicity. Moreover, the AP exhibits excellent physical integrity to match and withstand physiological mechanics and allows for customizable patch dimensions tailored to individual patients' pathological conditions. Notably, the AP enables facile loading of angiogenic cytokines during patch fabrication, allowing sustained release at a controlled rate through tunable network cross-linking. Subsequently, the AP, delivering a precisely formulated cocktail of angiogenic cytokines (VEGF, bFGF, EGF, and IGF), demonstrated significant effects on endothelial cell functions (migration and tubule formation) and survival under pathological conditions simulating ischemic injury. Likewise, in in vivo experiments using a mouse model of hindlimb ischemia, the AP encapsulating the angiogenic cocktail effectively restored blood flow following an ischemic insult, promoting muscle regeneration and preventing limb loss. With its simplicity and rapid processability, user-friendly applicability, physical tunability, and the ability to efficiently load and control the delivery of angiogenic factors, the AP holds great promise as a therapeutic means for treating patients with ischemic diseases.

Challenges and Limitations of Strategies to Promote Therapeutic Potential of Human Mesenchymal Stem Cells for Cell-Based Cardiac Repair.

Mesenchymal stem cells (MSCs) represent a population of adult stem cells residing in many tissues, mainly bone marrow, adipose tissue, and umbilical cord. Due to the safety and availability of standard procedures and protocols for isolation, culturing, and characterization of these cells, MSCs have emerged as one of the most promising sources for cell-based cardiac regenerative therapy. Once transplanted into a damaged heart, MSCs release paracrine factors that nurture the injured area, prevent further adverse cardiac remodeling, and mediate tissue repair along with vasculature. Numerous preclinical studies applying MSCs have provided significant benefits following myocardial infarction. Despite promising results from preclinical studies using animal models, MSCs are not up to the mark for human clinical trials. As a result, various approaches have been considered to promote the therapeutic potency of MSCs, such as genetic engineering, physical treatments, growth factor, and pharmacological agents. Each strategy has targeted one or multi-potentials of MSCs. In this review, we will describe diverse approaches that have been developed to promote the therapeutic potential of MSCs for cardiac regenerative therapy. Particularly, we will discuss major characteristics of individual strategy to enhance therapeutic efficacy of MSCs including scientific principles, advantages, limitations, and improving factors. This article also will briefly introduce recent novel approaches that MSCs enhanced therapeutic potentials of other cells for cardiac repair.