Administration of N-Acyl-Phosphatidylethanolamine Expressing Bacteria to Low Density Lipoprotein Receptor−/− Mice Improves Indices of Cardiometabolic Disease

Abstract

Obesity increases the risk for cardiometabolic diseases. N-acyl phosphatidylethanolamines (NAPEs) are precursors of N-acylethanolamides, which are endogenous lipid satiety factors. Incorporating engineered bacteria expressing NAPEs into the gut microbiota retards development of diet induced obesity in wild-type mice. Because NAPEs can also exert anti-inflammatory effects, we hypothesized that administering NAPE-expressing bacteria to low-density lipoprotein receptor (Ldlr)−/− mice fed a Western diet would improve various indices of cardiometabolic disease manifested by these mice. NAPE-expressing E. coli Nissle 1917 (pNAPE-EcN), control Nissle 1917 (pEcN), or vehicle (veh) were given via drinking water to Ldlr−/− mice for 12 weeks. Compared to pEcN or veh treatment, pNAPE-EcN significantly reduced body weight and adiposity, hepatic triglycerides, fatty acid synthesis genes, and increased expression of fatty acid oxidation genes. pNAPE-EcN also significantly reduced markers for hepatic inflammation and early signs of fibrotic development. Serum cholesterol was reduced with pNAPE-EcN, but atherosclerotic lesion size showed only a non-significant trend for reduction. However, pNAPE-EcN treatment reduced lesion necrosis by 69% indicating an effect on preventing macrophage inflammatory death. Our results suggest that incorporation of NAPE expressing bacteria into the gut microbiota can potentially serve as an adjuvant therapy to retard development of cardiometabolic disease.

Molecular Mechanisms of Obesity-Linked Cardiac Dysfunction: An Up-Date on Current Knowledge

“…Troseid et al [ 114 ] described the association of TMAO with disease severity and survival of patients with chronic HF; the results showed an elevated plasma level of TMAO in patients ( n = 155) with chronic HF compared with the control group. Approximately 50% of patients with the highest levels of TMAO died or received a heart transplant during 5.2 years of follow-up [ 115 ].…”

The gut microbiota and its interactions with cardiovascular disease

“…Notably, a growing body of clinical evidence related to the prognostic value of TMAO shows that elevated circulating TMAO levels are associated with the presence of coronary plaque vulnerability and that circulating TMAO can directly contribute to enhanced risk for CVD‐related consequences (Li, et al , ; Qi, et al , ) (Table ). Other gut microbiota‐generated metabolites, such as BAs and butyrate, exhibit atheroprotective effects (Jones, et al , ; Brown and Hazen, ), whereas N ‐acyl phosphatidylethanolamines (NAPEs) have no significant effects on aortic lesion size but can markedly decrease the necrotic core area within atherosclerotic lesions (May‐Zhang, et al , ). These observations suggest the potential involvement of gut microbiota metabolism in the development of atherosclerosis.…”

“…However, another study reported that the Coriobacteriaceae family, which is involved in urolithin B production, is positively associated with total cholesterol and LDL levels and is a potential CVD risk biomarker (Romo‐Vaquero, et al , ). Other molecules, such as indoleamine 2,3‐dioxygenase, serotonin (5‐HT) and NAPEs, are also correlated with gut microbiota changes that alter lipid absorption or lipid metabolism, consequently linking the gut microbiota to cardiometabolic phenotypes (Laurans, et al , ; May‐Zhang, et al , ; Singhal, et al , ). Melatonin improves lipid metabolism, and the potential mechanism is related to gut microbiota reprogramming, especially with respect to Bacteroides‐ and Alistipes‐ mediated acetic acid production (Yin, et al , ).…”

Human Microbiome and Its Medical Applications

“…Administration of high NAPEs-producing engineered E. coli Nissle 1917 (pNAPE-EcN) successfully improved the obesity of wild-type mice. Furthermore, administration of pNAPE-EcN ameliorated obesity and atherosclerosis lesion necrosis in a mice model of atherosclerosis ( May-Zhang et al, 2019 ). These results demonstrate the potential of engineered microbes in treating metabolic diseases.…”