Resveratrol Butyrate Ester Protects Adenine-Treated Rats against Hypertension and Kidney Disease by Regulating the Gut–Kidney Axis

Abstract

Despite recent advances in pharma-nutritional management, chronic kidney disease (CKD) remains an increasingly prevalent disorder. Resveratrol, a pleiotropic phytochemical, has been found to reduce the risk for several chronic diseases. Considering the low bioavailability of resveratrol, we recently synthesized resveratrol butyrate ester (RBE) via the esterification of resveratrol with butyrate. The aim of this study was to examine the effectiveness of RBE as regards protection from hypertension and kidney damage and explore the underlying mechanisms using a young rat adenine-induced CKD model. Three-week-old male Sprague Dawley rats received regular or 0.5% adenine chow for three weeks. Three groups of adenine-fed CKD rats (N = 8/group) received resveratrol (50 mg/L), or a low dose (25 mg/L) or high dose (50 mg/L) of RBE in drinking water from week 6 to week 12. As compared with the controls, adenine-treated rats had markedly increased creatinine levels and blood pressure, which was associated with renal hypertrophy and decreased creatinine clearance. Treatment with resveratrol or a low or high dose of RBE, similarly protected adenine-fed rats against hypertension and kidney damage. CKD-induced hypertension is associated with an altered gut microbiota profile, dysregulated renal short chain fatty acid (SCFA) receptor expression, activation of the aryl hydrocarbon receptor (AhR) signaling pathway, and reduced nitric oxide bioavailability. We found gut microbiota compositions were shaped differentially by resveratrol and RBE treatment in adenine-treated CKD rats. The beneficial effect of high-dose RBE was associated with reduced renal expression of SCFA G protein-coupled receptor 41 (GPR41) and olfactory receptor 78 (Olfr78), antagonizing the AhR signaling pathway, and increased abundance of beneficial bacteria such as genera Akkermansia, Blautia, and Enterococcus. Our study provided the first evidence documenting RBE as a novel phytochemical supplement targeting the gut–kidney axis to protect against adenine-induced kidney damage and hypertension.

Chronic Kidney Disease and Gut Microbiota: What Is Their Connection in Early Life?

“…Here, we list in Table 2 a summary of studies documenting gut microbiota-targeted interventions in animal models of CKD of developmental origins and its comorbidities [ 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 ]. The therapeutic duration is during fetal and childhood stages.…”

“…Since the above-mentioned renal programming models have been established and linked to adverse renal outcomes in adult offspring, readers are referred to original references. There was only one study conducting an adenine-induced pediatric CKD model to determine the effects of probiotic resveratrol on CKD progression [ 106 ].…”

“…Although there are many prebiotic foods, only garlic oil has shown beneficial effects against high-fat diet-induced hypertension in adult progeny [ 106 ]. These effects include increased α-diversity, increased plasma levels of acetic acid, butyric acid, and propionic acid, and increased beneficial bacteria Lactobacillus and Bifidobacterium .…”

Novel Insights on Dietary Polyphenols for Prevention in Early-Life Origins of Hypertension: A Review Focusing on Preclinical Animal Models

“…In this regard, we improved the efficacy of resveratrol via esterification to form resveratrol butyrate ester [ 123 ]. Our data show that low-dose resveratrol butyrate ester (25 mg/L) is as effective as resveratrol (50 mg/L) in preventing CKD-induced hypertension [ 124 ]. Considering that polyphenol bioavailability is mainly determined by gut microbiota, it would be important to further evaluate how gut microbiota affects polyphenol bioavailability involved in protecting against hypertension of developmental origins.…”

The Pharma-Nutritional Role of Antioxidant Phytochemicals in Health and Disease

“…Resveratrol butyrate ester (RBE), which is a novel resveratrol-synthesized derivative, exhibits increased biological activity. Using a rat model of chronic kidney disease (CKD), Hsu et al provides the first evidence that RBE may protect against kidney damage and hypertension by regulating the gut–kidney axis [ 15 ].…”