Protection by -Biotics against Hypertension Programmed by Maternal High Fructose Diet: Rectification of Dysregulated Expression of Short-Chain Fatty Acid Receptors in the Hypothalamic Paraventricular Nucleus of Adult Offspring

Abstract

The role of short-chain fatty acids (SCFAs) in the brain on the developmental programming of hypertension is poorly understood. The present study explored dysregulated tissue levels of SCFAs and expression of SCFA-sensing receptors in the hypothalamic paraventricular nucleus (PVN), a key forebrain region engaged in neural regulation of blood pressure of offspring to maternal high fructose diet (HFD) exposure. We further investigated the engagement of SCFA-sensing receptors in PVN in the beneficial effects of -biotics (prebiotic, probiotic, synbiotic, and postbiotic) on programmed hypertension. Maternal HFD during gestation and lactation significantly reduced circulating butyrate, along with decreased tissue level of butyrate and increased expression of SCFA-sensing receptors, GPR41 and olfr78, and tissue oxidative stress and neuroinflammation in PVN of HFD offspring that were rectified by oral supplement with -biotics. Gene silencing of GPR41 or olfr78 mRNA in PVN also protected adult HFD offspring from programmed hypertension and alleviated the induced oxidative stress and inflammation in PVN. In addition, oral supplement with postbiotic butyrate restored tissue butyrate levels, rectified expressions of GPR41 and olfr78 in PVN, and protected against programmed hypertension in adult HFD offspring. These data suggest that alterations in tissue butyrate level, expression of GPR41 and olfr78, and activation of SCFA-sensing receptor-dependent tissue oxidative stress and neuroinflammation in PVN could be novel mechanisms that underlie hypertension programmed by maternal HFD exposure in adult offspring. Furthermore, oral -biotics supplementation may exert beneficial effects on hypertension of developmental origin by targeting dysfunctional SCFA-sensing receptors in PVN to exert antioxidant and anti-inflammatory actions in the brain.

The Impact of Nutrient Intake and Metabolic Wastes during Pregnancy on Offspring Hypertension: Challenges and Future Opportunities

“…Various animal models have been established using insufficient or excessive intake of a specific nutrient during gestation and/or lactation to validate the associations between maternal malnutrition and offspring hypertension found in human observational studies. Here, we summarize current knowledge on maternal malnutrition-induced offspring hypertension in various rodent models ( Table 2 ) [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 ]. Considering that one rat month is comparable to three human years [ 56 ], the ages of rats developing hypertension are approximately equivalent to humans from childhood to old age.…”

“…On the other hand, over-nutrition arising from excessive intake of specific nutrients can lead to hypertension programming [ 58 ]. Feeding pregnant rats a diet high in sucrose or fructose induced hypertension in their offspring [ 41 , 42 , 43 , 44 , 45 , 46 ]. A maternal high-fructose diet not only caused hypertension, but also obesity, insulin resistance, and fatty liver [ 59 ].…”

Luteolin Attenuates Hypertension via Inhibiting NF-κB-Mediated Inflammation and PI3K/Akt Signaling Pathway in the Hypothalamic Paraventricular Nucleus

“…The basic reason is that the pathogenesis of this condition is not clearly elucidated. In recent years, more and more evidence support the crucial role played by the paraventricular nucleus of the hypothalamus (PVN) is important in the onset and progression of high blood pressure [ 4 , 5 ]. The PVN is a small bilateral structure located bilaterally around the third ventricle [ 5 ], which plays an important modulatory role in sympathetic and cardiovascular systems [ 6 , 7 ].…”

“…In recent years, more and more evidence support the crucial role played by the paraventricular nucleus of the hypothalamus (PVN) is important in the onset and progression of high blood pressure [ 4 , 5 ]. The PVN is a small bilateral structure located bilaterally around the third ventricle [ 5 ], which plays an important modulatory role in sympathetic and cardiovascular systems [ 6 , 7 ]. In hypertension, the hyperactivation of the sympathetic nerve is significantly principal to the changes of molecular signals within PVN.…”