Reprogramming Effects of Postbiotic Butyrate and Propionate on Maternal High-Fructose Diet-Induced Offspring Hypertension

Abstract

Maternal nutrition has a key role in the developmental programming of adult disease. Excessive maternal fructose intake contributes to offspring hypertension. Newly discovered evidence supports the idea that early-life gut microbiota are connected to hypertension later in life. Short-chain fatty acids (SCFAs), butyrate, and propionate are microbiota-derived metabolites, also known as postbiotics. The present study aimed to determine whether maternal butyrate or propionate supplementation can protect offspring from hypertension using a maternal high-fructose (HF) diet rat model. Female Sprague Dawley rats were allocated during pregnancy and lactation to (1) regular chow (ND); (2) 60% high-fructose diet (HF); (3) HF diet plus butyrate (HFB, 400 mg/kg/day); and (4) HF diet plus propionate (HFP, 200 mmol/L). Male offspring were sacrificed at 12 weeks of age. The maternal HF diet impaired the offspring’s BP, which was prevented by perinatal butyrate or propionate supplementation. Both butyrate and propionate treatments similarly increased plasma concentrations of propionic acid, isobutyric acid, and valeric acid in adult offspring. Butyrate supplementation had a more profound impact on trimethylamine N-oxide metabolism and nitric oxide parameters. Whilst propionate treatment mainly influenced gut microbiota composition, it directly altered the abundance of genera Anaerovorax, Lactobacillus, Macellibacteroides, and Rothia. Our results shed new light on targeting gut microbiota through the use of postbiotics to prevent maternal HF intake-primed hypertension, a finding worthy of clinical translation.

The NOS/NO System in Renal Programming and Reprogramming

“…Studies have applied various nutrients or diets to determine their impact on renal programming. A variety of nutritional insults can be clustered into diverse animal models that aim to limit calorie intake [ 90 , 91 , 92 ], limit protein intake [ 98 ], induce the insufficient intake of zinc [ 89 ] or iron [ 103 ], and increase the feeding of a diet with a high level of fructose [ 83 , 95 ] or fat [ 101 , 102 ]. Another aspect interfering with renal programming is maternal or fetal exposure to illness, such as diabetes [ 86 ], preeclampsia [ 81 , 93 , 94 ], CKD [ 97 ], and solitary kidneys [ 104 ].…”

“…Several NOS/NO-associated mechanisms participate in renal programming, including reduced L-arginine concentration [ 83 , 95 , 96 , 101 ], reduced L-arginine-to-ADMA ratios [ 81 , 84 , 89 , 90 , 91 , 93 , 94 , 95 , 99 ], reduced renal eNOS protein levels [ 98 , 100 ], reduced renal NOS activity [ 89 ], reduced urinary NOx levels [ 90 , 98 , 104 ], reduced urinary cGMP levels [ 81 , 94 ], reduced renal NO production [ 103 ], and increased ADMA [ 83 , 86 , 91 , 92 , 93 , 95 , 97 , 99 , 102 ] and SDMA [ 102 ]. These observations support the notion that NO deficiency is attributed to multiple mechanisms and is involved in the pathogenesis of renal programming.…”

“…In regard to renal programming, it should be noted that a diverse range of phenotypes has been reported, including reduced nephron number [ 87 ], glomerular hypertrophy [ 89 , 91 , 92 , 103 ], elevated blood pressure [ 81 , 86 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 103 , 104 , 105 ], reduced glomerular filtration rate (GFR) [ 90 , 104 ], tubulointerstitial injury [ 86 , 91 , 92 ], increased renal NHE3 protein levels [ 81 , 94 ], altered renal transcriptomes [ 81 , 94 , 100 ], increased plasma Cr concentration [ 94 , 100 ], and renal hypertrophy [ 97 , 99 ].…”

“…Additionally, maternal dimethyl fumarate treatment, a known activator of nuclear factor erythroid-derived 2-related factor 2 (Nrf2), prevents two-hit-induced programmed hypertension in male offspring, which has been associated with a reduction in ADMA [ 112 ]. Moreover, maternal butyrate supplementation reduced ADMA and prevented offspring hypertensions induced by concurrent maternal high-fructose consumption [ 95 ]. Another study showed that garlic oil supplementation during pregnancy and lactation prevented maternal CKD-induced offspring hypertension and that it was also relevant to a reduction in ADMA [ 108 ].…”

Nutrition and Supplements during Pregnancy: A Vital Component in Building the Health and Well-Being of Both the Mother and the Developing Baby

“…These short-chain fatty acids are commonly produced as metabolites by gut microbiota. Research conducted in rats indicates that supplementing with butyrate and propionate during pregnancy and lactation prevented hypertension in offspring that may arise due to maternal high-fructose intake during pregnancy [10]. This highlights early life postbiotic supplementation as a potential strategy for enhancing the health status of both mothers and their children.…”