Hypertension Programmed by Perinatal High-Fat Diet: Effect of Maternal Gut Microbiota-Targeted Therapy

Abstract

Hypertension can originate in early life caused by perinatal high-fat (HF) consumption. Gut microbiota and their metabolites short chain fatty acids (SCFAs), trimethylamine (TMA), and trimethylamine N-oxide (TMAO) are involved in the development of hypertension. Despite the beneficial effects of prebiotic/probiotic on human health, little is known whether maternal use of prebiotics/probiotics could protect offspring against the development of hypertension in adulthood. We investigated whether perinatal HF diet-induced programmed hypertension in adult offspring can be prevented by therapeutic uses of prebiotic inulin or probiotic Lactobacillus casei during gestation and lactation. Pregnant Sprague–Dawley rats received regular chow or HF diet (D12331, Research Diets), with 5% w/w long chain inulin (PRE), or 2 × 108 CFU/day Lactobacillus casei via oral gavage (PRO) during pregnancy and lactation. Male offspring (n = 8/group) were assigned to four groups: control, HF, PRE, and PRO. Rats were sacrificed at 16 weeks of age. Maternal prebiotic or probiotic therapy prevents elevated blood pressure (BP) programmed by perinatal HF consumption. Both prebiotic and probiotic therapies decreased the Firmicutes to Bacteroidetes ratio and renal mRNA expression of Ace, but increased abundance of genus Lactobacillus and Akkermansia. Additionally, prebiotic treatment prevents HF-induced elevation of BP is associated with reduced fecal propionate and acetate levels, while probiotic therapy restored several Lactobacillus species. Maternal probiotic or prebiotic therapy caused a reduction in plasma TMAO level and TMAO-to-TMA ratio. The beneficial effects of prebiotic or probiotic therapy on elevated BP programmed by perinatal HF diet are relevant to alterations of microbial populations, modulation of microbial-derived metabolites, and mediation of the renin-angiotensin system. Our results cast a new light on the use of maternal prebiotic/probiotic therapy to prevent hypertension programmed by perinatal HF consumption. The possibility of applying gut microbiota-targeted therapies as a reprogramming strategy for hypertension warrants further clinical translation.

Maternal Adenine-Induced Chronic Kidney Disease Programs Hypertension in Adult Male Rat Offspring: Implications of Nitric Oxide and Gut Microbiome Derived Metabolites

“…We analyzed plasma levels of TMAO, TMA (the precursor of TMAO), and dimethylamine (DMA, the metabolite of TMAO and TMA) by LC–MS/MS analysis using an Agilent 6410 Series Triple Quadrupole mass spectrometer (Agilent Technologies, Wilmington, DE, USA) equipped with an electrospray ionization source, as described previously [ 14 ]. We used diethylamine as an internal standard.…”

“…Plasma and fecal acetate, propionate, and butyrate levels were measured using gas chromatography-mass spectrometry (GCMS-QP2010; Shimadzu, Kyoto, Japan) with flame ionization detector (FID). According to our validated protocol [ 14 ], dry air, nitrogen, and hydrogen were supplied to the FID at 300, 20, and 30 mL/min, respectively. An aliquot of 2 µL sample was injected into the column.…”

“…Frozen fecal samples were analyzed with metagenomics focused on the V3-V4 of the 16S DNA gene. As described previously [ 14 ], all polymerase chain reaction amplicons were mixed together with the Biotools Co., Ltd. (Taipei, Taiwan) for sequencing using an Illumina Miseq platform (Illumina, CA, USA). The sequences were analyzed using QIIME version 1.9.1.…”

“…We previously reported that offspring hypertension programmed by various maternal insults is related to NO deficiency [ 13 ], alterations of gut microbiota composition and microbial metabolite TMAO [ 14 ], and dysregulation of the RAS [ 15 ], all of which are decisive mechanisms underlying hypertension. However, whether the above-mentioned mechanisms interconnect to maternal CKD-induced offspring hypertension and kidney disease of developmental origins is still largely unknown.…”

Maternal N-Acetylcysteine Therapy Prevents Hypertension in Spontaneously Hypertensive Rat Offspring: Implications of Hydrogen Sulfide-Generating Pathway and Gut Microbiota

“…Bacterial DNA from frozen stool specimens was extracted and analyzed with metagenomics focused on the V3-V4 of the 16S DNA gene, as described previously [35]. The amplicons were sequenced on an Illumina MiSeq sequencer (Illumina, CA, USA) at the Genomic and Proteomic Core Laboratory, Kaohsiung Chang Gung Memorial Hospital (Kaohsiung, Taiwan).…”