Sodium butyrate modulates blood pressure and gut microbiota in maternal tryptophan-free diet-induced hypertension rat offspring


Maternal nutrition, gut microbiome composition, and metabolites derived from gut microbiota are closely related to the development of hypertension in offspring. A plethora of metabolites generated from diverse tryptophan metabolic pathways show both beneficial and harmful effects. Butyrate, one of the short-chain fatty acids (SCFAs), has shown vasodilation effects. We examined whether sodium butyrate administration in pregnancy and lactation can prevent hypertension induced by a maternal tryptophan-free diet in adult progeny and explored the protective mechanisms. Pregnant Sprague–Dawley rats received normal chow (CN), tryptophan-free diet (TF), sodium butyrate 400 mg/kg/d in drinking water (CNSB), or TF diet plus sodium butyrate (TFSB) in pregnancy and lactation. Male offspring were sacrificed at the age of 16 weeks (n=8 per group). Compared with normal chow, offspring exposed to the maternal tryptophan-free diet had markedly increased blood pressure, associated with activation of the renin–angiotensin system (RAS). Treatment with sodium butyrate rescued maternal TF-exposed offspring from hypertension. The protective effect of sodium butyrate is related to alterations to microbiome composition, increased renal expression of SCFA receptor G protein-coupled receptor 41 (GPR41) and GPR109A, and restoration of RAS balance. In summary, these results suggest that sodium butyrate protects against maternal TF-induced offspring hypertension, likely by modulating gut microbiota, its derived metabolites, and the RAS.


Extensive data now highlight pregnancy and lactation as critical periods during which insults may shape health and disease in the resulting offspring, known as the Developmental Origins of Health and Disease (DOHaD) [1]. Maternal nutritional status is a significant determinant governing fetal development. Imbalances in maternal nutrition can adversely affect morphology and function of the fetus, leading to many adult diseases, including hypertension [2]. Considering that hypertension is highly prevalent all over the world [3], more attention should be paid to how to prevent the onset of hypertension instead of merely treating it. According to the DOHaD hypothesis, hypertension could be preventable by shifting interventions from adulthood to an earlier stage, referred to as reprogramming [4].

During pregnancy, low-protein diets or diets with certain amino acid deficiencies have been reported to program hypertension in offspring [5]. Tryptophan, a nutritionally essential amino acid, is indispensable during pregnancy for placental protein synthesis and fetal growth and development [6]. Prior research has demonstrated that maternal dietary tryptophan deficiency caused adverse offspring outcomes [7,8], but little is known about long-term effects of maternal tryptophan deficiency on offspring’s blood pressure (BP).

Maternal diet in pregnancy and lactation can shape the offspring gut microbiome, resulting in long-term consequences for the offspring [9]. Considering that the gut microbiome is critical for amino acid metabolism and certain functional amino acids that have beneficial effects on the gut-associated immune system [10,11], maternal tryptophan might impair gut microbiota and its derived metabolite production. Alterations of microbial metabolites such as short-chain fatty acids (SCFAs) and tryptophan-derived metabolites have been linked to the programming of hypertension [12,13]. Additionally, aberrant activation of the renin–angiotensin system (RAS) is a key mechanism behind the programming of hypertension [14].

Conversely, postbiotics are suggested to offer some health benefits as functional food supplements, including BP-lowering effects [15]. We previously demonstrated that maternal acetate supplementation protected offspring against hypertension programmed by a high-fructose diet [16]. Additionally, it has been recently found that alterations of SCFA receptors and the RAS components in the kidneys are involved in the pathogenesis of developmental programming of hypertension [17]. Considering that butyrate has shown vasodilation effects [18], we hypothesized that maternal butyrate treatment can afford protection for offspring rats against hypertension induced by a maternal tryptophan-deficient diet, with a focus on the kidneys.

Section snippets

Diet, animal care and experimental design

Virgin Sprague–Dawley (SD) rats were used at the beginning of study (8 weeks of age, purchased from BioLASCO Taiwan Co., Ltd., Taipei, Taiwan). On arrival, the rats were housed in our AAALAC full accreditation animal facility. Studies on rats were performed according to the rules of Care and Use of Laboratory Animals of the National Institutes of Health and the IACUC of Chang Gung Memorial Hospital (permit #2019050701; accession date: 04/11/2019).

Female rats were caged with male rats until

Body weight and blood pressure of male offspring

Table 2 shows there was no mortality in any group. The body weight (BW) of tryptophan-free diet (TF) and normal diet (CN) groups were divergent at 16 weeks old independently of sodium butyrate treatment. The kidney weight (KW) and the KW-to-BW ratio were lower in the TF and TFSB group compared to the CN group. The BP of rat offspring measured between week 4 and week 16 showed that the tryptophan-free diet caused a higher systolic BP (SBP) vs. controls, which was prevented by sodium butyrate


Our study affords new insights into the mechanisms behind maternal tryptophan deficiency-induced offspring hypertension, with specific emphasis on metabolites derived from gut microbes. The present study also highlights that sodium butyrate treatment during pregnancy and lactation protects TF diet-induced programmed hypertension, which is a postbiotics-based approach to mediate gut microbiota-derived metabolites. The major findings are as follows: (1) compared to dams fed a normal chow, adult…

Source: Author links open overlay panelChien-Ning Hsu a b, Hong-Ren Yu c, I-Chun Lin c, Mao-Meng Tiao c, Li-Tung Huang c, Chih-Yao Hou d, Guo-Ping Chang-Chien e f, Sufan Lin e f, You-Lin Tain c g

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