Maternal 3,3-Dimethyl-1-Butanol Therapy Protects Adult Male Rat Offspring against Hypertension Programmed by Perinatal TCDD Exposure

Maternal exposure to environmental pollutants affects fetal development, which can result in hypertension in adulthood. Gut microbiota-derived metabolite trimethylamine (TMA), trimethylamine-N-oxide (TMAO), and short chain fatty acids (SCFAs) have been associated with hypertension. We tested a hypothesis that maternal 3,3-Dimethyl-1-butanol (DMB, a TMA inhibitor) therapy prevents 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure-induced hypertension in adult offspring relevant to alterations of gut microbiota-derived metabolites, the mediation of aryl hydrocarbon receptor (AHR) signaling, and the renin-angiotensin system (RAS). Pregnant Sprague-Dawley rats were given weekly oral dose of TCDD 200 ng/kg for four doses (T), 1% DMB in drinking water (D), TCDD + DMB (TD), or vehicle (C) in pregnancy and lactation periods. Male progeny (n = 8/group) were sacrificed at the age of 12 weeks. Perinatal TCDD exposure caused hypertension in adult male offspring coinciding with reduced α-diversity, increased the Firmicutes to Bacteroidetes ratio, less abundant beneficial bacteria, impaired SCFA receptors’ expression, the activation of AHR signaling, and the aberrant activation of the RAS. Treatment with DMB during pregnancy and lactation rescued hypertension induced by perinatal TCDD exposure. This was accompanied by reshaping gut microbiota, mediating TMA-TMAO metabolic pathway, increasing acetic acid and its receptors, and restoring the AHR and RAS pathway. Our data provide new insights into the therapeutic potential of DMB, a microbiome-based metabolite treatment, for the prevention of hypertension of developmental origins.

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

Nutrients ◽

10.3390/nu11122908 ◽

2019 ◽

Vol 11 (12) ◽

pp. 2908 ◽

Cited By ~ 8

Author(s):

Chien-Ning Hsu ◽

Chih-Yao Hou ◽

Julie Y.H. Chan ◽

Chien-Te Lee ◽

You-Lin Tain

Keyword(s):

Gut Microbiota ◽

Lactobacillus Casei ◽

Renin Angiotensin System ◽

Short Chain Fatty Acids ◽

Lactobacillus Species ◽

Sprague Dawley ◽

High Fat ◽

Beneficial Effects ◽

Therapeutic Uses ◽

Pregnancy And Lactation

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.

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Altered Gut Microbiota and Its Metabolites in Hypertension of Developmental Origins: Exploring Differences between Fructose and Antibiotics Exposure

International Journal of Molecular Sciences ◽

10.3390/ijms22052674 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2674

Author(s):

Chien-Ning Hsu ◽

Julie Y. H. Chan ◽

Kay L. H. Wu ◽

Hong-Ren Yu ◽

Wei-Chia Lee ◽

...

Keyword(s):

Gut Microbiota ◽

Negative Impact ◽

Short Chain Fatty Acids ◽

Normal Diet ◽

Male Offspring ◽

Sprague Dawley ◽

Minocycline Treatment ◽

High Fructose ◽

Induced Hypertension ◽

Pregnancy And Lactation

Gut microbiota-derived metabolites, in particular short chain fatty acids (SCFAs) and their receptors, are linked to hypertension. Fructose and antibiotics are commonly used worldwide, and they have a negative impact on the gut microbiota. Our previous study revealed that maternal high-fructose (HF) diet-induced hypertension in adult offspring is relevant to altered gut microbiome and its metabolites. We, therefore, intended to examine whether minocycline administration during pregnancy and lactation may further affect blood pressure (BP) programmed by maternal HF intake via mediating gut microbiota and SCFAs. Pregnant Sprague-Dawley rats received a normal diet or diet containing 60% fructose throughout pregnancy and lactation periods. Additionally, pregnant dams received minocycline (50 mg/kg/day) via oral gavage or a vehicle during pregnancy and lactation periods. Four groups of male offspring were studied (n = 8 per group): normal diet (ND), high-fructose diet (HF), normal diet + minocycline (NDM), and HF + minocycline (HFM). Male offspring were killed at 12 weeks of age. We observed that the HF diet and minocycline administration, both individually and together, causes the elevation of BP in adult male offspring, while there is no synergistic effect between them. Four groups displayed distinct enterotypes. Minocycline treatment leads to an increase in the F/B ratio, but decreased abundance of genera Lactobacillus, Ruminococcus, and Odoribacter. Additionally, minocycline treatment decreases plasma acetic acid and butyric acid levels. Hypertension programmed by maternal HF diet plus minocycline exposure is related to the increased expression of several SCFA receptors. Moreover, minocycline- and HF-induced hypertension, individually or together, is associated with the aberrant activation of the renin–angiotensin system (RAS). Conclusively, our results provide a new insight into the support of gut microbiota and its metabolite SCAFs in the developmental programming of hypertension and cast new light on the role of RAS in this process, which will help prevent hypertension programmed by maternal high-fructose and antibiotic exposure.

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The Role of Short-Chain Fatty Acids in Mediating Very Low-Calorie Ketogenic Diet-Infant Gut Microbiota Relationships and Its Therapeutic Potential in Obesity

Nutrients ◽

10.3390/nu13113702 ◽

2021 ◽

Vol 13 (11) ◽

pp. 3702

Author(s):

Naser A. Alsharairi

Keyword(s):

Gut Microbiota ◽

Ketogenic Diet ◽

Therapeutic Potential ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Protective Effects ◽

Low Calorie ◽

Pregnancy And Lactation ◽

Gut Microbiota Composition

As the very low-calorie ketogenic diet (VLCKD) gains increased interest as a therapeutic approach for many diseases, little is known about its therapeutic use in childhood obesity. Indeed, the role of VLCKD during pregnancy and lactation in influencing short chain fatty acid (SCFA)-producing bacteria and the potential mechanisms involved in the protective effects on obesity are still unclear. Infants are characterized by a diverse gut microbiota composition with higher abundance of SCFA-producing bacteria. Maternal VLCKD during pregnancy and lactation stimulates the growth of diverse species of SCFA-producing bacteria, which may induce epigenetic changes in infant obese gene expression and modulate adipose tissue inflammation in obesity. Therefore, this review aims to determine the mechanistic role of SCFAs in mediating VLCKD-infant gut microbiota relationships and its protective effects on obesity.

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Maternal Exposure to Iodine Excess Throughout Pregnancy and Lactation Induces Hypothyroidism in Adult Male Rat Offspring

Scientific Reports ◽

10.1038/s41598-017-15529-9 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 11

Author(s):

Caroline Serrano-Nascimento ◽

Rafael Barrera Salgueiro ◽

Thiago Pantaleão ◽

Vânia Maria Corrêa da Costa ◽

Maria Tereza Nunes

Keyword(s):

Adult Male ◽

Maternal Exposure ◽

Male Rat ◽

Iodine Excess ◽

Rat Offspring ◽

Adult Male Rat ◽

Pregnancy And Lactation

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The Development of the Gut Microbiota and Short-Chain Fatty Acids of Layer Chickens in Different Growth Periods

Frontiers in Veterinary Science ◽

10.3389/fvets.2021.666535 ◽

2021 ◽

Vol 8 ◽

Author(s):

Baosheng Sun ◽

Linyue Hou ◽

Yu Yang

Keyword(s):

Fatty Acids ◽

Gut Microbiota ◽

Short Chain Fatty Acids ◽

Production Performance ◽

Short Chain ◽

Microbial Function ◽

Metabolism Pathway ◽

Fiber Degradation ◽

Α Diversity ◽

Chain Fatty Acids

A long-term observation of changes of the gut microbiota and its metabolites would be beneficial to improving the production performance of chickens. Given this, 1-day-old chickens were chosen in this study, with the aim of observing the development of the gut microbiota and gut microbial function using 16S rRNA gene sequencing and metabolites short-chain fatty acids (SCFAs) from 8 to 50 weeks. The results showed that the relative abundances of Firmicutes and genus Alistipes were higher and fiber-degradation bacteria were less at 8 weeks compared with 20 and 50 weeks (P < 0.05). Consistently, gut microbial function was enriched in ATP-binding cassette transporters, the energy metabolism pathway, and amino acid metabolism pathway at 8 weeks. In contrast, the abundance of Bacteroidetes and some SCFA-producing bacteria and fiber-degradation bacteria significantly increased at 20 and 50 weeks compared with 8 weeks (P < 0.05), and the two-component system, glycoside hydrolase and carbohydrate metabolism pathway, was significantly increased with age. The concentration of SCFAs in the cecum at 20 weeks was higher than at 8 weeks (P < 0.01), because the level of fiber and the number of dominant fiber-degradation bacteria and SCFA-producing bacteria were more those at 20 weeks. Notably, although operational taxonomic units (OTUs) and the gut microbial α-diversity including Chao1 and abundance-based coverage estimator (ACE) were higher at 50 than 20 weeks (P < 0.01), the concentration of SCFAs at 50 weeks was lower than at 20 weeks (P < 0.01), suggesting that an overly high level of microbial diversity may not be beneficial to the production of SCFAs.

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Cross-Talk Between Butyric Acid and Gut Microbiota in Ulcerative Colitis Following Fecal Microbiota Transplantation

Frontiers in Microbiology ◽

10.3389/fmicb.2021.658292 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hao-Ming Xu ◽

Hong-Li Huang ◽

Jing Xu ◽

Jie He ◽

Chong Zhao ◽

...

Keyword(s):

Ulcerative Colitis ◽

Gut Microbiota ◽

Butyric Acid ◽

Fecal Microbiota Transplantation ◽

Short Chain Fatty Acids ◽

Fecal Microbiota ◽

16S Sequencing ◽

Α Diversity ◽

The Impact

Fecal microbiota transplantation (FMT) can inhibit the progression of ulcerative colitis (UC). However, how FMT modulates the gut microbiota and which biomarker is valuable for evaluating the efficacy of FMT have not been clarified. This study aimed to determine the changes in the gut microbiota and their relationship with butyric acid following FMT for UC. Fecal microbiota (FM) was isolated from healthy individuals or mice and transplanted into 12 UC patients or colitis mice induced by dextran sulfate sodium (DSS). Their clinical colitis severities were monitored. Their gut microbiota were analyzed by 16S sequencing and bioinformatics. The levels of fecal short-chain fatty acids (SCFAs) from five UC patients with recurrent symptoms after FMT and individual mice were quantified by liquid chromatography–mass spectrometry (LC–MS). The impact of butyric acid on the abundance and diversity of the gut microbiota was tested in vitro. The effect of the combination of butyric acid-producing bacterium and FMT on the clinical responses of 45 UC patients was retrospectively analyzed. Compared with that in the controls, the FMT significantly increased the abundance of butyric acid-producing bacteria and fecal butyric acid levels in UC patients. The FMT significantly increased the α-diversity, changed gut microbial structure, and elevated fecal butyric acid levels in colitis mice. Anaerobic culture with butyrate significantly increased the α-diversity of the gut microbiota from colitis mice and changed their structure. FMT combination with Clostridium butyricum-containing probiotics significantly prolonged the UC remission in the clinic. Therefore, fecal butyric acid level may be a biomarker for evaluating the efficacy of FMT for UC, and addition of butyrate-producing bacteria may prolong the therapeutic effect of FMT on UC by changing the gut microbiota.

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Effects of combined d-fagomine and omega-3 PUFAs on gut microbiota subpopulations and diabetes risk factors in rats fed a high-fat diet

Scientific Reports ◽

10.1038/s41598-019-52678-5 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Mercè Hereu ◽

Sara Ramos-Romero ◽

Cristina Busquets ◽

Lidia Atienza ◽

Susana Amézqueta ◽

...

Keyword(s):

Risk Factors ◽

Gut Microbiota ◽

High Fat Diet ◽

Short Chain Fatty Acids ◽

Standard Diet ◽

Liver Inflammation ◽

Omega 3 ◽

Sprague Dawley ◽

High Fat ◽

Related Risk

Abstract Food contains bioactive compounds that may prevent changes in gut microbiota associated with Westernized diets. The aim of this study is to explore the possible additive effects of d-fagomine and ω-3 PUFAs (EPA/DHA 1:1) on gut microbiota and related risk factors during early stages in the development of fat-induced pre-diabetes. Male Sprague Dawley (SD) rats were fed a standard diet, or a high-fat (HF) diet supplemented with d-fagomine, EPA/DHA 1:1, a combination of both, or neither, for 24 weeks. The variables measured were fasting glucose and glucose tolerance, plasma insulin, liver inflammation, fecal/cecal gut bacterial subgroups and short-chain fatty acids (SCFAs). The animals supplemented with d-fagomine alone and in combination with ω-3 PUFAs accumulated less fat than those in the non-supplemented HF group and those given only ω-3 PUFAs. The combined supplements attenuated the high-fat-induced incipient insulin resistance (IR), and liver inflammation, while increasing the cecal content, the Bacteroidetes:Firmicutes ratio and the populations of Bifidobacteriales. The functional effects of the combination of d-fagomine and EPA/DHA 1:1 against gut dysbiosis and the very early metabolic alterations induced by a high-fat diet are mainly those of d-fagomine complemented by the anti-inflammatory action of ω-3 PUFAs.

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Guiqi Baizhu Decoction Alleviates Radiation Inflammation in Rats by Modulating the Composition of the Gut Microbiota

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/9017854 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Li-Ying Zhang ◽

Ting Zhou ◽

Yi-Ming Zhang ◽

Xiao-Min Xu ◽

Yang-Yang Li ◽

...

Keyword(s):

Gut Microbiota ◽

Immune Modulation ◽

Inflammatory Responses ◽

Intestinal Barrier ◽

Short Chain Fatty Acids ◽

Gut Dysbiosis ◽

Β Diversity ◽

Α Diversity ◽

Body Weights ◽

Immunity Function

The gut microbiota is important in metabolism and immune modulation, and compositional disruption of the gut microbiota population is closely associated with inflammation caused by ionizing radiation (IR). Guiqi Baizhu decoction (GQBZD) is a medicinal compound used in traditional Chinese medicine with anti-inflammatory and antioxidation effects, especially in the process of radiotherapy. However, the effect of GQBZD on reducing the damage to the normal immune system in radiotherapy remains unclear. Here, we show that GQBZD reduces body weights, water intake, food intake, diarrhea level and quality of life score, and inflammation and enhances immunity function in rats treated with X-ray radiation. Meanwhile, our data indicate that GQBZD not only reverses IR-induced gut dysbiosis as indicated change of α-diversity and β-diversity of microbiota, the composition of Desulfovibrio, Bacteroides, and Parabacteroides, except for Roseburia and Lachnoclostridium, but also maintains intestinal barrier integrity and promoting the formation of short-chain fatty acids (SCFAs). GQBZD can also reduce the level of phosphorylation P65 (p-P65). Our results demonstrate that GQBZD can significantly alleviate the inflammatory responses and improve the immune damage against IR, and may be used as prebiotic agents to prevent gut dysbiosis and radiation-related metabolic disorders in radiotherapy.

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Targeting on Gut Microbiota-Derived Metabolite Trimethylamine to Protect Adult Male Rat Offspring against Hypertension Programmed by Combined Maternal High-Fructose Intake and Dioxin Exposure

International Journal of Molecular Sciences ◽

10.3390/ijms21155488 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5488 ◽

Cited By ~ 2

Author(s):

Chien-Ning Hsu ◽

Julie Y. H. Chan ◽

Hong-Ren Yu ◽

Wei-Chia Lee ◽

Kay L. H. Wu ◽

...

Keyword(s):

Gut Microbiota ◽

Corn Oil ◽

Male Rat ◽

Adult Offspring ◽

Male Adult ◽

High Fructose Diet ◽

Fructose Intake ◽

High Fructose ◽

Pregnancy And Lactation ◽

Dioxin Exposure

Gut microbiota-dependent metabolites, in particular trimethylamine (TMA), are linked to hypertension. Maternal 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure or consumption of food high in fructose (HFR) can induce hypertension in adult offspring. We examined whether 3,3-maternal dimethyl-1-butanol (DMB, an inhibitor of TMA formation) therapy can protect adult offspring against hypertension arising from combined HFR and TCDD exposure. Pregnant Sprague–Dawley rats received regular chow or chow supplemented with fructose (60% diet by weight) throughout pregnancy and lactation. Additionally, the pregnant dams received TCDD (200 ng/kg BW orally) or a corn oil vehicle on days 14 and 21 of gestation, and days 7 and 14 after birth. Some mother rats received 1% DMB in their drinking water throughout pregnancy and lactation. Six groups of male offspring were studied (n = 8 for each group): regular chow (CV), high-fructose diet (HFR), regular diet+TCDD exposure (CT), HFR+TCDD exposure (HRT), high-fructose diet+DMB treatment (HRD), and HFR+TCDD+DMB treatment (HRTD). Our data showed that TCDD exacerbates HFR-induced elevation of blood pressure in male adult offspring, which was prevented by maternal DMB administration. We observed that different maternal insults induced distinct enterotypes in adult offspring. The beneficial effects of DMB are related to alterations of gut microbiota, the increase in nitric oxide (NO) bioavailability, the balance of the renin-angiotensin system, and antagonization of aryl hydrocarbon receptor (AHR) signaling. Our findings cast new light on the role of early intervention targeting of the gut microbiota-dependent metabolite TMA, which may allow us to prevent the development of hypertension programmed by maternal excessive fructose intake and environmental dioxin exposure.

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The Interplay between Maternal and Post-Weaning High-Fat Diet and Gut Microbiota in the Developmental Programming of Hypertension

Nutrients ◽

10.3390/nu11091982 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1982 ◽

Cited By ~ 10

Author(s):

Chien-Ning Hsu ◽

Chih-Yao Hou ◽

Chien-Te Lee ◽

Julie Y.H. Chan ◽

You-Lin Tain

Keyword(s):

Gut Microbiota ◽

Short Chain Fatty Acids ◽

Normal Diet ◽

Nutrient Sensing ◽

Male Offspring ◽

Peroxisome Proliferator ◽

Sprague Dawley ◽

High Fat ◽

Male Adult ◽

Peroxisome Proliferator Activated Receptor

Excessive intake of saturated fat has been linked to hypertension. Gut microbiota and their metabolites, short-chain fatty acids (SCFAs), are known to be involved in the development of hypertension. We examined whether maternal and post-weaning high-fat (HF) diet-induced hypertension in adult male offspring is related to alterations of gut microbiota, mediation of SCFAs and their receptors, and downregulation of nutrient-sensing signals. Female Sprague–Dawley rats received either a normal diet (ND) or HF diet (D12331, Research Diets) during pregnancy and lactation. Male offspring were put on either the ND or HF diet from weaning to 16 weeks of age, and designated to four groups (maternal diet/post-weaning diet; n = 8/group): ND/ND, HF/ND, ND/HF, and HF/HF. Rats were sacrificed at 16 weeks of age. Combined HF/HF diets induced elevated blood pressure (BP) and increased body weight and kidney damage in male adult offspring. The rise in BP is related to a downregulated AMP-activated protein kinase (AMPK)–peroxisome proliferator-activated receptor co-activator 1α (PGC-1α) pathway. Additionally, HF/HF diets decreased fecal concentrations of propionate and butyrate and decreased G protein-coupled receptor 41 (GPR41), but increased olfactory receptor 78 (Oflr78) expression. Maternal HF diet has differential programming effects on the offspring’s microbiota at 3 and 16 weeks of age. Combined HF/HF diet induced BP elevation was associated with an increased Firmicutes to Bacteroidetes ratio, increased abundance of genus Akkermansia and phylum Verrucomicrobia, and reduced abundance in genus Lactobacillus. Maternal gut microbiota-targeted dietary interventions might be reprogramming strategies to protect against programmed hypertension in children and their mothers on consumption of a fat-rich diet.

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