The prebiotic fiber inulin ameliorates cardiac, adipose tissue, and hepatic pathology, but exacerbates hypertriglyceridemia in rats with metabolic syndrome.

Prebiotics ameliorate dysbiosis and influence metabolism and the immune system, but their effects on cardiovascular complications in metabolic disorders remain largely unknown. We here investigated the effects of the soluble fiber inulin on cardiac, adipose tissue, and hepatic pathology as well as on metabolic disorders in DahlS.Z-Leprfa/Leprfa (DS/obese) rats, an animal model of metabolic syndrome (MetS). DS/obese rats and their homozygous lean (DahlS.Z-Lepr+/Lepr+, or DS/lean) littermate controls were fed a purified diet containing 5% or 20% inulin from 9 to 13 wk of age. The high-fiber diet ameliorated hypertension, left ventricular inflammation, fibrosis and diastolic dysfunction; attenuated adipose tissue inflammation and fibrosis; and alleviated the elevation of interleukin-6 levels, without affecting insulin resistance, in DS/obese rats. In addition, high fiber intake ameliorated lipid accumulation, inflammation, and fibrosis; attenuated the reduction in AMPK activity; upregulated sterol regulatory element-binding protein-1c gene expression; and increased the expression of microsomal triglyceride transfer protein gene in the liver of DS/obese rats. It also mitigated increases in total and non-high-density lipoprotein cholesterol levels but increased the triglyceride concentration in serum in these rats. None of these parameters were affected by high dietary fiber in DS/lean rats. The proportion of regulatory T cells in adipose tissue was influenced by dietary fiber but not by genotype. Our results indicate that inulin exacerbates hypertriglyceridemia but alleviates hypertension and cardiac injury as well as adipose tissue and hepatic pathology in MetS rats.NEW & NOTEWORTHY Prebiotics ameliorate dysbiosis and influence metabolism and the immune system, but their effects on cardiovascular complications in metabolic disorders remain largely unknown. Inulin ameliorated hypertension, cardiac injury, and diastolic dysfunction without affecting obesity or insulin resistance in a rat model of metabolic syndrome. The favorable cardiac effects of inulin may be related to inhibition of systemic inflammation associated with a reduction in circulating interleukin-6 levels. Additionally, inulin exacerbated hypertriglyceridemia but alleviates adipose tissue and hepatic pathology in these animals, as well as increased the number of regulatory T cells in adipose tissue.

A one-generation reproduction toxicity study in rats treated orally with a novel galacto-oligosaccharide.

Galacto-oligosaccharide (GOS) is a naturally occurring prebiotic that beneficially affects the host by selectively stimulating growth and/or activity of one or a limited number of colon bacteria to improve host health. A novel GOS was administered by gavage to male and female Sprague Dawley rats at 0, 500, 1000, and 2000 mg/kg/day for 10 weeks. In males, administration of GOS was initiated prior to mating and continued for 91 days. Females received GOS beginning 2 weeks prior to mating through day 20 of lactation. Parents were observed daily, and body weight (BW) and feed consumption were measured. Vaginal smears, mating behavior, and observation of delivery/lactation were evaluated in parents. Effects on the reproductive function of parents including gonad function, estrous cycle, mating performance, fertility, delivery and lactation, and effects on the growth and development of pups were examined. No deaths occurred, and no general toxicological effects or abnormal reproductive functions were observed in any dose group. Pups were observed at birth and the following measurements were undertaken: BW, external differentiations, sensory functions, and reflex reactions during lactation and just prior to necropsy. No external malformations or differences in the number of pups, in the sex ratio, or BW at birth occurred in any dose group. Growth and development of pups were normal. The No Observed Effect Level for reproductive function of male and female parent animals and for the growth and development of their offspring was at least 2000 mg/kg/day.

A 6-week oral gavage toxicity study of a novel galacto-oligosaccharide in juvenile rats.

A novel galacto-oligosaccharide (GOS) was administered by gavage to groups (10 males and 10 females) of Sprague-Dawley specific pathogen-free rats for 6 weeks from day 4 after birth at doses of 0, 500, 1000, or 2000 mg/kg/day. Each pup was subjected to a variety of observations to examine for development effects/changes after birth: general condition, clinical signs, functional examinations, grip strength and spontaneous movement, body weight and feed consumption, external differentiation, ophthalmological examination, urinalysis (including water consumption), hematology, blood chemistry, necropsy, organ weight, and histopathology. During the study period, no deaths occurred in any group and there were no observed effects from administration of GOS. Therefore, it was concluded that GOS had no effects on the development of animals 4 days after birth. Since, there were no abnormalities due to administration of GOS in the macroscopic examination, organ weight or histopathology of the reproductive organs or differentiation (incisor eruption and eyelid opening) of males or females, it was concluded that repeated oral administration of GOS at 2000 mg/kg/day for 6 weeks from day 4 after birth had : no effects on postnatal development. The no observed effect level of GOS by repeated oral administration for 6 weeks from day 4 after birth was 2000 mg/kg/day for both males and females under the conditions of this study.

Short chain fatty acids exchange: Is the cirrhotic, dysfunctional liver still able to clear them?

BACKGROUND & AIMS: Prebiotics are increasingly used to improve gut integrity. A presumed mechanism of their beneficial action is the synthesis of short chain fatty acids (SCFA: acetate, propionate and butyrate). High systemic concentrations of propionate and butyrate are toxic and can adversely affect the patient. In physiological situations the liver uses propionate and butyrate for energy metabolism. The aim of the present study was to investigate to which extent patients with liver cirrhosis are still able to metabolize portal derived SCFA in the liver. METHODS: Twelve patients with liver cirrhosis and an intrahepatic portosystemic shunt (TIPSS) were studied. Blood was sampled from the femoral artery, portal and hepatic vein. Organ plasma flow was measured. Net release or uptake was calculated by multiplying the arteriovenous differences by plasma flow. SCFA plasma concentrations were measured using LC-MS. RESULTS: Arterial concentrations were 124+/-12, 8+/-1 and 10+/-1micromol/l for acetate, propionate and butyrate, respectively. The gut produced 32.5+/-13.0, 4.8+/-1.3 and 6.2+/-2.1micromolkgbw(-1)h(-1) of acetate, propionate and butyrate, respectively. Assuming 70% portosystemic shunting, hepatic uptake of propionate and butyrate was 3.1+/-0.9 and 5.2+/-1.4micromolkgbw(-1)h(-1). Hepatic uptake of acetate was non significant (12.1+/-12.3micromolkgbw(-1)min(-1)). As a consequence of shunting, part of total acetate escaped from the splanchnic bed, which equalled 34.9+/-14.7micromolkgbw(-1)h(-1). CONCLUSION: The liver of patients with stable cirrhosis is able to use butyrate and propionate, most likely preventing increased systemic concentrations. This suggests that prebiotics can be administered safely, but monitoring butyrate levels may be advisable in patients with diminished liver function.

Safety of a novel galacto-oligosaccharide: Genotoxicity and repeated oral dose studies.

A series of safety tests were undertaken on a novel galacto-oligosaccharide (GOS) produced from lactose by a two-step enzymatic process involving Sporobolomyces singularis and Kluyveromyces lactis. Bacterial reverse mutation and chromosomal aberration tests, with or without metabolic activation, were performed. These tests showed no mutagenesis in the Ames assay or in Escherichia coli WP2uvrA, and no chromosomal aberrations in cultured fibroblast cells from Chinese hamster lungs (CHL/IU). Micronuclei were not induced in the reticulocytes of mouse peripheral blood following oral administration of GOS. In a 90-day repeated oral dose toxicity study in rats, GOS was administered at 0, 500, 1000 and 2000 mg/kg to male and female Sprague-Dawley rats. There were no GOS-related changes in clinical signs, body weight, water intake, feed intake, urinalysis, ophthalmology, haematology, blood chemistry, organ weights, gross pathology or histopathology in any of the treatment groups compared to the control group. The no observed adverse effect level (NOAEL) of GOS was at least 2000 mg/kg/day in both males and females.