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.

Self-assembled high molecular weight inulin nanoparticles: Enzymatic synthesis, physicochemical and biological properties.

Inulin has interesting physicochemical and functional properties, and therefore a wide range of applications in the food and medical industries. It has gained great traction due to its ability to form nanoparticles and its possible application as nanovehicle for drug delivery. In this work, we demonstrated that the enzymatically-synthesized high molecular weight (HMW) inulin forms stable spherical nanoparticles with an average diameter of 112 ± 5 nm. The self-assemblage of HMW inulin nanoparticles is carried out during enzymatic synthesis of the polymer, and become detectable after a certain critical aggregation concentration (CAC) is reached. Both, the CAC and nanoparticle size are influenced by the reaction temperature. These nanoparticles are not toxic for peripheral blood mononuclear cells, at concentrations below 200 µg/mL; no significant prebiotic potential was detected in cultures of 13 probiotic strains. This work contributes to a better understanding of the formation of HMW inulin nanoparticles and their biological properties.

Development and validation of a physiology-based model for the prediction of pharmacokinetics/toxicokinetics in rabbits.

The environmental fates of pharmaceuticals and the effects of crop protection products on non-target species are subjects that are undergoing intense review. Since measuring the concentrations and effects of xenobiotics on all affected species under all conceivable scenarios is not feasible, standard laboratory animals such as rabbits are tested, and the observed adverse effects are translated to focal species for environmental risk assessments. In that respect, mathematical modelling is becoming increasingly important for evaluating the consequences of pesticides in untested scenarios. In particular, physiologically based pharmacokinetic/toxicokinetic (PBPK/TK) modelling is a well-established methodology used to predict tissue concentrations based on the absorption, distribution, metabolism and excretion of drugs and toxicants. In the present work, a rabbit PBPK/TK model is developed and evaluated with data available from the literature. The model predictions include scenarios of both intravenous (i.v.) and oral (p.o.) administration of small and large compounds. The presented rabbit PBPK/TK model predicts the pharmacokinetics (Cmax, AUC) of the tested compounds with an average 1.7-fold error. This result indicates a good predictive capacity of the model, which enables its use for risk assessment modelling and simulations.

Dietary fructo-oligosaccharides and inulin decrease resistance of rats to salmonella: protective role of calcium.

BACKGROUND: We have shown recently that rapid fermentable fructo-oligosaccharides (FOS) decreased resistance of rats towards salmonella. It is not known whether inulin (which is fermented more gradually) has similar effects or whether buffering nutrients can counteract the adverse effects of rapid fermentation. AIMS: To compare the effects of dietary inulin and FOS on resistance of rats to Salmonella enterica serovar Enteritidis and to determine whether calcium phosphate counteracts the effects of fermentation. METHODS: Male Wistar rats (n = 8 per group) were fed a human "Western style diet". Diets with 60 g/kg cellulose (control), FOS, or inulin had either a low (30 mmol/kg) or high (100 mmol/kg) calcium concentration. After an adaptation period of two weeks, animals were orally infected with 2 x 10(9) colony forming units of Salmonella enterica serovar Enteritidis. Colonisation of salmonella was determined by quantification of salmonella in caecal contents. Translocation of salmonella was quantified by analysis of urinary nitric oxide metabolites in time. RESULTS: Inulin and FOS decreased intestinal pH and increased faecal lactobacilli and enterobacteria. Moreover, both prebiotics increased the cytotoxicity of faecal water and faecal mucin excretion. Both prebiotics increased colonisation of salmonella in caecal contents and enhanced translocation of salmonella. Dietary calcium phosphate counteracted most of the adverse effects of inulin and FOS. CONCLUSIONS: Both inulin and FOS impair resistance to intestinal infections in rats. This impairment is partially prevented by dietary calcium phosphate. The results of the present study await verification in other controlled animal and human studies.

Promotion of intestinal tumor formation by inulin is associated with an accumulation of cytosolic beta-catenin in Min mice.

Inulin, polydisperse beta (2-1) fructan, has been suggested to protect against colon carcinogenesis and is currently used in a number of food applications. However, the data regarding the role of inulin in intestinal carcinogenesis remains controversial since the results of our previous study suggested that inulin promotes intestinal tumor formation in Min mice, an animal model for intestinal cancer with a mutation in the Apc tumor suppressor gene (Carcinogenesis 2000;21:1167-73). In our present study, we further examined the effects of inulin on intestinal tumor formation in Min mice by carefully analyzing beta-catenin expression and cellular localization at 3 different time points during the tumorigenic process. Min mice were fed a high-fat inulin-enriched (10% w/w) diet or the high-fat diet without any added fiber from the age of 6 weeks to the ages of 9, 12 or 15 weeks. The results showed that inulin significantly increased the number (by 20%) and especially the size (by 44%) of adenomas in the small intestine. At week 15, the promotion of tumor development was accompanied by an accumulation of cytosolic beta-catenin in the adenoma tissue. In the normal appearing mucosa, levels of membrane beta-catenin and PCNA were reduced in the inulin-fed mice, possibly indicating impaired enterocyte migration. These data do not support the earlier suggestions on the cancer preventive effects of inulin and emphasize the need for further research and evaluation where health claims for inulin are concerned.

Toxicological profile of carboxymethyl inulin.

Carboxymethylinulin (CMI), formed by carboxylation of a natural carbohydrate obtained from the chicory plant, is particularly effective in sequestration of hard water cations, and thus serves as a unique anti-scalant which could find uses in food processing. A series of toxicological studies has been performed to investigate its toxiciologic properties following repeated exposure, possible sensitization, and its potential to elicit genotoxic activity; all studies conformed to internationally accepted safety test guidelines currently in force. Subacute (4-week) oral toxicity was investigated in groups of rats exposed via gavage to 0, 50, 150 and 1000 mg/kg/day CMI. No treatment-related effects were observed in body weight, food consumption, mortality, hematology, clinical blood chemistry, organ weights or gross or microscopic pathology up to the highest dose (1000 mg/kg/day) tested. Motor activity, as observed in a functional observation battery, was elevated in high-dose females, and is not considered of significance toxicologically. Lack of adverse toxicity seen with CMI at this dosage is consistent with a similar lack of significant toxicity exhibited by other dietary carbohydrates (sorbitol, sucrose, glucose), oligofructoses (inulin/FOS) and carboxylated cellulose in repeated-dose rat studies at approximately the same dosage. No evidence of dermal sensitization was observed in groups of guinea pigs following CMI testing by the Magnusson-Kligman maximization test methodology. No mutagenic activity was observed when CMI was tested in four Salmonella strains-TA1535, TA1537, TA98 and TA100-or in Escherichia coli WP2uvrA bacterial point mutation assays or in an in vitro Chinese hamster ovary cell chromosomal aberration assay. The results obtained in the present study with CMI are consistent with similar data derived on numerous dietary carbohydrate fibers generally recognized as safe in the human diet.

Non-toxic potentiation of cancer radiotherapy by dietary oligofructose or inulin.

Non-toxic, dietary treatment with oligofructose or inulin clearly inhibited the growth of a transplantable mouse liver tumor (TLT) and potentiated its chemotherapy. Thus, it appeared interesting to investigate the possible radiotherapy-potentiating effects of the same dietary treatment. Dietary treatment with 15% oligofructose or inulin incorporated in the basal diet was started four weeks before intramuscular transplantation of TLT tumor cells into young adult male mice of the NMRI strain and was continued until the end of the experiment. When the tumors reached approximately 1000 mm3 they were irradiated with a single X-ray dose of 5 to 20 Gy. Tumor dimensions were measured twice weekly and their mean volume per group of mice was compared to the control groups fed the basal diet. This non-toxic dietary treatment with oligofructose or inulin potentiated the effects of radiotherapy at an optimal dose of 10 Gy to a statistically very highly significant (p < 0.0001) level. They were similar for oligofructose and inulin. The introduction of such non-toxic adjuvant treatment potentiating the effect of cancer radiotherapy in classical protocols of human cancer treatment appears to be possible and without any additional risk for the patients.

Diets enriched with cereal brans or inulin modulate protein kinase C activity and isozyme expression in rat colonic mucosa.

The role of dietary fibres in colon carcinogenesis is controversial. To elucidate the mechanisms by which different dietary fibre sources may affect colonic tumour development, we studied the effects of diets enriched with cereal brans or inulin on protein kinase C (PKC) activity and isozyme expression in rat colon. Male Wistar rats (twelve per group) were fed one of the following AIN-93G-based diets (Reeves et al. 1993) for 4 weeks: a non-fibre high-fat diet or one of the four high-fat diets supplemented with either rye, oat or wheat bran or inulin at 100 g/kg diet. The fat concentration (20 g/100 g) and fatty acid composition of the non-fibre high-fat diet was designed to approximate that in a typical Western-type diet. In the proximal colon, rats fed the inulin diet had a significantly higher membrane PKC activity and a higher membrane PKC delta level than rats fed the non-fibre diet In the distal colon, rats fed the inulin and oat bran diets had a higher total PKC activity and a higher membrane PKC beta 2 level than rats fed the wheat-bran diet. Rats in the non-fibre and wheat-bran groups had the lowest concentrations of luminal diacylglycerol. In conclusion, feeding of wheat bran resulted in low distal PKC activity and expression of PKC beta 2, a PKC isozyme related to colonic cell proliferation and increased susceptibility for colon carcinogenesis, which may explain in part the protective effect of wheat bran against tumour development in a number of experimental colon cancer studies. The increase in PKC activity and PKC beta 2 expression by feeding inulin may be a drawback of inulin as a functional food.