Absence of intestinal microbiota increases ß‐cyclodextrin stimulated reverse cholesterol transport

Mistry, Rima H.; Verkade, Henkjan J.; Tietge, Uwe J. F.

doi:10.1002/mnfr.201600674

Cited by 4 publications

(6 citation statements)

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“…One of the major signs of the liver fibrogenesis involved free cholesterol accumulation in HSCs and thereby stimulated the cells to TGF β-induced activation via TLR-4 signals ( Tomita et al, 2014 ). Probably, enhanced antifibrotic effects of the complexes can be attributed additionally to β-cyclodextrin’s which can exert metabolic effects either directly through binding lipid molecules such as cholesterol or indirectly via microbiota-dependent generation of bioactive metabolites, translated in reduced plasma total cholesterol levels and lower HDL cholesterol ( Mistry et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Enhancement of Silymarin Anti-fibrotic Effects by Complexation With Hydroxypropyl (HPBCD) and Randomly Methylated (RAMEB) β-Cyclodextrins in a Mouse Model of Liver Fibrosis

et al. 2018

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Silymarin (Sy) shows limited water solubility and poor oral bioavailability. Water-soluble hydroxypropyl (HPBCD) and randomly methylated (RAMEB) β-cyclodextrins were designed to enhance anti-fibrotic efficiency of silymarin in CCl4-induced liver fibrosis in mice. Experimental fibrosis was induced by intraperitoneal injection with 2 ml/kg CCl4 (20% v/v) twice a week, for 7 weeks. Mice were orally treated with 50 mg/kg of Sy-HPBCD, Sy-RAMEB and free silymarin. For assessment of the spontaneous reversion of fibrosis, CCl4 treated animals were investigated after 2 weeks of recovery time. The CCl4 administration increased hepatic oxidative stress, augmented the expression of transforming growth factor-β1 (TGF-β1) and Smad 2/3, and decreased Smad 7 expression. Furthermore, increased α-smooth muscle actin (α-SMA) expression indicated activation of hepatic stellate cells (HSCs), while up-regulation of collagen I (Col I) and matrix metalloproteinases (MMPs) expression led to an altered extracellular matrix enriched in collagen, confirmed as well by trichrome staining and electron microscopy analysis. Treatment with Sy-HPBCD and Sy-RAMEB significantly reduced liver injury, attenuating oxidative stress, restoring antioxidant balance in the hepatic tissue, and significantly decreasing collagen deposits in the liver. The levels of pro-fibrogenic markers’ expression were also significantly down-regulated, whereas in the group for spontaneous regression of fibrosis, they remained significantly higher, even at 2 weeks after CCl4 administration was discontinued. The recovery was significantly lower for free silymarin group compared to silymarin/β cyclodextrins co-treatments. Sy-HPBCD was found to be the most potent anti-fibrotic complex. We demonstrated that Sy-HPBCD and Sy-RAMEB complexes decreased extracellular matrix accumulation by inhibiting HSC activation and diminished the oxidative damage. This might occur via the inhibition of TGF-β1/Smad signal transduction and MMP/tissue inhibitor of MMPs (TIMP) rebalance, by blocking the synthesis of Col I and decreasing collagen deposition. These results suggest that complexation of silymarin with HPBCD or RAMEB represent viable options for the its oral delivery, of the flavonoid as a potential therapeutic entity candidate, with applications in the treatment of liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

Enhancement of Silymarin Anti-fibrotic Effects by Complexation With Hydroxypropyl (HPBCD) and Randomly Methylated (RAMEB) β-Cyclodextrins in a Mouse Model of Liver Fibrosis

et al. 2018

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“…[37] Commercially available reagents (Roche, Diagnostic, Basel, Switzerland) were used to measure plasma and hepatic total cholesterol and triglycerides. [38] Fecal Mass Sterol, Fatty Acids, Bile, and Short-Chain Fatty Acids Measurements: Fecal samples were obtained from the bedding following collection over a 24 h period. The samples were dried, weighed, and ground.…”

Section: Methodsmentioning

confidence: 99%

Long‐Term β‐galacto‐oligosaccharides Supplementation Decreases the Development of Obesity and Insulin Resistance in Mice Fed a Western‐Type Diet

Mistry

Fan

Borewicz

et al. 2020

Molecular Nutrition Food Res

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Scope The gut microbiota might critically modify metabolic disease development. Dietary fibers such as galacto‐oligosaccharides (GOS) presumably stimulate bacteria beneficial for metabolic health. This study assesses the impact of GOS on obesity, glucose, and lipid metabolism. Methods and results Following Western‐type diet feeding (C57BL/6 mice) with or without β‐GOS (7% w/w, 15 weeks), body composition, glucose and insulin tolerance, lipid profiles, fat kinetics and microbiota composition are analyzed. GOS reduces body weight gain ( p < 0.01), accumulation of epididymal ( p < 0.05), perirenal ( p < 0.01) fat, and insulin resistance ( p < 0.01). GOS‐fed mice have lower plasma cholesterol ( p < 0.05), mainly within low‐density lipoproteins, lower intestinal fat absorption ( p < 0.01), more fecal neutral sterol excretion ( p < 0.05) and higher intestinal GLP‐1 expression ( p < 0.01). Fecal bile acid excretion is lower ( p < 0.01) in GOS‐fed mice with significant compositional differences, namely decreased cholic, α‐muricholic, and deoxycholic acid excretion, whereas hyodeoxycholic acid increased. Substantial changes in microbiota composition, conceivably beneficial for metabolic health, occurred upon GOS feeding. Conclusion GOS supplementation to a Western‐type diet improves body weight gain, dyslipidemia, and insulin sensitivity, supporting a therapeutic potential of GOS for individuals at risk of developing metabolic syndrome.

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“…Free cholesterol underwent acetylation followed by quantification using gas chromatography (GC, Agilent 6890, Amstelveen, the Netherlands) . Phospholipids were determined by measuring the phosphorus content of lipid extracts after perchloric acid treatment …”

Section: Methodsmentioning

confidence: 99%

“…[17] Phospholipids were determined by measuring the phosphorus content of lipid extracts after perchloric acid treatment. [24]…”

Section: Hepatic Lipidsmentioning

confidence: 99%

“…Breeding was initiated between 8 and 12 weeks of age. At weaning (postnatal day [20][21][22][23][24], male and female offspring originating from the germ-free (Former GF) and the conventional (Conv) group were conventionalized with aliquots of the same inoculum (as detailed below). From then on, all mice were individually housed in IVC cages, in temperature-controlled conditions with 12:12 light dark cycles, and kept on autoclaved germ-free diet (ssniff R/M-H autoclavable, V1534-3, ssniff Specialdiäten GmbH, Germany).…”

Section: Introductionmentioning

confidence: 99%

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Absence of Intestinal Microbiota during Gestation and Lactation Does Not Alter the Metabolic Response to a Western‐type Diet in Adulthood

Lohuis

Werkman

Harmsen

et al. 2018

Molecular Nutrition Food Res

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Scope Microbiota composition in early life is implied to affect the risk to develop obesity in adulthood. It is unclear whether this risk is due to long‐lasting microbiome‐induced changes in host metabolism. This study aims to identify whether the presence or total absence of early‐life microbiota affects host metabolism in adulthood. Methods and results The effects of a germ‐free (Former GF) versus conventional status during gestation and lactation on the metabolic status in adult offspring are compared. Upon conventionalization at weaning, all mice were metabolically challenged with a Western‐type diet (WTD) at 10 weeks age. Between age 10 and 30 weeks, a former GF status does not notably affect overall body weight gain, cholesterol metabolism, glucose tolerance or insulin sensitivity at adult age. However, Former GF mice have lower bile flow and bile acid secretion in adulthood, but similar bile acid composition. Conclusions A germ‐free status during gestation and lactation does not substantially affect key parameters of the metabolic status before 10 weeks of age on chow diet or in adulthood following a WTD challenge. These data imply that microbiota in early life does not critically affect adult metabolic plasticity.

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Absence of intestinal microbiota increases ß‐cyclodextrin stimulated reverse cholesterol transport

Abstract: In summary, this study demonstrates that ßCD lowers plasma cholesterol levels and increases fecal cholesterol excretion from a RCT-relevant pool. Intestinal bacteria decrease the impact of ßCD on RCT. These data suggest that dietary ßCD might have cardiovascular health benefits.

Cited by 4 publications

References 48 publications

Enhancement of Silymarin Anti-fibrotic Effects by Complexation With Hydroxypropyl (HPBCD) and Randomly Methylated (RAMEB) β-Cyclodextrins in a Mouse Model of Liver Fibrosis

Enhancement of Silymarin Anti-fibrotic Effects by Complexation With Hydroxypropyl (HPBCD) and Randomly Methylated (RAMEB) β-Cyclodextrins in a Mouse Model of Liver Fibrosis

Long‐Term β‐galacto‐oligosaccharides Supplementation Decreases the Development of Obesity and Insulin Resistance in Mice Fed a Western‐Type Diet

Absence of Intestinal Microbiota during Gestation and Lactation Does Not Alter the Metabolic Response to a Western‐type Diet in Adulthood

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