Gut Microbiota and Host Cyp450s Co-contribute to Pharmacokinetic Variability in Mice With Non-Alcoholic Steatohepatitis: Vary From Drug to Drug

2021 ◽  
Author(s):  
Jing Guo ◽  
Ying Xu ◽  
Li-Jie Chen ◽  
Song-xia Zhang ◽  
Tai Rao ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Gut Microbiota ◽  
Intravenous Administration ◽  
Underlying Mechanism ◽  
Control Group ◽  
Intragastric Administration ◽  
Minimal Effect ◽  
Pharmacokinetic Variability ◽  
Alcoholic Steatohepatitis ◽  
Nash Group

Abstract Background: Pharmacokinetic variability in disease state is common in clinical practice, but the underlying mechanism remains unclear. We aim to investigate the effects of gut microbiota and host Cyp450s on pharmacokinetic variability in mice with non-alcoholic steatohepatitis (NASH).Methods: The pharmacokinetic variability of mice with NASH was explored under intragastric and intravenous administration of a cocktail mixture of omeprazole, phenacetin, midazolam, tolbutamide, chlorzoxazone, and metoprolol compared with the control group. The pharmacokinetic variability of the drugs and its relation with changes of gut microbiota and host Cyp450s were compared and analyzed.Results: The exposure of all drugs, except metoprolol, significantly increased in the NASH group under intragastric administration. However, no significant increase in the exposure of all drugs, except tolbutamide, was observed in the NASH group under intravenous administration. The pharmacokinetic variabilities of phenacetin, midazolam, omeprazole, and chlorzoxazone were mainly associated with decreased elimination activity of the gut microbiota. By contrast, the pharmacokinetic variability of tolbutamide was mainly related to the change in host Cyp2c65. However, gut microbiota and host Cyp450s exerted minimal effect on the pharmacokinetic variability of metoprolol.Conclusions: Gut microbiota and host Cyp450s co-contribute the pharmacokinetic variability in mice with NASH, and the degree of contribution varies from drug to drug.

scholarly journals Effects of Dietary Intervention on Gut Microbiota and Metabolic-Nutritional Profile of Outpatients with Non-Alcoholic Steatohepatitis: a Randomized Clinical Trial

2019 ◽  
Vol 28 (3) ◽  
pp. 279-287 ◽  
Author(s):  
Fabiana De Faria Ghetti ◽  
Daiane Gonçalves De Oliveira ◽  
Juliano Machado De Oliveira ◽  
Lincoln Eduardo Villela Vieira de Castro Ferreira ◽  
Dionéia Evangelista Cesar ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Gut Microbiota ◽  
Randomized Clinical Trial ◽  
Bacterial Overgrowth ◽  
Diet Group ◽  
Control Group ◽  
Model Assessment ◽  
Nutritional Profile ◽  
Alcoholic Steatohepatitis ◽  
The Impact

Background & Aims: Modulation of the gut microbiota emerges as a therapeutic possibility to improve health. Our objective was to compare the impact of three months of intervention with diet plus nutritional orientation versus only nutritional orientation on the gut microbiota and metabolic-nutritional profile of outpatients with non-alcoholic steatohepatitis. Methods: It was a randomized clinical trial with 40 outpatients (49.48 ± 10.3 years), allocated in two groups: DIET group (n=20), who received diet (1.651.34 ± 263.25 kcal; 47% carbohydrates, 28% lipids, 25% proteins, 30 g fibers) and nutritional orientation, and control group (n = 20), which received only nutritional orientation. Results: The DIET group, in relation to baseline, presented a reduction in body weight (p<0.001), BMI (p<0.001), waist circumference (p=0.001), percentage of fat (p=0.002), serum aspartate aminotransferase (p<0.001), alanine aminotransferase (p<0.001), γ-glutamyltransferase (p=0.001), glycemia (p=0.003), homeostasis model assessment of insulin resistance (p=0.017), total cholesterol (p=0.014), and triacylglycerols (p=0.008), whereas the control group did not present changes. After intervention, the small intestinal bacterial overgrowth frequency was 30% in the DIET group and 45% in the control group (p=0.327). In the DIET group, an increase in the density of total microorganisms (3.76 ± 7.17 x 10 8 cells g -1 ; p=0.048) was detected, while in the control group reduced Bacteroidetes (-0.77 ± 2.01 x 10 8 cells g -1 , p=0.044) and Verrucomicrobiales (-0.46 ± 0.75 x 10 8 cells g -1 ; p=0.022) were observed. Conclusions: The results suggest that exclusively dietary modifications contribute to health promotion in non-alcoholic steatohepatitis and should be the basis of nutritional treatment for this condition.

scholarly journals Gegen Qinlian Decoction Attenuates High-Fat Diet-Induced Steatohepatitis in Rats via Gut Microbiota

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Yi Guo ◽  
Pang-hua Ding ◽  
Li-juan Liu ◽  
Lei Shi ◽  
Tang-you Mao ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Group Treatment ◽  
High Fat Diet ◽  
Metabolic Diseases ◽  
Intestinal Flora ◽  
Underlying Mechanism ◽  
Control Group ◽  
High Fat ◽  
Nonalcoholic Fatty Liver ◽  
Traditional Chinese Herbal Medicine

Gut microbiota play an important role in modulating energy contribution, metabolism, and inflammation, and disruption of the microbiome population is closely associated with chronic metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD). Gegen Qinlian decoction (GGQLD), a well-known traditional Chinese herbal medicine (CHM), was previously found to regulate lipid metabolism and attenuate inflammation during NAFLD pathogenesis. However, the underlying mechanism of this process, as well as how the gut microbiome is involved, remains largely unknown. In this study, we investigated the effect of varying doses of GGQLD on the total amount and distribution of gut bacteria in rats fed a high-fat diet (HFD) for 8 weeks. Our analysis indicates that Oscillibacter and Ruminococcaceae_g_unclassified are the dominant families in the HFD group. Further, HFD-dependent differences at the phylum, class, and genus levels appear to lead to dysbiosis, characterized by an increase in the Firmicutes/Bacteroidetes ratio and a dramatic increase in the Oscillibacter genus compared to the control group. Treatment with GGQLD, especially the GGQLL dose, improved these HFD-induced changes in intestinal flora, leading to increased levels of Firmicutes, Clostridia, Lactobacillus, bacilli, and Erysipelotrichales that were similar to the controls. Taken together, our data highlight the efficacy of GGQLD in treating NAFLD and support its clinical use as a treatment for NAFLD/NASH patients.

scholarly journals Chronic Exposure to Perfluorohexane Sulfonate Leads to a Reproduction Deficit by Suppressing Hypothalamic Kisspeptin Expression in Mice

2021 ◽  
Author(s):  
Xiaorui Yin ◽  
Tingting Di ◽  
Xinyuan Cao ◽  
Zhengnan Liu ◽  
Jingyan Xie ◽  
...  
Keyword(s):  
Estrous Cycle ◽  
Chronic Exposure ◽  
Corn Oil ◽  
Underlying Mechanism ◽  
Control Group ◽  
Intragastric Administration ◽  
Mrna Levels ◽  
Intraventricular Administration ◽  
Female Reproduction ◽  
Antral Follicles

Abstract BackgroundPerfluorohexane sulfonate (PFHxS) is a six-carbon perfluoroalkyl sulfonic acid found as an environmental contaminant. This study aims to investigate the effects of PFHxS exposure on female reproduction and the underlying mechanism in mice. MethodsEight-week-old ICR mice were divided randomly into four groups: corn oil (vehicle) and PFHxS at doses of 0.5, 5, and 50 mg/kg/day for 42 days by intragastric administration. Body weight, ovarian weight, estrous cycle, follicle counts, and serum sex hormone levels were evaluated. Expression of kisspeptin and gonadotropin releasing hormone (GnRH) in the hypothalamus was also detected. ResultsCompared to vehicle exposure, 5 mg/kg/day PFHxS prolonged the estrous cycle, especially the duration of diestrus, after 42 days of treatment. The numbers of antral follicles and corpus lutea were significantly reduced in PFHxS-treated mice. Moreover, compared with the control group, PFHxS-treated mice showed decreases in serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estrogen (E2), and reduced GnRH mRNA levels, along with the lack of an LH surge. Furthermore, PFHxS-treated mice had lower levels of kisspeptin immunoreactivity and kiss-1 mRNA in the arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV). After intraventricular administration of kisspeptin-10, the numbers of antral follicles and corpus lutea recovered, along with the levels of GnRH mRNA, FSH, and LH in mice treated with 5 mg/kg/day PFHxS. ConclusionThese results indicate that chronic exposure of mice to 5 mg/kg/day PFHxS affects reproductive functions by inhibiting kisspeptin expression in the ARC and AVPV regions, leading to the deficit of follicular development and ovulation.

scholarly journals Genistein Attenuates Nonalcoholic Steatohepatitis and Increases Hepatic PPARγin a Rat Model

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Warinda Susutlertpanya ◽  
Duangporn Werawatganon ◽  
Prasong Siriviriyakul ◽  
Naruemon Klaikeaw
Keyword(s):  
Nonalcoholic Steatohepatitis ◽  
High Fat Diet ◽  
Control Group ◽  
Intragastric Administration ◽  
Protective Effects ◽  
Sprague Dawley ◽  
High Fat ◽  
Liver Histopathology ◽  
Nash Group ◽  
Ad Libitum

Nonalcoholic steatohepatitis (NASH) has become a global chronic liver disease, but no effective medicine has been proven to cure it. This study investigated the protective effects of genistein, a phytoestrogen, on NASH and examined whether it has any effect on hepatic PPARγ. Male Sprague-Dawley rats were divided into four groups: control group fed ad libitum with standard rat diet, NASH group fed ad libitum with high-fat diet to induce NASH and NASH + Gen8 group and NASH + Gen16 group fed with high-fat diet plus intragastric administration of 8 or 16 mg/kg genistein once daily. After 6 weeks, liver samples were collected to determine MDA, TNF-α, PPARγ, and histopathology. The findings were that levels of hepatic MDA and TNF-αincreased in NASH group, but 16 mg/kg genistein reduced these levels significantly. Downregulation of hepatic PPARγwas observed in NASH group, but genistein significantly upregulated the expression of PPARγin both NASH + Gen groups. The histological appearance of liver in NASH group presented pathological features of steatohepatitis which were diminished in both NASH + Gen groups. The results suggest that genistein attenuates the liver histopathology of NASH with upregulation of hepatic PPARγ, reduction of oxidative stress, and inhibition of inflammatory cytokine.

Dietary Quercetin Alleviated DSS-induced Colitis in Mice Through Several Possible Pathways by Transcriptome Analysis

2020 ◽  
Vol 21 (15) ◽  
pp. 1666-1673 ◽  
Author(s):  
Yuanyang Dong ◽  
Jiaqi Lei ◽  
Bingkun Zhang
Keyword(s):  
Antioxidant Capacity ◽  
Underlying Mechanism ◽  
Control Group ◽  
Sequencing Analysis ◽  
Colon Tissue ◽  
Beneficial Effects ◽  
Intestinal Integrity ◽  
Inflammatory Bowel ◽  
Vegetables And Fruits ◽  
Key Pathways

Background: The prevalence of inflammatory bowel disease is rapidly increasing around the world. Quercetin is a flavonoid commonly found in vegetables and fruits and has been reported to exert numerous pharmacological activities such as enhancing antioxidant capacity or suppressing inflammation. Objective: We aimed to explore whether quercetin was effective for IBD and the underlying mechanism of quercetin for the ameliorative effects on the DSS-induced colitis in mice. Methods: Thirty-six mice were randomly assigned to three treatments, including the control group (Ctr), DSS-induced colitis group (DSS) and DSS-induced colitis supplemented with 500 ppm quercetin (DQ500). Colitis was induced by DSS intake, and body weight was recorded every day. After six days administration of DSS, intestinal permeability was measured, and the liver was taken for antioxidant enzyme tests. Colonic tissue was taken for the histopathlogical score and RNA-sequencing analysis. Results: In this experiment, dietary quercetin for 500ppm alleviated the DSS-induced colitis, possibly by strengthening intestinal integrity, liver antioxidant capacity. Based on the results of the transcriptome of colon tissue, several key genes were modulated by quercetin. ERK1/2-FKBP pathway and RXR-STAT3 pathway were involved in the development of IBD, furthermore, in the down-regulation of S100a8/9, FBN2 contributed to lowering the risk of colongenesis. Conclusion: We demonstrated that dietary quercetin alleviated the DSS-induced colitis in mice. This is most likely due to its beneficial effects on intestinal integrity and modulation of several key pathways. Based on our research, quercetin was a promising candidate for IBD and its pharmaceutical effects on both IBD and colongenesis need further research.

scholarly journals Modulation of Gut Microbiota and Oxidative Status by β-Carotene in Late Pregnant Sows

2020 ◽  
Vol 7 ◽  
Author(s):  
Xupeng Yuan ◽  
Jiahao Yan ◽  
Ruizhi Hu ◽  
Yanli Li ◽  
Ying Wang ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Dietary Supplementation ◽  
Basal Diet ◽  
Fecal Microbiota ◽  
Control Group ◽  
Metabolic Activities ◽  
The Impact ◽  
Positive Effect ◽  
Β Carotene

Recent evidences suggest that gut microbiota plays an important role in regulating physiological and metabolic activities of pregnant sows, and β-carotene has a potentially positive effect on reproduction, but the impact of β-carotene on gut microbiota in pregnant sows remains unknown. This study aimed to explore the effect and mechanisms of β-carotene on the reproductive performance of sows from the aspect of gut microbiota. A total of 48 hybrid pregnant sows (Landrace × Yorkshire) with similar parity were randomly allocated into three groups (n = 16) and fed with a basal diet or a diet containing 30 or 90 mg/kg of β-carotene from day 90 of gestation until parturition. Dietary supplementation of 30 or 90 mg/kg β-carotene increased the number of live birth to 11.82 ± 1.54 and 12.29 ± 2.09, respectively, while the control group was 11.00 ± 1.41 (P = 0.201). Moreover, β-carotene increased significantly the serum nitric oxide (NO) level and glutathione peroxidase (GSH-Px) activity (P &lt; 0.05). Characterization of fecal microbiota revealed that 90 mg/kg β-carotene increased the diversity of the gut flora (P &lt; 0.05). In particular, β-carotene decreased the relative abundance of Firmicutes including Lachnospiraceae AC2044 group, Lachnospiraceae NK4B4 group and Ruminococcaceae UCG-008, but enriched Proteobacteria including Bilophila and Sutterella, and Actinobacteria including Corynebacterium and Corynebacterium 1 which are related to NO synthesis. These data demonstrated that dietary supplementation of β-carotene may increase antioxidant enzyme activity and NO, an important vasodilator to promote the neonatal blood circulation, through regulating gut microbiota in sows.

scholarly journals Protective effect of snail secretion filtrate against ethanol-induced gastric ulcer in mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Enrico Gugliandolo ◽  
Marika Cordaro ◽  
Roberta Fusco ◽  
Alessio Filippo Peritore ◽  
Rosalba Siracusa ◽  
...  
Keyword(s):  
Gastric Ulcer ◽  
Inflammatory Response ◽  
Protective Effect ◽  
Underlying Mechanism ◽  
New Drugs ◽  
Ethanol Administration ◽  
Common Disease ◽  
Intragastric Administration ◽  
Human Disorders ◽  
Interest In Research

AbstractGastric ulcer or peptic ulcer is a common disease worldwide. Basically, it develops when there is an imbalance between the protective and aggressive factors, especially at the luminal surface of epithelial cells. Thus, there is a constant interest in research new drugs for treatment of gastric ulcer. The snail secretion is a dense mucous, that covers the external surface of the snails, with important functions for the survival of snails. The biological proprieties of snail Helix Aspersa Muller mucus it has been known for centuries to treat human disorders in particular for skin disease. Recently the use of snail mucus has seen a worldwide increase, as a component in cosmetic product and it has been used in particular for the management of wound and skin disorders. In this study we use a murine model of ethanol intragastric administration which has been widely used to test the drugs efficacies and to explore the underlying mechanism for gastric ulcer development. The intragastric ethanol administration causes several mucosal damages and an induction of a severe inflammatory response. Our results show a significant protective effect of snail secretion filtrate in reducing macroscopic and histological lesions, as well the protective effect on mucus content, oxidative stress and inflammatory response. In conclusion this study demonstrate the protective effect of intragastrical snail secretion filtrate, in a model of ethanol-induced gastric ulcer in mice, suggesting its possible useful use in the treatment or prevention of gastric ulcer.

scholarly journals Dietary fermented rapeseed or/and soybean meal additives on performance and intestinal health of piglets

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anna Czech ◽  
Eugeniusz Ryszard Grela ◽  
Martyna Kiesz
Keyword(s):  
Gastrointestinal Tract ◽  
Gut Microbiota ◽  
Soybean Meal ◽  
Rapeseed Meal ◽  
Nutrient Digestibility ◽  
Control Group ◽  
Feed Conversion ◽  
Weaned Piglets ◽  
Feed Conversion Rate ◽  
Positive Effect

AbstractThe aim of the study was to assess the effect of fermented dried soybean (FSBM) and/or fermented rapeseed meal (FRSM) in diets for weaned piglets on production results, nutrient digestibility, gastrointestinal tract histology, and the composition of the gut microbiota. Piglets in the control group received standard diets with soybean meal. Animals in all experimental groups received diets in which a portion of the soybean meal was replaced: in group FR—8% FRSM; in group FR/FS—6% FRSM and 2% FSBM; in group FS/FR—2% FRSM and 6% FSBM and in group FS—8% FSBM. The use of 8% FRSM or 6% FRSM and 2% FSBM in the piglet diets had a positive effect on average daily gains. Piglets from the FR and FR/FS groups had the highest feed conversion rate. Group FS/FR and FS piglets had significantly lower mortality and lower incidence of diarrhoea. Piglets fed a diet with the fermented components, in particular with 8% FRSM or 6% FRSM and 2% FSBM, exhibited a positive effect on the microbiological composition and histology of intestines, which resulted in improved nutrient digestibility coefficients (ATTD and AID).

scholarly journals Evaluating the Effectiveness of Diabetes Shared Medical Appointments (SMAs) as Implemented in Five Veterans Affairs Health Systems: a Multi-site Cluster Randomized Pragmatic Trial

2021 ◽  
Author(s):  
Michele Heisler ◽  
Jennifer Burgess ◽  
Jeffrey Cass ◽  
John F. Chardos ◽  
Alexander B. Guirguis ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Usual Care ◽  
Health Systems ◽  
Pragmatic Trial ◽  
Veterans Affairs ◽  
Control Group ◽  
Shared Medical Appointments ◽  
Site Cluster ◽  
Cluster Randomized

Abstract Objective To examine whether diabetes shared medical appointments (SMAs) implemented as part of usual clinical practice in diverse health systems are more effective than usual care in improving and sustaining A1c improvements. Research Design and Methods A multi-site cluster randomized pragmatic trial examining implementation in clinical practice of diabetes SMAs in five Veterans Affairs (VA) health systems was conducted from 2016 to 2020 among 1537 adults with type 2 diabetes and elevated A1cs. Eligible patients were randomly assigned to either: (1) invitation to participate in a series of SMAs totaling 8–9 h; or (2) continuation of usual care. Relative change in A1c (primary outcome) and in systolic blood pressure, insulin starts, statin starts, and anti-hypertensive medication classes (secondary outcomes) were measured as part of usual clinical care at baseline, at 6 months and at 12 months (~7 months after conclusion of the final SMA in four of five sites). We examined outcomes in three samples of SMA participants: all those scheduled for a SMA, those attending at least one SMA, and those attending at least half of SMAs. Results Baseline mean A1c was 9.0%. Participants scheduled for an SMA achieved A1c reductions 0.35% points greater than the control group between baseline and 6-months follow up (p = .001). Those who attended at least one SMA achieved reductions 0.42 % points greater (p < .001), and those who attended at least half of scheduled SMAs achieved reductions 0.53 % points greater (p < .001) than the control group. At 12-month follow-up, the three SMA analysis samples achieved reductions from baseline ranging from 0.16 % points (p = 0.12) to 0.29 % points (p = .06) greater than the control group. Conclusions Diabetes SMAs as implemented in real-life diverse clinical practices improve glycemic control more than usual care immediately after the SMAs, but relative gains are not maintained. Our findings suggest the need for further study of whether a longer term SMA model or other follow-up strategies would sustain relative clinical improvements associated with this intervention. Trial Registration ClinicalTrials.gov ID NCT02132676

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