scholarly journals Effects of Gut Microbiota and Ingredient-Ingredient Interaction on the Pharmacokinetic Properties of Rotundic Acid and Pedunculoside

Planta Medica ◽  
2019 ◽  
Vol 85 (09/10) ◽  
pp. 729-737 ◽  
Author(s):  
Bao Yang ◽  
Hui Li ◽  
Qingfeng Ruan ◽  
Shenxin Xuan ◽  
Xiaojing Chen ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Oral Administration ◽  
Systemic Exposure ◽  
Lipid Lowering ◽  
Maximum Plasma ◽  
Dependent Manner ◽  
Monomer Mixture ◽  
Germ Free ◽  
Pharmacokinetic Interactions ◽  
Rotundic Acid

AbstractRotundic acid and pedunculoside are the most abundant constituents in Ilicis Rotundae Cortex, and possess lipid-lowering activity. In this study, we evaluated the pharmacokinetic interactions of rotundic acid with pedunculoside and other ingredients from Ilicis Rotundae Cortex with rotundic acid and pedunculoside, and preliminarily investigated the effects of gut microbiota on their pharmacokinetics using a pseudo-germ-free rat model. After a single oral administration of each monomer, a monomer mixture, and Ilicis Rotundae Cortex extract to the conventional and pseudo-germ-free rats, rotundic acid and pedunculoside were quantified in plasma by an UPLC/Q-TOF-MS/MS method. The systemic exposure (maximum plasma concentration and area under concentration-time curve) of two analytes in conventional rats were increased in an approximately dose-dependent manner. Oral administration of rotundic acid and pedunculoside in the forms of a monomer mixture and Ilicis Rotundae Cortex extract to the conventional rats significantly decreased the systemic exposure compared with the monomer groups, which demonstrated the existence of significant pharmacokinetic interactions. The pseudo-germ-free rats were prepared by nonabsorbable antibiotic treatment, and the systemic exposure of two analytes were significantly decreased and most of the “time to reach the maximum” values were delayed in comparison to conventional rats, therefore gut microbiota might serve as an efficient absorption promoter. These results provide a scientific basis for the clinical application of the two bioactive constituents and Ilicis Rotundae Cortex.

scholarly journals Rotundic Acid Protects against Metabolic Disturbance and Improves Gut Microbiota in Type 2 Diabetes Rats

Nutrients ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 67 ◽  
Author(s):  
Zenghao Yan ◽  
Hao Wu ◽  
Hongliang Yao ◽  
Wenjun Pan ◽  
Minmin Su ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Gut Microbiota ◽  
Southern China ◽  
16S Rrna Gene Sequencing ◽  
Metabolic Disturbance ◽  
Lipid Lowering ◽  
Rrna Gene ◽  
Illumina Hiseq ◽  
Rotundic Acid

Rotundic acid (RA) is a major triterpene constituent in the barks of Ilex rotunda Thunb, which have been widely used to make herbal tea for health care in southern China. RA has a variety of bioactivities such as anti-inflammation and lipid-lowering effect. However, little is known about the effects and mechanisms of RA on metabolic disturbance in type 2 diabetes (T2D) and its effect on gut microbiota. A T2D rat model induced by high fat diet (HFD) feeding and low-dose streptozotocin (STZ) injection was employed and RA showed multipronged effects on T2D and its complications, including improving glucolipid metabolism, lowering blood pressure, protecting against cardiovascular and hepatorenal injuries, and alleviating oxidative stress and inflammation. Furthermore, 16s rRNA gene sequencing was carried out on an Illumina HiSeq 2500 platform and RA treatment could restore the gut microbial dysbiosis in T2D rats to a certain extent. RA treatment significantly enhanced the richness and diversity of gut microbiota. At the genus level, beneficial or commensal bacteria Prevotella, Ruminococcus, Leuconostoc and Streptococcus were significantly increased by RA treatment, while RA-treated rats had a lower abundance of opportunistic pathogen Klebsiella and Proteus. Spearman’s correlation analysis showed that the abundances of these bacteria were strongly correlated with various biochemical parameters, suggesting that the improvement of gut microbiota might help to prevent or attenuate T2D and its complication. In conclusion, our findings support RA as a nutraceutical agent or plant foods rich in this compound might be helpful for the alleviation of T2D and its complications through improving gut microbiota.

scholarly journals IgA dysfunction induced by the early-lifetime disruption of gut microbiota aggravates diet–induced metabolic syndrome in mice

2021 ◽  
Author(s):  
Jielong Guo ◽  
Xue Han ◽  
Yilin You ◽  
Weidong Huang ◽  
Zhan Jicheng
Keyword(s):  
Metabolic Syndrome ◽  
Gut Microbiota ◽  
Early Life ◽  
Low Dose ◽  
Dependent Manner ◽  
Wild Type ◽  
Bacterial Composition ◽  
Germ Free ◽  
Iga Response ◽  
Intestinal Iga

Abstract BackgroundLow-dose antibiotic contamination in animal food is still a severe food safety problem worldwide. Penicillin is one of the main classes of antibiotics being detected in food. Previous studies have shown that transient exposure of low-dose penicillin (LDP) during early life resulted in metabolic syndrome (MetS) in mice. However, the underlying mechanism(s) and efficient approaches to counteracting this are largely unknown.MethodsWild-type (WT) or secretory IgA (SIgA)-deficient (Pigr-/-) C57BL/6 mice were exposed to LDP or not from several days before birth to 30 d of age. Five times of FMT or probiotics (a mixture of Lactobacillus bulgaricus and L. rhamnosus GG) treatments were applied to parts of these LDP-treated mice from 12 d to 28 d of life. Bacterial composition from different regions (mucosa and lumen) of the colon and ileum were analyzed through 16S rDNA sequencing. Intestinal IgA response was analyzed. Multiple parameters related to MetS were also determined. In addition, germ-free animals and in vitro tissue culture were also used to determine the correlations between LDP, gut microbiota (GM) and intestinal IgA response.ResultsLDP disturbed the intestinal bacterial composition, especially for ileal mucosa, the main inductive and effective sites of IgA response, in 30-d-old mice. The alteration of early GM resulted in a persistent inhibition of the intestinal IgA response, leading to a constant reduction of fecal and caecal SIgA levels throughout the 25-week experiment, which is early life-dependent, as transfer of LDP-GM to 30 d germ-free mice only resulted in a transient reduction in fecal SIgA. LDP-induced reduction in SIgA led to a decrease in IgA+ bacteria and a dysbiosis in the ileal mucosal samples of 25 week wild-type but not Pigr-/- mice. Moreover, LDP also resulted in increases in ileal bacterial encroachment and adipose inflammation, along with an enhancement of diet-induced MetS in an intestinal SIgA-dependent manner. Furthermore, several times of FMT or probiotic treatments during LDP treatment are efficient to fully (for FMT) or partially (for probiotics) counteract the LDP-effect on both GM and metabolism.ConclusionsEarly-life LDP-induced enhancement of diet-induced MetS is mediated by intestinal SIgA, which could be (partially) restored by FMT or probiotics treatment.

scholarly journals Pharmacological Activation of PXR and CAR Downregulates Distinct Bile Acid-Metabolizing Intestinal Bacteria and Alters Bile Acid Homeostasis

2018 ◽  
Vol 168 (1) ◽  
pp. 40-60 ◽  
Author(s):  
Joseph L Dempsey ◽  
Dongfang Wang ◽  
Gunseli Siginir ◽  
Qiang Fei ◽  
Daniel Raftery ◽  
...  
Keyword(s):  
Bile Acid ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Corn Oil ◽  
Constitutive Androstane Receptor ◽  
Intestinal Bacteria ◽  
Pregnane X Receptor ◽  
Bile Salt Hydrolase ◽  
Dependent Manner ◽  
Germ Free

AbstractThe gut microbiome regulates important host metabolic pathways including xenobiotic metabolism and intermediary metabolism, such as the conversion of primary bile acids (BAs) into secondary BAs. The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are well-known regulators for xenobiotic biotransformation in liver. However, little is known regarding the potential effects of PXR and CAR on the composition and function of the gut microbiome. To test our hypothesis that activation of PXR and CAR regulates gut microbiota and secondary BA synthesis, 9-week-old male conventional and germ-free mice were orally gavaged with corn oil, PXR agonist PCN (75 mg/kg), or CAR agonist TCPOBOP (3 mg/kg) once daily for 4 days. PCN and TCPOBOP decreased two taxa in the Bifidobacterium genus, which corresponded with decreased gene abundance of the BA-deconjugating enzyme bile salt hydrolase. In liver and small intestinal content of germ-free mice, there was a TCPOBOP-mediated increase in total, primary, and conjugated BAs corresponding with increased Cyp7a1 mRNA. Bifidobacterium, Dorea, Peptociccaceae, Anaeroplasma, and Ruminococcus positively correlated with T-UDCA in LIC, but negatively correlated with T-CDCA in serum. In conclusion, PXR and CAR activation downregulates BA-metabolizing bacteria in the intestine and modulates BA homeostasis in a gut microbiota-dependent manner.

Gut microbiota regulate Alzheimer’s disease pathologies and cognitive disorders via PUFA-associated neuroinflammation

Gut ◽  
2022 ◽  
pp. gutjnl-2021-326269
Author(s):  
Chun Chen ◽  
Jianming Liao ◽  
Yiyuan Xia ◽  
Xia Liu ◽  
Rheinallt Jones ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Amyloid Β ◽  
Microglia Activation ◽  
Oxidative Enzymes ◽  
Dependent Manner ◽  
Germ Free ◽  
Healthy Donors

ObjectiveThis study is to investigate the role of gut dysbiosis in triggering inflammation in the brain and its contribution to Alzheimer’s disease (AD) pathogenesis.DesignWe analysed the gut microbiota composition of 3×Tg mice in an age-dependent manner. We generated germ-free 3×Tg mice and recolonisation of germ-free 3×Tg mice with fecal samples from both patients with AD and age-matched healthy donors.ResultsMicrobial 16S rRNA sequencing revealed Bacteroides enrichment. We found a prominent reduction of cerebral amyloid-β plaques and neurofibrillary tangles pathology in germ-free 3×Tg mice as compared with specific-pathogen-free mice. And hippocampal RNAseq showed that inflammatory pathway and insulin/IGF-1 signalling in 3×Tg mice brain are aberrantly altered in the absence of gut microbiota. Poly-unsaturated fatty acid metabolites identified by metabolomic analysis, and their oxidative enzymes were selectively elevated, corresponding with microglia activation and inflammation. AD patients’ gut microbiome exacerbated AD pathologies in 3×Tg mice, associated with C/EBPβ/asparagine endopeptidase pathway activation and cognitive dysfunctions compared with healthy donors’ microbiota transplants.ConclusionsThese findings support that a complex gut microbiome is required for behavioural defects, microglia activation and AD pathologies, the gut microbiome contributes to pathologies in an AD mouse model and that dysbiosis of the human microbiome might be a risk factor for AD.

Evaluation of Glucose and Lipid Lowering Activity of Arganimide A in Normal and Streptozotocin-Induced Diabetic Rats

2019 ◽  
Vol 19 (4) ◽  
pp. 503-510 ◽  
Author(s):  
Mohamed Eddouks ◽  
Farid Khallouki ◽  
Robert W. Owen ◽  
Morad Hebi ◽  
Remy Burcelin
Keyword(s):  
Body Weight ◽  
Blood Glucose ◽  
Oral Administration ◽  
Lipid Profile ◽  
Plasma Cholesterol ◽  
Diabetic Rats ◽  
Lipid Lowering ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Lowering Activity

Aims: Arganimide A (4,4-dihydroxy-3,3-imino-di-benzoic acid) is a compound belonging to a family of aminophenolics found in fruit of Argania spinosa. The purpose of this study was to investigate the glucose and lipid lowering activity of Arganimide A (ARG A). Methods: The effect of a single dose and daily oral administration of Arganimide A (ARG A) on blood glucose levels and plasma lipid profile was tested in normal and streptozotocin (STZ) diabetic rats at a dose of 2 mg/kg body weight. Results: Single oral administration of ARG A reduced blood glucose levels from 26.50±0.61 mmol/L to 14.27±0.73 mmol/L (p<0.0001) six hours after administration in STZ diabetic rats. Furthermore, blood glucose levels were decreased from 5.35±0.30 mmol/L to 3.57±0.17 mmol/L (p<0.0001) and from 26.50±0.61 mmol/L to 3.67±0.29 mmol/L (p<0.0001) in normal and STZ diabetic rats, respectively, after seven days of treatment. Moreover, no significant changes in body weight in normal and STZ rats were shown. According to the lipid profile, the plasma triglycerides levels were decreased significantly in diabetic rats after seven days of ARG treatment (p<0.05). Moreover, seven days of ARG A treatment decreased significantly the plasma cholesterol concentrations (p<0.001). Conclusion: ARG A possesses glucose and lipid-lowering activity in diabetic rats and this natural compound may be beneficial in the treatment of diabetes.

10 THE ROLE OF DIETARY L-SERINE IN THE REGULATION OF INTESTINAL MUCUS BARRIER DURING INFLAMMATION

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S42-S42
Author(s):  
Kohei Sugihara ◽  
Nobuhiko Kamada
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Gut Microbiota ◽  
Control Diet ◽  
Bacterial Strains ◽  
Germ Free ◽  
Intestinal Mucus ◽  
Gnotobiotic Mice ◽  
Mucus Barrier

Abstract Background Recent accumulating evidence suggests that amino acids have crucial roles in the maintenance of intestinal homeostasis. In inflammatory bowel disease (IBD), amino acid metabolism is changed in both host and the gut microbiota. Among amino acids, L-serine plays a central role in several metabolic processes that are essential for the growth and survival of both mammalian and bacterial cells. However, the role of L-serine in intestinal homeostasis and IBD remains incompletely understood. In this study, we investigated the effect of dietary L-serine on intestinal inflammation in a murine model of colitis. Methods Specific pathogen-free (SPF) mice were fed either a control diet (amino acid-based diet) or an L-serine-deficient diet (SDD). Colitis was induced by the treatment of dextran sodium sulfate (DSS). The gut microbiome was analyzed by 16S rRNA sequencing. We also evaluate the effect of dietary L-serine in germ-free mice and gnotobiotic mice that were colonized by a consortium of non-mucolytic bacterial strains or the consortium plus mucolytic bacterial strains. Results We found that the SDD exacerbated experimental colitis in SPF mice. However, the severity of colitis in SDD-fed mice was comparable to control diet-fed mice in germ-free condition, suggesting that the gut microbiota is required for exacerbation of colitis caused by the restriction of dietary L-serine. The gut microbiome analysis revealed that dietary L-serine restriction fosters the blooms of a mucus-degrading bacterium Akkermansia muciniphila and adherent-invasive Escherichia coli in the inflamed gut. Consistent with the expansion of mucolytic bacteria, SDD-fed mice showed a loss of the intestinal mucus layer. Dysfunction of the mucus barrier resulted in increased intestinal permeability, thereby leading to bacterial translocation to the intestinal mucosa, which subsequently increased the severity of colitis. The increased intestinal permeability and subsequent bacterial translocation were observed in SDD-fed gnotobiotic mice that colonized by mucolytic bacteria. In contrast, dietary L-serine restriction did not alter intestinal barrier integrity in gnotobiotic mice that colonized only by non-mucolytic bacteria. Conclusion Our results suggest that dietary L-serine regulates the integrity of the intestinal mucus barrier during inflammation by limiting the expansion of mucus degrading bacteria.

scholarly journals A9 DORSAL ROOT GANGLIA NEURONAL RESPONSES AND SUBSTANCE P PRODUCTION ARE HIGHER IN MALE MICE

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 10-11
Author(s):  
J Pujo ◽  
G De Palma ◽  
J Lu ◽  
S M Collins ◽  
P Bercik
Keyword(s):  
Abdominal Pain ◽  
Substance P ◽  
Gut Microbiota ◽  
Sensory Neurons ◽  
Dorsal Root ◽  
Neuronal Response ◽  
Neuronal Responses ◽  
Visceral Sensitivity ◽  
Germ Free

Abstract Background Abdominal pain is a common complaint in patients with chronic gastrointestinal disorders. Accumulating evidence suggests that gut microbiota is an important determinant of gut function, including visceral sensitivity. Germ-free (GF) mice have been shown to display visceral hypersensitivity, which normalizes after colonization. Sex also appears to play a key role in visceral sensitivity, as women report more abdominal pain than men. Thus, both gut bacteria and sex are important in the regulation of gut nociception, but the underlying mechanisms remain poorly understood. Aims To investigate the role of gut microbiota and sex in abdominal pain. Methods We used primary cultures of sensory neurons from dorsal root ganglia (DRG) of female and male conventionally raised (SPF) or germ-free (GF) mice (7–18 weeks old). To study the visceral afferent activity in vitro, calcium mobilization in DRG sensory neurons was measured by inverted fluorescence microscope using a fluorescent calcium probe Fluo-4 (1mM). Two parameters were considered i) the percentage of responding neurons ii) the intensity of the neuronal response. First, DRG sensory neurons were stimulated by a TRPV1 agonist capsaicin (12.5nM, 125nM and 1.25µM) or by a mixture of G-protein coupled receptors agonist (GPCR: bradykinin, histamine and serotonin; 1µM, 10µM and 100µM). We next measured the neuronal production of substance P and calcitonin gene-related peptide (CGRP), two neuropeptides associated with nociception, in response to capsaicin (1.25µM) or GPCR agonists (100µM) by ELISA and EIA, respectively. Results The percentage of neurons responding to capsaicin and GPCR agonists was similar in male and female SPF and GF mice. However, the intensity of the neuronal response was higher in SPF male compared to SPF female in response to capsaicin (125nM: p=0.0336; 1.25µM: p=0.033) but not to GPCR agonists. Neuronal activation was similar in GF and SPF mice of both sexes after administration of capsaicin or GPCR agonists. Furthermore, substance P and CGRP production by sensory neurons induced by capsaicin or GPCR agonists was similar in SPF and GF mice, regardless of sex. However, while the response to capsaicin was similar, the GPCR agonists-induced production of substance P was higher in SPF male mice compared to SPF females (p=0.003). The GPCR agonists-induced production of CGRP was similar in SPF male and female mice. Conclusions Our data suggest that at the level of DRG neurons, the absence of gut microbiota does not predispose to visceral hypersensitivity. The intensity of DRG neuronal responses to capsaicin and the GPCR agonists-induced production of substance P are higher in male compared to female mice, in contrast to previously published studies in various models of acute and chronic pain. Further studies are thus needed to investigate the role of sex in visceral sensitivity. Funding Agencies CIHR

scholarly journals Relationships of gut microbiota, short-chain fatty acids, inflammation, and the gut barrier in Parkinson’s disease

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Velma T. E. Aho ◽  
Madelyn C. Houser ◽  
Pedro A. B. Pereira ◽  
Jianjun Chang ◽  
Knut Rudi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Fatty Acids ◽  
Parkinson's Disease ◽  
Gut Microbiota ◽  
Inflammatory Responses ◽  
Disease Onset ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Dependent Manner ◽  
Chain Fatty Acids

Abstract Background Previous studies have reported that gut microbiota, permeability, short-chain fatty acids (SCFAs), and inflammation are altered in Parkinson’s disease (PD), but how these factors are linked and how they contribute to disease processes and symptoms remains uncertain. This study sought to compare and identify associations among these factors in PD patients and controls to elucidate their interrelations and links to clinical manifestations of PD. Methods Stool and plasma samples and clinical data were collected from 55 PD patients and 56 controls. Levels of stool SCFAs and stool and plasma inflammatory and permeability markers were compared between patients and controls and related to one another and to the gut microbiota. Results Calprotectin was increased and SCFAs decreased in stool in PD in a sex-dependent manner. Inflammatory markers in plasma and stool were neither intercorrelated nor strongly associated with SCFA levels. Age at PD onset was positively correlated with SCFAs and negatively correlated with CXCL8 and IL-1β in stool. Fecal zonulin correlated positively with fecal NGAL and negatively with PD motor and non-motor symptoms. Microbiota diversity and composition were linked to levels of SCFAs, inflammatory factors, and zonulin in stool. Certain relationships differed between patients and controls and by sex. Conclusions Intestinal inflammatory responses and reductions in fecal SCFAs occur in PD, are related to the microbiota and to disease onset, and are not reflected in plasma inflammatory profiles. Some of these relationships are distinct in PD and are sex-dependent. This study revealed potential alterations in microbiota-host interactions and links between earlier PD onset and intestinal inflammatory responses and reduced SCFA levels, highlighting candidate molecules and pathways which may contribute to PD pathogenesis and clinical presentation and which warrant further investigation.

scholarly journals Lactobacillus rhamnosus HDB1258 modulates gut microbiota-mediated immune response in mice with or without lipopolysaccharide-induced systemic inflammation

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Sang-Kap Han ◽  
Yeon-Jeong Shin ◽  
Dong-Yeon Lee ◽  
Kyung Min Kim ◽  
Seo-Jin Yang ◽  
...  
Keyword(s):  
Immune Response ◽  
Gut Microbiota ◽  
Oral Administration ◽  
Systemic Inflammation ◽  
Nk Cell ◽  
Lactobacillus Rhamnosus ◽  
Expression Ratio ◽  
Macrophage Phagocytosis ◽  
Tnf Α ◽  
Gut Microbiota Composition

Abstract Background Gut microbiota closely communicate in the immune system to maintain a balanced immune homeostasis in the gastrointestinal tract of the host. Oral administration of probiotics modulates gut microbiota composition. In the present study, we isolated Lactobacillus rhamnosus HDB1258, which induced tumor necrosis factor (TNF)-α and interleukin (IL)-10 expression in macrophages, from the feces of breastfeeding infants and examined how HDB1258 could regulate the homeostatic immune response in mice with or without lipopolysaccharide (LPS)-induced systemic inflammation. Results Oral administration of HDB1258 significantly increased splenic NK cell cytotoxicity, peritoneal macrophage phagocytosis, splenic and colonic TNF-α expression, TNF-α to IL-10 expression ratio, and fecal IgA level in control mice, while Th1 and Treg cell differentiation was not affected in the spleen. However, HDB1258 treatment significantly suppressed peritoneal macrophage phagocytosis and blood prostaglandin E2 level in mice with LPS-induced systemic inflammation. Its treatment increased LPS-suppressed ratios of Treg to Th1 cell population, Foxp3 to T-bet expression, and IL-10 to TNF-α expression. Oral administration of HDB1258 significantly decreased LPS-induced colon shortening, myeloperoxidase activity and NF-κB+/CD11c+ cell population in the colon, while the ratio of IL-10 to TNF-α expression increased. Moreover, HDB1258 treatment shifted gut microbiota composition in mice with and without LPS-induced systemic inflammation: it increased the Cyanobacteria and PAC000664_g (belonging to Bacteroidetes) populations and reduced Deferribacteres and EU622763_s group (belonging to Bacteroidetes) populations. In particular, PAC001066_g and PAC001072_s populations were negatively correlated with the ratio of IL-10 to TNF-α expression in the colon, while the PAC001070_s group population was positively correlated. Conclusions Oral administered HDB1258 may enhance the immune response by activating innate immunity including to macrophage phagocytosis and NK cell cytotoxicity in the healthy host and suppress systemic inflammation in the host with inflammation by the modulation of gut microbiota and IL-10 to TNF-α expression ratio in immune cells.

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