scholarly journals Melatonin Alleviates Neuroinflammation and Metabolic Disorder in DSS-Induced Depression Rats

2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Wei-jie Lv ◽  
Cui Liu ◽  
Lin-zeng Yu ◽  
Jia-hao Zhou ◽  
Yue Li ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Signaling Pathways ◽  
Metabolic Disorder ◽  
Farnesoid X Receptor ◽  
Bile Salt Hydrolase ◽  
Immobility Time ◽  
Bidirectional Relationship ◽  
Inflammatory Processes ◽  
Inflammatory Bowel ◽  
Swimming Test

There is a bidirectional relationship between inflammatory bowel disease (IBD) and depression/anxiety. Emerging evidences indicate that the liver may be involved in microbiota-gut-brain axis. This experiment focused on the role of melatonin in regulating the gut microbiota and explores its mechanism on dextran sulphate sodium- (DSS-) induced neuroinflammation and liver injury. Long-term DSS-treatment increased lipopolysaccharide (LPS), proinflammation cytokines IL-1β and TNF-α, and gut leak in rats, breaking blood-brain barrier and overactivated astrocytes and microglia. Ultimately, the rats showed depression-like behavior, including reduction of sucrose preference and central time in open field test and elevation of immobility time in a forced swimming test. Oral administration with melatonin alleviated neuroinflammation and depression-like behaviors. However, melatonin supplementation did not decrease the level of LPS but increase short-chain fatty acid (SCFA) production to protect DSS-induced neuroinflammation. Additionally, western blotting analysis suggested that signaling pathways farnesoid X receptor-fibroblast growth factor 15 (FXR-FGF 15) in gut and apoptosis signal-regulating kinase 1 (ASK1) in the liver overactivated in DSS-treated rats, indicating liver metabolic disorder. Supplementation with melatonin markedly inhibited the activation of these two signaling pathways and its downstream p38. As for the gut microbiota, we found that immune response- and SCFA production-related microbiota, like Lactobacillus and Clostridium significantly increased, while bile salt hydrolase activity-related microbiota, like Streptococcus and Enterococcus, significantly decreased after melatonin supplementation. These altered microbiota were consistent with the alleviation of neuroinflammation and metabolic disorder. Taken together, our findings suggest melatonin contributes to reshape gut microbiota and improves inflammatory processes in the hippocampus (HPC) and metabolic disorders in the liver of DSS rats.

Alterations in Bile Acid Metabolism Associated With Inflammatory Bowel Disease

2021 ◽  
Author(s):  
Na Li ◽  
Shukai Zhan ◽  
Zhenyi Tian ◽  
Caiguang Liu ◽  
Zonglin Xie ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Gut Microbiota ◽  
Bowel Disease ◽  
Patient Characteristics ◽  
Bile Acid Metabolism ◽  
Inflammatory Disorder ◽  
Sample Type ◽  
Fecal Samples ◽  
Inflammatory Processes ◽  
Inflammatory Bowel

Abstract Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder closely related to gut dysbiosis, which is associated with alterations in an important bacterial metabolite, bile acids (BAs). Although certain findings pertinent to BA changes in IBD vary among studies owing to the differences in sample type, quantitated BA species, study methodology, and patient characteristics, a specific trend concerning variations of BAs in IBD has been identified. In elaborating on this observation, it was noted that primary BAs and conjugated BAs are augmented in fecal samples but there is a reduction in secondary BAs in fecal samples. It is not entirely clear why patients with IBD manifest these changes and what role these changes play in the onset and development of IBD. Previous studies have shown that IBD-associated BA changes may be caused by alterations in BA absorption, synthesis, and bacterial modification. The complex relationship between bacteria and BAs may provide additional and deeper insight into host-gut microbiota interactions in the pathogenesis of IBD. The characteristic BA changes may generate profound effects in patients with IBD by shaping the gut microbiota community, affecting inflammatory processes, causing BA malabsorption associated with diarrhea, and even leading to intestinal dysplasia and cancer. Thus, therapeutic strategies correcting the alterations in the composition of BAs, including the elimination of excess BAs and the supplementation of deficient BAs, may prove promising in IBD.

scholarly journals The triterpenoid sapogenin (2α-OH-Protopanoxadiol) ameliorates metabolic syndrome via the intestinal FXR/GLP-1 axis through gut microbiota remodelling

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Zhifu Xie ◽  
Haowen Jiang ◽  
Wei Liu ◽  
Xinwen Zhang ◽  
Dakai Chen ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Gut Microbiota ◽  
Cell Function ◽  
Chronic Administration ◽  
Fecal Microbiota ◽  
Farnesoid X Receptor ◽  
Bile Salt Hydrolase ◽  
L Cell ◽  
Oral Therapeutic

Abstract Gypenosides, extracts of Gynostemma yixingense, have been traditionally prescribed to improve metabolic syndrome in Asian folk and local traditional medicine hospitals. However, the mechanism of its action remains unclarified. In this work, our results indicated that chronic administration of 2α-OH-protopanoxadiol (GP2), a metabolite of gypenosides in vivo, protected mice from high-fat diet-induced obesity and improved glucose tolerance by improving intestinal L-cell function. Mechanistically, GP2 treatment inhibited the enzymatic activity of bile salt hydrolase and modulated the proportions of the gut microbiota, which led to an increase in the accumulation of tauro-β-muricholic acid (TβMCA) in the intestine. TβMCA induced GLP-1 production and secretion by reducing the transcriptional activity of nuclear receptor farnesoid X receptor (FXR). Transplantation of GP2-remodelled fecal microbiota into antibiotic-treated mice also increased the intestinal TβMCA content and improved intestinal L-cell function. These findings demonstrate that GP2 ameliorates metabolic syndrome at least partly through the intestinal FXR/GLP-1 axis via gut microbiota remodelling and also suggest that GP2 may serve as a promising oral therapeutic agent for metabolic syndrome.

scholarly journals Resveratrol Attenuates Trimethylamine- N -Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota

mBio ◽  
2016 ◽  
Vol 7 (2) ◽  
Author(s):  
Ming-liang Chen ◽  
Long Yi ◽  
Yong Zhang ◽  
Xi Zhou ◽  
Li Ran ◽  
...  
Keyword(s):  
Bile Acid ◽  
Growth Factor ◽  
Gut Microbiota ◽  
Fibroblast Growth Factor ◽  
Farnesoid X Receptor ◽  
Fecal Excretion ◽  
Bile Acid Metabolism ◽  
Bile Salt Hydrolase ◽  
Fibroblast Growth ◽  
As Effects

ABSTRACT The gut microbiota is found to be strongly associated with atherosclerosis (AS). Resveratrol (RSV) is a natural phytoalexin with anti-AS effects; however, its mechanisms of action remain unclear. Therefore, we sought to determine whether the anti-AS effects of RSV were related to changes in the gut microbiota. We found that RSV attenuated trimethylamine- N -oxide (TMAO)-induced AS in ApoE −/− mice. Meanwhile, RSV decreased TMAO levels by inhibiting commensal microbial trimethylamine (TMA) production via gut microbiota remodeling in mice. Moreover, RSV increased levels of the genera Lactobacillus and Bifidobacterium , which increased the bile salt hydrolase activity, thereby enhancing bile acid (BA) deconjugation and fecal excretion in C57BL/6J and ApoE −/− mice. This was associated with a decrease in ileal BA content, repression of the enterohepatic farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) axis, and increased cholesterol 7a-hydroxylase (CYP7A1) expression and hepatic BA neosynthesis. An FXR antagonist had the same effect on FGF15 and CYP7A1 expression as RSV, while an FXR agonist abolished RSV-induced alterations in FGF15 and CYP7A1 expression. In mice treated with antibiotics, RSV neither decreased TMAO levels nor increased hepatic BA synthesis. Additionally, RSV-induced inhibition of TMAO-caused AS was also markedly abolished by antibiotics. In conclusion, RSV attenuated TMAO-induced AS by decreasing TMAO levels and increasing hepatic BA neosynthesis via gut microbiota remodeling, and the BA neosynthesis was partially mediated through the enterohepatic FXR-FGF15 axis. IMPORTANCE Recently, trimethylamine- N -oxide (TMAO) has been identified as a novel and independent risk factor for promoting atherosclerosis (AS) partially through inhibiting hepatic bile acid (BA) synthesis. The gut microbiota plays a key role in the pathophysiology of TMAO-induced AS. Resveratrol (RSV) is a natural phytoalexin with prebiotic benefits. A growing body of evidence supports the hypothesis that phenolic phytochemicals with poor bioavailability are possibly acting primarily through remodeling of the gut microbiota. The current study showed that RSV attenuated TMAO-induced AS by decreasing TMAO levels and increasing hepatic BA neosynthesis via gut microbiota remodeling. And RSV-induced hepatic BA neosynthesis was partially mediated through downregulating the enterohepatic farnesoid X receptor-fibroblast growth factor 15 axis. These results offer new insights into the mechanisms responsible for RSV’s anti-AS effects and indicate that the gut microbiota may become an interesting target for pharmacological or dietary interventions to decrease the risk of developing cardiovascular diseases.

scholarly journals Farnesoid X Receptor Signaling Shapes the Gut Microbiota and Controls Hepatic Lipid Metabolism

mSystems ◽  
2016 ◽  
Vol 1 (5) ◽  
Author(s):  
Limin Zhang ◽  
Cen Xie ◽  
Robert G. Nichols ◽  
Siu H. J. Chan ◽  
Changtao Jiang ◽  
...  
Keyword(s):  
Community Structure ◽  
Gut Microbiota ◽  
Bile Salt ◽  
Structure And Function ◽  
Farnesoid X Receptor ◽  
Bile Salt Hydrolase ◽  
Metabolic Models ◽  
And Function ◽  
Genome Scale ◽  
Bile Salt Hydrolase Activity

ABSTRACT The farnesoid X receptor (FXR) plays an important role in mediating the dialog between the host and gut microbiota, particularly through modulation of enterohepatic circulation of bile acids. Mounting evidence suggests that genetic ablation of Fxr in the gut or gut-restricted chemical antagonism of the FXR promotes beneficial health effects, including the prevention of nonalcoholic fatty liver disease in rodent models. However, questions remain unanswered, including whether modulation of FXR activity plays a role in shaping the gut microbiota community structure and function and what metabolic pathways of the gut microbiota contribute in an FXR-dependent manner to the host phenotype. In this report, new insights are gained into the metabolic contribution of the gut microbiota to the metabolic phenotypes, including establishing a link between FXR antagonism, bacterial bile salt hydrolase activity, and fermentation. Multiple approaches, including unique mouse models as well as metabolomics and genome-scale metabolic models, were employed to confirm these results. The gut microbiota modulates obesity and associated metabolic phenotypes in part through intestinal farnesoid X receptor (FXR) signaling. Glycine-β-muricholic acid (Gly-MCA), an intestinal FXR antagonist, has been reported to prevent or reverse high-fat diet (HFD)-induced and genetic obesity, insulin resistance, and fatty liver; however, the mechanism by which these phenotypes are improved is not fully understood. The current study investigated the influence of FXR activity on the gut microbiota community structure and function and its impact on hepatic lipid metabolism. Predictions about the metabolic contribution of the gut microbiota to the host were made using 16S rRNA-based PICRUSt (phylogenetic investigation of communities by reconstruction of unobserved states), then validated using 1H nuclear magnetic resonance-based metabolomics, and results were summarized by using genome-scale metabolic models. Oral Gly-MCA administration altered the gut microbial community structure, notably reducing the ratio of Firmicutes to Bacteroidetes and its PICRUSt-predicted metabolic function, including reduced production of short-chain fatty acids (substrates for hepatic gluconeogenesis and de novo lipogenesis) in the ceca of HFD-fed mice. Metabolic improvement was intestinal FXR dependent, as revealed by the lack of changes in HFD-fed intestine-specific Fxr-null (Fxr ΔIE) mice treated with Gly-MCA. Integrative analyses based on genome-scale metabolic models demonstrated an important link between Lactobacillus and Clostridia bile salt hydrolase activity and bacterial fermentation. Hepatic metabolite levels after Gly-MCA treatment correlated with altered levels of gut bacterial species. In conclusion, modulation of the gut microbiota by inhibition of intestinal FXR signaling alters host liver lipid metabolism and improves obesity-related metabolic dysfunction. IMPORTANCE The farnesoid X receptor (FXR) plays an important role in mediating the dialog between the host and gut microbiota, particularly through modulation of enterohepatic circulation of bile acids. Mounting evidence suggests that genetic ablation of Fxr in the gut or gut-restricted chemical antagonism of the FXR promotes beneficial health effects, including the prevention of nonalcoholic fatty liver disease in rodent models. However, questions remain unanswered, including whether modulation of FXR activity plays a role in shaping the gut microbiota community structure and function and what metabolic pathways of the gut microbiota contribute in an FXR-dependent manner to the host phenotype. In this report, new insights are gained into the metabolic contribution of the gut microbiota to the metabolic phenotypes, including establishing a link between FXR antagonism, bacterial bile salt hydrolase activity, and fermentation. Multiple approaches, including unique mouse models as well as metabolomics and genome-scale metabolic models, were employed to confirm these results.

scholarly journals Absence of gut microbiota affects lipid metabolism in the prefrontal cortex of mice

2021 ◽  
Author(s):  
Jian-Jun Chen ◽  
Jing Xie ◽  
Ben-hua Zeng ◽  
Wen-wen Li ◽  
Shun-jie Bai ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Lipid Metabolism ◽  
Gut Microbiota ◽  
Behavioral Activity ◽  
Immobility Time ◽  
Liquid Chromatography Tandem Mass ◽  
Specific Pathogen ◽  
Swimming Test ◽  
Lipid Metabolites ◽  
One Way Anova

Abstract Objectives: Lipid metabolism is closely associated with many important biological functions. Here, we conducted this study to explore the effects of gut microbiota on the lipid metabolism in the prefrontal cortex of mice.Methods: Germ-free (GF) mice, specific pathogen-free (SPF) and colonized GF (CGF) mice were used in this study. The open field test (OFT), forced swimming test (FST) and novelty suppressed feeding test (NSFT) were conducted to assess the changes in general behavioral activity. The liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) was used to obtain the lipid metabolites. Both one-way analysis of variance (one-way ANOVA) and orthogonal partial least-squares discriminant analysis (OPLS-DA) were used to obtain the key differential lipid metabolites.Results: The behavioral tests showed that compared to SPF mice, GF mice had more center distance, more center time, less immobility time and less latency to familiar food. Meanwhile, 142 key differential lipid metabolites between SPF mice and GF mice were identified. These lipid metabolites mainly belonged to glycerophospholipids, glycerolipids, sphingolipids, and saccharolipids. The gut microbiota colonization did not reverse these changed behavioral phenotypes, but could restore 25 key differential lipid metabolites.Discussion: These results showed that the absence of gut microbiota could influence host behaviors and lipid metabolism. Our findings could provide original and valuable data for future studies to further investigate the microbiota-gut-brain axis.

scholarly journals Absence of gut microbiota affects lipid metabolism in the prefrontal cortex of mice

2021 ◽  
Author(s):  
Jian-Jun Chen ◽  
Jing Xie ◽  
Ben-hua Zeng ◽  
Wen-wen Li ◽  
Shun-jie Bai ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Lipid Metabolism ◽  
Gut Microbiota ◽  
Behavioral Activity ◽  
Immobility Time ◽  
Liquid Chromatography Tandem Mass ◽  
Specific Pathogen ◽  
Swimming Test ◽  
Lipid Metabolites ◽  
One Way Anova

Abstract Objectives: Lipid metabolism is closely associated with many important biological functions. Here, we conducted this study to explore the effects of gut microbiota on the lipid metabolism in the prefrontal cortex of mice. Methods: Germ-free (GF) mice, specific pathogen-free (SPF) and colonized GF (CGF) mice were used in this study. The open field test (OFT), forced swimming test (FST) and novelty suppressed feeding test (NSFT) were conducted to assess the changes in general behavioral activity. The liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) was used to obtain the lipid metabolites. Both one-way analysis of variance (one-way ANOVA) and orthogonal partial least-squares discriminant analysis (OPLS-DA) were used to obtain the key differential lipid metabolites.Results: The behavioral tests showed that compared to SPF mice, GF mice had more center distance, more center time, less immobility time and less latency to familiar food. Meanwhile, 142 key differential lipid metabolites between SPF mice and GF mice were identified. These lipid metabolites mainly belonged to glycerophospholipids, glycerolipids, sphingolipids, and saccharolipids. The gut microbiota colonization did not reverse these changed behavioral phenotypes, but could restore 25 key differential lipid metabolites.Discussion: These results showed that the absence of gut microbiota could influence host behaviors and lipid metabolism. Our findings could provide original and valuable data for future studies to further investigate the microbiota-gut-brain axis.

scholarly journals In Silico Evaluation of Putative S100B Interacting Proteins in Healthy and IBD Gut Microbiota

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1697
Author(s):  
Massimiliano Orsini ◽  
Rosa Di Liddo ◽  
Federica Valeriani ◽  
Marzia Mancin ◽  
Renata D’Incà ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Intestinal Wall ◽  
Proteomics Data ◽  
Human Gut ◽  
Pathological Conditions ◽  
Signalling Molecule ◽  
Inflammatory Processes ◽  
Inflammatory Bowel ◽  
Bioinformatics Workflow

The crosstalk between human gut microbiota and intestinal wall is essential for the organ’s homeostasis and immune tolerance. The gut microbiota plays a role in healthy and pathological conditions mediated by inflammatory processes or by the gut-brain axes, both involving a possible role for S100B protein as a diffusible cytokine present not only in intestinal mucosa but also in faeces. In order to identify target proteins for a putative interaction between S100B and the microbiota proteome, we developed a bioinformatics workflow by integrating the interaction features of known domains with the proteomics data derived from metataxonomic studies of the gut microbiota from healthy and inflammatory bowel disease (IBD) subjects. On the basis of the microbiota composition, proteins putatively interacting with S100B domains were in fact found, both in healthy subjects and IBD patients, in a reduced number in the latter samples, also exhibiting differences in interacting domains occurrence between the two groups. In addition, differences between ulcerative colitis and Crohn disease samples were observed. These results offer the conceptual framework for where to investigate the role of S100B as a candidate signalling molecule in the microbiota/gut communication machinery, on the basis of interactions differently conditioned by healthy or pathological microbiota.

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