The gut microbiome modulates nitroglycerin-induced migraine-related hyperalgesia in mice

Cephalalgia ◽  
2021 ◽  
pp. 033310242110500
Author(s):  
Li Kang ◽  
Wenjing Tang ◽  
Yaofen Zhang ◽  
Mingjie Zhang ◽  
Jing Liu ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Gut Microbiome ◽  
Expression Level ◽  
Specific Pathogen Free ◽  
Trigeminal Nucleus ◽  
Germ Free ◽  
Microbial Profile ◽  
Matched Healthy Control ◽  
Specific Pathogen ◽  
Healthy Control

Background Gut microbiota disturbance is increasingly suggested to be involved in the pathogenesis of migraine but this connection remains unsubstantiated. This study aimed to investigate whether the gut microbiome influences migraine-related hyperalgesia. Methods Nitroglycerin-induced hyperalgesia was evaluated in mice with different gut microbiota statuses as follows: Specific pathogen-free mice; germ-free mice; specific pathogen-free mice treated with antibiotics to deplete the gut microbiome (ABX mice); and germ-free mice transplanted with the gut microbial profile from specific pathogen-free mice (GFC mice). Moreover, nitroglycerin-induced hyperalgesia was compared between recipient mice transplanted with gut microbiota from a patient with migraine and those that received gut microbiota from a sex- and age-matched healthy control. Results In specific pathogen-free mice, a decreased mechanical threshold in the hind paw, increased grooming time, increased c-Fos expression level and decreased calcitonin gene-related peptide expression level as well as increased tumor necrosis factor-α concentration in the trigeminal nucleus caudalis were observed after nitroglycerin administration compared with saline treatment. However, increased basal sensitivity and higher basal concentrations of TNF-α in the trigeminal nucleus caudalis were observed in germ-free and ABX mice, while no significant difference in hyperalgesia was observed between the nitroglycerin group and saline group in germ-free and ABX mice. Moreover, significant hyperalgesia was induced by nitroglycerin administration in GFC mice. The mice transplanted with the gut microbial profile from a patient with migraine had more severe nitroglycerin-induced hyperalgesia than the mice receiving microbiota from a matched healthy control. Conclusion Our findings highlight the involvement of the gut microbiome in normal mechanical pain sensation and pathogenesis of migraine.

scholarly journals Microbiota Facilitates the Formation of the Aminated Metabolite of Tea Polyphenols Which Trap Deleterious Reactive Endogenous Metabolites (P06-022-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Shuwei Zhang ◽  
Yantao Zhao ◽  
Christina Ohland ◽  
Christian Jobin ◽  
Shengmin Sang
Keyword(s):  
Gut Microbiota ◽  
Chronic Diseases ◽  
Green Tea ◽  
Tea Polyphenols ◽  
Specific Pathogen Free ◽  
Tea Polyphenol ◽  
Germ Free ◽  
Specific Pathogen ◽  
Conjugated Metabolites

Abstract Objectives The in vivo mechanism of tea polyphenol-mediated prevention of many chronic diseases is still largely unknown. Studies have shown that accumulation of toxic reactive cellular metabolites, such as ammonia and reactive carbonyl species (RCS), is one of the causing factors to the development of many chronic diseases. The objective of this study is to investigated the in vivo interaction between tea polyphenols and ammonia and RCS. Methods In mice, we gave 200 mg/kg tea polyphenol ((-)-epigallocatechin-3-gallate (EGCG) or theaflavin) to CD-1 mice, 129/SvEv specific-pathogen-free (SPF) mice, or germ-free (GF) mice. Urinary and fecal samples were collected in metabolic cages for 24 h. In humans, two healthy volunteers drank 4 cups of Lipton green tea every day for four days. On the fourth day, 24 h urinary and fecal samples were collected after consuming the first cup of tea. Using LC tandem mass, we searched the formation of the aminated and RCS conjugated metabolites of tea polyphenols. Chemical standards were synthesized to confirm the structures of these metabolites. In order to study the impact of gut microbiota on the formation of these metabolites, we also quantified the concentrations of these metabolites in SPF and GF mice. Results We found that both EGCG and theaflavin could rapidly react with ammonia to generate the aminated metabolites. Both tea polyphenols and their aminated metabolites could further scavenge RCS, such as methylglyoxal (MGO), malondialdehyde (MDA), and trans-4-hydroxy-2-nonenal (4-HNE), to produce the RCS conjugates of tea polyphenols and the aminated tea polyphenols. Both the aminated and the RCS conjugated metabolites of EGCG were detected in human after drinking four cups of green tea per day. By comparing the levels of the aminated and the RCS conjugated metabolites in EGCG or theaflavin exposed germ-free (GF) mice and specific-pathogen-free (SPF) mice, we demonstrated that gut microbiota facilitate the formation of the aminated metabolites of tea polyphenols, the RCS conjugates of tea polyphenols, and the RCS conjugates of the aminated tea polyphenols. Conclusions Altogether, this study provides in vivo evidences that tea polyphenols have the capacity to scavenge toxic reactive metabolic wastes. This finding opens a new window to understand the underlying mechanisms by which drinking tea could prevent the development of chronic diseases. Funding Sources We gratefully acknowledge financial support from NIH R01 grant AT008623 to this work.

scholarly journals Mice, Models, Microbiota: How Can We More Accurately Reflect Human Disease?

2021 ◽  
Vol 15 (1) ◽  
pp. 8
Author(s):  
Rahman Ladak ◽  
Dana Philpott
Keyword(s):  
Gut Microbiota ◽  
Translational Research ◽  
Mouse Models ◽  
Human Disease ◽  
Specific Pathogen Free ◽  
Germ Free ◽  
Stage Of Development ◽  
Specific Pathogen

With growing evidence that human disease is affected by the microbiota, many researchers have sought to modulate the microbiomes of mice to improve translational research. Altering their microbiomes, which are usually germ-free or specific pathogen-free, might allow mice to more accurately model human disease and hence produce more applicable findings. However, this has been difficult to apply to individual projects due to the disparity of explained methods and results. In this review, we first describe the immunological functions of the gut microbiota and the methods of altering mice microbiota, from transplantation route to age of transplantation to microbiota source. We then present an approach for how the gut microbiota might be considered when modelling human disease in mice. By organizing findings by type of disease - neurological, immunological, chronic inflammatory, and cancer - we propose that mouse models can be improved by considering the source of the microbiota, the presence or absence of certain microbial phyla, and by timing the transplantation during a physiologically relevant stage of development, such as the first five weeks of life.

scholarly journals Enterococcus Faecium is a Risk Factor for The Outbreak of Anxiety and Depression in Patients With Inflammatory Bowel Disease

2020 ◽  
Author(s):  
Hyo-Min Jang ◽  
Jeon-Kyung Kim ◽  
Min-Kyung Joo ◽  
Yun-Jung Shin ◽  
Kyung-Eon Lee ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Gut Microbiota ◽  
Cell Population ◽  
Enterococcus Faecium ◽  
Fecal Microbiota ◽  
Specific Pathogen Free ◽  
Germ Free ◽  
Specific Pathogen ◽  
Inflammatory Bowel ◽  
Anxiety Depression

Abstract BackgroundThe gut microbiota closely communicate with the brain through the microbiota-gut-brain axis. The interaction between gut microbiota may regulate the occurrence of neuropsychiatric disorders, including depression. Therefore, we transplanted the fecal microbiota of patients with inflammatory bowel disease (IBD) or their overpopulated gut bacteria into specific-pathogen-free or germ-free mice and examined their effects regarding the occurrence of colitis and anxiety/depression. ResultsFecal microbiota transplantations (FMTs) from patients with IBD with (/D+) or without depression (/D-) caused IBD-like colitis in the transplanted mice: they increased myeloperoxidase activity and NF-κB+/CD11c+ cell population in the colon. FMTs from patients with IBD/D+ caused anxiety-/depression-like behaviors and NF-κB+/Iba1+ and lipopolysaccharide (LPS)+/Iba1+ cell population and decreased the BDNF+/NeuN+ cell population in the hippocampus. FMTs from patients with IBD/D- caused anxiety-like, but not depression-like, behaviors. α-/β-diversities and composition of microbiota in the feces of patients with IBD (IBD-F) were different from those of healthy-control feces (HC-F). The Enterobacteriaceae and Enterococcaceae populations and fecal lipopolysaccharide levels were higher in IBD-F vs. HC-F. Moreover, the Enterococcaceae population was higher in IBD/D+-F vs. IBD/D--F, while the Bifidobacteria population was lower in IBD/D+-F. FMT from HC alleviated the IBD/D+-F-induced anxiety-/depression-like behaviors and colitis in the transplanted mice. Furthermore, it suppressed IBD/D+-F-induced Enterococcus sp. population in the feces. Enterobacteriaceae Klebsiella oxytoca, Klebsiella pneumoniae, Escherichia coli, and Cronobacter sakazakii abundant in IBD-F, singly or together, caused depression with colitis in germ-free and specific-pathogen-free mice, while Enterococcus faecium abundant in IBD/D+-F did not cause not anxiety/depression and colitis. However, the combination of Enterobacteriaceae with Enterococcus faecium synergistically deteriorated depression and colitis, while its combination with Bifidobacterium longum attenuated them. ConclusionThe interaction between gut microbiota Enterobacteriaceae, Enterococci, and Bifidobacteria may regulate the outbreak of anxiety/depression and IBD through the modulation of NF-κB-involved BDNF expression and gut microbiota. Enterococcus faecium, a probiotic strain, is a risk factor for the outbreak of anxiety/depression in patients with IBD.

scholarly journals Metabolomic signature of the maternal microbiota in the fetus

2020 ◽  
Author(s):  
Tiina Pessa-Morikawa ◽  
Aleksi Husso ◽  
Olli Kärkkäinen ◽  
Ville Koistinen ◽  
Kati Hanhineva ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Metabolic Response ◽  
Microbial Metabolites ◽  
Specific Pathogen Free ◽  
Germ Free ◽  
Molecular Features ◽  
Specific Pathogen ◽  
Hydroxyindoleacetic Acid ◽  
Fetal Organs ◽  
Derivatives Of

AbstractThe maternal microbiota affects the development of the offspring by microbial metabolites translocating to the fetus. We investigated samples of placenta, fetal intestine and brain from germ-free (GF) and specific pathogen free (SPF) mouse dams by non-targeted metabolic profiling. One hundred one annotated metabolites and altogether 3680 molecular features were present in significantly different amounts in the placenta and/or fetal organs of GF and SPF mice. The concentrations of more than half of the annotated and differentially expressed metabolites were lower in the GF organs, suggesting their microbial origin or a metabolic response of the host to the presence of gut microbiota. The clearest separation was observed in the placenta. Metabolites that were detected in lower amounts in the fetal organs in the GF mice included 5-aminovaleric acid betaine, trimethylamine N-oxide, catechol-O-sulphate, hippuric and pipecolic acid. Derivatives of the amino acid tryptophan, such as kynurenine, 3-indolepropionic acid and hydroxyindoleacetic acid were also decreased in the absence of microbiota. Several metabolites had higher levels in the GF mice. These could be precursors of microbial metabolites or indicators of host metabolic response to the absence of gut microbiota. 99 molecular features were only detected in the SPF mice, suggesting the existence of yet unidentified microbially modified metabolites that potentially influence fetal development.

scholarly journals Early Exposure to Gut Microbiome Reduces Hepatocellular Carcinoma Risks in Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Yang-Ming Lee ◽  
Wei-Chun Chang ◽  
Fu-Ju Lei ◽  
Chew-Teng Kor ◽  
Hsueh-Chou Lai ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Liver Tumors ◽  
Male Mice ◽  
Germ Free ◽  
Housing Environment ◽  
Male Sex ◽  
Group 10 ◽  
Group 5

Aims. Liver cancer is a multietiological disease that has multiple factors contributing to the hepatocarcinogenic process, e.g., hepatitis viruses, carcinogens, male sex, or metabolic factors. Notably, emerging evidence reported that gut microbiota is crucial to the pathogenesis of hepatocellular carcinoma (HCC) via activation of innate immunity. However, the effect of time to gut microbiota exposure after birth is unknown. Using a germ-free animal housing environment, instead of antibiotics, we examined the effects of various time-to-exposure (TTE) to gut microbiota durations on HCC risk. Methods. HBV or carcinogen-mediated spontaneous HCC models were implemented in this study. The HCC incidence rates in mice either kept germ-free (GF; that is, with no exposure to gut microbiota) or exposed to gut microbiota after being moved to a specific pathogen-free (SPF) housing environment and with various time-to-exposure (TTE) durations, namely, 5 weeks after birth, 10 weeks after birth, or since conception (that is, 5-week TTE group, 10-week TTE group, and SPF group, respectively), were recorded. The mice were sacrificed at 30 or 40 weeks after birth, and macro-/microscopic observations and pathological diagnosis were performed. Results. The incidence of liver tumors among the male mice was higher than that among the female mice in the carcinogen-induced HCC mice sacrificed at 40 weeks after birth (with P=0.011, 0.035, 0.0003, and 0.012, respectively, in the GF group, 5-week TTE group, 10-week TTE group, and SPF group). Similarly, in the HBV-HCC model, the incidence of liver tumors among the male mice was significantly higher than that among the female mice (with P=0.013, 0.020, 0.012, and 0.002, respectively, in the GF group, 5-week TTE group, 10-week TTE group, and SPF group). These results suggest that gut microbiota exposure is irrelevant to the male sex preference of HCC. Surprisingly, when comparing carcinogen-induced HCC male mice in the 10-week TTE group (90%; n=10), 5-week TTE group (56%; n=9), and SPF group (30%; n=10) (P=0.020), we found that the incidence of liver tumors was higher in the mice with later exposure to gut microbiome. Similarly, when comparing HBV-HCC male mice in the 10-week TTE group (100%; n=11), 5-week TTE group (70%; n=10), and SPF group (33%; n=9) (P=0.080), we also found that the incidence of liver tumors was higher in the mice with later exposure to gut microbiome. Conclusions. Early (prepubertal) exposure to gut microbiome reduces the risk of HCC development, indicating a potentially important factor for cancer surveillance. Exploring the mechanisms by which such exposure affects HCC risk might lead to novel cancer vaccines.

Comparative analysis of microRNA expression profiles in the colons of specific pathogen-free mice and germ-free mice

2021 ◽  
Author(s):  
Ayako Aoki ◽  
Reiji Aoki ◽  
Madoka Yatagai ◽  
Toshiyuki Kawasumi
Keyword(s):  
Gene Ontology ◽  
Comparative Analysis ◽  
Expression Profiles ◽  
Microrna Expression ◽  
Gene Ontology Analysis ◽  
Specific Pathogen Free ◽  
Germ Free ◽  
Mrna Targets ◽  
Significant Gene ◽  
Specific Pathogen

ABSTRACT MicroRNAs play an important role in microbiota–host crosstalk. In this study, we compared microRNA expression in whole colons of specific pathogen-free mice and germ-free mice. Forty-eight microRNAs were differentially expressed by more than 2-fold. Gene ontology analysis of the predicted mRNA targets revealed that the majority of the most significant gene ontology terms were related to GTPases and nerves.

scholarly journals Altered diversity and composition of gut microbiota in Wilson's disease

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Xiangsheng Cai ◽  
Lin Deng ◽  
Xiaogui Ma ◽  
Yusheng Guo ◽  
Zhiting Feng ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Gut Microbiome ◽  
Wilson’S Disease ◽  
Wilson's Disease ◽  
Healthy Individuals ◽  
Lower Abundance ◽  
Rrna Sequencing ◽  
Healthy Control ◽  
The Impact ◽  
Bacterial Groups

AbstractWilson’s disease (WD) is an autosomal recessive inherited disorder of chronic copper toxicosis with high mortality and disability. Recent evidence suggests a correlation between dysbiosis in gut microbiome and multiple diseases such as genetic and metabolic disease. However, the impact of intestinal microbiota polymorphism in WD have not been fully elaborated and need to be explore for seeking some microbiota benefit for WD patients. In this study, the 16S rRNA sequencing was performed on fecal samples from 14 patients with WD and was compared to the results from 16 healthy individuals. The diversity and composition of the gut microbiome in the WD group were significantly lower than those in healthy individuals. The WD group presented unique richness of Gemellaceae, Pseudomonadaceae and Spirochaetaceae at family level, which were hardly detected in healthy controls. The WD group had a markedly lower abundance of Actinobacteria, Firmicutes and Verrucomicrobia, and a higher abundance of Bacteroidetes, Proteobacteria, Cyanobacteria and Fusobacteria than that in healthy individuals. The Firmicutes to Bacteroidetes ratio in the WD group was significantly lower than that of healthy control. In addition, the functional profile of the gut microbiome from WD patients showed a lower abundance of bacterial groups involved in the host immune and metabolism associated systems pathways such as transcription factors and ABC-type transporters, compared to healthy individuals. These results implied dysbiosis of gut microbiota may be influenced by the host metabolic disorders of WD, which may provide a new understanding of the pathogenesis and new possible therapeutic targets for WD.

scholarly journals Gut Microbiome: Profound Implications for Diet and Disease

Nutrients ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1613 ◽  
Author(s):  
Ronald Hills ◽  
Benjamin Pontefract ◽  
Hillary Mishcon ◽  
Cody Black ◽  
Steven Sutton ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Gut Microbiome ◽  
Bacterial Species ◽  
Intestinal Bacteria ◽  
Short Chain Fatty Acids ◽  
E Coli ◽  
Beneficial Effects ◽  
Microbial Profile ◽  
Irritable Bowel ◽  
Prebiotic Fiber

The gut microbiome plays an important role in human health and influences the development of chronic diseases ranging from metabolic disease to gastrointestinal disorders and colorectal cancer. Of increasing prevalence in Western societies, these conditions carry a high burden of care. Dietary patterns and environmental factors have a profound effect on shaping gut microbiota in real time. Diverse populations of intestinal bacteria mediate their beneficial effects through the fermentation of dietary fiber to produce short-chain fatty acids, endogenous signals with important roles in lipid homeostasis and reducing inflammation. Recent progress shows that an individual’s starting microbial profile is a key determinant in predicting their response to intervention with live probiotics. The gut microbiota is complex and challenging to characterize. Enterotypes have been proposed using metrics such as alpha species diversity, the ratio of Firmicutes to Bacteroidetes phyla, and the relative abundance of beneficial genera (e.g., Bifidobacterium, Akkermansia) versus facultative anaerobes (E. coli), pro-inflammatory Ruminococcus, or nonbacterial microbes. Microbiota composition and relative populations of bacterial species are linked to physiologic health along different axes. We review the role of diet quality, carbohydrate intake, fermentable FODMAPs, and prebiotic fiber in maintaining healthy gut flora. The implications are discussed for various conditions including obesity, diabetes, irritable bowel syndrome, inflammatory bowel disease, depression, and cardiovascular disease.

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.

Sign in / Sign up

Export Citation Format

Share Document