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1.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 4204-4207, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018924

RESUMO

The gastrointestinal (GI) tract is in part controlled by slow wave electrical activity. Recordings of slow waves with high-resolution (HR) electrode arrays are used to characterize normal and abnormal conduction pathways. Improving the quality of these electrical recordings is important for developing a better understanding of abnormal activity. Contact pressure is one factor that can affect the quality of electrical recordings. We compared the performance of two pressure sensing devices for measuring HR electrode array contact pressure. A Velostat-based sensor array was custom designed and built in a 4 × 2 conguration (area: 30 mm2 per sensor) to be integrated into electrical recordings. Commercially available FlexiForce A201 sensors were used to compare to the Velostat-based sensors. Benchtop testing of these sensors was performed; the error of the Velostat-based sensors (14-31%) was better than that of the FlexiForce sensors (20-49%) within a range of 2666-6666 Pa. The Velostat-based sensors were also more repeatable than the FlexiForce sensors over the same pressure range. Simultaneous pressure and slow wave recordings were performed in vivo on a rabbit small intestine. The Velostat-based sensors were able to resolve spatiotemporal changes in contact pressure in the range of 0-10 000 Pa.


Assuntos
Microbioma Gastrointestinal , Trato Gastrointestinal , Animais , Eletricidade , Eletrodos , Intestino Delgado , Coelhos
2.
Nat Commun ; 11(1): 4982, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020474

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is associated with obesity but also found in non-obese individuals. Gut microbiome profiles of 171 Asians with biopsy-proven NAFLD and 31 non-NAFLD controls are analyzed using 16S rRNA sequencing; an independent Western cohort is used for external validation. Subjects are classified into three subgroups according to histological spectra of NAFLD or fibrosis severity. Significant alterations in microbiome diversity are observed according to fibrosis severity in non-obese, but not obese, subjects. Ruminococcaceae and Veillonellaceae are the main microbiota associated with fibrosis severity in non-obese subjects. Furthermore, stool bile acids and propionate are elevated, especially in non-obese subjects with significant fibrosis. Fibrosis-related Ruminococcaceae and Veillonellaceae species undergo metagenome sequencing, and four representative species are administered in three mouse NAFLD models to evaluate their effects on liver damage. This study provides the evidence for the role of the microbiome in the liver fibrosis pathogenesis, especially in non-obese subjects.


Assuntos
Bactérias/isolamento & purificação , Microbioma Gastrointestinal/fisiologia , Hepatopatia Gordurosa não Alcoólica/microbiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/metabolismo , Ácidos e Sais Biliares/análise , Ácidos e Sais Biliares/metabolismo , Biomarcadores , Fezes/química , Fezes/microbiologia , Fibrose , Microbioma Gastrointestinal/genética , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/metabolismo , Cirrose Hepática/microbiologia , Cirrose Hepática/patologia , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Obesidade/microbiologia , Obesidade/patologia , Propionatos/análise , Propionatos/metabolismo , RNA Ribossômico 16S/genética , Reprodutibilidade dos Testes
3.
Medicine (Baltimore) ; 99(40): e22442, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019428

RESUMO

Delivery methods during childbirth and their related gut microbiota profiles have important impacts on health later in life, they can contribute to the development of diseases such as obesity, whose highest prevalence rate is found among the Mexican child population. Coincidentally, Mexico has one of the highest global average annual rate increase in cesarean births (C-section). Since Mexico leads the world in childhood obesity, studying the relationship between childbirth delivery methods and gut microbiota profiles in this vulnerable population may be used to identify early risk factors for obesity in other developed and developing countries. The objective of this study is to determine the association between child delivery method and gut microbiota profiles in healthy Mexican newborns.Fecal samples of 57 term infants who participated in a randomized clinical trial in 2013 to study the safety of Agave fructans in newborns, were used in this study. DNA samples were extracted and used to characterize the microbiota composition using high-throughput 16S rRNA gene sequencing. The samples were further divided based on childbirth delivery method, as well as early diet. Gut microbiota profiles were determined and analyzed using cluster analysis followed by multiple correspondence analysis.An unusual high abundance of Proteobacteria was found in the gut microbiota of all Mexican infants studied, regardless of delivery method. Feces from infants born by C-section had low levels of Bacteroidetes, high levels of Firmicutes, especially Clostridium and Enterococcus, and a strikingly high ratio of Firmicutes/Bacteroidetes (F:B). Profiles enriched in Bacteroidetes and low F:B ratios, were strongly associated with vaginal delivery.The profile of gut microbiota associated with feces from Mexican infants born by C-section, may be added to the list of boosting factors for the worrying obesity epidemic in Mexico.


Assuntos
Cesárea/estatística & dados numéricos , Microbioma Gastrointestinal , Obesidade/epidemiologia , Cesárea/efeitos adversos , Fezes/microbiologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , México/epidemiologia , Fatores de Risco
4.
Cell Host Microbe ; 28(4): 501-502, 2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-33031733

RESUMO

The intestinal microbiota promote myriad functions that affect the host. In this issue of Cell Host & Microbe, Caballero-Flores et al. (2020) demonstrate that resident microbes can thwart gut colonization by the enteric bacterial pathogen Citrobacter rodentium by consuming amino acids, thus starving the invading organism of essential nutrients.


Assuntos
Aminoácidos , Microbioma Gastrointestinal , Bactérias
5.
Front Immunol ; 11: 2192, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33072084

RESUMO

During the last years probiotics gained the attention of clinicians for their use in the prevention and treatment of multiple diseases. Probiotics main mechanisms of action include enhanced mucosal barrier function, direct antagonism with pathogens, inhibition of bacterial adherence and invasion capacity in the intestinal epithelium, boosting of the immune system and regulation of the central nervous system. It is accepted that there is a mutual communication between the gut microbiota and the liver, the so-called "microbiota-gut-liver axis" as well as a reciprocal communication between the intestinal microbiota and the central nervous system through the "microbiota-gut-brain axis." Moreover, recently the "gut-lung axis" in bacterial and viral infections is considerably discussed for bacterial and viral infections, as the intestinal microbiota amplifies the alveolar macrophage activity having a protective role in the host defense against pneumonia. The importance of the normal human intestinal microbiota is recognized in the preservation of health. Disease states such as, infections, autoimmune conditions, allergy and other may occur when the intestinal balance is disturbed. Probiotics seem to be a promising approach to prevent and even reduce the symptoms of such clinical states as an adjuvant therapy by preserving the balance of the normal intestinal microbiota and improving the immune system. The present review states globally all different disorders in which probiotics can be given. To date, Stronger data in favor of their clinical use are provided in the prevention of gastrointestinal disorders, antibiotic-associated diarrhea, allergy and respiratory infections. We hereby discuss the role of probiotics in the reduction of the respiratory infection symptoms and we focus on the possibility to use them as an adjuvant to the therapeutic approach of the pandemic COVID-19. Nevertheless, it is accepted by the scientific community that more clinical studies should be undertaken in large samples of diseased populations so that the assessment of their therapeutic potential provide us with strong evidence for their efficacy and safety in clinical use.


Assuntos
Bactérias/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus , Microbioma Gastrointestinal/imunologia , Pandemias , Pneumonia Viral , Probióticos/uso terapêutico , Aderência Bacteriana/imunologia , Encéfalo/imunologia , Encéfalo/microbiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/microbiologia , Infecções por Coronavirus/terapia , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/microbiologia , Pneumonia Viral/terapia
6.
Psychiatr Danub ; 32(Suppl 1): 158-163, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32890382

RESUMO

BACKGROUND: Some behaviors or psychiatric conditions seem to be inherited from parents or explain by family environment. We hypothesized interactions between epigenetic processes, inflammatory response and gut microbiota with family surroundings or environmental characteristics. SUBJECTS AND METHODS: We searched in literature interactions between epigenetic processes and psychiatric disorders with a special interest for environmental factors such as traumatic or stress events, family relationships and also gut microbiota. We searched on Pubmed, PsycINFO, PsycARTICLES and Sciencedirect articles with the keywords psychiatric disorders, epigenome, microbiome and family relationships. RESULTS: Some gene polymorphisms interact with negative environment and lead to psychiatric disorders. Negative environment is correlated with different epigenetic modifications in genes implicated in mental health. Gut microbiota diversity affect host epigenetic. Animal studies showed evidences for a transgenerational transmission of epigenetic characteristics. CONCLUSIONS: Our findings support the hypothesis that epigenetic mediate gene-environment interactions and psychiatric disorders. Several environmental characteristics such as traumatic life events, family adversity, psychological stress or internal environment such as gut microbiota diversity and diet showed an impact on epigenetic. These epigenetic modifications are also correlated with neurophysiological, inflammatory or hypothalamic-pituitary-adrenal axis dysregulations.


Assuntos
Epigênese Genética , Microbioma Gastrointestinal , Transtornos Mentais , Animais , Sistema Hipotálamo-Hipofisário , Transtornos Mentais/genética , Transtornos Mentais/microbiologia , Sistema Hipófise-Suprarrenal
7.
Zhongguo Zhong Yao Za Zhi ; 45(15): 3726-3739, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32893565

RESUMO

This study is to explore the effect of Qingfei Paidu Decoction(QPD) on the host metabolism and gut microbiome of rats with metabolomics and 16 S rDNA sequencing. Based on 16 S rDNA sequencing of gut microbiome and metabolomics(GC-MS and LC-MS/MS), we systematically studied the serum metabolites profile and gut microbiota composition of rats treated with QPD for continued 5 days by oral gavage. A total of 23 and 43 differential metabolites were identified based on QPD with GC-MS and LC-MS/MS, respectively. The involved metabolic pathways of these differential metabolites included glycerophospholipid metabolism, linoleic acid metabolism, TCA cycle and pyruvate metabolism. Meanwhile, we found that QPD significantly regulated the composition of gut microbiota in rats, such as enriched Romboutsia, Turicibacter, and Clostridium_sensu_stricto_1, and decreased norank_f_Lachnospiraceae. Our current study indicated that short-term intervention of QPD could significantly regulate the host metabolism and gut microbiota composition of rats dose-dependently, suggesting that the clinical efficacy of QPD may be related with the regulation on host metabolism and gut microbiome.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Bactérias/classificação , Cromatografia Líquida , Metabolômica , Ratos , Espectrometria de Massas em Tandem
8.
Rev Med Liege ; 75(9): 588-592, 2020 Sep.
Artigo em Francês | MEDLINE | ID: mdl-32909410

RESUMO

The gut microbiota refers to the community of microorganisms living in the mammalian digestive tract. Over the past decades, numerous preclinical and clinical studies have suggested that gut microbiota is involved in the physiological homeostasis of the host, particularly in the immune and metabolic systems. Furthermore, the dysfunction of gut microbiota, also called "dysbiosis", has been associated with various diseases, such as the metabolic syndrome or chronic kidney disease. In this review, we summarize the knowledge about the possible role of gut microbiota in the development of arterial hypertension. We detail the pathophysiological mechanisms, namely involving short-chain fatty acids produced by the bacterial fermentation of food carbohydrates. These metabolites are reabsorbed by the intestinal mucosa and interact with a multitude of G-protein coupled receptors at the surface of cells involved in blood pressure regulation, including renal tubular cells. These observations open up innovative diagnostic and therapeutic approaches in arterial hypertension, which is a major public health problem.


Assuntos
Microbioma Gastrointestinal , Hipertensão , Insuficiência Renal Crônica , Animais , Pressão Sanguínea , Humanos , Rim
9.
Wei Sheng Yan Jiu ; 49(4): 574-579, 2020 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-32928355

RESUMO

OBJECTIVE: To evaluate the cholesterol-lowering effects of Lactobacillus paragasseri Y20 on rats with high cholesterol diet and its effect on the gut microbiota of rats, and to explore the potential mechanism of Lactobacillus paragasseri regulating hypercholesterolemia in rats. METHODS: Thirty rats were randomly divided into three groups and were treated with normal diet, high cholesterol diet+PBS, and high cholesterol diet+Lactobacillus paragasseri Y20, respectively. After five consecutive weeks of treatment, serum lipids were measured by ELISA. Rat feces were collected and DNA was extracted for 16 S rRNA amplicon sequencing analysis. Rat livers were collected and analyzed for non-targeted metabolites using high performance liquid chromatography. RESULTS: Compared with the high-cholesterol model group, Lactobacillus paragasseri Y20 treatment could reduce the serum triglyceride and low-density lipoprotein concentrations and increase the high-density lipoprotein concentration in rats. High-cholesterol diet decreased the intestinal flora diversity and richness of rats, while Y20 intervention can effectively restore the change of intestinal flora of high-cholesterol rats. High cholesterol dietsmainly caused the changes in the relative abundance in phylum of Firmicutes, Deferribacteres, Verrucomicrobia, and Proteobacteria, increasing Akkermansia, Clostridium_III, and Clostridium_XIVbgenera, and decreasing the intestinimonasgenus. However, Y20 intervention restored the diversity of gut microbiota and alteration in relative abundance of these bacteria caused by high-cholesterol diet. Y20 could effectively decrease the higher relative abundance of Akkermansiahigh-cholesterol diet. CONCLUSION: Lactobacillus paragasseri Y20 can alleviate hypercholesterolemia in rats, regulate the gut microbiotadiversity and composition and affect liver metabolism in hypercholesterol rats.


Assuntos
Microbioma Gastrointestinal , Hipercolesterolemia , Probióticos , Animais , Colesterol , Lactobacillus , Fígado , Ratos
10.
Clin Exp Rheumatol ; 38 Suppl 125(3): 73-84, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865168

RESUMO

OBJECTIVES: Systemic sclerosis (SSc) is a rare multi-organ disorder with a prominent gastrointestinal (GI) involvement. Altered gut microbiota is now considered a pivotal factor associated with the development of immune-mediated and inflammatory diseases. We performed a 16S ribosomal RNA (rRNA) gene-sequencing analysis of fecal microbiota in a cohort of SSc patients and matched healthy controls (HCs), with the aim to obtain some hints about a possible role of dysbiosis in the onset, progression, and severity of the disease. METHODS: We analysed stool samples from 63 SSc patients with different disease duration, phenotype, and nutritional status and from 17 HCs through 16S ribosomal RNA (rRNA) gene-sequencing. RESULTS: Microbial richness was lower for patients with long-standing disease. A similar observation was made for patients with diffuse cutaneous SSc (dsSSc) compared to those with limited variant (lcSSc) and for patients who reported a recent weight loss. Consistent with previous reports, we noted a deviation of the intestinal microbial composition in patients with SSc compared to HCs, with a greater expression of Lactobacillus and Streptococcus and a depletion of Sutterella. Nutritional status, assessed using BMI as a surrogate, appeared to have a marked impact on the gut microbiota, with overweight patients showing lower richness compared both to underweight and normal-BMI patients. CONCLUSIONS: Our findings expand the current knowledge of gut microbiota in SSc and could be useful to identify patients who would most benefit from treatments aimed at restoring the eu-biosis.


Assuntos
Microbioma Gastrointestinal , Escleroderma Sistêmico , Disbiose , Fezes , Humanos , Estado Nutricional , RNA Ribossômico 16S
11.
Nat Commun ; 11(1): 4635, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934239

RESUMO

Providing insight into one's health status from a gut microbiome sample is an important clinical goal in current human microbiome research. Herein, we introduce the Gut Microbiome Health Index (GMHI), a biologically-interpretable mathematical formula for predicting the likelihood of disease independent of the clinical diagnosis. GMHI is formulated upon 50 microbial species associated with healthy gut ecosystems. These species are identified through a multi-study, integrative analysis on 4347 human stool metagenomes from 34 published studies across healthy and 12 different nonhealthy conditions, i.e., disease or abnormal bodyweight. When demonstrated on our population-scale meta-dataset, GMHI is the most robust and consistent predictor of disease presence (or absence) compared to α-diversity indices. Validation on 679 samples from 9 additional studies results in a balanced accuracy of 73.7% in distinguishing healthy from non-healthy groups. Our findings suggest that gut taxonomic signatures can predict health status, and highlight how data sharing efforts can provide broadly applicable discoveries.


Assuntos
Bactérias/isolamento & purificação , Microbioma Gastrointestinal , Nível de Saúde , Bactérias/classificação , Bactérias/genética , Fezes/microbiologia , Humanos , Metagenoma , Microbiota
12.
Proc Biol Sci ; 287(1934): 20200820, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32873208

RESUMO

Sequencing technologies have fuelled a rapid rise in descriptions of microbial communities associated with hosts, but what is often harder to ascertain is the evolutionary significance of these symbioses. Here, we review the role of vertical (VT), horizontal (HT), environmental acquisition and mixed modes of transmission (MMT), in the establishment of animal host-microbe associations. We then model four properties of gut microbiota proposed as key to promoting animal host-microbe relationships: modes of transmission, host reproductive mode, host mate choice and host fitness. We found that: (i) MMT led to the highest frequencies of host-microbe associations, and that some environmental acquisition or HT of microbes was required for persistent associations to form unless VT was perfect; (ii) host reproductive mode (sexual versus asexual) and host mate choice (for microbe carriers versus non-carriers) had little impact on the establishment of host-microbe associations; (iii) host mate choice did not itself lead to reproductive isolation, but could reinforce it; and (iv) changes in host fitness due to host-microbe associations had a minimal impact upon the formation of co-associations. When we introduced a second population, into which host-microbe carriers could disperse but in which environmental acquisition did not occur, highly efficient VT was required for host-microbe co-associations to persist. Our study reveals that transmission mode is of key importance in establishing host-microbe associations.


Assuntos
Microbiota , Animais , Evolução Biológica , Microbioma Gastrointestinal , Simbiose
13.
Yonsei Med J ; 61(10): 891-894, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32975064

RESUMO

The cellular entry of severe respiratory syndrome coronavirus-2 (SARS-CoV-2) is mediated by interaction with the human angiotensin-converting enzyme 2 (ACE2), a receptor that is expressed on both lung and intestinal epithelial cells. We performed a quantitative proteomic analysis to investigate the expression of possible receptors for SARS-CoV-2 in the intestinal mucosa of 23 patients with chronic colitis. ACE2 expression was low and remained unaltered in the gut of patients with ulcerative colitis (UC), Crohn's disease (CD), intestinal Behcet's disease (BD), and intestinal tuberculosis (TB), when compared with that of healthy individuals. Additionally, the expression levels of some probable co-receptors, including dipeptidyl peptidase 4 (DPP4), aminopeptidase N (AMPN), and glutamyl aminopeptidase (AMPE), were unchanged in the affected UC, CD, intestinal BD, and intestinal TB colon mucosa samples. In conclusion, gut inflammation associated with chronic colitis does not mediate a further increase in the cellular entry of SARS-CoV-2.


Assuntos
Infecções por Coronavirus , Enterocolite , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral , Proteômica , Betacoronavirus , Dipeptidil Peptidase 4/metabolismo , Enterocolite/metabolismo , Microbioma Gastrointestinal , Humanos , Pulmão/metabolismo , Pandemias
14.
Nat Commun ; 11(1): 4766, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958778

RESUMO

Germline telomere maintenance defects are associated with an increased incidence of inflammatory diseases in humans, yet whether and how telomere dysfunction causes inflammation are not known. Here, we show that telomere dysfunction drives pATM/c-ABL-mediated activation of the YAP1 transcription factor, up-regulating the major pro-inflammatory factor, pro-IL-18. The colonic microbiome stimulates cytosolic receptors activating caspase-1 which cleaves pro-IL-18 into mature IL-18, leading to recruitment of interferon (IFN)-γ-secreting T cells and intestinal inflammation. Correspondingly, patients with germline telomere maintenance defects exhibit DNA damage (γH2AX) signaling together with elevated YAP1 and IL-18 expression. In mice with telomere dysfunction, telomerase reactivation in the intestinal epithelium or pharmacological inhibition of ATM, YAP1, or caspase-1 as well as antibiotic treatment, dramatically reduces IL-18 and intestinal inflammation. Thus, telomere dysfunction-induced activation of the ATM-YAP1-pro-IL-18 pathway in epithelium is a key instigator of tissue inflammation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ciclo Celular/metabolismo , Inflamação/patologia , Telômero/patologia , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Antibacterianos/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Caspase 1/metabolismo , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Criança , Colo/metabolismo , Colo/microbiologia , Colo/patologia , Gastroenteropatias/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/microbiologia , Interleucina-18/genética , Interleucina-18/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Camundongos Mutantes , Fosforilação , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Transdução de Sinais , Telomerase/genética , Telomerase/metabolismo
15.
PLoS Comput Biol ; 16(9): e1008108, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32898133

RESUMO

Existing models for assessing microbiome sequencing such as operational taxonomic units (OTUs) can only test predictors' effects on OTUs. There is limited work on how to estimate the correlations between multiple OTUs and incorporate such relationship into models to evaluate longitudinal OTU measures. We propose a novel approach to estimate OTU correlations based on their taxonomic structure, and apply such correlation structure in Generalized Estimating Equations (GEE) models to estimate both predictors' effects and OTU correlations. We develop a two-part Microbiome Taxonomic Longitudinal Correlation (MTLC) model for multivariate zero-inflated OTU outcomes based on the GEE framework. In addition, longitudinal and other types of repeated OTU measures are integrated in the MTLC model. Extensive simulations have been conducted to evaluate the performance of the MTLC method. Compared with the existing methods, the MTLC method shows robust and consistent estimation, and improved statistical power for testing predictors' effects. Lastly we demonstrate our proposed method by implementing it into a real human microbiome study to evaluate the obesity on twins.


Assuntos
Biologia Computacional/métodos , DNA Bacteriano , Microbioma Gastrointestinal/genética , Modelos Estatísticos , Análise de Sequência de DNA/métodos , DNA Bacteriano/classificação , DNA Bacteriano/genética , Bases de Dados Genéticas , Humanos
16.
Nat Commun ; 11(1): 4822, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973149

RESUMO

Abiraterone acetate (AA) is an inhibitor of androgen biosynthesis, though this cannot fully explain its efficacy against androgen-independent prostate cancer. Here, we demonstrate that androgen deprivation therapy depletes androgen-utilizing Corynebacterium spp. in prostate cancer patients and that oral AA further enriches for the health-associated commensal, Akkermansia muciniphila. Functional inferencing elucidates a coinciding increase in bacterial biosynthesis of vitamin K2 (an inhibitor of androgen dependent and independent tumor growth). These results are highly reproducible in a host-free gut model, excluding the possibility of immune involvement. Further investigation reveals that AA is metabolized by bacteria in vitro and that breakdown components selectively impact growth. We conclude that A. muciniphila is a key regulator of AA-mediated restructuring of microbial communities, and that this species may affect treatment response in castrate-resistant cohorts. Ongoing initiatives aimed at modulating the colonic microbiota of cancer patients may consider targeted delivery of poorly absorbed selective bacterial growth agents.


Assuntos
Acetato de Abiraterona/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Verrucomicrobia/efeitos dos fármacos , Acetato de Abiraterona/metabolismo , Acetato de Abiraterona/uso terapêutico , Antagonistas de Androgênios/farmacologia , Androgênios/metabolismo , Bactérias/metabolismo , Fezes/microbiologia , Humanos , Masculino , RNA Ribossômico 16S/genética , Verrucomicrobia/genética , Verrucomicrobia/metabolismo , Vitamina K 2/metabolismo , Vitamina K 2/farmacologia
17.
Nat Commun ; 11(1): 4844, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973204

RESUMO

Akkermansia muciniphila is a mucin-degrading bacterium commonly found in the human gut that promotes a beneficial effect on health, likely based on the regulation of mucus thickness and gut barrier integrity, but also on the modulation of the immune system. In this work, we focus in OgpA from A. muciniphila, an O-glycopeptidase that exclusively hydrolyzes the peptide bond N-terminal to serine or threonine residues substituted with an O-glycan. We determine the high-resolution X-ray crystal structures of the unliganded form of OgpA, the complex with the glycodrosocin O-glycopeptide substrate and its product, providing a comprehensive set of snapshots of the enzyme along the catalytic cycle. In combination with O-glycopeptide chemistry, enzyme kinetics, and computational methods we unveil the molecular mechanism of O-glycan recognition and specificity for OgpA. The data also contribute to understanding how A. muciniphila processes mucins in the gut, as well as analysis of post-translational O-glycosylation events in proteins.


Assuntos
Microbioma Gastrointestinal/fisiologia , Mucinas/metabolismo , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/química , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/metabolismo , Verrucomicrobia/metabolismo , Animais , Sítios de Ligação , Cristalografia por Raios X , Glicopeptídeos/química , Humanos , Mamíferos , Simulação de Acoplamento Molecular , Mucina-1/metabolismo , Polissacarídeos/química , Conformação Proteica , Alinhamento de Sequência , Verrucomicrobia/enzimologia
18.
Am J Chin Med ; 48(6): 1385-1407, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32907359

RESUMO

Accumulating evidence suggests that gut microbiota plays a crucial role in the development of metabolic diseases, especially type 2 diabetes mellitus (T2DM). The nutrient-rich resource Cornus Fructus (CF) showed curative effects on diabetes mellitus. However, the mechanism underlying its hyperglycemic activity remains obscure. Herein, the antidiabetic potential of four extracts from CF, including saponin (CTS), iridoid glycoside (CIG), tannin (CT), and alcohol extract (CCA) was evaluated in vivo. The results showed that all four extracts could increase the body weight, decrease the blood glucose levels, and elevate the glucose tolerance. Moreover, insulin sensitivity and lipid profile were significantly improved in fed mice. In the [Formula: see text]-diversity index of samples, compared to the DM group, the diversity and richness of gut microbiota in mice to a certain extent were reduced in both CF extracts and Metformin (PC). Among them, there was statistical significance in PC (ACE, [Formula: see text]) and CCA (ACE, [Formula: see text]; chao1: [Formula: see text]). Beta diversity showed the same trend as the UPGMA clustering trees, which revealed that CF extracts could improve intestinal homeostasis in T2DM mice. Also, CF extracts could elevate the production of short-chain fatty acids, as well as regulate the composition of gut microbiota. The key bacteria related to T2DM including Firmicutes, Bacteroides, Lactobacillus, and Clostridium were modulated by metformin and CF. Altogether, CF is a potential nutrient-rich candidate that can be used in functional foods for the treatment of T2DM, and the change of gut microbiota might be a novel mechanism underlying its hyperglycemic activity.


Assuntos
Cornus/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/etiologia , Modelos Animais de Doenças , Alimento Funcional , Resistência à Insulina , Glicosídeos Iridoides , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos ICR , Extratos Vegetais/química , Saponinas , Taninos
19.
Am J Chin Med ; 48(6): 1409-1433, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32907360

RESUMO

Scutellaria baicalensis (SB), a herbal medicine, is commonly used to treat metabolic diseases, while Metformin (MF) is a widely used drug for type 2 diabetes. The purpose of this study was to investigate whether co-treatment of SB with MF could produce a potential therapeutic effect on high-fat and high-fructose diet (HFFD)-induced metabolic dysregulation. First, we optimized the dose of SB (100, 200, 400, and 800[Formula: see text]mg/kg) with MF (200[Formula: see text]mg/kg) in HFFD-induced C57BL6J mice. Next, the optimized dose of SB (400[Formula: see text]mg/kg) was co-administered with MF (50, 100, and 200[Formula: see text]mg/kg) in a similar animal model to find the effective combinations of SB and MF. Metabolic markers were determined in serum and tissues using different assays, histology, gene expression, and gut microbial population. The SB and MF co-treatment significantly decreased the body, liver, and VAT weights. The outcome of OGTT was improved, and the fasting insulin, HbA1c, TG, TC, LDL-c, AST, and ALT were decreased, while HDL-c was significantly increased. Histological analyses revealed maintained the integrity of liver, adipose tissue, and intestine prevented lipid accumulation in the liver and intestine and combated neuronal damage in the brain. Importantly, controlled the expression of PPAR[Formula: see text], and IL-6 genes in the liver, and expression of BDNF, Glut1, Glut3, and Glut4 genes in the brain. Treatment-specific gut microbial segregation was observed in the PCA chart. Our findings indicate that SB and MF co-treatment is an effective therapeutic approach for HFFD-induced metabolic dysregulation which is operated through the gut-liver-brain axis.


Assuntos
Encéfalo/metabolismo , Microbioma Gastrointestinal , Fígado/metabolismo , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Metformina/administração & dosagem , Metformina/farmacologia , Fitoterapia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Dieta da Carga de Carboidratos/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Quimioterapia Combinada , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Doenças Metabólicas/genética , Doenças Metabólicas/microbiologia , Camundongos Endogâmicos C57BL , PPAR gama/genética , PPAR gama/metabolismo
20.
PLoS Biol ; 18(9): e3000813, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32991574

RESUMO

Short-chain fatty acids (SCFAs) produced by gastrointestinal microbiota regulate immune responses, but host molecular mechanisms remain unknown. Unbiased screening using SCFA-conjugated affinity nanobeads identified apoptosis-associated speck-like protein (ASC), an adaptor protein of inflammasome complex, as a noncanonical SCFA receptor besides GPRs. SCFAs promoted inflammasome activation in macrophages by binding to its ASC PYRIN domain. Activated inflammasome suppressed survival of Salmonella enterica serovar Typhimurium (S. Typhimurium) in macrophages by pyroptosis and facilitated neutrophil recruitment to promote bacterial elimination and thus inhibit systemic dissemination in the host. Administration of SCFAs or dietary fibers, which are fermented to SCFAs by gut bacteria, significantly prolonged the survival of S. Typhimurium-infected mice through ASC-mediated inflammasome activation. SCFAs penetrated into the inflammatory region of the infected gut mucosa to protect against infection. This study provided evidence that SCFAs suppress Salmonella infection via inflammasome activation, shedding new light on the therapeutic activity of dietary fiber.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/metabolismo , Ácidos Graxos Voláteis/metabolismo , Inflamassomos/imunologia , Inflamassomos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Infecções por Salmonella/prevenção & controle , Animais , Proteínas Adaptadoras de Sinalização CARD/genética , Feminino , Microbioma Gastrointestinal/imunologia , Células HEK293 , Humanos , Imunidade Inata/fisiologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ligação Proteica , Receptores Acoplados a Proteínas-G/genética , Infecções por Salmonella/genética , Infecções por Salmonella/imunologia , Infecções por Salmonella/metabolismo , Salmonella typhimurium/imunologia , Células U937
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