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1.
Artigo em Inglês | MEDLINE | ID: mdl-33572734

RESUMO

The gut-brain axis describes a complex interplay between the central nervous system and organs of the gastrointestinal tract. Sensory neurons of dorsal root and nodose ganglia, neurons of the autonomic nervous system, and immune cells collect and relay information about the status of the gut to the brain. A critical component in this bi-directional communication system is the vagus nerve which is essential for coordinating the immune system's response to the activities of commensal bacteria in the gut and to pathogenic strains and their toxins. Local control of gut function is provided by networks of neurons in the enteric nervous system also called the 'gut-brain'. One element common to all of these gut-brain systems is the expression of nicotinic acetylcholine receptors. These ligand-gated ion channels serve myriad roles in the gut-brain axis including mediating fast synaptic transmission between autonomic pre- and postganglionic neurons, modulation of neurotransmitter release from peripheral sensory and enteric neurons, and modulation of cytokine release from immune cells. Here we review the role of nicotinic receptors in the gut-brain axis with a focus on the interplay of these receptors with the gut microbiome and their involvement in dysregulation of gut function and inflammatory bowel diseases.


Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais/fisiopatologia , Receptores Nicotínicos/fisiologia , Encéfalo/fisiologia , Humanos , Doenças Inflamatórias Intestinais/microbiologia , Nervo Vago
2.
Int J Mol Sci ; 22(3)2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33498177

RESUMO

The pathophysiological processes of inflammatory bowel diseases (IBDs), i.e., Crohn's disease (CD) and ulcerative colitis (UC), are still not completely understood. The exact etiology remains unknown, but it is well established that the pathogenesis of the inflammatory lesions is due to a dysregulation of the gut immune system resulting in over-production of pro-inflammatory cytokines. Increasing evidence underlines the involvement of both environmental and genetic factors. Regarding the environment, the microbiota seems to play a crucial role. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that exert pleiotropic effects on glucose homeostasis, lipid metabolism, inflammatory/immune processes, cell proliferation, and fibrosis. Furthermore, PPARs modulate interactions with several environmental factors, including microbiota. A significantly impaired PPARγ expression was observed in UC patients' colonic epithelial cells, suggesting that the disruption of PPARγ signaling may represent a critical step of the IBD pathogenesis. This paper will focus on the role of PPARγ in the interaction between environmental factors and IBD, and it will analyze the most suitable in vitro and in vivo models available to better study these relationships.


Assuntos
Meio Ambiente , Doenças Inflamatórias Intestinais/metabolismo , PPAR gama/metabolismo , Animais , Microbioma Gastrointestinal , Homeostase , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/microbiologia , PPAR gama/genética
3.
Postepy Biochem ; 66(3): 256-262, 2020 09 30.
Artigo em Polonês | MEDLINE | ID: mdl-33315320

RESUMO

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic diseases. The exact etiology of IBD is not well elucidated, however it is defined as a multifactorial disease. In addition, IBD carries the risk of serious complications and increases the risk of colorectal cancer. Also, in recent years, an increased rate of IBD cases has been noted. So far, there is no effective and well-defined therapy for IBD, and currently available drugs mainly provide symptomatic treatment. Unfortunately, conventional treatment does not always bring the expected benefits, moreover, it is often associated with unpleasant side effects. Currently, some research have been focused on unconventional forms of IBD treatment, testing therapies based on natural products. Individual polyphenols, as well as polyphenol-rich preparations and extracts are also valuable in IBD treatment through antioxidant, anti-inflammatory and bactericidal activity. Moreover, described here results of clinical trials suggest that polyphenols can alleviate symptoms and prevent recurrence of IBD.


Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Polifenóis/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/microbiologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/microbiologia , Humanos , Doenças Inflamatórias Intestinais/microbiologia
4.
Int J Mol Sci ; 21(24)2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33322538

RESUMO

BACKGROUND: Since acyl-homoserine lactone (AHL) profiling has been described in the gut of healthy subjects and patients with inflammatory bowel disease (IBD), the potential effects of these molecules on host cells have raised interest in the medical community. In particular, natural AHLs such as the 3-oxo-C12-HSL exhibit anti-inflammatory properties. Our study aimed at finding stable 3-oxo-C12-HSL-derived analogues with improved anti-inflammatory effects on epithelial and immune cells. METHODS: We first studied the stability and biological properties of the natural 3-oxo-C12-HSL on eukaryotic cells and a bacterial reporter strain. We then constructed and screened a library of 22 AHL-derived molecules. Anti-inflammatory effects were assessed by cytokine release in an epithelial cell model, Caco-2, and a murine macrophage cell line, RAW264.7, (respectively, IL-8 and IL-6) upon exposure to the molecule and after appropriate stimulation (respectively, TNF-α 50 ng/mL and IFN-γ 50 ng/mL, and LPS 10 ng/mL and IFN-γ 20 U/mL). RESULTS: We found two molecules of interest with amplified anti-inflammatory effects on mammalian cells without bacterial-activating properties in the reporter strain. The molecules furthermore showed improved stability in biological medium compared to the native 3-oxo-C12-HSL. CONCLUSIONS: We provide new bio-inspired AHL analogues with strong anti-inflammatory properties that will need further study from a therapeutic perspective.


Assuntos
Acil-Butirolactonas/uso terapêutico , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Acil-Butirolactonas/química , Análise de Variância , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Doenças Inflamatórias Intestinais/microbiologia , Camundongos , Pirrolidinonas/química , Células RAW 264.7
5.
Proc Natl Acad Sci U S A ; 117(35): 21536-21545, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32817490

RESUMO

The building evidence for the contribution of microbiota to human disease has spurred an effort to develop therapies that target the gut microbiota. This is particularly evident in inflammatory bowel diseases (IBDs), where clinical trials of fecal microbiota transplantation have shown some efficacy. To aid the development of novel microbiota-targeted therapies and to better understand the biology underpinning such treatments, we have used gnotobiotic mice to model microbiota manipulations in the context of microbiotas from humans with inflammatory bowel disease. Mice colonized with IBD donor-derived microbiotas exhibit a stereotypical set of phenotypes, characterized by abundant mucosal Th17 cells, a deficit in the tolerogenic RORγt+ regulatory T (Treg) cell subset, and susceptibility to disease in colitis models. Transplanting healthy donor-derived microbiotas into mice colonized with human IBD microbiotas led to induction of RORγt+ Treg cells, which was associated with an increase in the density of the microbiotas following transplant. Microbiota transplant reduced gut Th17 cells in mice colonized with a microbiota from a donor with Crohn's disease. By culturing strains from this microbiota and screening them in vivo, we identified a specific strain that potently induces Th17 cells. Microbiota transplants reduced the relative abundance of this strain in the gut microbiota, which was correlated with a reduction in Th17 cells and protection from colitis.


Assuntos
Transplante de Microbiota Fecal , Doenças Inflamatórias Intestinais/microbiologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Colite/prevenção & controle , Colo/microbiologia , Doença de Crohn/metabolismo , Doença de Crohn/microbiologia , Citocinas/imunologia , Modelos Animais de Doenças , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/imunologia , Humanos , Doenças Inflamatórias Intestinais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/microbiologia , Células Th17/microbiologia
6.
Nat Commun ; 11(1): 4018, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32782301

RESUMO

The gut microbiome is an ecosystem that involves complex interactions. Currently, our knowledge about the role of the gut microbiome in health and disease relies mainly on differential microbial abundance, and little is known about the role of microbial interactions in the context of human disease. Here, we construct and compare microbial co-abundance networks using 2,379 metagenomes from four human cohorts: an inflammatory bowel disease (IBD) cohort, an obese cohort and two population-based cohorts. We find that the strengths of 38.6% of species co-abundances and 64.3% of pathway co-abundances vary significantly between cohorts, with 113 species and 1,050 pathway co-abundances showing IBD-specific effects and 281 pathway co-abundances showing obesity-specific effects. We can also replicate these IBD microbial co-abundances in longitudinal data from the IBD cohort of the integrative human microbiome (iHMP-IBD) project. Our study identifies several key species and pathways in IBD and obesity and provides evidence that altered microbial abundances in disease can influence their co-abundance relationship, which expands our current knowledge regarding microbial dysbiosis in disease.


Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais/microbiologia , Consórcios Microbianos , Obesidade/microbiologia , Adulto , Bactérias/crescimento & desenvolvimento , Bactérias/isolamento & purificação , Bactérias/metabolismo , Estudos de Coortes , Disbiose/metabolismo , Disbiose/microbiologia , Feminino , Microbioma Gastrointestinal/genética , Especificidade de Hospedeiro , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Masculino , Redes e Vias Metabólicas , Pessoa de Meia-Idade , Obesidade/metabolismo
7.
Virus Res ; 286: 198103, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32717345

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into a major pandemic called coronavirus disease 2019 (COVID-19) that has created unprecedented global health emergencies, and emerged as a serious threat due to its strong ability for human-to-human transmission. The reports indicate the ability of SARS-CoV-2 to affect almost any organ due to the presence of a receptor known as angiotensin converting enzyme 2 (ACE2) across the body. ACE2 receptor is majorly expressed in the brush border of gut enterocytes along with the ciliated cells and alveolar epithelial type II cells in the lungs. The amino acid transport function of ACE2 has been linked to gut microbial ecology in gastrointestinal (GI) tract, thereby suggesting that COVID-19 may, to some level, be linked to the enteric microbiota. The significant number of COVID-19 patients shows extra-pulmonary symptoms in the GI tract. Many subsequent studies revealed viral RNA of SARS-CoV-2 in fecal samples of COVID-19 patients. This presents a new challenge in the diagnosis and control of COVID-19 infection with a caution for proper sanitation and hygiene. Here, we aim to discuss the immunological co-ordination between gut and lungs that facilitates SARS-CoV-2 to infect and multiply in the inflammatory bowel disease (IBD) and non-IBD patients.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Disbiose/imunologia , Trato Gastrointestinal/imunologia , Doenças Inflamatórias Intestinais/imunologia , Pulmão/imunologia , Pneumonia Viral/imunologia , Anticorpos Monoclonais/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/imunologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/microbiologia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/microbiologia , Síndrome da Liberação de Citocina/virologia , Citocinas/antagonistas & inibidores , Citocinas/genética , Citocinas/imunologia , Disbiose/tratamento farmacológico , Disbiose/microbiologia , Disbiose/virologia , Microbioma Gastrointestinal/imunologia , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/microbiologia , Trato Gastrointestinal/virologia , Expressão Gênica , Interações Hospedeiro-Patógeno/imunologia , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/virologia , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Pulmão/virologia , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/microbiologia , Pneumonia Viral/virologia , Receptores Virais/genética , Receptores Virais/imunologia
8.
Zhonghua Er Ke Za Zhi ; 58(7): 564-569, 2020 Jul 02.
Artigo em Chinês | MEDLINE | ID: mdl-32605340

RESUMO

Objective: To explore the infection rate and clinical characteristics of toxigenic Clostridium difficile in children with inflammatory bowel disease (IBD). Methods: From July 2015 to October 2016, the fecal samples and clinical data of 30 IBD children admitted to Department of Gastroenterology, Beijing Children's Hospital, Capital Medical University, as well as the specimens and data of 30 healthy children were collected in the meantime. The toxin gene of Clostridium difficile was detected and clinical characteristics of children with positive toxin gene were analyzed retrospectively. χ(2) test was used to compare the variables between groups. Results: Among the 30 IBD patients, 15 were in ulcerative colitis (UC) group and 15 in Crohn's disease (CD) group. In the IBD group, 6 (3 in UC and 3 in CD group) had positive result of toxigenic Clostridium difficile (20%), among whom 5 were toxin Clostridium difficile A (tcdA) +toxin Clostridium difficile B (tcdB) -, and 1 was tcdA+tcdB+. In the healthy group, only one had positive result of toxigenic Clostridium difficile (3%), which was tcdA+tcdB-. Binary toxin gene was negative in both groups. The infection rate of toxigenic Clostridium difficile in IBD group was significantly higher than that in healthy control group (χ(2)=4.043, P=0.044). In UC group, no Clostridium difficile toxin gene was detected during the remission period (0/1), one case was positive for toxin gene (1/11) during mild active period, and 2 cases were (2/3) during moderately active period. There were significant differences in the infection rate of toxigenic Clostridium difficile between patients in different active period (χ(2)=4.000, P=0.046). The main manifestations of the 6 cases were diarrhea, abdominal pain and bloody stool, and the relapsed case was characterized by sudden aggravation. TcdA was detected in all toxin gene positive samples, and 1 case combined with tcdB had more serious bloody mucopurulent stool. Five cases had colonoscopy, but there was no obvious characteristics of toxigenic Clostridium difficile colitis such as yellow white plaques or pseudomembranous spot. Three cases had antibiotic exposure history. All 6 cases were sensitive to metronidazole treatment, and stable without relapse during the 3-month follow-up. Conclusions: The infection rate of toxigenic Clostridium difficile in children with IBD is higher than that in healthy children. The patients with both tcdA and tcdB could have more serious clinical symptoms, although there may not be specific pathological changes of toxigenic Clostridium difficile colitis. The recognition of toxigenic Clostridium difficile infection in IBD children should be strengthened in clinical work.


Assuntos
Toxinas Bacterianas , Infecções por Clostridium , Doenças Inflamatórias Intestinais , Proteínas de Bactérias , Toxinas Bacterianas/genética , Criança , /patogenicidade , Infecções por Clostridium/tratamento farmacológico , Infecções por Clostridium/epidemiologia , Enterotoxinas/genética , Fezes , Humanos , Doenças Inflamatórias Intestinais/microbiologia , Estudos Retrospectivos
9.
PLoS Genet ; 16(6): e1008866, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32530914

RESUMO

Escherichia coli is mostly a commensal of birds and mammals, including humans, where it can act as an opportunistic pathogen. It is also found in water and sediments. We investigated the phylogeny, genetic diversification, and habitat-association of 1,294 isolates representative of the phylogenetic diversity of more than 5,000 isolates from the Australian continent. Since many previous studies focused on clinical isolates, we investigated mostly other isolates originating from humans, poultry, wild animals and water. These strains represent the species genetic diversity and reveal widespread associations between phylogroups and isolation sources. The analysis of strains from the same sequence types revealed very rapid change of gene repertoires in the very early stages of divergence, driven by the acquisition of many different types of mobile genetic elements. These elements also lead to rapid variations in genome size, even if few of their genes rise to high frequency in the species. Variations in genome size are associated with phylogroup and isolation sources, but the latter determine the number of MGEs, a marker of recent transfer, suggesting that gene flow reinforces the association of certain genetic backgrounds with specific habitats. After a while, the divergence of gene repertoires becomes linear with phylogenetic distance, presumably reflecting the continuous turnover of mobile element and the occasional acquisition of adaptive genes. Surprisingly, the phylogroups with smallest genomes have the highest rates of gene repertoire diversification and fewer but more diverse mobile genetic elements. This suggests that smaller genomes are associated with higher, not lower, turnover of genetic information. Many of these genomes are from freshwater isolates and have peculiar traits, including a specific capsule, suggesting adaptation to this environment. Altogether, these data contribute to explain why epidemiological clones tend to emerge from specific phylogenetic groups in the presence of pervasive horizontal gene transfer across the species.


Assuntos
Escherichia coli/genética , Evolução Molecular , Transferência Genética Horizontal , Variação Genética , Genoma Bacteriano/genética , Animais , Animais Selvagens/microbiologia , Austrália , Galinhas/microbiologia , Farmacorresistência Bacteriana/genética , Escherichia coli/isolamento & purificação , Escherichia coli/patogenicidade , Fezes/microbiologia , Água Doce/microbiologia , Tamanho do Genoma , Humanos , Doenças Inflamatórias Intestinais/microbiologia , Sequências Repetitivas Dispersas/genética , Mucosa Intestinal/microbiologia , Carne/microbiologia , Anotação de Sequência Molecular , Filogenia , Microbiologia do Solo , Fatores de Virulência/genética , Sequenciamento Completo do Genoma
10.
Aliment Pharmacol Ther ; 52(2): 247-266, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32525605

RESUMO

BACKGROUND: Psychiatric co-morbidities including depression and anxiety are common in inflammatory bowel diseases (IBD). Emerging evidence suggests that interactions between the gut microbiota and brain may play a role in the pathogenesis of psychiatric symptoms in IBD. AIM: To review the literature on microbiota-brain-gut interactions in gut inflammation, psychosocial stress and mental disorders and to discuss the putative mediating role of gut microbiota in the development of psychiatric symptoms or co-morbidities in IBD. METHODS: A literature search was conducted on Ovid and Pubmed to select relevant animal and human studies reporting an association between IBD, mental disorders and gut microbiota. RESULTS: Gut microbial alterations are frequently reported in subjects with IBD and with mental disorders. Both have been associated with reduced faecal bacterial diversity, decreased taxa within the phylum Firmicutes and increased Gammaproteobacteria. In animal studies, microbial perturbations induce behavioural changes and modulate inflammation in mice. Anxiety- and depression-like behaviours in animals can be transferred via faecal microbiota. In humans, modulation of the gut microbiota with probiotics is associated with behavioural and mood changes. Recent data show correlations in changes of faecal and mucosal microbiota and psychological distress in patients with IBD independent of disease activity. CONCLUSION: Both IBD and mental disorders are associated with gut microbial alterations. Preclinical and preliminary human studies have shown a mediating role of the gut microbiota in intestinal inflammation and anxiety, depression and stress. Targeting the gut microbiota may represent a useful therapeutic approach for the treatment of psychiatric co-morbidities in IBD.


Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Transtornos Mentais , Animais , Humanos , Inflamação/microbiologia , Inflamação/psicologia , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/psicologia , Transtornos Mentais/microbiologia , Transtornos Mentais/psicologia
11.
PLoS Comput Biol ; 16(5): e1007859, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32365061

RESUMO

Microbiomes are complex ecological systems that play crucial roles in understanding natural phenomena from human disease to climate change. Especially in human gut microbiome studies, where collecting clinical samples can be arduous, the number of taxa considered in any one study often exceeds the number of samples ten to one hundred-fold. This discrepancy decreases the power of studies to identify meaningful differences between samples, increases the likelihood of false positive results, and subsequently limits reproducibility. Despite the vast collections of microbiome data already available, biome-specific patterns of microbial structure are not currently leveraged to inform studies. Here, we derive microbiome-level properties by applying an embedding algorithm to quantify taxon co-occurrence patterns in over 18,000 samples from the American Gut Project (AGP) microbiome crowdsourcing effort. We then compare the predictive power of models trained using properties, normalized taxonomic count data, and another commonly used dimensionality reduction method, Principal Component Analysis in categorizing samples from individuals with inflammatory bowel disease (IBD) and healthy controls. We show that predictive models trained using property data are the most accurate, robust, and generalizable, and that property-based models can be trained on one dataset and deployed on another with positive results. Furthermore, we find that properties correlate significantly with known metabolic pathways. Using these properties, we are able to extract known and new bacterial metabolic pathways associated with inflammatory bowel disease across two completely independent studies. By providing a set of pre-trained embeddings, we allow any V4 16S amplicon study to apply the publicly informed properties to increase the statistical power, reproducibility, and generalizability of analysis.


Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais/microbiologia , Terminologia como Assunto , Algoritmos , Bactérias/classificação , Bactérias/genética , Humanos , Redes e Vias Metabólicas , Modelos Biológicos , Filogenia , Reprodutibilidade dos Testes
12.
Nature ; 581(7808): 310-315, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32433607

RESUMO

Microbiome community typing analyses have recently identified the Bacteroides2 (Bact2) enterotype, an intestinal microbiota configuration that is associated with systemic inflammation and has a high prevalence in loose stools in humans1,2. Bact2 is characterized by a high proportion of Bacteroides, a low proportion of Faecalibacterium and low microbial cell densities1,2, and its prevalence varies from 13% in a general population cohort to as high as 78% in patients with inflammatory bowel disease2. Reported changes in stool consistency3 and inflammation status4 during the progression towards obesity and metabolic comorbidities led us to propose that these developments might similarly correlate with an increased prevalence of the potentially dysbiotic Bact2 enterotype. Here, by exploring obesity-associated microbiota alterations in the quantitative faecal metagenomes of the cross-sectional MetaCardis Body Mass Index Spectrum cohort (n = 888), we identify statin therapy as a key covariate of microbiome diversification. By focusing on a subcohort of participants that are not medicated with statins, we find that the prevalence of Bact2 correlates with body mass index, increasing from 3.90% in lean or overweight participants to 17.73% in obese participants. Systemic inflammation levels in Bact2-enterotyped individuals are higher than predicted on the basis of their obesity status, indicative of Bact2 as a dysbiotic microbiome constellation. We also observe that obesity-associated microbiota dysbiosis is negatively associated with statin treatment, resulting in a lower Bact2 prevalence of 5.88% in statin-medicated obese participants. This finding is validated in both the accompanying MetaCardis cardiovascular disease dataset (n = 282) and the independent Flemish Gut Flora Project population cohort (n = 2,345). The potential benefits of statins in this context will require further evaluation in a prospective clinical trial to ascertain whether the effect is reproducible in a randomized population and before considering their application as microbiota-modulating therapeutics.


Assuntos
Disbiose/epidemiologia , Disbiose/prevenção & controle , Microbioma Gastrointestinal/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Bacteroides/isolamento & purificação , Estudos de Coortes , Estudos Transversais , Faecalibacterium/isolamento & purificação , Fezes/microbiologia , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Doenças Inflamatórias Intestinais/microbiologia , Masculino , Obesidade/microbiologia , Prevalência
13.
Aliment Pharmacol Ther ; 52(1): 155-167, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32412673

RESUMO

BACKGROUND: Small intestinal bacterial overgrowth may play a role in gastrointestinal and non-gastrointestinal diseases. AIMS: To use quantitative polymerase chain reaction (qPCR) to determine and compare bacterial loads of duodenal biopsies in asymptomatic controls, and patients with functional gastrointestinal disorders (FGIDs) and inflammatory bowel disease (IBD) including ulcerative colitis (UC) and Crohn's disease (CD). To define effects of gastric acid inhibition on bacterial load, explore links of bacterial load and gastrointestinal symptoms in response to a standardised nutrient challenge and compare bacterial load with glucose breath test results. METHODS: In 237 patients (63 controls, 84 FGID and 90 IBD), we collected mucosal samples under aseptic conditions during endoscopy extracted and total DNA. Bacterial load metric was calculated utilising qPCR measurements of the bacterial 16S rRNA gene, normalised to human beta-actin expression. Standard glucose breath test and nutrient challenge test were performed. RESULTS: The duodenal microbial load was higher in patients with FGID (0.22 ± 0.03) than controls (0.07 ± 0.05; P = 0.007) and patients with UC (0.01 ± 0.05) or CD (0.02 ± 0.09), (P = 0.0001). While patients treated with proton pump inhibitors (PPI) had significantly higher bacterial loads than non-users (P < 0.05), this did not explain differences between patient groups and controls. Bacterial load was significantly (r = 0.21, P < 0.016) associated with the symptom response to standardised nutrient challenge test. Methane, but not hydrogen values on glucose breath test were associated with bacterial load measured utilising qPCR. CONCLUSIONS: Utilising qPCR, a diagnosis of FGID and treatment with PPI were independently associated with increased bacterial loads. Increased bacterial loads are associated with an augmented symptom response to a standardised nutrient challenge.


Assuntos
Duodeno/microbiologia , Gastroenteropatias/microbiologia , Doenças Inflamatórias Intestinais/microbiologia , Adulto , Idoso , Bactérias/genética , Bactérias/isolamento & purificação , Carga Bacteriana , Biópsia , Testes Respiratórios/métodos , Feminino , Gastroenteropatias/metabolismo , Glucose/metabolismo , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase/métodos , RNA Ribossômico 16S/genética
14.
PLoS Pathog ; 16(5): e1008553, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32453761

RESUMO

IRGM and its mouse orthologue Irgm1 are dynamin-like proteins that regulate vesicular remodeling, intracellular microbial killing, and pathogen immunity. IRGM dysfunction is linked to inflammatory bowel disease (IBD), and while it is thought that defective intracellular killing of microbes underscores IBD susceptibility, studies have yet to address how IRGM/Irgm1 regulates immunity to microbes relevant to intestinal inflammation. Here we find that loss of Irgm1 confers marked susceptibility to Citrobacter rodentium, a noninvasive intestinal pathogen that models inflammatory responses to intestinal bacteria. Irgm1-deficient mice fail to control C. rodentium outgrowth in the intestine, leading to systemic pathogen spread and host mortality. Surprisingly, susceptibility due to loss of Irgm1 function was not linked to defective intracellular killing of C. rodentium or exaggerated inflammation, but was instead linked to failure to remodel specific colon lamina propria (C-LP) myeloid cells that expand in response to C. rodentium infection and are essential for C. rodentium immunity. Defective immune remodeling was most striking in C-LP monocytes, which were successfully recruited to the infected C-LP, but subsequently underwent apoptosis. Apoptotic susceptibility was induced by C. rodentium infection and was specific to this setting of pathogen infection, and was not apparent in other settings of intestinal inflammation. These studies reveal a novel role for Irgm1 in host defense and suggest that deficiencies in survival and remodeling of C-LP myeloid cells that control inflammatory intestinal bacteria may underpin IBD pathogenesis linked to IRGM dysfunction.


Assuntos
Citrobacter rodentium/imunologia , Colo/imunologia , Infecções por Enterobacteriaceae/imunologia , Proteínas de Ligação ao GTP/deficiência , Doenças Inflamatórias Intestinais/imunologia , Monócitos/imunologia , Animais , Colo/microbiologia , Colo/patologia , Infecções por Enterobacteriaceae/genética , Infecções por Enterobacteriaceae/patologia , Proteínas de Ligação ao GTP/imunologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/patologia , Camundongos , Camundongos Knockout , Monócitos/microbiologia , Monócitos/patologia , Membrana Mucosa/imunologia , Membrana Mucosa/microbiologia , Membrana Mucosa/patologia
15.
Adv Exp Med Biol ; 1238: 11-22, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32323177

RESUMO

The gastrointestinal (GI) tract is inhabited by a diverse array of microbes, which play crucial roles in health and disease. Dysbiosis of microbiota has been tightly linked to gastrointestinal inflammatory and malignant diseases. Here we highlight the role of Helicobacter pylori alongside gastric microbiota associated with gastric inflammation and cancer. We summarize the taxonomic and functional aspects of intestinal microbiota linked to inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS), and colorectal cancer in clinical investigations. We also discuss microbiome-related animal models. Nevertheless, there are tremendous opportunities to reveal the causality of microbiota in health and disease and detailed microbe-host interaction mechanisms by which how dysbiosis is causally linked to inflammatory disease and cancer, in turn, potentializing clinical interventions with a personalized high efficacy.


Assuntos
Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/patologia , Disbiose/microbiologia , Disbiose/patologia , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/patologia , Animais , Helicobacter pylori/patogenicidade , Humanos , Síndrome do Intestino Irritável/microbiologia , Síndrome do Intestino Irritável/patologia
16.
Nucleic Acids Res ; 48(W1): W572-W579, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32338757

RESUMO

Microbial association networks are frequently used for understanding and comparing community dynamics from microbiome datasets. Inferring microbial correlations for such networks and obtaining meaningful biological insights, however, requires a lengthy data management workflow, choice of appropriate methods, statistical computations, followed by a different pipeline for suitably visualizing, reporting and comparing the associations. The complexity is further increased with the added dimension of multi-group 'meta-data' and 'inter-omic' functional profiles that are often associated with microbiome studies. This not only necessitates the need for categorical networks, but also integrated and bi-partite networks. Multiple options of network inference algorithms further add to the efforts required for performing correlation-based microbiome interaction studies. We present MetagenoNets, a web-based application, which accepts multi-environment microbial abundance as well as functional profiles, intelligently segregates 'continuous and categorical' meta-data and allows inference as well as visualization of categorical, integrated (inter-omic) and bi-partite networks. Modular structure of MetagenoNets ensures logical flow of analysis (inference, integration, exploration and comparison) in an intuitive and interactive personalized dashboard driven framework. Dynamic choice of filtration, normalization, data transformation and correlation algorithms ensures, that end-users get a one-stop solution for microbial network analysis. MetagenoNets is freely available at https://web.rniapps.net/metagenonets.


Assuntos
Microbiota , Software , Algoritmos , Humanos , Doenças Inflamatórias Intestinais/microbiologia , Metagenômica
17.
Am J Gastroenterol ; 115(6): 814-822, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32250997

RESUMO

Primary sclerosing cholangitis (PSC) is a rare, immune-mediated, chronic cholestatic liver disease associated with a unique phenotype of inflammatory bowel disease that frequently manifests as pancolitis with right-sided predominance. Available data suggest a bidirectional interplay of the gut-liver axis with critical roles for the gastrointestinal microbiome and circulating bile acids (BAs) in the pathophysiology of PSC. BAs shape the gut microbiome, whereas gut microbes have the potential to alter BAs, and there are emerging data that alterations of BAs and the microbiome are not simply a consequence but the cause of PSC. Clustering of PSC in families may suggest that PSC occurs in genetically susceptible individuals. After exposure to an environmental trigger (e.g., microbial byproducts or BAs), an aberrant or exaggerated cholangiocyte-induced immune cascade occurs, ultimately leading to bile duct damage and progressive fibrosis. The pathophysiology can be conceptualized as a triad of (1) gut dysbiosis, (2) altered BA metabolism, and (3) immune-mediated biliary injury. Immune activation seems to be central to the disease process, but immunosuppression does not improve clinical outcomes or alter the natural history of PSC. Currently, orthoptic liver transplantation is the only established life-saving treatment, whereas antimicrobial therapy or fecal transplantation is an emerging therapeutic option for PSC. The beneficial effects of these microbiome-based therapies are likely mediated by a shift of the gut microbiome with favorable effects on BA metabolism. In the future, personalized approaches will allow to better target the interdependence between microbiome, immune function, and BA metabolism and potentially cure patients with PSC.


Assuntos
Anti-Infecciosos/uso terapêutico , Ácidos e Sais Biliares/metabolismo , Colangite Esclerosante/terapia , Disbiose/terapia , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais/microbiologia , Colangite Esclerosante/imunologia , Colangite Esclerosante/metabolismo , Colangite Esclerosante/microbiologia , Disbiose/imunologia , Disbiose/metabolismo , Transplante de Microbiota Fecal , Humanos , Imunidade nas Mucosas/imunologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Transplante de Fígado
18.
Nat Rev Gastroenterol Hepatol ; 17(4): 223-237, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32076145

RESUMO

A key role of the gut microbiota in the establishment and maintenance of health, as well as in the pathogenesis of disease, has been identified over the past two decades. One of the primary modes by which the gut microbiota interacts with the host is by means of metabolites, which are small molecules that are produced as intermediate or end products of microbial metabolism. These metabolites can derive from bacterial metabolism of dietary substrates, modification of host molecules, such as bile acids, or directly from bacteria. Signals from microbial metabolites influence immune maturation, immune homeostasis, host energy metabolism and maintenance of mucosal integrity. Alterations in the composition and function of the microbiota have been described in many studies on IBD. Alterations have also been described in the metabolite profiles of patients with IBD. Furthermore, specific classes of metabolites, notably bile acids, short-chain fatty acids and tryptophan metabolites, have been implicated in the pathogenesis of IBD. This Review aims to define the key classes of microbial-derived metabolites that are altered in IBD, describe the pathophysiological basis of these associations and identify future targets for precision therapeutic modulation.


Assuntos
Microbioma Gastrointestinal/fisiologia , Doenças Inflamatórias Intestinais/microbiologia , Animais , Ácidos e Sais Biliares/metabolismo , Ácidos Graxos Voláteis/fisiologia , Transplante de Microbiota Fecal/métodos , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologia , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/terapia , Metabolômica/métodos , Probióticos/uso terapêutico , Triptofano/metabolismo
19.
Benef Microbes ; 11(1): 47-57, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32066260

RESUMO

This study evaluated the effects of Bifidobacterium longum 51A on the intestinal mucosa and inflammatory response in experimental colitis. Colitis was induced by administration of 3.5% dextran sodium sulphate (DSS) solution for 7 days. Two periods of administration were performed: treatment (T) group, mice received Bifidobacterium only during disease induction (7 days); total treatment (TT) group, mice received Bifidobacterium for 10 days before and during disease induction. The probiotic effects on intestinal permeability, inflammatory infiltrate, histological analysis, cytokines, chemokines and sIgA were evaluated. Bifidobacterium administration in the T group showed reduction in intestinal permeability and lower IL-1ß, myeloperoxidase, and eosinophil peroxidase levels compared to those in the colitis group (P<0.05). Bifidobacterium administration in the TT group attenuated severe lesions in the colon and reduced eosinophil peroxidase level (P<0.05). B. longum 51A treatment modality was more effective than total treatment and reduced the inflammatory response and its consequences on intestinal epithelium.


Assuntos
Bifidobacterium longum , Doenças Inflamatórias Intestinais/tratamento farmacológico , Probióticos/uso terapêutico , Animais , Colite/induzido quimicamente , Colo/efeitos dos fármacos , Colo/microbiologia , Colo/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Peroxidase de Eosinófilo/metabolismo , Feminino , Imunoglobulina A Secretora/metabolismo , Inflamação/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/microbiologia , Interleucina-1beta/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Intestinos/efeitos dos fármacos , Intestinos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Peroxidase/metabolismo
20.
Nat Rev Immunol ; 20(7): 411-426, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32005980

RESUMO

The mammalian intestine is colonized by trillions of microorganisms that have co-evolved with the host in a symbiotic relationship. The presence of large numbers of symbionts near the epithelial surface of the intestine poses an enormous challenge to the host because it must avoid the activation of harmful inflammatory responses to the microorganisms while preserving its ability to mount robust immune responses to invading pathogens. In patients with inflammatory bowel disease, there is a breakdown of the multiple strategies that the immune system has evolved to promote the separation between symbiotic microorganisms and the intestinal epithelium and the effective killing of penetrant microorganisms, while suppressing the activation of inappropriate T cell responses to resident microorganisms. Understanding the complex interactions between intestinal microorganisms and the host may provide crucial insight into the pathogenesis of inflammatory bowel disease as well as new avenues to prevent and treat the disease.


Assuntos
Microbioma Gastrointestinal/imunologia , Doenças Inflamatórias Intestinais/imunologia , Mucosa Intestinal/imunologia , Intestinos/imunologia , Animais , Microbioma Gastrointestinal/fisiologia , Homeostase/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/microbiologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Intestinos/microbiologia , Simbiose/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/microbiologia
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