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1.
Nat Commun ; 12(1): 261, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431850

RESUMO

Intestinal microfold cells are the primary pathway for translocation of secretory IgA (SIgA)-pathogen complexes to gut-associated lymphoid tissue. Uptake of SIgA/commensals complexes is important for priming adaptive immunity in the mucosa. This study aims to explore the effect of SIgA retrograde transport of immune complexes in Crohn's disease (CD). Here we report a significant increase of SIgA transport in CD patients with NOD2-mutation compared to CD patients without NOD2 mutation and/or healthy individuals. NOD2 has an effect in the IgA transport through human and mouse M cells by downregulating Dectin-1 and Siglec-5 expression, two receptors involved in retrograde transport. These findings define a mechanism of NOD2-mediated regulation of mucosal responses to intestinal microbiota, which is involved in CD intestinal inflammation and dysbiosis.


Assuntos
Doença de Crohn/metabolismo , Imunoglobulina A Secretora/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Animais , Colite/microbiologia , Colite/patologia , Doença de Crohn/patologia , Humanos , Lectinas Tipo C/metabolismo , Camundongos Knockout , Modelos Biológicos , Mutação/genética , Proteína Adaptadora de Sinalização NOD2/deficiência , Proteína Adaptadora de Sinalização NOD2/genética , Nódulos Linfáticos Agregados/metabolismo , Transporte Proteico , Salmonella/fisiologia , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo , Transcitose
2.
Nat Commun ; 11(1): 4457, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901017

RESUMO

Innate lymphoid cells (ILCs) and CD4+ T cells produce IL-22, which is critical for intestinal immunity. The microbiota is central to IL-22 production in the intestines; however, the factors that regulate IL-22 production by CD4+ T cells and ILCs are not clear. Here, we show that microbiota-derived short-chain fatty acids (SCFAs) promote IL-22 production by CD4+ T cells and ILCs through G-protein receptor 41 (GPR41) and inhibiting histone deacetylase (HDAC). SCFAs upregulate IL-22 production by promoting aryl hydrocarbon receptor (AhR) and hypoxia-inducible factor 1α (HIF1α) expression, which are differentially regulated by mTOR and Stat3. HIF1α binds directly to the Il22 promoter, and SCFAs increase HIF1α binding to the Il22 promoter through histone modification. SCFA supplementation enhances IL-22 production, which protects intestines from inflammation. SCFAs promote human CD4+ T cell IL-22 production. These findings establish the roles of SCFAs in inducing IL-22 production in CD4+ T cells and ILCs to maintain intestinal homeostasis.


Assuntos
Ácidos Graxos Voláteis/imunologia , Microbioma Gastrointestinal/imunologia , Imunidade Inata , Interleucinas/biossíntese , Animais , Butiratos/imunologia , Butiratos/metabolismo , Butiratos/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/microbiologia , Citrobacter rodentium , Colite/imunologia , Colite/microbiologia , Colite/prevenção & controle , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/prevenção & controle , Ácidos Graxos Voláteis/metabolismo , Ácidos Graxos Voláteis/farmacologia , Microbioma Gastrointestinal/fisiologia , Inibidores de Histona Desacetilases/farmacologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Técnicas In Vitro , Interleucinas/deficiência , Interleucinas/genética , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Regiões Promotoras Genéticas , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo
3.
PLoS Pathog ; 16(8): e1008763, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32834002

RESUMO

The various sub-species of Salmonella enterica cause a range of disease in human hosts. The human-adapted Salmonella enterica serovar Typhi enters the gastrointestinal tract and invades systemic sites to cause enteric (typhoid) fever. In contrast, most non-typhoidal serovars of Salmonella are primarily restricted to gut tissues. Across Africa, invasive non-typhoidal Salmonella (iNTS) have emerged with an ability to spread beyond the gastrointestinal tract and cause systemic bloodstream infections with increased morbidity and mortality. To investigate this evolution in pathogenesis, we compared the genomes of African iNTS isolates with other Salmonella enterica serovar Typhimurium and identified several macA and macB gene variants unique to African iNTS. MacAB forms a tripartite efflux pump with TolC and is implicated in Salmonella pathogenesis. We show that macAB transcription is upregulated during macrophage infection and after antimicrobial peptide exposure, with macAB transcription being supported by the PhoP/Q two-component system. Constitutive expression of macAB improves survival of Salmonella in the presence of the antimicrobial peptide C18G. Furthermore, these macAB variants affect replication in macrophages and influence fitness during colonization of the murine gastrointestinal tract. Importantly, the infection outcome resulting from these macAB variants depends upon both the Salmonella Typhimurium genetic background and the host gene Nramp1, an important determinant of innate resistance to intracellular bacterial infection. The variations we have identified in the MacAB-TolC efflux pump in African iNTS may reflect evolution within human host populations that are compromised in their ability to clear intracellular Salmonella infections.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Proteínas de Bactérias/genética , Colite/patologia , Variação Genética , Macrófagos/imunologia , Salmonelose Animal/patologia , Salmonella typhimurium/imunologia , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Proteínas de Bactérias/metabolismo , Linhagem da Célula , Colite/induzido quimicamente , Colite/imunologia , Colite/microbiologia , Análise Mutacional de DNA , Modelos Animais de Doenças , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Salmonelose Animal/imunologia , Salmonelose Animal/microbiologia , Replicação Viral
4.
Ann R Coll Surg Engl ; 102(7): e176-e179, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32803988

RESUMO

Spain has been one of the most affected countries by the COVID-19 outbreak. After the high impact of the pandemic, a wide clinical spectrum of late complications associated with COVID-19 are being observed. We report a case of a severe Clostridium difficile colitis in a post-treatment and recovered COVID-19 patient. A 64-year-woman with a one-month hospital admission for severe bilateral pneumonia associated with COVID-19 and 10 days after discharge presented with diarrhoea and abdominal pain. Severe C. difficile-associated colitis is diagnosed according to clinical features and CT findings. An urgent pancolectomy was performed due to her bad response to conservative treatment. Later evolution slowly improved to recovery. C. difficile-associated colitis is one of the most common hospital-acquired infections. Significant patient-related risk factors for C. difficile infection are antibiotic exposure, older age, and hospitalisation. Initial therapeutic recommendations in our country included administration broad-spectrum antibiotics to all patients with bilateral pneumonia associated with SARS-CoV-2. These antibiotics are strongly associated with C. difficile infection. Our patient developed a serious complication of C. difficile due to the use of broad-spectrum antibiotics. The appearance of late digestive symptoms in patients diagnosed and treated for COVID-19 should alert clinicians to the possibility of C. difficile infection. The updated criteria for severe colitis and severe C. difficile infection should be considered to ensure an early effective treatment for the complication.


Assuntos
Antibacterianos/uso terapêutico , Betacoronavirus , Clostridium difficile/isolamento & purificação , Colite/etiologia , Infecções por Coronavirus/complicações , Infecção Hospitalar/etiologia , Pneumonia Viral/complicações , Colite/tratamento farmacológico , Colite/microbiologia , Infecções por Coronavirus/epidemiologia , Infecção Hospitalar/diagnóstico , Infecção Hospitalar/tratamento farmacológico , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/epidemiologia , Fatores de Risco , Fatores de Tempo , Tomografia Computadorizada por Raios X
5.
Nihon Shokakibyo Gakkai Zasshi ; 117(6): 514-520, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32565509

RESUMO

The patient, a man in his 80s, presented with diarrhea following one year of treatment for non-small cell lung cancer with Nivolumab. CT results showed discontinuous wall thickening of the large bowel and cholangitis. Blood and stool culture tests ruled out immune-related adverse events and identified Edwardsiella tarda;bacterial colitis was diagnosed in the patient. This case confirmed that basic examination should not be neglected, and culture tests should be performed.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas , Colite/microbiologia , Infecções por Enterobacteriaceae/diagnóstico , Neoplasias Pulmonares , Nivolumabe/efeitos adversos , Idoso de 80 Anos ou mais , Edwardsiella tarda , Humanos , Masculino
6.
Nat Commun ; 11(1): 2577, 2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32444671

RESUMO

The gut microbiome consists of a multi-kingdom microbial community. Whilst the role of bacteria as causal contributors governing host physiological development is well established, the role of fungi remains to be determined. Here, we use germ-free mice colonized with defined species of bacteria, fungi, or both to differentiate the causal role of fungi on microbiome assembly, immune development, susceptibility to colitis, and airway inflammation. Fungal colonization promotes major shifts in bacterial microbiome ecology, and has an independent effect on innate and adaptive immune development in young mice. While exclusive fungal colonization is insufficient to elicit overt dextran sulfate sodium-induced colitis, bacterial and fungal co-colonization increase colonic inflammation. Ovalbumin-induced airway inflammation reveals that bacterial, but not fungal colonization is necessary to decrease airway inflammation, yet fungi selectively promotes macrophage infiltration in the airway. Together, our findings demonstrate a causal role for fungi in microbial ecology and host immune functionality, and therefore prompt the inclusion of fungi in therapeutic approaches aimed at modulating early life microbiomes.


Assuntos
Fungos/fisiologia , Microbioma Gastrointestinal/fisiologia , Sistema Imunitário/crescimento & desenvolvimento , Intestinos/microbiologia , Animais , Fenômenos Fisiológicos Bacterianos , Colite/induzido quimicamente , Colite/microbiologia , Sulfato de Dextrana/toxicidade , Fezes/microbiologia , Feminino , Fungos/isolamento & purificação , Microbioma Gastrointestinal/imunologia , Vida Livre de Germes , Humanos , Inflamação/induzido quimicamente , Inflamação/microbiologia , Metaboloma , Camundongos Endogâmicos C57BL , Ovalbumina/toxicidade
7.
Nat Commun ; 11(1): 1522, 2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-32251280

RESUMO

Foxp3+ regulatory T (Treg) cells are essential for maintaining peripheral tolerance and preventing autoimmunity. While genetic factors may predispose for autoimmunity, additional environmental triggers, such as viral infections, are usually required to initiate the onset of disease. Here, we show that viral infection with LCMV results in type I IFN-dependent Treg cell loss that is rapidly compensated by the conversion and expansion of Vß5+ conventional T cells into iTreg cells. Using Vß5-deficient mice, we show that these Vß5+ iTreg cells are dispensable for limiting anti-viral immunity. Rather, the delayed replenishment of Treg cells in Vß5-deficient mice compromises suppression of microbiota-dependent activation of CD8+ T cells, resulting in colitis. Importantly, recovery from clinical symptoms in IBD patients is marked by expansion of the corresponding Vß2+ Treg population in humans. Collectively, we provide a link between a viral trigger and an impaired Treg cell compartment resulting in the initiation of immune pathology.


Assuntos
Infecções por Arenaviridae/imunologia , Autoimunidade , Linfócitos T CD8-Positivos/imunologia , Colite/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Linfócitos T Reguladores/imunologia , Animais , Infecções por Arenaviridae/complicações , Linhagem Celular , Colite/microbiologia , Colo/imunologia , Colo/microbiologia , Fatores de Transcrição Forkhead/metabolismo , Microbioma Gastrointestinal/imunologia , Voluntários Saudáveis , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Ativação Linfocitária/genética , Masculino , Camundongos , Camundongos Knockout , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Linfócitos T Reguladores/metabolismo
8.
Nat Commun ; 11(1): 1802, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286276

RESUMO

Inflammatory bowel disease patients have a greatly increased risk of developing colitis-associated colon cancer (CAC); however, the basis for inflammation-induced genetic damage requisite for neoplasia is unclear. Using three models of CAC, we find that sustained inflammation triggers 8-oxoguanine DNA lesions. Strikingly, antioxidants or iNOS inhibitors reduce 8-oxoguanine and polyps in CAC models. Because the mismatch repair (MMR) system repairs 8-oxoguanine and is frequently defective in colorectal cancer (CRC), we test whether 8-oxoguanine mediates oncogenesis in a Lynch syndrome (MMR-deficient) model. We show that microbiota generates an accumulation of 8-oxoguanine lesions in MMR-deficient colons. Accordingly, we find that 8-oxoguanine is elevated in neoplastic tissue of Lynch syndrome patients compared to matched untransformed tissue or non-Lynch syndrome neoplastic tissue. While antioxidants reduce 8-oxoguanine, they do not reduce CRC in Lynch syndrome models. Hence, microbe-induced oxidative/nitrosative DNA damage play causative roles in inflammatory CRC models, but not in Lynch syndrome models.


Assuntos
Colite/complicações , Colite/patologia , Neoplasias Colorretais/complicações , Neoplasias Colorretais/patologia , Dano ao DNA , Helicobacter pylori/fisiologia , Estresse Oxidativo , Polipose Adenomatosa do Colo/complicações , Polipose Adenomatosa do Colo/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antioxidantes/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Colite/induzido quimicamente , Colite/microbiologia , Colo/efeitos dos fármacos , Colo/patologia , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo do DNA/efeitos dos fármacos , Sulfato de Dextrana , Modelos Animais de Doenças , Disbiose/complicações , Disbiose/patologia , Escherichia coli/metabolismo , Feminino , Guanosina/análogos & derivados , Guanosina/metabolismo , Infecções por Helicobacter/complicações , Helicobacter pylori/efeitos dos fármacos , Humanos , Inflamação/complicações , Inflamação/patologia , Interleucina-10/deficiência , Interleucina-10/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mutação/genética , Estresse Oxidativo/efeitos dos fármacos
9.
Sci Rep ; 10(1): 3829, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32123204

RESUMO

Exposure to cigarette smoke (CS) causes detrimental health effects, increasing the risk of cardiovascular, pulmonary diseases and carcinogenesis in exposed individuals. The impact of CS on Inflammatory Bowel Disease (IBD) has been established by a number of epidemiological and clinical studies. In fact, CS is associated with a higher risk of developing Crohn's disease (CD) while inversely correlates with the development, disease risks, and relapse rate of ulcerative colitis (UC). To investigate the effect of CS exposure on experimental colitis, we performed a comprehensive and integrated comparative analysis of colon transcriptome and microbiome in mice exposed to dextran sodium sulfate (DSS) and CS. Colon transcriptome analysis revealed that CS downregulated specific pathways in a concentration-dependent manner, affecting both the inflammatory state and composition of the gut microbiome. Metagenomics analysis demonstrated that CS can modulate DSS-induced dysbiosis of specific bacterial genera, contributing to resolve the inflammation or accelerate recovery. The risks of smoking far outweigh any possible benefit, thus smoking cessation must always be encouraged because of its significant health benefits. However, the inverse association between active smoking and the development of UC cannot be ignored and the present study lays the foundation for investigating potential molecular mechanisms responsible for the attenuation of colitis by certain compounds of tobacco when decoupled from combustion.


Assuntos
Colite/imunologia , Colite/microbiologia , Sulfato de Dextrana/farmacologia , Fumaça/efeitos adversos , Produtos do Tabaco/efeitos adversos , Animais , Colite/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microbiota/efeitos dos fármacos
10.
PLoS One ; 15(3): e0228358, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32208434

RESUMO

Inflammatory bowel disease results from alterations in the immune system and intestinal microbiota. The role of intestinal epithelial cells (IECs) in maintaining gut homeostasis is well known and its perturbation often causes gastrointestinal disorders including IBD. The epithelial specific adaptor protein (AP)-1B is involved in the establishment of the polarity of IECs. Deficiency of the AP-1B µ subunit (Ap1m2-/-) leads to the development of chronic colitis in mice. However, how this deficiency affects the gut microbes and its potential functions remains elusive. To gain insights into the gut microbiome of Ap1m2-/- mice having the colitis phenotype, we undertook shotgun metagenomic sequencing analysis of knockout mice. We found important links to the microbial features involved in altering various physiological pathways, including carbohydrate metabolism, nutrient transportation, oxidative stress, and bacterial pathogenesis (cell motility). In addition, an increased abundance of sulfur-reducing and lactate-producing bacteria has been observed which may aggravate the colitis condition.


Assuntos
Complexo 1 de Proteínas Adaptadoras/deficiência , Complexo 1 de Proteínas Adaptadoras/genética , Colite/genética , Colite/microbiologia , Disbiose/microbiologia , Microbioma Gastrointestinal , Animais , Colite/complicações , Disbiose/complicações , Metagenômica , Camundongos
11.
Nat Microbiol ; 5(5): 746-756, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32152589

RESUMO

A complex microbiota inhabits various microenvironments of the gut, with some symbiotic bacteria having evolved traits to invade the epithelial mucus layer and reside deep within the intestinal tissue of animals. Whether these distinct bacterial communities across gut biogeographies exhibit divergent behaviours is largely unknown. Global transcriptomic analysis to investigate microbial physiology in specific mucosal niches has been hampered technically by an overabundance of host RNA. Here, we employed hybrid selection RNA sequencing (hsRNA-Seq) to enable detailed spatial transcriptomic profiling of a prominent human commensal as it colonizes the colonic lumen, mucus or epithelial tissue of mice. Compared to conventional RNA-Seq, hsRNA-Seq increased reads mapping to the Bacteroides fragilis genome by 48- and 154-fold in mucus and tissue, respectively, allowing for high-fidelity comparisons across biogeographic sites. Near the epithelium, B. fragilis upregulated numerous genes involved in protein synthesis, indicating that bacteria inhabiting the mucosal niche are metabolically active. Further, a specific sulfatase (BF3086) and glycosyl hydrolase (BF3134) were highly induced in mucus and tissue compared to bacteria in the lumen. In-frame deletion of these genes impaired in vitro growth on mucus as a carbon source, as well as mucosal colonization of mice. Mutants in either B. fragilis gene displayed a fitness defect in competing for colonization against bacterial challenge, revealing the importance of site-specific gene expression for robust host-microbial symbiosis. As a versatile tool, hsRNA-Seq can be deployed to explore the in vivo spatial physiology of numerous bacterial pathogens or commensals.


Assuntos
Bacteroides fragilis/genética , Bacteroides fragilis/fisiologia , Colo/microbiologia , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Bacteroides fragilis/crescimento & desenvolvimento , Colite/microbiologia , Feminino , Regulação Bacteriana da Expressão Gênica , Vida Livre de Germes , Humanos , Mucosa Intestinal/microbiologia , Masculino , Camundongos , Ácidos Sulfônicos , Simbiose , Transcriptoma
12.
Int J Mol Sci ; 21(3)2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-32013191

RESUMO

Chronic inflammation has been linked to colitis-associated colorectal cancer in humans. The human symbiont enterotoxigenic Bacteroides fragilis (ETBF), a pro-carcinogenic bacterium, has the potential to initiate and/or promote colorectal cancer. Antibiotic treatment of ETBF has shown promise in decreasing colonic polyp formation in murine models of colon cancer. However, there are no reported natural products that have shown efficacy in decreasing polyp burden. In this study, we investigated the chemopreventive effects of oral administration of zerumbone in ETBF-colonized mice with azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced tumorigenesis. Zerumbone significantly reduced the severity of disease activity index (DAI) scores as well as several parameters of colonic inflammation (i.e., colon weight, colon length, cecum weight and spleen weight). In addition, inflammation of the colon and cecum as well as hyperplasia was reduced. Zerumbone treatment significantly inhibited colonic polyp numbers and prevented macroadenoma progression. Taken together, these findings suggest that oral treatment with zerumbone inhibited ETBF-promoted colon carcinogenesis in mice indicating that zerumbone could be employed as a promising protective agent against ETBF-mediated colorectal cancer.


Assuntos
Bacteroides fragilis/patogenicidade , Neoplasias do Colo/prevenção & controle , Substâncias Protetoras/uso terapêutico , Sesquiterpenos/uso terapêutico , Administração Oral , Animais , Azoximetano/toxicidade , Peso Corporal/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Colite/complicações , Colite/microbiologia , Colite/patologia , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/patologia , Sulfato de Dextrana/toxicidade , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Substâncias Protetoras/farmacologia , Sesquiterpenos/farmacologia , Índice de Gravidade de Doença
13.
Nat Microbiol ; 5(4): 610-619, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32015497

RESUMO

Although much research has been done on the diversity of the gut microbiome, little is known about how it influences intestinal homeostasis under normal and pathogenic conditions. Epigenetic mechanisms have recently been suggested to operate at the interface between the microbiota and the intestinal epithelium. We performed whole-genome bisulfite sequencing on conventionally raised and germ-free mice, and discovered that exposure to commensal microbiota induced localized DNA methylation changes at regulatory elements, which are TET2/3-dependent. This culminated in the activation of a set of 'early sentinel' response genes to maintain intestinal homeostasis. Furthermore, we demonstrated that exposure to the microbiota in dextran sodium sulfate-induced acute inflammation results in profound DNA methylation and chromatin accessibility changes at regulatory elements, leading to alterations in gene expression programs enriched in colitis- and colon-cancer-associated functions. Finally, by employing genetic interventions, we show that microbiota-induced epigenetic programming is necessary for proper intestinal homeostasis in vivo.


Assuntos
Colite/genética , DNA/genética , Epigênese Genética , Microbioma Gastrointestinal/fisiologia , Genoma , Simbiose/genética , Animais , Colite/induzido quimicamente , Colite/microbiologia , Colite/patologia , Colo/metabolismo , Colo/microbiologia , DNA/metabolismo , Metilação de DNA , Sulfato de Dextrana/administração & dosagem , Vida Livre de Germes , Homeostase/genética , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sequenciamento Completo do Genoma
14.
Int J Med Sci ; 17(2): 145-152, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32038097

RESUMO

The azoxymethane (AOM)/dextran sulfate sodium (DSS) murine model is commonly used to study colitis-associated cancer. The human commensal bacterium, enterotoxigenic Bacteroides fragilis (ETBF) secretes the Bacteroides fragilis toxin (BFT) which is necessary and sufficient to cause colitis. We report that BALB/c mice infected with WT-ETBF and administered three cycles of AOM/DSS developed numerous, large-sized polyps predominantly in the colorectal region. In addition, AOM/DSS-treated BALB/c mice orally inoculated with wild-type nontoxigenic Bacteroides fragilis (WT-NTBF) overexpressing bft (rETBF) developed numerous polyps whereas mice infected with WT-NTBF overexpressing a biologically inactive bft (rNTBF) did not promote polyp formation. Unexpectedly, the combination of AOM+ETBF did not induce polyp formation whereas ETBF+DSS did induce polyp development in a subset of BALB/c mice. In conclusion, WT-ETBF promoted polyp development in AOM/DSS murine model with increased colitis in BALB/c mice. The model described herein provides an experimental platform for understanding ETBF-induced colonic tumorigenesis and studying colorectal cancer in wild-type mice.


Assuntos
Infecções por Bacteroides/patologia , Carcinogênese/genética , Colite/patologia , Neoplasias Colorretais/patologia , Animais , Azoximetano/toxicidade , Toxinas Bacterianas/toxicidade , Infecções por Bacteroides/induzido quimicamente , Infecções por Bacteroides/complicações , Infecções por Bacteroides/microbiologia , Bacteroides fragilis/patogenicidade , Carcinogênese/induzido quimicamente , Colite/induzido quimicamente , Colite/complicações , Colite/microbiologia , Colo/efeitos dos fármacos , Colo/patologia , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/complicações , Neoplasias Colorretais/microbiologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Humanos , Metaloendopeptidases/toxicidade , Camundongos , Pólipos/induzido quimicamente
15.
Artigo em Inglês | MEDLINE | ID: mdl-32075741

RESUMO

During short-lived perturbations, such as inflammation, the gut microbiota exhibits resilience and reverts to its original configuration. Although microbial access to the micronutrient iron is decreased during colitis, pathogens can scavenge iron by using siderophores. How commensal bacteria acquire iron during gut inflammation is incompletely understood. Curiously, the human commensal Bacteroides thetaiotaomicron does not produce siderophores but grows under iron-limiting conditions using enterobacterial siderophores. Using RNA-seq, we identify B. thetaiotaomicron genes that were upregulated during Salmonella-induced gut inflammation and were predicted to be involved in iron uptake. Mutants in the xusABC locus (BT2063-2065) were defective for xenosiderophore-mediated iron uptake in vitro. In the normal mouse gut, the XusABC system was dispensable, while a xusA mutant colonized poorly during colitis. This work identifies xenosiderophore utilization as a critical mechanism for B. thetaiotaomicron to sustain colonization during inflammation and suggests a mechanism of how interphylum iron metabolism contributes to gut microbiota resilience.


Assuntos
Bacteroides thetaiotaomicron/metabolismo , Colite/microbiologia , Enterobacteriaceae/genética , Microbioma Gastrointestinal , Ferro/metabolismo , Sideróforos/genética , Animais , Bacteroides thetaiotaomicron/genética , Feminino , Genes Bacterianos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA-Seq , Simbiose
16.
FASEB J ; 34(2): 2929-2943, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31908045

RESUMO

Diet plays a significant role in the pathogenesis of inflammatory bowel disease (IBD). A recent epidemiological study has shown an inverse relationship between nutritional manganese (Mn) status and IBD patients. Mn is an essential micronutrient required for normal cell function and physiological processes. To date, the roles of Mn in intestinal homeostasis remain unknown and the contribution of Mn to IBD has yet to be explored. Here, we provide evidence that Mn is critical for the maintenance of the intestinal barrier and that Mn deficiency exacerbates dextran sulfate sodium (DSS)-induced colitis in mice. Specifically, when treated with DSS, Mn-deficient mice showed increased morbidity, weight loss, and colon injury, with a concomitant increase in inflammatory cytokine levels and oxidative and DNA damage. Even without DSS treatment, dietary Mn deficiency alone increased intestinal permeability by impairing intestinal tight junctions. In contrast, mice fed a Mn-supplemented diet showed slightly increased tolerance to DSS-induced experimental colitis, as judged by the colon length. Despite the well-appreciated roles of intestinal microbiota in driving inflammation in IBD, the gut microbiome composition was not altered by changes in dietary Mn. We conclude that Mn is necessary for proper maintenance of the intestinal barrier and provides protection against DSS-induced colon injury.


Assuntos
Colite , Colo , Suplementos Nutricionais , Microbioma Gastrointestinal/efeitos dos fármacos , Manganês/farmacologia , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/microbiologia , Colite/patologia , Colo/metabolismo , Colo/microbiologia , Colo/patologia , Dano ao DNA , Sulfato de Dextrana/toxicidade , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/microbiologia , Inflamação/patologia , Camundongos , Oxirredução/efeitos dos fármacos
17.
Int J Biol Macromol ; 147: 284-294, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31926226

RESUMO

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, has gradually emerged as a public health challenge worldwide. Carrageenan is a popular food additive that has been in use for decades. However, controversy exists regarding to the safety of carrageenan due to its exacerbation of colitis in experimental models. In this study, we studied the effects of vehicle and host intestinal microflora on carrageenan inflammatory properties in C57BL/6 J mice. We found that in high-fat diet model, native carrageenan in drinking water increased the disease activity index (DAI), myeloperoxidase (MPO) activity and the mRNA expression of TLR4 in colon, whereas carrageenan-supplemented diet has no visible effects. However, no signs of colitis were observed under low-fat diet regardless of the mode of vehicle used. Moreover, we discovered that carrageenan-induced colitis in high-fat diet model was robustly correlated with changes in the composition of gut microbiota, specifically Alistipes finegoldii and Bacteroides acidifaciens. Hence, we propose that the inflammatory property of carrageenan is influenced greatly by its intake form via modification of host intestinal microecology.


Assuntos
Colite/induzido quimicamente , Colite/microbiologia , Microbioma Gastrointestinal , Interações Hospedeiro-Patógeno , Intestinos/microbiologia , Animais , Carragenina , Colo/patologia , Dieta Hiperlipídica , Modelos Animais de Doenças , Água Potável/química , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Peso Molecular , Monossacarídeos/análise , Peroxidase/metabolismo , Análise de Componente Principal , Espectroscopia de Infravermelho com Transformada de Fourier , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
18.
Carbohydr Polym ; 230: 115726, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31887919

RESUMO

The study tried to investigate whether apple polysaccharide (AP) could prevent colitis associated colorectal cancer (CACC) through the regulation of intestinal microbiota disorders. 10 % AP (w/v) was administrated to ICR mice by gavage for 15 wk. It was found that AP treatment protected against CACC in mice effectively. The level of Lactobacillus in the intestine of AOM/DSS-treated mice was significantly decreased and that of Fusobacterium increased; while AP could reverse this trend and increase the intestinal microbiota diversity. The number of T cells and macrophages in the colon tissue of mice in AOM/DSS group elevated; while AP could reduce the number of these cells significantly. AP suppressed nuclear aggregation of ß-catenin, inhibited the activation of Wnt pathway in colon tissues. These data suggest that AP prevented ICR mice from CACC at least in part through regulating intestinal flora disorder and Wnt pathway.


Assuntos
Colite , Neoplasias do Colo , Neoplasias Colorretais , Disbiose , Microbioma Gastrointestinal/efeitos dos fármacos , Polissacarídeos/farmacologia , Animais , Colite/dietoterapia , Colite/microbiologia , Neoplasias do Colo/dietoterapia , Neoplasias do Colo/microbiologia , Neoplasias Colorretais/dietoterapia , Neoplasias Colorretais/microbiologia , Disbiose/dietoterapia , Disbiose/microbiologia , Intestinos/microbiologia , Intestinos/patologia , Masculino , Malus/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Via de Sinalização Wnt
19.
Nat Commun ; 11(1): 513, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980634

RESUMO

Gut microbiota and their metabolites are instrumental in regulating intestinal homeostasis. However, early-life microbiota associated influences on intestinal development remain incompletely understood. Here we demonstrate that co-housing of germ-free (GF) mice with specific-pathogen free (SPF) mice at weaning (exGF) results in altered intestinal gene expression. Our results reveal that one highly differentially expressed gene, erythroid differentiation regulator-1 (Erdr1), is induced during development in SPF but not GF or exGF mice and localizes to Lgr5+ stem cells and transit amplifying (TA) cells. Erdr1 functions to induce Wnt signaling in epithelial cells, increase Lgr5+ stem cell expansion, and promote intestinal organoid growth. Additionally, Erdr1 accelerates scratch-wound closure in vitro, increases Lgr5+ intestinal stem cell regeneration following radiation-induced injury in vivo, and enhances recovery from dextran sodium sulfate (DSS)-induced colonic damage. Collectively, our findings indicate that early-life microbiota controls Erdr1-mediated intestinal epithelial proliferation and regeneration in response to mucosal damage.


Assuntos
Proteínas de Membrana/metabolismo , Microbiota , Regeneração , Células-Tronco/citologia , Proteínas Supressoras de Tumor/metabolismo , Animais , Proliferação de Células/genética , Colite/induzido quimicamente , Colite/microbiologia , Colite/patologia , Sulfato de Dextrana , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Vida Livre de Germes , Humanos , Luciferases/metabolismo , Camundongos Endogâmicos C57BL , Microbiota/genética , Organoides/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Células-Tronco/metabolismo , Via de Sinalização Wnt/genética , Cicatrização/genética
20.
Proc Natl Acad Sci U S A ; 117(5): 2570-2578, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-31964813

RESUMO

The thymus generates cells of the T cell lineage that seed the lymphatic and blood systems. Transcription factor regulatory networks control the lineage programming and maturation of thymic precursor cells. Whether extrathymic antigenic events, such as the microbial colonization of the mucosal tract also shape the thymic T cell repertoire is unclear. We show here that intestinal microbes influence the thymic homeostasis of PLZF-expressing cells in early life. Impaired thymic development of PLZF+ innate lymphocytes in germ-free (GF) neonatal mice is restored by colonization with a human commensal, Bacteroides fragilis, but not with a polysaccharide A (PSA) deficient isogenic strain. Plasmacytoid dendritic cells influenced by microbes migrate from the colon to the thymus in early life to regulate PLZF+ cell homeostasis. Importantly, perturbations in thymic PLZF+ cells brought about by alterations in early gut microbiota persist into adulthood and are associated with increased susceptibility to experimental colitis. Our studies identify a pathway of communication between intestinal microbes and thymic lymphocytes in the neonatal period that can modulate host susceptibility to immune-mediated diseases later in life.


Assuntos
Microbioma Gastrointestinal , Linfócitos/imunologia , Timo/crescimento & desenvolvimento , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Bacteroides fragilis/fisiologia , Diferenciação Celular , Colite/genética , Colite/imunologia , Colite/microbiologia , Colo/microbiologia , Humanos , Linfócitos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Proteína com Dedos de Zinco da Leucemia Promielocítica/genética , Proteína com Dedos de Zinco da Leucemia Promielocítica/imunologia , Timo/citologia , Timo/imunologia
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