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1.
Psychiatr Danub ; 31(Suppl 3): 381-385, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31488756

RESUMO

BACKGROUND: Psychiatric disorders may be correlated with a low-grade systemic inflammation but the origin of this inflammatory response remains unclear and both genetics and environmental factors seems to be concerned. Recent researches observed that gut microbiota seems to have an impact on the brain and immune processes. METHOD: We review recent literature to a better understanding of how microbiota interacts with brain, immunity and psychiatric disorders. We search on Pubmed, PsycINFO, PsycARTICLES and Sciencedirect articles with the keywords "gastrointestinal microbiota" and "mental disorders" or "psychological stress". RESULTS: We showed links between gut microbiota and brain-gut axis regulation, immune and endocrine system activity, neurophysiological changes, behavior variations and neuropsychiatric disorders. Communications between brain and gut are bidirectional via neural, endocrine and immune pathway. Microbiota dysbiosis and increase gut permeability with subsequent immune challenges seems to be the source of the chronic mild inflammation associated with neuropsychiatric disorders. Repeated immune or stress events early in life may lead to neurodevelopmental disorders or sickness behavior later in life. CONCLUSIONS: Psychological stress impact gut microbiota with subsequent immune activation leading to neurodevelopmental disorders or sickness behavior and altering neurophysiology and reactivity to stress or lifestyle.


Assuntos
Encéfalo/imunologia , Encéfalo/fisiopatologia , Microbioma Gastrointestinal/imunologia , Microbioma Gastrointestinal/fisiologia , Inflamação/imunologia , Inflamação/psicologia , Transtornos Mentais/imunologia , Transtornos Mentais/microbiologia , Disbiose/imunologia , Disbiose/microbiologia , Disbiose/psicologia , Sistema Endócrino/imunologia , Sistema Endócrino/metabolismo , Sistema Endócrino/microbiologia , Humanos , Inflamação/microbiologia , Neuropsiquiatria , Estresse Psicológico/imunologia , Estresse Psicológico/microbiologia
2.
Nat Commun ; 10(1): 3031, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292453

RESUMO

Maternal immune dysregulation seems to affect fetal or postnatal immune development. Preeclampsia is a pregnancy-associated disorder with an immune basis and is linked to atopic disorders in offspring. Here we show reduction of fetal thymic size, altered thymic architecture and reduced fetal thymic regulatory T (Treg) cell output in preeclamptic pregnancies, which persists up to 4 years of age in human offspring. In germ-free mice, fetal thymic CD4+ T cell and Treg cell development are compromised, but rescued by maternal supplementation with the intestinal bacterial metabolite short chain fatty acid (SCFA) acetate, which induces upregulation of the autoimmune regulator (AIRE), known to contribute to Treg cell generation. In our human cohorts, low maternal serum acetate is associated with subsequent preeclampsia, and correlates with serum acetate in the fetus. These findings suggest a potential role of acetate in the pathogenesis of preeclampsia and immune development in offspring.


Assuntos
Acetatos/sangue , Feto/imunologia , Pré-Eclâmpsia/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Linfócitos T Reguladores/imunologia , Acetatos/administração & dosagem , Acetatos/imunologia , Acetatos/metabolismo , Adulto , Animais , Animais Recém-Nascidos , Estudos de Casos e Controles , Desenvolvimento Infantil , Pré-Escolar , Suplementos Nutricionais , Feminino , Feto/citologia , Feto/diagnóstico por imagem , Microbioma Gastrointestinal/imunologia , Vida Livre de Germes/imunologia , Humanos , Tolerância Imunológica/imunologia , Lactente , Recém-Nascido , Estudos Longitudinais , Troca Materno-Fetal/imunologia , Camundongos , Tamanho do Órgão/imunologia , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/diagnóstico , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Estudos Prospectivos , Timo/citologia , Timo/diagnóstico por imagem , Timo/crescimento & desenvolvimento , Timo/imunologia , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Ultrassonografia Pré-Natal , Adulto Jovem
3.
Scand J Immunol ; 90(3): e12799, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31211854

RESUMO

Pemphigus vulgaris (PV) is an autoimmune disease characterized by the production of IgG autoantibodies owing to an imbalance in the Th1/Th2 and Th17/Tregs cell pathways. The role of gut microbiota in the development of immune system and autoimmune diseases has been unraveled in the last two decades. However, data pertaining to gut microbiota of PV patients is largely lacking. We aimed to compare the gut microbiota of PV patients and healthy controls and assessed potential correlation with circulating cytokines of Th1/Th2/Th17 cell. Faecal bacterial diversity was analysed in 18 PV patients and 14 age- and gender-matched healthy individuals using hypervariable tag sequencing of the V3-V4 region of the 16S rRNA gene. Plasma levels of 20 inflammatory cytokines were assessed using the Luminex screening system. As a result, we identified 10 differentially abundant taxa between patients and controls. At the genera level, Lachnospiracea_incertae_sedis and Coprococcus decreased, while Granulicatella, Flavonifractor enriched in PV. Plasma levels of C5a, interleukin (IL)-2R, IL-6, IL-8, IL-7, IL-1ß, IL17A, IL-5 and IL-21 were significantly increased in PV Flavonifractor exhibited a positive correlation with C5a, IL-6, IL-8, IL-7, IL-1ß, IL17A and IL-21. Lachnospiracea_incertae_sedis and Coprococcus showed a negative correlation with IL-17A. Our results are consistent with the hypothesis that PV patients have gut microbial dysbiosis which might contribute to the immune disorder and the development of PV.


Assuntos
Doenças Autoimunes/imunologia , Citocinas/imunologia , Microbioma Gastrointestinal/imunologia , Inflamação/imunologia , Pênfigo/imunologia , Plasma/imunologia , Adulto , Autoanticorpos/imunologia , Doenças Autoimunes/microbiologia , Fezes/microbiologia , Feminino , Humanos , Inflamação/microbiologia , Masculino , Pessoa de Meia-Idade , Pênfigo/microbiologia , Plasma/microbiologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/microbiologia , Células Th1/imunologia , Células Th1/microbiologia , Células Th17/imunologia , Células Th17/microbiologia , Células Th2/imunologia , Células Th2/microbiologia
4.
Nat Commun ; 10(1): 2443, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164642

RESUMO

Ageing is a complex multifactorial process associated with a plethora of disorders, which contribute significantly to morbidity worldwide. One of the organs significantly affected by age is the gut. Age-dependent changes of the gut-associated microbiome have been linked to increased frailty and systemic inflammation. This change in microbial composition with age occurs in parallel with a decline in function of the gut immune system; however, it is not clear whether there is a causal link between the two. Here we report that the defective germinal centre reaction in Peyer's patches of aged mice can be rescued by faecal transfers from younger adults into aged mice and by immunisations with cholera toxin, without affecting germinal centre reactions in peripheral lymph nodes. This demonstrates that the poor germinal centre reaction in aged animals is not irreversible, and that it is possible to improve this response in older individuals by providing appropriate stimuli.


Assuntos
Envelhecimento/imunologia , Disbiose/imunologia , Transplante de Microbiota Fecal , Microbioma Gastrointestinal/imunologia , Centro Germinativo/imunologia , Nódulos Linfáticos Agregados/imunologia , Animais , Toxina da Cólera/imunologia , Feminino , Imunização , Imunoglobulina A/imunologia , Camundongos , Nitrofenóis/imunologia , Fenilacetatos/imunologia
5.
Cell Mol Life Sci ; 76(20): 3917-3937, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31250035

RESUMO

The gastrointestinal tract is the site of nutrient digestion and absorption and is also colonized by diverse, highly mutualistic microbes. The intestinal microbiota has diverse effects on the development and function of the gut-specific immune system, and provides some protection from infectious pathogens. However, interactions between intestinal immunity and microorganisms are very complex, and recent studies have revealed that this intimate crosstalk may depend on the production and sensing abilities of multiple bioactive small molecule metabolites originating from direct produced by the gut microbiota or by the metabolism of dietary components. Here, we review the interplay between the host immune system and the microbiota, how commensal bacteria regulate the production of metabolites, and how these microbiota-derived products influence the function of several major innate and adaptive immune cells involved in modulating host immune homeostasis.


Assuntos
Imunidade Adaptativa , Disbiose/metabolismo , Microbioma Gastrointestinal/imunologia , Imunidade Inata , Mucosa Intestinal/metabolismo , Metaboloma/imunologia , Aminoácidos/imunologia , Aminoácidos/metabolismo , Animais , Ácidos e Sais Biliares/imunologia , Ácidos e Sais Biliares/metabolismo , Disbiose/imunologia , Disbiose/microbiologia , Disbiose/terapia , Ácidos Graxos/imunologia , Ácidos Graxos/metabolismo , Transplante de Microbiota Fecal , Vida Livre de Germes/imunologia , Homeostase/imunologia , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Linfócitos/imunologia , Linfócitos/metabolismo , Linfócitos/microbiologia , Células Mieloides/imunologia , Células Mieloides/metabolismo , Células Mieloides/microbiologia , Simbiose/imunologia
6.
Crit Rev Oncol Hematol ; 141: 1-12, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31202124

RESUMO

The human microbiome is an emerging target in cancer development and therapeutics. It may be directly oncogenic, through promotion of mucosal inflammation or systemic dysregulation, or may alter anti-cancer immunity/therapy. Microorganisms within, adjacent to and distant from tumors may affect cancer progression, and interactions and differences between these populations can influence the course of disease. Here we review the microbiome as it pertains to cancer for clinicians. The microbiota of cancers including colorectal, pancreas, breast and prostate are discussed. We examine "omics" technologies, microbiota associated with tumor tissue and tumor-site fluids such as feces and urine, as well as indirect effects of the gut microbiome. We describe roles of the microbiome in immunotherapy, and how it can be modulated to improve cancer therapeutics. While research is still at an early stage, there is potential to exploit the microbiome, as modulation may increase efficacy of treatments, reduce toxicities and prevent carcinogenesis.


Assuntos
Microbiota/fisiologia , Neoplasias/microbiologia , Neoplasias/terapia , Carcinogênese , Feminino , Microbioma Gastrointestinal/imunologia , Microbioma Gastrointestinal/fisiologia , Humanos , Imunidade/fisiologia , Fatores Imunológicos/uso terapêutico , Imunoterapia , Masculino , Microbiota/imunologia , Neoplasias/imunologia
7.
Mol Immunol ; 112: 322-329, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31238287

RESUMO

OBJECTIVE: The morbidity and prevalence of type 2 diabetes mellitus (DM) are increasing in the elderly population. Interleukin 37 (IL-37) play important roles in anti-inflammatory and anti-bacteria immune responses, but its role in the development of type 2 DM in the elderly is unclear. Therefore, we investigated whether IL-37 is associated with type 2 DM in the elderly and the underlying mechanism. METHODS: Hospitalized patients (aged 65-95 years) with recently diagnosed type 2 diabetes mellitus were studied retrospectively and compared with healthy subjects without glucose metabolism abnormalities. A diabetic mouse model was established by feeding ob/ob mice (C57BL/6) a high-fat, carbohydrate-free diet. Plasma glucose and insulin levels were determined by glucose oxidase assay and radioimmunoassay, respectively. The IL-37 expression level was determined by real-time PCR, western blot and ELISA (Enzyme-linked immunoassay). RESULTS: Statistic analysis showed that the IL-37 level was significantly associated with type 2 DM and insulin resistance in the elderly. The patients were then divided into insulin therapy sensitive and resistant group according to their response to insulin therapy. Data showed that the IL-37 was highly expressed in the insulin therapy sensitive group. And this was related to the less severe gut microbiota dysbiosis. In the mice model, overexpressing the IL-37 could suppress the gut microbiota dysbiosis and also the diabetes development. CONCLUSION: Thus our results showed that higher IL-37 was associated with increased insulin sensitive in elderly type 2 DM patients through suppressing the gut microbiota dysbiosis.


Assuntos
Diabetes Mellitus Tipo 2/imunologia , Disbiose/imunologia , Microbioma Gastrointestinal/imunologia , Interleucina-1/imunologia , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/microbiologia , Diabetes Mellitus Tipo 2/microbiologia , Dieta Hiperlipídica/efeitos adversos , Disbiose/microbiologia , Feminino , Células HEK293 , Humanos , Resistência à Insulina/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
8.
Nat Commun ; 10(1): 2712, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221971

RESUMO

Clostridium difficile (C. difficile) incidence has tripled over the past 15 years and is attributed to the emergence of hypervirulent strains. While it is clear that C. difficile toxins cause damaging colonic inflammation, the immune mechanisms protecting from tissue damage require further investigation. Through a transcriptome analysis, we identify IL-33 as an immune target upregulated in response to hypervirulent C. difficile. We demonstrate that IL-33 prevents C. difficile-associated mortality and epithelial disruption independently of bacterial burden or toxin expression. IL-33 drives colonic group 2 innate lymphoid cell (ILC2) activation during infection and IL-33 activated ILC2s are sufficient to prevent disease. Furthermore, intestinal IL-33 expression is regulated by the microbiota as fecal microbiota transplantation (FMT) rescues antibiotic-associated depletion of IL-33. Lastly, dysregulated IL-33 signaling via the decoy receptor, sST2, predicts C. difficile-associated mortality in human patients. Thus, IL-33 signaling to ILC2s is an important mechanism of defense from C. difficile colitis.


Assuntos
Clostridium difficile/imunologia , Enterocolite Pseudomembranosa/imunologia , Imunidade Inata , Interleucina-33/metabolismo , Linfócitos/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antibacterianos/efeitos adversos , Toxinas Bacterianas/imunologia , Toxinas Bacterianas/metabolismo , Clostridium difficile/patogenicidade , Colo/citologia , Colo/imunologia , Colo/microbiologia , Colo/patologia , Modelos Animais de Doenças , Enterocolite Pseudomembranosa/microbiologia , Enterocolite Pseudomembranosa/mortalidade , Enterocolite Pseudomembranosa/terapia , Transplante de Microbiota Fecal , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Perfilação da Expressão Gênica , Humanos , Interleucina-33/imunologia , Linfócitos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologia , Virulência/imunologia , Adulto Jovem
9.
Curr Top Microbiol Immunol ; 421: 303-318, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31123894

RESUMO

Microbes within the gastrointestinal tract communicate with each other and with the host, which has profound effects on health and disease development. Only now, it is becoming apparent that how and when we acquire our own unique collection of "gut microbes" and also how we choose to maintain them is fundamental to our health. Helicobacter pylori is the most common bacterial infection worldwide, colonizing around half of the world's population, and is the major risk factor for gastric adenocarcinoma. More recently, it has also been shown to have some beneficial effects in terms of protecting against the development of other diseases. Here, we review the current knowledge on how H. pylori has shaped gastrointestinal microbiota colonization and the host immune system with specific focus on the impact of H. pylori on the various microbiome niches of the gastrointestinal tract. We discuss how the presence of H. pylori influences the physiology of three major regions within the gastrointestinal tract-specifically the oesophagus, stomach and colon. We pay particular attention to the role of H. pylori under chronic inflammatory conditions including the development of cancer. With increased incidence of diseases such as eosinophilic oesophagitis, oesophageal adenocarcinoma and squamous cell carcinoma being attributed to the decline in H. pylori, their disease pathogenesis in light of changing H. pylori colonization is also discussed.


Assuntos
Microbioma Gastrointestinal/imunologia , Microbioma Gastrointestinal/fisiologia , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/imunologia , Helicobacter pylori/patogenicidade , Sistema Imunitário/imunologia , Sistema Imunitário/microbiologia , Colo/imunologia , Colo/microbiologia , Esôfago/imunologia , Esôfago/microbiologia , Helicobacter pylori/fisiologia , Humanos , Estômago/imunologia , Estômago/microbiologia
10.
World J Gastroenterol ; 25(15): 1865-1878, 2019 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-31057300

RESUMO

BACKGROUND: Unconjugated bilirubin (UCB) is generally considered toxic but has gained recent prominence for its anti-inflammatory properties. However, the effects of it on the interaction between intestinal flora and organisms and how it influences immune responses remain unresolved. AIM: To investigate the role of UCB in intestinal barrier function and immune inflammation in mice with dextran-sulfate-sodium-induced colitis. METHODS: Acute colitis was induced by 3% (w/v) dextran sulfate sodium salt in drinking water for 6 d followed by untreated water for 2 d. Concurrently, mice with colitis were administered 0.2 mL UCB (400 µmol/L) by intra-gastric gavage for 7 d. Disease activity index (DAI) was monitored daily. Mice were sacrificed at the end of the experiment. The length of the colon and weight of the spleen were recorded. Serum level of D-lactate, intestinal digestive proteases activity, and changes to the gut flora were analyzed. In addition, colonic specimens were analyzed by histology and for expression of inflammatory markers and proteins. RESULTS: Mice treated with UCB had significantly relieved severity of colitis, including lower DAI, longer colon length, and lower spleen weight (colon length: 4.92 ± 0.09 cm vs 3.9 ± 0.15 cm; spleen weight: 0.33 ± 0.04 vs 0.74 ± 0.04, P < 0.001). UCB administration inactivated digestive proteases (chymotrypsin: 18.70 ± 0.69 U/g vs 44.81 ± 8.60 U/g; trypsin: 1.52 ± 0.23 U/g vs 9.05 ± 1.77 U/g, P < 0.01), increased expression of tight junction (0.99 ± 0.05 vs 0.57 ± 0.03, P < 0.001), decreased serum level of D-lactate (31.76 ± 3.37 µmol/L vs 54.25 ± 1.45 µmol/L, P < 0.001), and lowered histopathological score (4 ± 0.57 vs 7 ± 0.57, P < 0.001) and activity of myeloperoxidase (46.79 ± 2.57 U/g vs 110.32 ± 19.19 U/g, P < 0.001). UCB also regulated the intestinal microbiota, inhibited expression of tumor necrosis factor (TNF) α and interleukin 1ß (TNF-α: 52.61 ± 7.81 pg/mg vs 105.04 ± 11.92 pg/mg, interleukin 1ß: 13.43 ± 1.68 vs 32.41 ± 4.62 pg/mg, P < 0.001), decreased expression of Toll-like receptor 4 (0.61 ± 0.09 vs 1.07 ± 0.03, P < 0.001) and myeloid differentiation primary response gene 88 (0.73 ± 0.08 vs 1.01 ± 0.07, P < 0.05), and increased expression of TNF-receptor-associated factor 6 (0.79 ± 0.02 vs 0.43 ± 0.09 P < 0.05) and inhibitor of kappa B α (0.93 ± 0.07 vs 0.72 ± 0.07, P < 0.05) in the colon. CONCLUSION: UCB can protect intestinal barrier function, regulate normal intestinal homeostasis, and suppress inflammation via the Toll-like receptor 4/ nuclear factor-κB signaling pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Bilirrubina/farmacologia , Colite Ulcerativa/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Anti-Inflamatórios/uso terapêutico , Bilirrubina/uso terapêutico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/imunologia , Colite Ulcerativa/microbiologia , Colo/imunologia , Colo/metabolismo , Colo/microbiologia , Colo/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Microbioma Gastrointestinal/imunologia , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/imunologia , NF-kappa B/metabolismo , Permeabilidade , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/imunologia , Receptor 4 Toll-Like/metabolismo , Resultado do Tratamento
11.
Nat Commun ; 10(1): 2153, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31089128

RESUMO

The gut commensal Bacteroides fragilis or its capsular polysaccharide A (PSA) can prevent various peripheral and CNS sterile inflammatory disorders. Fatal herpes simplex encephalitis (HSE) results from immune pathology caused by uncontrolled invasion of the brainstem by inflammatory monocytes and neutrophils. Here we assess the immunomodulatory potential of PSA in HSE by infecting PSA or PBS treated 129S6 mice with HSV1, followed by delayed Acyclovir (ACV) treatment as often occurs in the clinical setting. Only PSA-treated mice survived, with dramatically reduced brainstem inflammation and altered cytokine and chemokine profiles. Importantly, PSA binding by B cells is essential for induction of regulatory CD4+ and CD8+ T cells secreting IL-10 to control innate inflammatory responses, consistent with the lack of PSA mediated protection in Rag-/-, B cell- and IL-10-deficient mice. Our data reveal the translational potential of PSA as an immunomodulatory symbiosis factor to orchestrate robust protective anti-inflammatory responses during viral infections.


Assuntos
Bacteroides fragilis/imunologia , Encefalite por Herpes Simples/imunologia , Microbioma Gastrointestinal/imunologia , Herpesvirus Humano 1/imunologia , Polissacarídeos Bacterianos/imunologia , Aciclovir/uso terapêutico , Animais , Antivirais/uso terapêutico , Linfócitos B/imunologia , Linfócitos B/metabolismo , Bacteroides fragilis/metabolismo , Cercopithecus aethiops , Modelos Animais de Doenças , Encefalite por Herpes Simples/tratamento farmacológico , Encefalite por Herpes Simples/virologia , Feminino , Herpesvirus Humano 1/patogenicidade , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-10/metabolismo , Masculino , Camundongos , Camundongos Knockout , Polissacarídeos Bacterianos/metabolismo , Simbiose/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Células Vero
12.
Discov Med ; 27(147): 93-100, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30939293

RESUMO

The microbial community is present abundantly in mucosal organs including the intestine, the oral cavity, and the vagina, and is referred to as the microbiota. The microbiota is composed of commensal bacteria and other microorganisms. Intestinal colonization by commensal microorganisms is essential for host physiological functions from the maintenance of barrier homeostasis locally to the regulation of metabolism, hematopoiesis, inflammation, immune development, and other functions systemically. Evidence is growing that the gut microbiota can modulate the host response to cancer immunotherapy. In this review, we discuss the evidence for the ability of the microbiota to modulate immunotherapy, their mechanisms of action, and the possibility of altering the microbiota to improve immunotherapy efficacy.


Assuntos
Bactérias/imunologia , Microbioma Gastrointestinal/imunologia , Imunidade Inata , Imunoterapia , Mucosa Intestinal , Neoplasias , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Neoplasias/imunologia , Neoplasias/microbiologia , Neoplasias/terapia
13.
Int J Mol Sci ; 20(7)2019 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-30970593

RESUMO

The crosstalk between gut microbiota (GM) and the immune system is intense and complex. When dysbiosis occurs, the resulting pro-inflammatory environment can lead to bacterial translocation, systemic immune activation, tissue damage, and cancerogenesis. GM composition seems to impact both the therapeutic activity and the side effects of anticancer treatment; in particular, robust evidence has shown that the GM modulates the response to immunotherapy in patients affected by metastatic melanoma. Despite accumulating knowledge supporting the role of GM composition in lymphomagenesis, unexplored areas still remain. No studies have been designed to investigate GM alteration in patients diagnosed with lymphoproliferative disorders and treated with chemo-free therapies, and the potential association between GM, therapy outcome, and immune-related adverse events has never been analyzed. Additional studies should be considered to create opportunities for a more tailored approach in this set of patients. In this review, we describe the possible role of the GM during chemo-free treatment of lymphoid malignancies.


Assuntos
Disbiose/imunologia , Transtornos Linfoproliferativos/microbiologia , Animais , Disbiose/complicações , Microbioma Gastrointestinal/imunologia , Humanos , Transtornos Linfoproliferativos/imunologia , Microbiota , Medicina de Precisão
14.
World J Gastroenterol ; 25(12): 1465-1477, 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30948910

RESUMO

BACKGROUND: Anti-tumor necrosis factor α (TNFα) represents the best therapeutic option to induce mucosal healing and clinical remission in patients with moderate-severe ulcerative colitis. On the other side gut microbiota plays a crucial role in pathogenesis of ulcerative colitis but few information exists on how microbiota changes following anti-TNFα therapy and on microbiota role in mucosal healing. AIM: To elucidate whether gut microbiota and immune system changes appear following anti TNFα therapy during dextran sulfate sodium (DSS) colitis. METHODS: Eighty C57BL/6 mice were divided into four groups: "No DSS", "No DSS + anti-TNFα", "DSS" and "DSS + anti-TNFα". "DSS" and "DSS + anti-TNFα" were treated for 5 d with 3% DSS. At day 3, mice whithin "No DSS+anti-TNFα" and "DSS+anti-TNFα" group received 5 mg/kg of an anti-TNFα agent. Forty mice were sacrificed at day 5, forty at day 12, after one week of recovery post DSS. The severity of colitis was assessed by a clinical score (Disease Activity Index), colon length and histology. Bacteria such as Bacteroides, Clostridiaceae, Enterococcaceae and Fecalibacterium prausnitzii (F. prausnitzii) were evaluated by quantitative PCR. Type 1 helper T lymphocytes (Th1), type 17 helper T lymphocytes (Th17) and CD4+ regulatory T lymphocytes (Treg) distributions in the mesenteric lymph node (MLN) were studied by flow cytometry. RESULTS: Bacteria associated with a healthy state (i.e., such as Bacteroides, Clostridiaceae and F. prausnitzii) decreased during colitis and increased in course of anti-TNFα treatment. Conversely, microorganisms belonging to Enterococcaceae genera, which are linked to inflammatory processes, showed an opposite trend. Furthermore, in colitic mice treated with anti-TNFα microbial changes were associated with an initial increase (day 5 of the colitis) in Treg cells and a consequent decrease (day 12 post DSS) in Th1 and Th17 frequency cells. Healthy mice treated with anti-TNFα showed the same histological, microbial and immune features of untreated colitic mice. "No DSS + anti-TNFα" group showed a lymphomononuclear infiltrate both at 5th and 12th d at hematoxylin and eosin staining, an increase of in Th1 and Th17 frequency at day 12, an increase of Enterococcaceae at day 5, a decrease of Bacteroides and Clostridiaceae at day 12. CONCLUSION: Anti-TNFα treatment in experimental model of colitis improves disease activity but it is associated to an increase in Th17 pathway together with gut microbiota alteration.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Fármacos Gastrointestinais/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Bactérias/efeitos dos fármacos , Bactérias/imunologia , Bactérias/isolamento & purificação , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/imunologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/microbiologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Microbioma Gastrointestinal/imunologia , Humanos , Infliximab/efeitos adversos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Índice de Gravidade de Doença , Células Th17/imunologia , Fator de Necrose Tumoral alfa/imunologia
15.
Parasit Vectors ; 12(1): 174, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992084

RESUMO

BACKGROUND: Vector control remains the most important tool to prevent malaria transmission. However, it is now severely constrained by the appearance of physiological and behavioral insecticide resistance. Therefore, the development of new vector control tools is warranted. Such tools could include immunization of blood hosts of vector mosquitoes with mosquito proteins involved in midgut homeostasis (anti-mosquito vaccines) or genetic engineering of mosquitoes that can drive population-wide knockout of genes producing such proteins to reduce mosquito lifespan and malaria transmission probability. METHODS: To achieve this, candidate genes related to midgut homeostasis regulation need to be assessed for their effect on mosquito survival. Here, different such candidate genes were silenced through dsRNA injection in the naturally occurring Anopheles arabiensis mosquitoes and the effect on mosquito survival was evaluated. RESULTS: Significantly higher mortality rates were observed in the mosquitoes silenced for FN3D1 (AARA003032), FN3D3 (AARA007751) and GPRGr9 (AARA003963) genes as compared to the control group injected with dsRNA against a non-related bacterial gene (LacZ). This observed difference in mortality rate between the candidate genes and the control disappeared when gene-silenced mosquitoes were treated with antibiotic mixtures, suggesting that gut microbiota play a key role in the observed reduction of mosquito survival. CONCLUSIONS: We demonstrated that interference with the expression of the FN3D1, FN3D3 or GPRGr9 genes causes a significant reduction of the longevity of An. arabiensis mosquito in the wild.


Assuntos
Anopheles/genética , Longevidade/genética , Controle de Mosquitos/métodos , Mosquitos Vetores/genética , Animais , Anopheles/efeitos dos fármacos , Anopheles/imunologia , Antibacterianos/farmacologia , Etiópia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/imunologia , Genes de Insetos , Longevidade/imunologia , Mosquitos Vetores/imunologia , Interferência de RNA
16.
PLoS Pathog ; 15(4): e1007672, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30973942

RESUMO

Gastrointestinal (GI) mucosal dysfunction predicts and likely contributes to non-infectious comorbidities and mortality in HIV infection and persists despite antiretroviral therapy. However, the mechanisms underlying this dysfunction remain incompletely understood. Neutrophils are important for containment of pathogens but can also contribute to tissue damage due to their release of reactive oxygen species and other potentially harmful effector molecules. Here we used a flow cytometry approach to investigate increased neutrophil lifespan as a mechanism for GI neutrophil accumulation in chronic, treated HIV infection and a potential role for gastrointestinal dysbiosis. We report that increased neutrophil survival contributes to neutrophil accumulation in colorectal biopsy tissue, thus implicating neutrophil lifespan as a new therapeutic target for mucosal inflammation in HIV infection. Additionally, we characterized the intestinal microbiome of colorectal biopsies using 16S rRNA sequencing. We found that a reduced Lactobacillus: Prevotella ratio associated with neutrophil survival, suggesting that intestinal bacteria may contribute to GI neutrophil accumulation in treated HIV infection. Finally, we provide evidence that Lactobacillus species uniquely decrease neutrophil survival and neutrophil frequency in vitro, which could have important therapeutic implications for reducing neutrophil-driven inflammation in HIV and other chronic inflammatory conditions.


Assuntos
Colo/imunologia , Microbioma Gastrointestinal/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Inflamação/imunologia , Neutrófilos/imunologia , Reto/imunologia , Colo/microbiologia , Colo/patologia , Feminino , Infecções por HIV/virologia , Humanos , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/citologia , Reto/microbiologia , Reto/patologia
17.
PLoS Pathog ; 15(4): e1007611, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30947289

RESUMO

Men who have sex with men (MSM) have differences in immune activation and gut microbiome composition compared with men who have sex with women (MSW), even in the absence of HIV infection. Gut microbiome differences associated with HIV itself when controlling for MSM, as assessed by 16S rRNA sequencing, are relatively subtle. Understanding whether gut microbiome composition impacts immune activation in HIV-negative and HIV-positive MSM has important implications since immune activation has been associated with HIV acquisition risk and disease progression. To investigate the effects of MSM and HIV-associated gut microbiota on immune activation, we transplanted feces from HIV-negative MSW, HIV-negative MSM, and HIV-positive untreated MSM to gnotobiotic mice. Following transplant, 16S rRNA gene sequencing determined that the microbiomes of MSM and MSW maintained distinct compositions in mice and that specific microbial differences between MSM and MSW were replicated. Immunologically, HIV-negative MSM donors had higher frequencies of blood CD38+ HLADR+ and CD103+ T cells and their fecal recipients had higher frequencies of gut CD69+ and CD103+ T cells, compared with HIV-negative MSW donors and recipients, respectively. Significant microbiome differences were not detected between HIV-negative and HIV-positive MSM in this small donor cohort, and immune differences between their recipients were trending but not statistically significant. A larger donor cohort may therefore be needed to detect immune-modulating microbes associated with HIV. To investigate whether our findings in mice could have implications for HIV replication, we infected primary human lamina propria cells stimulated with isolated fecal microbiota, and found that microbiota from MSM stimulated higher frequencies of HIV-infected cells than microbiota from MSW. Finally, we identified several microbes that correlated with immune readouts in both fecal recipients and donors, and with in vitro HIV infection, which suggests a role for gut microbiota in immune activation and potentially HIV acquisition in MSM.


Assuntos
Microbioma Gastrointestinal/imunologia , Vida Livre de Germes/imunologia , Infecções por HIV/imunologia , HIV/imunologia , Homossexualidade Masculina , Adolescente , Adulto , Idoso , Animais , Estudos de Coortes , DNA Bacteriano/genética , Fezes/microbiologia , Feminino , HIV/genética , Infecções por HIV/microbiologia , Infecções por HIV/virologia , Humanos , Técnicas In Vitro , Masculino , Camundongos , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , Comportamento Sexual , Adulto Jovem
18.
Microb Pathog ; 131: 158-163, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30953746

RESUMO

Mycobacterium tuberculosis (Mtb) has the extraordinary ability to persist for decades within granulomas in the human host. These histopathological structures involved in both protection and pathogenesis, are subject to various influences from the host systemically and through micro-niche environments. Despite the fact that vitamin D (VD) has a key role in macrophage activation and mycobacterial clearance in the early stages of Mtb infection, the overall role of VD in granuloma maintenance or functionality has been scarcely studied. VD deficiency has long time been known to influence on gut microbiota composition, and recent studies have shown that it can also impact on respiratory microbiome. The human microbiota plays an important role in pathogen colonization resistance, and it has been proposed to play a potential role in TB pathogenesis. In this article, we have reviewed current knowledge on the interaction between VD, the lung microbiome and TB, and propose mechanisms by which the tuberculous granuloma's outcome could be modulated by these two factors. The determinants of the final fate of lung granulomas are still unclear, and deciphering the underlying drivers of Mtb infection outcome within those structures is of critical importance.


Assuntos
Microbioma Gastrointestinal/fisiologia , Granuloma/imunologia , Pulmão/microbiologia , Mycobacterium tuberculosis/patogenicidade , Tuberculose/imunologia , Vitamina D/metabolismo , Disbiose , Microbioma Gastrointestinal/imunologia , Granuloma/patologia , Interações Hospedeiro-Patógeno , Humanos , Pulmão/patologia , Ativação de Macrófagos , Tuberculose/patologia , Vitamina D/imunologia , Deficiência de Vitamina D/complicações
19.
Nat Commun ; 10(1): 1198, 2019 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-30867416

RESUMO

Microbe-host interactions are generally homeostatic, but when dysfunctional, they can incite food sensitivities and chronic diseases. Celiac disease (CeD) is a food sensitivity characterized by a breakdown of oral tolerance to gluten proteins in genetically predisposed individuals, although the underlying mechanisms are incompletely understood. Here we show that duodenal biopsies from patients with active CeD have increased proteolytic activity against gluten substrates that correlates with increased Proteobacteria abundance, including Pseudomonas. Using Pseudomonas aeruginosa producing elastase as a model, we show gluten-independent, PAR-2 mediated upregulation of inflammatory pathways in C57BL/6 mice without villus blunting. In mice expressing CeD risk genes, P. aeruginosa elastase synergizes with gluten to induce more severe inflammation that is associated with moderate villus blunting. These results demonstrate that proteases expressed by opportunistic pathogens impact host immune responses that are relevant to the development of food sensitivities, independently of the trigger antigen.


Assuntos
Proteínas de Bactérias/metabolismo , Doença Celíaca/imunologia , Proteínas na Dieta/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Metaloendopeptidases/metabolismo , Receptor PAR-2/imunologia , Adulto , Idoso , Animais , Antígenos/imunologia , Antígenos/metabolismo , Proteínas de Bactérias/genética , Biópsia , Estudos de Casos e Controles , Doença Celíaca/diagnóstico por imagem , Doença Celíaca/microbiologia , Doença Celíaca/patologia , Estudos de Coortes , Colonoscopia , Proteínas na Dieta/metabolismo , Modelos Animais de Doenças , Duodeno/imunologia , Duodeno/metabolismo , Duodeno/microbiologia , Duodeno/patologia , Feminino , Microbioma Gastrointestinal/imunologia , Vida Livre de Germes , Glutens/imunologia , Glutens/metabolismo , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/imunologia , Antígenos HLA-DQ/metabolismo , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Masculino , Metaloendopeptidases/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Pessoa de Meia-Idade , Proteólise , Pseudomonas aeruginosa/imunologia , Pseudomonas aeruginosa/metabolismo , Receptor PAR-2/metabolismo , Regulação para Cima , Adulto Jovem
20.
Immunology ; 156(4): 297-298, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30873603

RESUMO

Th17-derived IL-17 might be considered the archetypal pro-inflammatory cytokine of adaptive immunity, to be targeted by new therapeutics for alleviation of autoimmune and inflammatory disease. However, the IL-17 family of cytokines is produced by diverse innate and adaptive cells, including Th17, Tc17, ILC3, NK cells and γδ T-cells. These responses are appreciated to underpin diverse aspects of protective, physiological immunity, from dialogue with the gut microbiota to bacterial and fungal immunity in the lung.


Assuntos
Células Th17/imunologia , Imunidade Adaptativa/imunologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/microbiologia , Bactérias/imunologia , Fungos/imunologia , Microbioma Gastrointestinal/imunologia , Humanos
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