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1.
Curr Opin Microbiol ; 67: 102147, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35461008

RESUMO

Significant increases in potential microbial translocation, especially along the oral-gut axis, have been identified in many immune-related and inflammatory diseases, such as inflammatory bowel disease, colorectal cancer, rheumatoid arthritis, and liver cirrhosis, for which we currently have no cure or long-term treatment options. Recent advances in computational and experimental omics approaches now enable strain tracking, functional profiling, and strain isolation in unprecedented detail, which has the potential to elucidate the causes and consequences of microbial translocation. In this review, we discuss current evidence for the detection of bacterial translocation, examine different translocation axes with a primary focus on the oral-gut axis, and outline currently known translocation mechanisms and how they adversely affect the host in disease. Finally, we conclude with an overview of state-of-the-art computational and experimental tools for strain tracking and highlight the required next steps to elucidate the role of bacterial translocation in human health.


Assuntos
Translocação Bacteriana , Doenças Inflamatórias Intestinais , Humanos , Cirrose Hepática
2.
Front Cell Infect Microbiol ; 12: 824547, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35273923

RESUMO

Aeromonas sobria is a Gram-negative pathogen that causes food-borne illness. In immunocompromised patients and the elderly, A. sobria opportunistically leads to severe extraintestinal diseases including sepsis, peritonitis, and meningitis. If A. sobria that infects the intestinal tract causes such an extraintestinal infection, the pathogen must pass through the intestinal epithelial barrier. In our earlier study using intestinal cultured cells (T84 cells), we observed that an A. sobria strain with higher A. sobria serine protease (ASP) production caused a marked level of bacterial translocation across the T84 intestinal epithelial monolayer. Herein, we investigated the effect of ASP on tight junctions (TJs) in T84 cells. We observed that ASP acts on TJs and causes the destruction of ZO-1, ZO-2, ZO-3, and claudin-7 (i.e., some of the protein components constituting TJs), especially in the strains with high ASP productivity. Based on the present results together with those of our earlier study, we propose that ASP may cause a disruption of the barrier function of the intestinal epithelium as a whole due to the destruction of TJs (in addition to the destruction of adherens junctions) and that ASP may assist invasion of the pathogens from the intestinal epithelium into deep sites in the human body.


Assuntos
Aeromonas , Translocação Bacteriana , Serina Proteases , Junções Íntimas , Aeromonas/enzimologia , Linhagem Celular , Humanos , Mucosa Intestinal/microbiologia , Serina Proteases/metabolismo , Junções Íntimas/metabolismo
3.
BMC Cancer ; 22(1): 245, 2022 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-35248004

RESUMO

BACKGROUND: Cancer patients experience gastrointestinal and behavioral symptoms, and are at increased risk of systemic infection and inflammation. These conditions are a major source of morbidity and decreased quality of life prior to cancer treatment, but poorly defined etiologies impede successful treatment. The gastrointestinal microbiota shape inflammation, influence cancer progression and treatment, and colonize tumors. However, research has not directly determined if peripheral tumors influence the microbiome and intestinal physiology, thus influencing gastrointestinal and behavioral symptoms. Therefore, the purpose of this study was to examine consequences of orthotopic, syngeneic mammary tumor implantation, growth, and resection on fecal bacteriome composition and intestinal barrier function in relation to systemic inflammation and enteric bacterial translocation in mice. METHODS: Female mice were randomized to 3 experimental groups: sham surgical control, tumor recipients, and tumor recipients later receiving tumor-resection. Mice were sacrificed three weeks after tumor implantation or resection for collection of stool, colon, spleen, and brain tissue and analysis. RESULTS: Tumor-bearing mice exhibited several markers of colonic barrier disruption, including dampened expression of tight junction proteins (Cldn1 and Ocln) and elevated circulating lipopolysaccharide binding protein (LBP). Compromised colonic barrier integrity was associated with altered fecal bacterial profiles in tumor-mice, including lower relative abundance of Lactobacillus, but higher Bacteroides. Consistent with colonic barrier disruption and altered microbiomes, tumor-mice displayed markers of systemic inflammation including splenomegaly, higher splenic bacterial load, and elevated splenic and brain pro-inflammatory cytokines. Several  bacteria cultured from spleens had 16S rRNA gene amplicons matching those in fecal samples, suggesting they were of intestinal origin. Fecal Lactobacillus was highly-interrelated to physiological parameters disrupted by tumors via correlation network analysis. Tumor resection ameliorated circulating LBP, splenomegaly, and splenic cytokines, but not other parameters associated with loss of colonic barrier integrity and bacterial translocation. CONCLUSIONS: Orthotopic mammary tumors alter the microbiome, reduce intestinal barrier function, increase translocation of enteric bacteria, and alter systemic inflammation. This provides insight into how tumors commence gastrointestinal and behavioral symptoms prior to treatment, and identify targets for future therapeutics, such as probiotic Lactobacillus supplementation.


Assuntos
Translocação Bacteriana , Neoplasias da Mama/microbiologia , Fezes/microbiologia , Microbioma Gastrointestinal , Mucosa Intestinal/microbiologia , Animais , Colo/microbiologia , Modelos Animais de Doenças , Feminino , Inflamação/microbiologia , Camundongos , RNA Ribossômico 16S/metabolismo
4.
Int J Mol Sci ; 23(6)2022 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-35328624

RESUMO

Leaky gut syndrome is a medical condition characterized by intestinal hyperpermeability. Since the intestinal barrier is one of the essential components maintaining homeostasis along the gastrointestinal tract, loss of its integrity due to changes in bacterial composition, decreased expression levels of tight junction proteins, and increased concentration of pro-inflammatory cytokines may lead to intestinal hyperpermeability followed by the development of gastrointestinal and non-gastrointestinal diseases. Translocation of microorganisms and their toxic metabolites beyond the gastrointestinal tract is one of the fallouts of the leaky gut syndrome. The presence of intestinal bacteria in sterile tissues and distant organs may cause damage due to chronic inflammation and progression of disorders, including inflammatory bowel diseases, liver cirrhosis, and acute pancreatitis. Currently, there are no medical guidelines for the treatment or prevention of bacterial translocation in patients with the leaky gut syndrome; however, several studies suggest that dietary intervention can improve barrier function and restrict bacteria invasion. This review contains current literature data concerning the influence of diet, dietary supplements, probiotics, and drugs on intestinal permeability and bacterial translocation.


Assuntos
Microbioma Gastrointestinal , Pancreatite , Doença Aguda , Bactérias , Translocação Bacteriana , Humanos , Mucosa Intestinal/metabolismo , Pancreatite/metabolismo
5.
PLoS One ; 17(3): e0264278, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35286322

RESUMO

BACKGROUND AND AIMS: Alcoholic hepatitis (AH) is characterized by acute liver failure, neurocognitive impairment and renal failure. Severe inflammatory reactions are also known to occur in AH. Inflammation and bacterial translocation in the gut are thought to have major impact on disease development and progression. The mortality rate for AH is close to 50%. We aimed to assess the efficacy of rifaximin in treating AH and its impact on inflammation and metabolism. METHODS: The trial was approved by relevant authorities (EudraCT no: 2014-02264-33, Scientific Ethics Committee, jr. no: H-1-2014-056). Primary outcomes were changes in metabolic and inflammatory markers. Secondary outcomes were portal hypertension, kidney and neurocognitive function. RESULTS: Thirty-two patients were randomized to standard medical therapy (SMT) or SMT plus rifaximin, allocation was concealed. Four patients in the SMT group and five patients in the SMT + rifaximin group died due to AH and liver failure. No adverse events related to the study medication were observed. We found no significant differences in amino acids or inflammation markers (IL-2, IL-6, IL-8, IL-10, TNF-α, interferon-γ) between the groups after 28 and 90 days. CONCLUSION: Rifaximin does not alter inflammation or metabolism in patients with AH.


Assuntos
Hepatite Alcoólica , Hipertensão Portal , Translocação Bacteriana , Biomarcadores , Hepatite Alcoólica/tratamento farmacológico , Humanos , Hipertensão Portal/tratamento farmacológico , Inflamação/tratamento farmacológico , Rifaximina/uso terapêutico
6.
Phytother Res ; 36(5): 2143-2160, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35229912

RESUMO

Gut microbiota imbalance plays a key pathological role in hepatocellular carcinoma (HCC) progression; however, the mechanism is poorly understood. We previously showed nimbolide impede tumor development by improving hepatic tight junction (TJ) proteins expression and attenuating inflammation in HCC mice. Here, we aimed to study the role of nimbolide in regulating gut microbiota imbalance and bacterial translocation (BT) through modulating intestinal TJ proteins in an experimental hepatocarcinogenesis. Nimbolide (6 mg/kg) was administered orally for 4 weeks following induction of HCC in mice at the 28th week. Nimbolide treatment attenuated the gut microbiota imbalance by decreasing 16 s rRNA levels of Escherichia coli, Enterococcus, Bacteroides and increasing Bifidobacterium, and Lactobacillus in the intestinal tissue, which was otherwise altered in HCC mice. Furthermore, nimbolide improved intestinal barrier integrity in HCC mice by upregulating TJ proteins such as occludin and ZO-1 expression and subsequently prevented hepatic BT and decreased BT markers such as LBP, sCD14, and procalcitonin in the plasma of HCC mice. Moreover, nimbolide ameliorated intestinal and hepatic inflammation by downregulating TLR4, MyD88, and NF-κB protein expression in HCC mice. Thus, nimbolide represents a novel therapeutic drug for HCC treatment by targeting the gut-liver axis, which plays an imperative role in HCC pathogenesis.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Translocação Bacteriana , Carcinoma Hepatocelular/tratamento farmacológico , Disbiose/tratamento farmacológico , Inflamação/tratamento farmacológico , Limoninas , Neoplasias Hepáticas/tratamento farmacológico , Camundongos
7.
J Am Soc Nephrol ; 33(6): 1105-1119, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35264456

RESUMO

BACKGROUND: In recent years, many studies have focused on the intestinal environment to elucidate pathogenesis of various diseases, including kidney diseases. Impairment of the intestinal barrier function, the "leaky gut," reportedly contributes to pathologic processes in some disorders. Mitochondrial antiviral signaling protein (MAVS), a component of innate immunity, maintains intestinal integrity. The effects of disrupted intestinal homeostasis associated with MAVS signaling in diabetic kidney disease remains unclear. METHODS: To evaluate the contribution of intestinal barrier impairment to kidney injury under diabetic conditions, we induced diabetic kidney disease in wild-type and MAVS knockout mice through unilateral nephrectomy and streptozotocin treatment. We then assessed effects on the kidney, intestinal injuries, and bacterial translocation. RESULTS: MAVS knockout diabetic mice showed more severe glomerular and tubular injuries compared with wild-type diabetic mice. Owing to impaired intestinal integrity, the presence of intestine-derived Klebsiella oxytoca and elevated IL-17 were detected in the circulation and kidneys of diabetic mice, especially in diabetic MAVS knockout mice. Stimulation of tubular epithelial cells with K. oxytoca activated MAVS pathways and the phosphorylation of Stat3 and ERK1/2, leading to the production of kidney injury molecule-1 (KIM-1). Nevertheless, MAVS inhibition induced inflammation in the intestinal epithelial cells and KIM-1 production in tubular epithelial cells under K. oxytoca supernatant or IL-17 stimulation. Treatment with neutralizing anti-IL-17 antibody treatment had renoprotective effects. In contrast, LPS administration accelerated kidney injury in the murine diabetic kidney disease model. CONCLUSIONS: Impaired MAVS signaling both in the kidney and intestine contributes to the disrupted homeostasis, leading to diabetic kidney disease progression. Controlling intestinal homeostasis may offer a novel therapeutic approach for this condition.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Animais , Translocação Bacteriana , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Interleucina-17 , Rim/metabolismo , Camundongos , Camundongos Knockout
8.
Gut Microbes ; 14(1): 2029674, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35130114

RESUMO

Portal hypertension (PH) in liver cirrhosis leads to increased gut permeability and the translocation of bacteria across the gut-liver axis. Microbial DNA has recently been detected in different blood compartments; however, this phenomenon has not been thoroughly analyzed in PH. This study aimed to explore circulating bacterial DNA signatures, inflammatory cytokines, and gut permeability markers in different blood compartments (peripheral and hepatic veins) of patients with cirrhosis and PH. The 16S rRNA blood microbiome profiles were determined in 58 patients with liver cirrhosis and 46 control patients. Taxonomic differences were analyzed in relation to PH, liver function, inflammatory cytokines, and gut permeability markers. Circulating plasma microbiome profiles in patients with cirrhosis were distinct from those of the controls and were characterized by enrichment of Comamonas, Cnuella, Dialister, Escherichia/Shigella, and Prevotella and the depletion of Bradyrhizobium, Curvibacter, Diaphorobacter, Pseudarcicella, and Pseudomonas. Comparison of peripheral and hepatic vein blood compartments of patients with cirrhosis did not reveal differentially abundant taxa. Enrichment of the genera Bacteroides, Escherichia/Shigella, and Prevotella was associated with severe PH (SPH) in both blood compartments; however, circulating microbiome profiles could not predict PH severity. Escherichia/Shigella and Prevotella abundance was correlated with IL-8 levels in the hepatic vein. In conclusion, we demonstrated a distinct circulating blood microbiome profile in patients with cirrhosis, showing that specific bacterial genera in blood are marginally associated with SPH, Model for End-Stage Liver Disease score, and inflammation biomarkers; however, circulating microbial composition failed to predict PH severity.


Assuntos
Bactérias/genética , Sangue/microbiologia , DNA Bacteriano/sangue , Microbioma Gastrointestinal , Hipertensão Portal/microbiologia , Cirrose Hepática/microbiologia , Adulto , Bactérias/classificação , Bactérias/isolamento & purificação , Fenômenos Fisiológicos Bacterianos , Translocação Bacteriana , Biomarcadores/sangue , Feminino , Humanos , Hipertensão Portal/sangue , Hipertensão Portal/complicações , Interleucina-8/sangue , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade
9.
Microbiol Spectr ; 10(1): e0251221, 2022 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-35196821

RESUMO

Mastitis, a highly prevalent disease in dairy cows, is commonly caused by local infection of the mammary gland. Our previous studies have suggested that the gut microbiota plays an important role in the development of mastitis in mice. However, the effects of rumen microbiota on bovine mastitis and the related mechanisms remain unclear. In this study, we assessed the effects and mechanisms of rumen microbiota on bovine mastitis based on the subacute rumen acidosis (SARA) model induced by feeding Holstein Frisian cows a high-concentrate diet for 8 weeks. Then, the inflammatory responses in the mammary gland and the bacterial communities of rumen fluid, feces, and milk were analyzed. The results showed that SARA induced mastitis symptoms in the mammary gland; activated a systemic inflammatory response; and increased the permeability of the blood-milk barrier, gut barrier, and rumen barrier. Further research showed that lipopolysaccharides (LPS), derived from the gut of SARA cows, translocated into the blood and accumulated in the mammary glands. Furthermore, the abundance of Stenotrophomonas was increased in the rumen of SARA cows, and mastitis was induced by oral administration of Stenotrophomonas in lactating mice. In conclusion, our findings suggested that mastitis is induced by exogenous pathogenic microorganisms as well as by endogenous pathogenic factors. Specifically, the elevated abundance of Stenotrophomonas in the rumen and LPS translocation from the rumen to the mammary gland were important endogenous factors that induced mastitis. Our study provides a foundation for novel therapeutic strategies that target the rumen microbiota in cow mastitis. IMPORTANCE Mastitis is a common and frequently occurring disease of humans and animals, especially in dairy farming, which has caused huge economic losses and brought harmful substance residues, drug-resistant bacteria, and other public health risks. The traditional viewpoint indicates that mastitis is mainly caused by exogenous pathogenic bacteria infecting the mammary gland. Our study found that the occurrence of mastitis was induced by the endogenous pathway. Evidence has shown that rumen-derived LPS enters the mammary gland through blood circulation, damaging the blood-milk barrier and then inducing inflammation of the mammary gland in cows. In addition, a higher abundance of Stenotrophomonas in the rumen was closely associated with the development of mastitis. This study provides a basis for novel therapeutic strategies that exploit the rumen microbiota against mastitis in cows.


Assuntos
Microbioma Gastrointestinal , Mastite Bovina/microbiologia , Rúmen/microbiologia , Animais , Translocação Bacteriana , Bovinos , Fezes/microbiologia , Feminino , Lactação , Glândulas Mamárias Animais/imunologia , Glândulas Mamárias Animais/microbiologia , Mastite Bovina/imunologia , Mastite Bovina/fisiopatologia , Leite/metabolismo , Stenotrophomonas/fisiologia
10.
Food Res Int ; 151: 110897, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34980418

RESUMO

High-fat diets seem to have a negative influence on the development of obesity and the processes associated with low-grade chronic systemic inflammation. In recent years, partial hydrogenated oil, rich in trans isomers, has been associated with deleterious health effects. It has been replaced by interesterified fat (IF). However, there is no evidence whether IF ingestion can exert adverse effects on the intestinal mucosa. Thus, this study aimed to evaluate the effect of IF on the intestinal mucosa of male Swiss mice fed a normal or high-fat diet, focusing on its effects on intestinal permeability and bacterial translocation and its possible damage to the intestinal epithelium. The animals were divided into 4 groups: Control (C) and Interesterified Control (IC) groups (10 En% lipids from unmodified fat or interesterified fat, respectively) and High Fat (HF) and Interesterified High Fat (IHF) groups (45 En% lipids from unmodified fat or interesterified fat, respectively). Compare to C, the IC, HF, and IHF groups presented flattened epithelium, a shorter villi length and a lower percentage of goblet cells, less mucin 2, an increased oxidative stress and more inflammatory cells, higher IL-1ß, IL-17, and IL-23 levels. These groups also presented increased intestinal permeability and gene expression of the protein claudin 2, while JAM-A and claudin 1 gene expression was reduced. IC and IHF increased IL-6 levels while reducing occludin expression. In addition, the IC group also presented a mucosa with lesions of low intensity in the ileum, an increased mucin 5ac, TNF-α levels, and reduced occludin expression in the distal jejunum. Moreover, there was a significant increase in bacterial translocation in the IC group to blood, liver, and lungs, while HF and IHF groups presented bacterial translocation which was restricted to the mesenteric lymph nodes. In summary, our results supported the hypothesis that IF added to a normolipidic diet can be considered harmful or even worse when compared to a HF.


Assuntos
Translocação Bacteriana , Ácidos Graxos , Animais , Dieta Hiperlipídica/efeitos adversos , Expressão Gênica , Masculino , Camundongos , Óleo de Palmeira , Permeabilidade , Proteínas de Junções Íntimas/genética
11.
Nutrients ; 14(2)2022 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-35057424

RESUMO

Elucidating the mechanisms of bacterial translocation is crucial for the prevention and treatment of neonatal sepsis. In the present study, we aimed to evaluate the potential of lactoferrin to inhibit the development of late-onset blood infection in neonates. Our investigation evaluates the role of key stress factors leading to the translocation of intestinal bacteria into the bloodstream and, consequently, the development of life-threatening sepsis. Three stress factors, namely weaning, intraperitoneal administration of Gram-positive cocci and oral intake of Gram-negative rods, were found to act synergistically. We developed a novel model of rat pups sepsis induced by bacterial translocation and observed the inhibition of this process by supplementation of various forms of lactoferrin: iron-depleted (apolactoferrin), iron-saturated (hololactoferrin) and manganese-saturated lactoferrin. Additionally, lactoferrin saturated with manganese significantly increases the Lactobacillus bacterial population, which contributes to the fortification of the intestinal barrier and inhibits the translocation phenomenon. The acquired knowledge can be used to limit the development of sepsis in newborns in hospital neonatal intensive care units.


Assuntos
Translocação Bacteriana/efeitos dos fármacos , Escherichia coli , Microbioma Gastrointestinal/efeitos dos fármacos , Lactoferrina/administração & dosagem , Sepse Neonatal/prevenção & controle , Staphylococcus haemolyticus , Animais , Animais Recém-Nascidos , Apoproteínas/administração & dosagem , Infecções Transmitidas por Sangue/microbiologia , Infecções Transmitidas por Sangue/prevenção & controle , Temperatura Corporal , Peso Corporal , Infecção Hospitalar/prevenção & controle , Modelos Animais de Doenças , Esquema de Medicação , Escherichia coli/efeitos dos fármacos , Escherichia coli/fisiologia , Microbioma Gastrointestinal/fisiologia , Humanos , Recém-Nascido , Masculino , Manganês/administração & dosagem , Sepse Neonatal/diagnóstico , Sepse Neonatal/microbiologia , Permeabilidade , Distribuição Aleatória , Ratos , Ratos Wistar , Staphylococcus haemolyticus/efeitos dos fármacos , Staphylococcus haemolyticus/fisiologia , Desmame
12.
Sci Rep ; 12(1): 381, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013389

RESUMO

GPR120 (encoded by FFAR4 gene) is a receptor for long chain fatty acids, activated by ω-3 Polyunsaturated Fatty Acids (PUFAs), and expressed in many cell types. Its role in the context of colorectal cancer (CRC) is still puzzling with many controversial evidences. Here, we explored the involvement of epithelial GPR120 in the CRC development. Both in vitro and in vivo experiments were conducted to mimic the conditional deletion of the receptor from gut epithelium. Intestinal permeability and integrity of mucus layer were assessed by using Evans blue dye and immunofluorescence for MUC-2 protein, respectively. Microbiota composition, presence of lipid mediators and short chain fatty acids were analyzed in the stools of conditional GPR120 and wild type (WT) mice. Incidence and grade of tumors were evaluated in all groups of mice before and after colitis-associated cancer. Finally, GPR120 expression was analyzed in 9 human normal tissues, 9 adenomas, and 17 primary adenocarcinomas. Our work for the first time highlights the role of the receptor in the progression of colorectal cancer. We observed that the loss of epithelial GPR120 in the gut results into increased intestinal permeability, microbiota translocation and dysbiosis, which turns into hyperproliferation of epithelial cells, likely through the activation of ß -catenin signaling. Therefore, the loss of GPR120 represents an early event of CRC, but avoid its progression as invasive cancer. these results demonstrate that the epithelial GPR120 receptor is essential to maintain the mucosal barrier integrity and to prevent CRC developing. Therefore, our data pave the way to GPR120 as an useful marker for the phenotypic characterization of CRC lesions and as new potential target for CRC prevention.


Assuntos
Adenocarcinoma/metabolismo , Neoplasias Associadas a Colite/metabolismo , Colo/metabolismo , Mucosa Intestinal/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/microbiologia , Adenocarcinoma/patologia , Animais , Translocação Bacteriana , Proliferação de Células , Neoplasias Associadas a Colite/genética , Neoplasias Associadas a Colite/microbiologia , Neoplasias Associadas a Colite/patologia , Colo/microbiologia , Colo/patologia , Progressão da Doença , Disbiose , Microbioma Gastrointestinal , Humanos , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Camundongos Knockout , Permeabilidade , Receptores Acoplados a Proteínas G/genética , Carga Tumoral
13.
J Acquir Immune Defic Syndr ; 89(Suppl 1): S29-S33, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35015743

RESUMO

ABSTRACT: The intestinal epithelial layer acts as a mechanical and functional barrier between the intraluminal microbiota and the immunologically active submucosa. A progressive loss of gut barrier function (leaky gut) leads to enhanced translocation of microbial products, which in turn contributes as endotoxins to inflammaging. Th17 T cell represents the main immune sentinels in the gut epithelium, preventing aggression from commensal and pathogenic microbes. As HIV infection deeply affects gut Th17 function and increases gut permeability, microbial translocation occurs at high level in people living with HIV (PLWH) and has been associated with the development of non-AIDS comorbidities. Although the inflammatory role of endotoxins like lipopolysaccharide produced by Gram-negative bacteria is well-established, fungal products such as ß-D-glucan emerge as new contributors. In addition, PLWH are more frequently infected with cytomegalovirus (CMV) than the general population. CMV infection is a well-described accelerator of immune aging, through the induction of expansion of dysfunctional CD8 T-cells as well as through enhancement of gut microbial translocation. We critically review immune mechanisms related to bacterial and fungal translocation, with a focus on the contribution of CMV coinfection in PLWH. Improving gut barrier dysfunction, microbial composition, and reducing microbial translocation constitute emerging strategies for the prevention and treatment of HIV-associated inflammation and may be relevant for age-related inflammatory conditions.


Assuntos
Coinfecção , Infecções por HIV , Envelhecimento , Translocação Bacteriana , Citomegalovirus , Humanos , Mucosa Intestinal , Células Th17
14.
Gut ; 71(3): 580-592, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-33707230

RESUMO

OBJECTIVE: Spontaneous bacterial peritonitis (SBP) is a life-threatening complication of liver cirrhosis with a 1-year mortality of 66%. Bacterial translocation (BT) from the intestine to the mesenteric lymph nodes is crucial for the pathogenesis of SBP. DESIGN: Since BT presupposes a leaky intestinal epithelium, the integrity of mucus and epithelial cell junctions (E-cadherin and occludin) was examined in colonic biopsies from patients with liver cirrhosis and controls. SBP-inducing Escherichia coli (E. coli) and Proteus mirabilis (P. mirabilis) were isolated from ascites of patients with liver cirrhosis and co-cultured with Caco-2 cells to characterise bacteria-to-cell effects. RESULTS: SBP-derived E. coli and P. mirabilis led to a marked reduction of cell-to-cell junctions in a dose-dependent and time-dependent manner. This effect was enhanced by a direct interaction of live bacteria with epithelial cells. Degradation of occludin is mediated via increased ubiquitination by the proteasome. Remarkably, a novel bacterial protease activity is of pivotal importance for the cleavage of E-cadherin. CONCLUSION: Patients with liver cirrhosis show a reduced thickness of colonic mucus, which allows bacteria-to-epithelial cell contact. Intestinal bacteria induce degradation of occludin by exploiting the proteasome of epithelial cells. We identified a novel bacterial protease activity of patient-derived SBP-inducing bacteria, which is responsible for the cleavage of E-cadherin structures. Inhibition of this protease activity leads to stabilisation of cell junctions. Thus, targeting these mechanisms by blocking the ubiquitin-proteasome system and/or the bacterial protease activity might interfere with BT and constitute a novel innovative therapeutic strategy to prevent SBP in patients with liver cirrhosis.


Assuntos
Ascite/microbiologia , Translocação Bacteriana/fisiologia , Escherichia coli/fisiologia , Cirrose Hepática/complicações , Peritonite/etiologia , Proteus mirabilis/fisiologia , Células CACO-2 , Caderinas/metabolismo , Estudos de Casos e Controles , Técnicas de Cocultura , Colo/microbiologia , Colo/patologia , Feminino , Humanos , Junções Intercelulares , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Ocludina/metabolismo , Peptídeo Hidrolases , Peritonite/metabolismo
15.
Gastroenterology ; 162(1): 135-149.e2, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34461052

RESUMO

BACKGROUND AND AIMS: Dietary fat intake is associated with increased risk of colorectal cancer (CRC). We examined the role of high-fat diet (HFD) in driving CRC through modulating gut microbiota and metabolites. METHODS: HFD or control diet was fed to mice littermates in CRC mouse models of an azoxymethane (AOM) model and Apcmin/+ model, with or without antibiotics cocktail treatment. Germ-free mice for fecal microbiota transplantation were used for validation. Gut microbiota and metabolites were detected using metagenomic sequencing and high-performance liquid chromatography-mass spectrometry, respectively. Gut barrier function was determined using lipopolysaccharides level and transmission electron microscopy. RESULTS: HFD promoted colorectal tumorigenesis in both AOM-treated mice and Apcmin/+ mice compared with control diet-fed mice. Gut microbiota depletion using antibiotics attenuated colon tumor formation in HFD-fed mice. A significant shift of gut microbiota composition with increased pathogenic bacteria Alistipessp.Marseille-P5997 and Alistipessp.5CPEGH6, and depleted probiotic Parabacteroides distasonis, along with impaired gut barrier function was exhibited in HFD-fed mice. Moreover, HFD-modulated gut microbiota promotes colorectal tumorigenesis in AOM-treated germ-free mice, indicating gut microbiota was essential in HFD-associated colorectal tumorigenesis. Gut metabolites alteration, including elevated lysophosphatidic acid, which was confirmed to promote CRC cell proliferation and impair cell junction, was also observed in HFD-fed mice. Moreover, transfer of stools from HFD-fed mice to germ-free mice without interference increased colonic cell proliferation, impaired gut barrier function, and induced oncogenic genes expression. CONCLUSIONS: HFD drives colorectal tumorigenesis through inducing gut microbial dysbiosis, metabolomic dysregulation with elevated lysophosphatidic acid, and gut barrier dysfunction in mice.


Assuntos
Bactérias/metabolismo , Colo/microbiologia , Neoplasias Colorretais/microbiologia , Dieta Hiperlipídica , Microbioma Gastrointestinal , Animais , Antibacterianos/farmacologia , Azoximetano , Bactérias/efeitos dos fármacos , Translocação Bacteriana , Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/ultraestrutura , Colo/metabolismo , Colo/ultraestrutura , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/ultraestrutura , Modelos Animais de Doenças , Disbiose , Transplante de Microbiota Fecal , Fezes/microbiologia , Genes APC , Vida Livre de Germes , Humanos , Lisofosfolipídeos/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Permeabilidade , Células Tumorais Cultivadas
16.
Clin Oral Investig ; 26(2): 1375-1389, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34401947

RESUMO

OBJECTIVES: A conometric concept was recently introduced in which conical implant abutments hold the matching crown copings by friction alone, eliminating the need for cement or screws. The aim of this in vitro study was to assess the presence of microgap formation and bacterial leakage at the Acuris conometric restorative interface of three different implant abutment systems. MATERIAL AND METHODS: A total of 75 Acuris samples of three implant-abutment systems (Ankylos, Astra Tech EV, Xive) were subjected to microbiological (n = 60) and scanning electron microscopic (SEM) investigation (n = 15). Bacterial migration into and out of the conical coupling system were analyzed in an anaerobic workstation for 48, 96, 144, and 192 h. Bacterial DNA quantification using qrt-PCR was performed at each time point. The precision of the conometric coupling and internal fit of cemented CAD/CAM crowns on corresponding Acuris TiN copings were determined by means of SEM. RESULTS: qrt-PCR results failed to demonstrate microbial leakage from or into the Acuris system. SEM analysis revealed minute punctate microgaps at the apical aspect of the conometric junction (2.04 to 2.64 µm), while mean cement gaps of 12 to 145 µm were observed at the crown-coping interface. CONCLUSIONS: The prosthetic morse taper connection of all systems examined does not allow bacterial passage. Marginal integrity and internal luting gap between the ceramic crown and the coping remained within the clinically acceptable limits. CLINICAL RELEVANCE: Conometrically seated single crowns provide sufficient sealing efficiency, relocating potential misfits from the crown-abutment interface to the crown-coping interface.


Assuntos
Projeto do Implante Dentário-Pivô , Implantes Dentários , Translocação Bacteriana , Coroas , Dente Suporte , Porcelana Dentária
17.
J Surg Res ; 272: 51-60, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34936912

RESUMO

BACKGROUND: The aim of this study was to investigate bacterial translocation and its possible role in the development of post-resuscitation inflammatory response following Cardio-Pulmonary Resuscitation (CPR) after cardiac arrest. METHODS: Munich female swine were employed for a model of cardiac arrest via application of electrical current. After 7 min, CPR was initiated, and animals were either successfully return to spontaneous circulation (ROSC) within 40 min or not (no-ROSC). At the end of experimental period and prior to sacrifice, samples from the intestine, mesenteric lymph nodes (MLN), liver and portal vein blood were obtained. Evaluation of inflammation and gut permeability was performed; MLN, liver and portal vein samples were analyzed for 16 s rRNA detection and cytokine mRNA expression. RESULTS: A decreased expression of the tight junction protein Occludin, with higher levels of inflammation, greater epithelial disintegration, ulceration, loss of crypts and villi height were found in the intestines of the ROSC swine in comparison to no-ROSC. The macrophage surface antigen CD-14 staining was relatively more intense in the ROSC than in no-ROSC. Higher levels of TNF-α mRNA expression were present in the liver of the ROSC group. Finally, despite the inflammatory response and the gut mucosal alterations in ROSC group, no bacterial translocation was detected in liver, MLN and portal vein. CONCLUSIONS: We show that resuscitation from cardiac arrest induces inflammatory response and intestinal permeability in swine 4h after resuscitation, but not a bacterial translocation. Bacterial translocation is not an early phase phenomenon but probably part of the pathophysiologic sequelae.


Assuntos
Reanimação Cardiopulmonar , Parada Cardíaca , Síndrome Pós-Parada Cardíaca , Animais , Translocação Bacteriana , Feminino , Parada Cardíaca/complicações , Parada Cardíaca/terapia , Inflamação , RNA Mensageiro , Suínos
18.
Curr HIV Res ; 19(5): 384-390, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34109914

RESUMO

BACKGROUND: Although the association between HIV infection and airways obstruction is well known, its etiopathogenesis is not clear. OBJECTIVES: Our aim was to analyze the association between biomarkers of systemic inflammation and bacterial translocation and pulmonary function tests in HIV infected patients and compare it between smokers and non-smokers. METHODS: Cross-sectional, observational study. Inclusion criteria: people living with HIV with undetectable plasma viral load. Exclusion criteria: other comorbidities associated with systemic inflammation. Outcome variables: spirometry and diffusing capacity for carbon monoxide; explanatory variables: inflammatory biomarkers (interleukin-6, tumor necrosis factor-alpha), bacterial translocation (soluble CD14 [sCD14] and bacterial 16S rDNA), and variables related to HIV infection. Associations were tested using the Pearson/Spearman correlation tests, the student t test, and multivariable linear regression. RESULTS: We included 71 patients (54.9% smokers). We did not observe significant differences in pulmonary function tests according to biomarkers of inflammation or bacterial translocation. In non-smokers (n=32), sCD14 was negatively correlated with forced expiratory volume in 1 second (R = -0.35, P = 0.048) and forced vital capacity (R= -0.40, P=0.023). Age, time since HIV diagnosis and CD4+ nadir were associated with alterations in PFTs. In smokers, the only association observed was between the pack-years and pulmonary obstruction. CONCLUSION: In non-smokers HIV patients, lung dysfunction can be, at least partially, related to bacterial translocation (sCD14), CD4+ nadir and time since HIV diagnosis.


Assuntos
Infecções por HIV , Translocação Bacteriana , Biomarcadores , Estudos Transversais , Infecções por HIV/patologia , Humanos , Carga Viral
19.
Front Immunol ; 12: 767155, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34868020

RESUMO

Stroke is a common central nervous system disease in clinical practice. Stroke patients often have infectious complications, such as pneumonia and infections of the urinary tract and gastrointestinal tract. Although it has been shown that translocation of the host gut microbiota to the lungs and immune dysfunction plays a vital role in the development of infection after ischemic stroke, the occurrence and mechanism of pulmonary infection at different time points after hemorrhagic cerebral remain unclear. In this study, the changes in the immune system and intestinal barrier function in mice during disease development were investigated at 1 day (M 1 d), 3 days (M 3 d) and 7 days (M 7 d) following hemorrhagic stroke to clarify the mechanism of secondary pulmonary infection. The experimental results revealed that after hemorrhagic stroke, model mice showed increased brain damage from day 1 to 3, followed by a trend of brain recovery from day 3 to 7 . After hemorrhagic stroke, the immune system was disturbed in model mice. Significant immunosuppression of the peripheral immune system was observed in the M 3 d group but improved in the M 7 d group. Staining of lung tissues with hematoxylin and eosin (H&E) and for inflammatory factors revealed considerable disease and immune disorders in the M 7 d group. Stroke seriously impaired intestinal barrier function in mice and significantly changed the small intestine structure. From 1 to 7 d after stroke, intestinal permeability was increased, whereas the levels of markers for intestinal tight junctions, mucus and immunoglobulin A were decreased. Analysis based on 16S rRNA suggested that the microflora in the lung and ileum was significantly altered after stroke. The composition of microflora in lung and ileum tissue was similar in the M 7d group, suggesting that intestinal bacteria had migrated to lung tissue and caused lung infection at this time point after hemorrhagic stroke. In stroke mice, the aggravation of intestinal barrier dysfunction and immune disorders after intracerebral hemorrhage, promoted the migration of enteric bacteria, and increased the risk of pneumonia poststroke. Our findings reveal the dynamic process of infection after hemorrhagic stroke and provide clues for the optimal timing of intervention for secondary pulmonary infection in stroke patients.


Assuntos
Infecções Bacterianas/genética , Hemorragia Cerebral/genética , Coinfecção/genética , Expressão Gênica , Pulmão/metabolismo , Animais , Bactérias/classificação , Bactérias/genética , Infecções Bacterianas/complicações , Infecções Bacterianas/microbiologia , Translocação Bacteriana , Hemorragia Cerebral/complicações , Hemorragia Cerebral/fisiopatologia , Coinfecção/complicações , Coinfecção/microbiologia , Modelos Animais de Doenças , Microbioma Gastrointestinal/genética , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Pulmão/microbiologia , Masculino , Camundongos Endogâmicos C57BL , RNA Ribossômico 16S/genética , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/fisiopatologia , Fatores de Tempo
20.
Nat Commun ; 12(1): 7172, 2021 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-34887405

RESUMO

Complement receptor of immunoglobulin superfamily (CRIg) is expressed on liver macrophages and directly binds complement component C3b or Gram-positive bacteria to mediate phagocytosis. CRIg plays important roles in several immune-mediated diseases, but it is not clear how its pathogen recognition and phagocytic functions maintain homeostasis and prevent disease. We previously associated cytolysin-positive Enterococcus faecalis with severity of alcohol-related liver disease. Here, we demonstrate that CRIg is reduced in liver tissues from patients with alcohol-related liver disease. CRIg-deficient mice developed more severe ethanol-induced liver disease than wild-type mice; disease severity was reduced with loss of toll-like receptor 2. CRIg-deficient mice were less efficient than wild-type mice at clearing Gram-positive bacteria such as Enterococcus faecalis that had translocated from gut to liver. Administration of the soluble extracellular domain CRIg-Ig protein protected mice from ethanol-induced steatohepatitis. Our findings indicate that ethanol impairs hepatic clearance of translocated pathobionts, via decreased hepatic CRIg, which facilitates progression of liver disease.


Assuntos
Enterococcus faecalis/imunologia , Infecções por Bactérias Gram-Positivas/imunologia , Hepatopatias Alcoólicas/imunologia , Macrófagos/imunologia , Receptores de Complemento 3b/imunologia , Receptores de Complemento/imunologia , Animais , Translocação Bacteriana , Complemento C3b/imunologia , Enterococcus faecalis/fisiologia , Etanol/efeitos adversos , Feminino , Trato Gastrointestinal/microbiologia , Infecções por Bactérias Gram-Positivas/genética , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/microbiologia , Hepatopatias Alcoólicas/etiologia , Hepatopatias Alcoólicas/genética , Hepatopatias Alcoólicas/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Complemento/deficiência , Receptores de Complemento/genética , Receptores de Complemento 3b/genética
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