RESUMO
Immunoglobulin A (IgA) secretion by plasma cells, terminally differentiated B cells residing in the intestinal lamina propria, assures microbiome homeostasis and protects the host against enteric infections. Exposure to diet-derived and commensal-derived signals provides immune cells with organizing cues that instruct their effector function and dynamically shape intestinal immune responses at the mucosal barrier. Recent data have described metabolic and microbial inputs controlling T cell and innate lymphoid cell activation in the gut; however, whether IgA-secreting lamina propria plasma cells are tuned by local stimuli is completely unknown. Although antibody secretion is considered to be imprinted during B cell differentiation and therefore largely unaffected by environmental changes, a rapid modulation of IgA levels in response to intestinal fluctuations might be beneficial to the host. In the present study, we showed that dietary cholesterol absorption and commensal recognition by duodenal intestinal epithelial cells lead to the production of oxysterols, evolutionarily conserved lipids with immunomodulatory functions. Using conditional cholesterol 25-hydroxylase deleter mouse line we demonstrated that 7α,25-dihydroxycholesterol from epithelial cells is critical to restrain IgA secretion against commensal- and pathogen-derived antigens in the gut. Intestinal plasma cells sense oxysterols via the chemoattractant receptor GPR183 and couple their tissue positioning with IgA secretion. Our findings revealed a new mechanism linking dietary cholesterol and humoral immune responses centered around plasma cell localization for efficient mucosal protection.
Assuntos
Imunidade Inata , Plasmócitos , Animais , Camundongos , Colesterol na Dieta , Células Epiteliais , Imunoglobulina A , Mucosa Intestinal , Receptores Acoplados a Proteínas G , IntestinosRESUMO
The mammalian gut microbiota provides essential metabolites to the host and promotes the differentiation and accumulation of extrathymically generated regulatory T (pTreg) cells. To explore the impact of these cells on intestinal microbial communities, we assessed the composition of the microbiota in pTreg cell-deficient and -sufficient mice. pTreg cell deficiency led to heightened type 2 immune responses triggered by microbial exposure, which disrupted the niche of border-dwelling bacteria early during colonization. Moreover, impaired pTreg cell generation led to pervasive changes in metabolite profiles, altered features of the intestinal epithelium, and reduced body weight in the presence of commensal microbes. Absence of a single species of bacteria depleted in pTreg cell-deficient animals, Mucispirillum schaedleri, partially accounted for the sequelae of pTreg cell deficiency. These observations suggest that pTreg cells modulate the metabolic function of the intestinal microbiota by restraining immune defense mechanisms that may disrupt a particular bacterial niche.
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Microbioma Gastrointestinal/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Imunidade nas Mucosas/imunologia , Mucosa Intestinal/imunologia , CamundongosRESUMO
There is a growing appreciation for the importance of the gut microbiota as a therapeutic target in various diseases. However, there are only a handful of known commensal strains that can potentially be used to manipulate host physiological functions. Here we isolate a consortium of 11 bacterial strains from healthy human donor faeces that is capable of robustly inducing interferon-γ-producing CD8 T cells in the intestine. These 11 strains act together to mediate the induction without causing inflammation in a manner that is dependent on CD103+ dendritic cells and major histocompatibility (MHC) class Ia molecules. Colonization of mice with the 11-strain mixture enhances both host resistance against Listeria monocytogenes infection and the therapeutic efficacy of immune checkpoint inhibitors in syngeneic tumour models. The 11 strains primarily represent rare, low-abundance components of the human microbiome, and thus have great potential as broadly effective biotherapeutics.
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Adenocarcinoma/imunologia , Adenocarcinoma/terapia , Bactérias/classificação , Linfócitos T CD8-Positivos/imunologia , Microbioma Gastrointestinal/imunologia , Listeriose/prevenção & controle , Simbiose/imunologia , Adenocarcinoma/patologia , Animais , Antígenos CD/metabolismo , Bactérias/imunologia , Bactérias/isolamento & purificação , Linfócitos T CD8-Positivos/citologia , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Fezes/microbiologia , Feminino , Voluntários Saudáveis , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Cadeias alfa de Integrinas/metabolismo , Interferon gama/biossíntese , Interferon gama/imunologia , Listeria monocytogenes/imunologia , Listeriose/imunologia , Listeriose/microbiologia , Masculino , Camundongos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The gastrointestinal tracts of mammals are colonized by hundreds of microbial species that contribute to health, including colonization resistance against intestinal pathogens. Many antibiotics destroy intestinal microbial communities and increase susceptibility to intestinal pathogens. Among these, Clostridium difficile, a major cause of antibiotic-induced diarrhoea, greatly increases morbidity and mortality in hospitalized patients. Which intestinal bacteria provide resistance to C. difficile infection and their in vivo inhibitory mechanisms remain unclear. Here we correlate loss of specific bacterial taxa with development of infection, by treating mice with different antibiotics that result in distinct microbiota changes and lead to varied susceptibility to C. difficile. Mathematical modelling augmented by analyses of the microbiota of hospitalized patients identifies resistance-associated bacteria common to mice and humans. Using these platforms, we determine that Clostridium scindens, a bile acid 7α-dehydroxylating intestinal bacterium, is associated with resistance to C. difficile infection and, upon administration, enhances resistance to infection in a secondary bile acid dependent fashion. Using a workflow involving mouse models, clinical studies, metagenomic analyses, and mathematical modelling, we identify a probiotic candidate that corrects a clinically relevant microbiome deficiency. These findings have implications for the rational design of targeted antimicrobials as well as microbiome-based diagnostics and therapeutics for individuals at risk of C. difficile infection.
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Ácidos e Sais Biliares/metabolismo , Clostridioides difficile/fisiologia , Suscetibilidade a Doenças/microbiologia , Mucosa Intestinal/metabolismo , Intestinos/microbiologia , Microbiota/fisiologia , Animais , Antibacterianos/farmacologia , Evolução Biológica , Clostridioides difficile/efeitos dos fármacos , Clostridium/metabolismo , Colite/metabolismo , Colite/microbiologia , Colite/prevenção & controle , Colite/terapia , Fezes/microbiologia , Feminino , Humanos , Intestinos/efeitos dos fármacos , Metagenoma/genética , Camundongos , Camundongos Endogâmicos C57BL , Microbiota/efeitos dos fármacos , Microbiota/genética , SimbioseRESUMO
Certain anaerobic bacteria are important for maintenance of gut barrier integrity and immune tolerance and may influence the risk of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a single-center retrospective cohort study of allogeneic HSCT recipients to evaluate associations between receipt of antibiotics with an anaerobic spectrum of activity and GVHD outcomes. We identified 1214 children and adults who developed febrile neutropenia between 7 days before and 28 days after HSCT and compared GVHD risk and mortality among patients who received anaerobic antibiotics (piperacillin-tazobactam or carbapenems; n = 491) to patients who received only antibiotics with minimal activity against anaerobes (aztreonam, cefepime, or ceftazidime; n = 723). We performed metagenomic sequencing of serial fecal samples from 36 pediatric patients to compare the effects of specific antibiotics on the gut metagenome. Receipt of anaerobic antibiotics was associated with higher hazards of acute gut/liver GVHD (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.03 to 1.54) and acute GVHD mortality (HR, 1.63; 95% CI, 1.08 to 2.46), but not chronic GVHD diagnosis (HR, 1.04; 95% CI: .84 to 1.28) or chronic GVHD mortality (HR, .88; 95% CI, .53 to 1.45). Anaerobic antibiotics resulted in decreased gut bacterial diversity, reduced abundances of Bifidobacteriales and Clostridiales, and loss of bacterial genes encoding butyrate biosynthesis enzymes from the gut metagenome. Acute gut/liver GVHD was preceded by a sharp decline in bacterial butyrate biosynthesis genes with antibiotic treatment. Our findings demonstrate that exposure to anaerobic antibiotics is associated with increased risks of acute gut/liver GVHD and acute GVHD mortality after allogeneic HSCT. Use of piperacillin-tazobactam or carbapenems should be reserved for febrile neutropenia cases in which anaerobic or multidrug-resistant infections are suspected.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Adulto , Anaerobiose , Antibacterianos/uso terapêutico , Criança , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Estudos Retrospectivos , Transplante HomólogoRESUMO
The gastrointestinal tract is the predicted reservoir for most bloodstream infections (BSIs) after hematopoietic stem cell transplantation (HSCT). Whole-genome sequencing and comparative genomics have the potential to improve our understanding of the dynamics of gut colonization that precede BSI in HSCT recipients. Within a prospective cohort study of children (age <18 years) undergoing HSCT, 9 subjects met criteria for mucosal barrier injury BSI. We performed whole-genome sequencing of the blood culture isolate and weekly fecal samples preceding the BSI to compare the genetic similarity of BSI isolates to fecal strains. We evaluated temporal associations between antibiotic exposures and the abundances of BSI strains in the gut microbiota and correlated the detection of antibiotic resistance genes with the phenotypic antibiotic resistance of these strains. The median patient age was 2.6 years, and 78% were male. BSIs were caused by Escherichia coli (nâ¯=â¯5), Enterococcus faecium (nâ¯=â¯2), Enterobacter cloacae (nâ¯=â¯1), and Rothia mucilaginosa (nâ¯=â¯1). In the 6 BSI episodes with evaluable comparative genomics, the fecal strains were identical to the blood culture isolate (>99.99% genetic similarity). Gut domination by these strains preceded only 4 of 7 E. coli or E. faecium BSIs by a median of 17 days (range, 6 to 21 days). Increasing abundances of the resulting BSI strains in the gut microbiota were frequently associated with specific antibiotic exposures. E. cloacae and R. mucilaginosa were not highly abundant in fecal samples preceding BSIs caused by these species. The detection of antibiotic resistance genes for ß-lactam antibiotics and vancomycin predicted phenotypic resistance in BSI strains. Bacterial strains causing mucosal barrier injury BSI in pediatric HSCT recipients were observed in the gut microbiota before BSI onset, and changes in the abundances of these strains within the gut preceded most BSI episodes. However, frequent sampling of the gut microbiota and sampling of other ecological niches is likely necessary to effectively predict BSI in HSCT recipients.
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Bactérias , Infecções Bacterianas , Farmacorresistência Bacteriana , Microbioma Gastrointestinal , Transplante de Células-Tronco Hematopoéticas , Mucosa Intestinal , Aloenxertos , Bactérias/classificação , Bactérias/genética , Bactérias/crescimento & desenvolvimento , Infecções Bacterianas/genética , Infecções Bacterianas/microbiologia , Criança , Pré-Escolar , Feminino , Humanos , Mucosa Intestinal/lesões , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Masculino , Estudos ProspectivosRESUMO
Harmful bacteria may be the most significant threat to human gut and lake ecosystem health, and they are often managed using similar tools, like poisoning with antibiotics or algicides. Out-of-the-box thinking in human microbiome engineering is leading to novel methods, like engineering bacteria to kill pathogens, "persuade" them not to produce toxins, or "mop up" their toxins. The bacterial agent can be given a competitive edge via an exclusive nutrient, and they can be engineered to commit suicide once their work is done. Viruses can kill pathogens with specific DNA sequences or knock out their antibiotic resistance genes using CRISPR technology. Some of these ideas may work for lakes. We critically review novel methods for managing harmful bacteria in the gut from the perspective of managing toxic cyanobacteria in lakes, and discuss practical aspects such as modifying bacteria using genetic engineering or directed evolution, mass culturing and controlling the agents. A key knowledge gap is in the ecology of strains, like toxigenic vs nontoxigenic Microcystis, including allelopathic and Black Queen interactions. Some of the "gut methods" may have future potential for lakes, but there presently is no substitute for established management approaches, including reducing N and P nutrient inputs, and mitigating climate change.
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Cianobactérias , Microcystis , Ecossistema , Humanos , LagosRESUMO
Drastic metabolic alterations, such as the Warburg effect, are found in most if not all types of malignant tumors. Emerging evidence shows that cancer cells benefit from these alterations, but little is known about how they affect noncancerous stromal cells within the tumor microenvironment. Here we show that cancer cells are better adapted to metabolic changes in the microenvironment, leading to the emergence of spatial structure. A clear example of tumor spatial structure is the localization of tumor-associated macrophages (TAMs), one of the most common stromal cell types found in tumors. TAMs are enriched in well-perfused areas, such as perivascular and cortical regions, where they are known to potentiate tumor growth and invasion. However, the mechanisms of TAM localization are not completely understood. Computational modeling predicts that gradients--of nutrients, gases, and metabolic by-products such as lactate--emerge due to altered cell metabolism within poorly perfused tumors, creating ischemic regions of the tumor microenvironment where TAMs struggle to survive. We tested our modeling prediction in a coculture system that mimics the tumor microenvironment. Using this experimental approach, we showed that a combination of metabolite gradients and differential sensitivity to lactic acid is sufficient for the emergence of macrophage localization patterns in vitro. This suggests that cancer metabolic changes create a microenvironment where tumor cells thrive over other cells. Understanding differences in tumor-stroma sensitivity to these alterations may open therapeutic avenues against cancer.
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Glicólise/fisiologia , Macrófagos/fisiologia , Modelos Biológicos , Neoplasias/metabolismo , Microambiente Tumoral/fisiologia , Linhagem Celular Tumoral , Imunofluorescência , Humanos , Concentração de Íons de Hidrogênio , Processamento de Imagem Assistida por Computador , Macrófagos/citologia , Microscopia de Fluorescência , Estatísticas não ParamétricasRESUMO
OBJECTIVE: The Infectious Disease Society of America (IDSA) publishes evidence-based guidelines for the treatment of skin and soft tissue infections. How closely physicians follow these guidelines is unknown, particularly in the emergency department observation unit (EDOU) where increasing numbers of patients are treatment for these infections. Our objectives were to describe (1) the antibiotic treatment patterns EDOU patients, (2) physicians' adherence to the IDSA guidelines, and (3) factors that influence physician's prescribing practices. METHODS: This prospective cohort enrolled adult patients discharged from an EDOU at an academic medical center after treatment for a skin or soft tissue infection. Information was collected from chart review and patient interview pertaining to the patient's sociodemographic characteristics, presenting illness, and antibiotic treatment regimens. Treatment regimens were compared with national guidelines. RESULTS: The study included 193 patients of which only 43% were treated according to IDSA guidelines, 42% were overtreated, and 15% were undertreated. Women were more likely to be undertreated (relative risk, 1.58; 95% confidence interval, 1.21-2.06), whereas patients 50 years and older were at risk for overtreatment (relative risk, 1.44; 95% confidence interval, 1.03-2.02). Women also received shorter courses of antibiotic therapy with an average of 9.6 days of treatment compared with 10.6 days for men. CONCLUSIONS: Physician antibiotic prescribing practices demonstrated poor adherence to IDSA guidelines and were influenced by the patient's age and sex. Standardized antibiotic protocols for treatment of skin and soft tissue infections to IDSA guidelines in the EDOU would minimize physician bias.
Assuntos
Antibacterianos/uso terapêutico , Serviço Hospitalar de Emergência , Padrões de Prática Médica , Dermatopatias Bacterianas/tratamento farmacológico , Infecções dos Tecidos Moles/tratamento farmacológico , Adulto , Fatores Etários , Idoso , Estudos de Coortes , Feminino , Fidelidade a Diretrizes , Humanos , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Fatores SexuaisRESUMO
The intestinal microbiota is a microbial ecosystem of crucial importance to human health. Understanding how the microbiota confers resistance against enteric pathogens and how antibiotics disrupt that resistance is key to the prevention and cure of intestinal infections. We present a novel method to infer microbial community ecology directly from time-resolved metagenomics. This method extends generalized Lotka-Volterra dynamics to account for external perturbations. Data from recent experiments on antibiotic-mediated Clostridium difficile infection is analyzed to quantify microbial interactions, commensal-pathogen interactions, and the effect of the antibiotic on the community. Stability analysis reveals that the microbiota is intrinsically stable, explaining how antibiotic perturbations and C. difficile inoculation can produce catastrophic shifts that persist even after removal of the perturbations. Importantly, the analysis suggests a subnetwork of bacterial groups implicated in protection against C. difficile. Due to its generality, our method can be applied to any high-resolution ecological time-series data to infer community structure and response to external stimuli.
Assuntos
Clostridioides difficile/isolamento & purificação , Ecologia , Intestinos/microbiologia , Modelos Teóricos , Animais , Camundongos , Modelos Animais , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Despite their therapeutic benefits, antibiotics exert collateral damage on the microbiome and promote antimicrobial resistance. However, the mechanisms governing microbiome recovery from antibiotics are poorly understood. Treatment of Mycobacterium tuberculosis, the world's most common infection, represents the longest antimicrobial exposure in humans. Here, we investigate gut microbiome dynamics over 20 months of multidrug-resistant tuberculosis (TB) and 6 months of drug-sensitive TB treatment in humans. We find that gut microbiome dynamics and TB clearance are shared predictive cofactors of the resolution of TB-driven inflammation. The initial severe taxonomic and functional microbiome disruption, pathobiont domination, and enhancement of antibiotic resistance that initially accompanied long-term antibiotics were countered by later recovery of commensals. This resilience was driven by the competing evolution of antimicrobial resistance mutations in pathobionts and commensals, with commensal strains with resistance mutations reestablishing dominance. Fecal-microbiota transplantation of the antibiotic-resistant commensal microbiome in mice recapitulated resistance to further antibiotic disruption. These findings demonstrate that antimicrobial resistance mutations in commensals can have paradoxically beneficial effects by promoting microbiome resilience to antimicrobials and identify microbiome dynamics as a predictor of disease resolution in antibiotic therapy of a chronic infection.
Assuntos
Microbioma Gastrointestinal , Microbiota , Resiliência Psicológica , Humanos , Animais , Camundongos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana/genéticaRESUMO
Metabolic byproducts of the intestinal microbiota are crucial in maintaining host immune tone and shaping inter-species ecological dynamics. Among these metabolites, succinate is a driver of tuft cell (TC) differentiation and consequent type 2 immunity-dependent protection against invading parasites in the small intestine. Succinate is also a growth enhancer of the nosocomial pathogen Clostridioides difficile in the large intestine. To date, no research has shown the role of succinate in modulating TC dynamics in the large intestine, or the relevance of this immune pathway to C. difficile pathophysiology. Here we reveal the existence of a three-way circuit between commensal microbes, C. difficile and host epithelial cells which centers around succinate. Through selective microbiota depletion experiments we demonstrate higher levels of type 2 cytokines leading to expansion of TCs in the colon. We then demonstrate the causal role of the microbiome in modulating colonic TC abundance and subsequent type 2 cytokine induction using rational supplementation experiments with fecal transplants and microbial consortia of succinate-producing bacteria. We show that administration of a succinate-deficient Bacteroides thetaiotaomicron knockout (Δfrd) significantly reduces the enhanced type 2 immunity in mono-colonized mice. Finally, we demonstrate that mice prophylactically administered with the consortium of succinate-producing bacteria show reduced C. difficile-induced morbidity and mortality compared to mice administered with heat-killed bacteria or the vehicle. This effect is reduced in a partial tuft cell knockout mouse, Pou2f3+/-, and nullified in the tuft cell knockout mouse, Pou2f3-/-, confirming that the observed protection occurs via the TC pathway. Succinate is an intermediary metabolite of the production of short-chain fatty acids, and its concentration often increases during dysbiosis. The first barrier to enteric pathogens alike is the intestinal epithelial barrier, and host maintenance and strengthening of barrier integrity is vital to homeostasis. Considering our data, we propose that activation of TC by the microbiota-produced succinate in the colon is a mechanism evolved by the host to counterbalance microbiome-derived cues that facilitate invasion by intestinal pathogens.
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Antibiotic resistance is a global threat driven primarily by antibiotic use. We evaluated the effects of antibiotic exposures on the gut microbiomes and resistomes of children at high risk of colonization by antibiotic-resistant bacteria. We performed shotgun metagenomic sequencing of 691 serially collected fecal samples from 80 children (<18 years) undergoing hematopoietic cell transplantation. We evaluated the effects of aerobic (cefepime, vancomycin, fluoroquinolones, aminoglycosides, macrolides, and trimethoprim-sulfamethoxazole) and anaerobic (piperacillin-tazobactam, carbapenems, metronidazole, and clindamycin) antibiotic exposures on the diversity and composition of the gut microbiome and resistome. We identified 372 unique antibiotic resistance genes (ARGs); the most frequent ARGs identified encode resistance to tetracyclines (n = 88), beta-lactams (n = 84), and fluoroquinolones (n = 79). Both aerobic and anaerobic antibiotic exposures were associated with a decrease in the number of bacterial species (aerobic, ß = 0.71, 95% CI: 0.64, 0.79; anaerobic, ß = 0.66, 95% CI: 0.53, 0.82) and the number of unique ARGs (aerobic, ß = 0.81, 95% CI: 0.74, 0.90; anaerobic, ß = 0.73, 95% CI: 0.61, 0.88) within the gut metagenome. However, only antibiotic regimens that included anaerobic activity were associated with an increase in acquisition of new ARGs (anaerobic, ß = 1.50; 95% CI: 1.12, 2.01) and an increase in the relative abundance of ARGs in the gut resistome (anaerobic, ß = 1.62; 95% CI: 1.15, 2.27). Specific antibiotic exposures were associated with distinct changes in the number and abundance of ARGs for individual antibiotic classes. Our findings detail the impact of antibiotics on the gut microbiome and resistome and demonstrate that anaerobic antibiotics are particularly likely to promote acquisition and expansion of antibiotic-resistant bacteria.
Assuntos
Microbioma Gastrointestinal , Transplante de Células-Tronco Hematopoéticas , Criança , Humanos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bactérias/genética , Fluoroquinolonas/farmacologia , Microbioma Gastrointestinal/genéticaRESUMO
BACKGROUND: Fecal microbiota transplantation (FMT) shows some efficacy in treating patients with ulcerative colitis (UC), although variability has been observed among donors and treatment regimens. We investigated the effect of FMT using rationally selected donors after pretreatment with budesonide or placebo in active UC. METHODS: Patients ≥ 18 years old with mild to moderate active UC were randomly assigned to three weeks budesonide (9 mg) or placebo followed by four weekly infusions of a donor feces suspension. Two donors were selected based on microbiota composition, Treg induction and SCFA production in mice. The primary endpoint was engraftment of donor microbiota after FMT. In addition, clinical efficacy was assessed. RESULTS: In total, 24 patients were enrolled. Pretreatment with budesonide did not increase donor microbiota engraftment (p=0.56) nor clinical response, and engraftment was not associated with clinical response. At week 14, 10/24 (42%) of patients achieved (partial) remission. Remarkably, patients treated with FMT suspensions from one donor were associated with clinical response (80% of responders, p<0.05) but had lower overall engraftment of donor microbiota. Furthermore, differences in the taxonomic composition of the donors and the engraftment of certain taxa were associated with clinical response. CONCLUSION: In this small study, pretreatment with budesonide did not significantly influence engraftment or clinical response after FMT. However, clinical response appeared donor-dependent. Response to FMT may be related to transfer of specific strains instead of overall engraftment, demonstrating the need to characterize mechanisms of actions of strains that maximize therapeutic benefit in ulcerative colitis.
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Bacteria causing infections in hospitalized patients are increasingly antibiotic resistant. Classical infection control practices are only partially effective at preventing spread of antibiotic-resistant bacteria within hospitals. Because the density of intestinal colonization by the highly antibiotic-resistant bacterium vancomycin-resistant Enterococcus (VRE) can exceed 10(9) organisms per gram of feces, even optimally implemented hygiene protocols often fail. Decreasing the density of intestinal colonization, therefore, represents an important approach to limit VRE transmission. We demonstrate that reintroduction of a diverse intestinal microbiota to densely VRE-colonized mice eliminates VRE from the intestinal tract. While oxygen-tolerant members of the microbiota are ineffective at eliminating VRE, administration of obligate anaerobic commensal bacteria to mice results in a billionfold reduction in the density of intestinal VRE colonization. 16S rRNA gene sequence analysis of intestinal bacterial populations isolated from mice that cleared VRE following microbiota reconstitution revealed that recolonization with a microbiota that contains Barnesiella correlates with VRE elimination. Characterization of the fecal microbiota of patients undergoing allogeneic hematopoietic stem cell transplantation demonstrated that intestinal colonization with Barnesiella confers resistance to intestinal domination and bloodstream infection with VRE. Our studies indicate that obligate anaerobic bacteria belonging to the Barnesiella genus enable clearance of intestinal VRE colonization and may provide novel approaches to prevent the spread of highly antibiotic-resistant bacteria.
Assuntos
Bacteroidaceae/fisiologia , Enterococcus faecium/efeitos dos fármacos , Infecções por Bactérias Gram-Positivas/terapia , Intestinos/microbiologia , Resistência a Vancomicina , Animais , DNA Bacteriano , Feminino , Camundongos , Camundongos Endogâmicos C57BL , RNA Bacteriano/genética , RNA Ribossômico 16S/genéticaRESUMO
Via strength in numbers, groups of cells can influence their environments in ways that individual cells cannot. Large-scale structural patterns and collective functions underpinning virulence, tumour growth and bacterial biofilm formation are emergent properties of coupled physical and biological processes within cell groups. Owing to the abundance of factors influencing cell group behaviour, deriving general principles about them is a daunting challenge. We argue that combining mechanistic theory with theoretical ecology and evolution provides a key strategy for clarifying how cell groups form, how they change in composition over time, and how they interact with their environments. Here, we review concepts that are critical for dissecting the complexity of cell collectives, including dimensionless parameter groups, individual-based modelling and evolutionary theory. We then use this hybrid modelling approach to provide an example analysis of the evolution of cooperative enzyme secretion in bacterial biofilms.
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Bactérias/enzimologia , Fenômenos Fisiológicos Bacterianos , Biofilmes , Seleção Genética , Bactérias/genética , Bactérias/crescimento & desenvolvimento , Evolução Biológica , Modelos Biológicos , Percepção de QuorumRESUMO
The intestinal microbiota plays important roles in digestion and resistance against entero-pathogens. As with other ecosystems, its species composition is resilient against small disturbances but strong perturbations such as antibiotics can affect the consortium dramatically. Antibiotic cessation does not necessarily restore pre-treatment conditions and disturbed microbiota are often susceptible to pathogen invasion. Here we propose a mathematical model to explain how antibiotic-mediated switches in the microbiota composition can result from simple social interactions between antibiotic-tolerant and antibiotic-sensitive bacterial groups. We build a two-species (e.g. two functional-groups) model and identify regions of domination by antibiotic-sensitive or antibiotic-tolerant bacteria, as well as a region of multistability where domination by either group is possible. Using a new framework that we derived from statistical physics, we calculate the duration of each microbiota composition state. This is shown to depend on the balance between random fluctuations in the bacterial densities and the strength of microbial interactions. The singular value decomposition of recent metagenomic data confirms our assumption of grouping microbes as antibiotic-tolerant or antibiotic-sensitive in response to a single antibiotic. Our methodology can be extended to multiple bacterial groups and thus it provides an ecological formalism to help interpret the present surge in microbiome data.
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Antibacterianos/farmacologia , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/fisiologia , Intestinos/microbiologia , Modelos Biológicos , Modelos Estatísticos , Comportamento Social , Simulação por Computador , Intestinos/efeitos dos fármacosRESUMO
BACKGROUND: Infants receive their first bacteria from their birthing parent. This newly acquired microbiome plays a pivotal role in developing a robust immune system, the cornerstone of long-term health. RESULTS: We demonstrated that the gut, vaginal, and oral microbial diversity of pregnant women with SARS-CoV-2 infection is reduced, and women with early infections exhibit a different vaginal microbiota composition at the time of delivery compared to their healthy control counterparts. Accordingly, a low relative abundance of two Streptococcus sequence variants (SV) was predictive of infants born to pregnant women with SARS-CoV-2 infection. CONCLUSIONS: Our data suggest that SARS-CoV-2 infections during pregnancy, particularly early infections, are associated with lasting changes in the microbiome of pregnant women, compromising the initial microbial seed of their infant. Our results highlight the importance of further exploring the impact of SARS-CoV-2 on the infant's microbiome-dependent immune programming. Video Abstract.
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COVID-19 , Microbiota , Humanos , Lactente , Feminino , Gravidez , SARS-CoV-2 , Gestantes , PartoRESUMO
SARS-CoV-2-positive patients exhibit gut and oral microbiome dysbiosis, which is associated with various aspects of COVID-19 disease (1-4). Here, we aim to identify gut and oral microbiome markers that predict COVID-19 severity in hospitalized patients, specifically severely ill patients compared to moderately ill ones. Moreover, we investigate whether hospital feeding (solid versus enteral), an important cofounder, influences the microbial composition of hospitalized COVID-19 patients. We used random forest classification machine learning models with interpretable secondary analyses. The gut, but not the oral microbiota, was a robust predictor of both COVID-19-related fatality and severity of hospitalized patients, with a higher predictive value than most clinical variables. In addition, perturbations of the gut microbiota due to enteral feeding did not associate with species that were predictive of COVID-19 severity. IMPORTANCE SARS-CoV-2 infection leads to wide-ranging, systemic symptoms with sometimes unpredictable morbidity and mortality. It is increasingly clear that the human microbiome plays an important role in how individuals respond to viral infections. Our study adds to important literature about the associations of gut microbiota and severe COVID-19 illness during the early phase of the pandemic before the availability of vaccines. Increased understanding of the interplay between microbiota and SARS-CoV-2 may lead to innovations in diagnostics, therapies, and clinical predictions.
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COVID-19 , Microbioma Gastrointestinal , Humanos , SARS-CoV-2 , Métodos de Alimentação , HospitaisRESUMO
Persistent colonization and outgrowth of pathogenic organisms in the intestine may occur due to long-term antibiotic usage or inflammatory conditions, which perpetuate dysregulated immunity and tissue damage1,2. Gram-negative Enterobacteriaceae gut pathobionts are particularly recalcitrant to conventional antibiotic treatment3,4, though an emerging body of evidence suggests that manipulation of the commensal microbiota may be a practical alternative therapeutic strategy5-7. In this study, we rationally isolated and down-selected commensal bacterial consortia from healthy human stool samples capable of strongly and specifically suppressing intestinal Enterobacteriaceae. One of the elaborated consortia, consisting of 18 commensal strains, effectively controlled ecological niches by regulating gluconate availability, thereby reestablishing colonization resistance and alleviating antibiotic-resistant Klebsiella-driven intestinal inflammation in mice. Harnessing these microbial activities in the form of live bacterial therapeutics may represent a promising solution to combat the growing threat of proinflammatory, antimicrobial-resistant bacterial infection.