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1.
Cell ; 187(1): 62-78.e20, 2024 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-38096822

RESUMO

The microbiota influences intestinal health and physiology, yet the contributions of commensal protists to the gut environment have been largely overlooked. Here, we discover human- and rodent-associated parabasalid protists, revealing substantial diversity and prevalence in nonindustrialized human populations. Genomic and metabolomic analyses of murine parabasalids from the genus Tritrichomonas revealed species-level differences in excretion of the metabolite succinate, which results in distinct small intestinal immune responses. Metabolic differences between Tritrichomonas species also determine their ecological niche within the microbiota. By manipulating dietary fibers and developing in vitro protist culture, we show that different Tritrichomonas species prefer dietary polysaccharides or mucus glycans. These polysaccharide preferences drive trans-kingdom competition with specific commensal bacteria, which affects intestinal immunity in a diet-dependent manner. Our findings reveal unappreciated diversity in commensal parabasalids, elucidate differences in commensal protist metabolism, and suggest how dietary interventions could regulate their impact on gut health.


Assuntos
Microbioma Gastrointestinal , Parabasalídeos , Polissacarídeos , Animais , Humanos , Camundongos , Fibras na Dieta , Intestino Delgado/metabolismo , Polissacarídeos/metabolismo , Parabasalídeos/metabolismo , Carboidratos da Dieta/metabolismo , Biodiversidade
2.
Appl Environ Microbiol ; 89(7): e0058323, 2023 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-37404180

RESUMO

Microbial source tracking (MST) identifies sources of fecal contamination in the environment using host-associated fecal markers. While there are numerous bacterial MST markers that can be used herein, there are few such viral markers. Here, we designed and tested novel viral MST markers based on tomato brown rugose fruit virus (ToBRFV) genomes. We assembled eight nearly complete genomes of ToBRFV from wastewater and stool samples from the San Francisco Bay Area in the United States. Next, we developed two novel probe-based reverse transcription-PCR (RT-PCR) assays based on conserved regions of the ToBRFV genome and tested the markers' sensitivities and specificities using human and non-human animal stool as well as wastewater. The ToBRFV markers are sensitive and specific; in human stool and wastewater, they are more prevalent and abundant than a commonly used viral marker, the pepper mild mottle virus (PMMoV) coat protein (CP) gene. We used the assays to detect fecal contamination in urban stormwater samples and found that the ToBRFV markers matched cross-assembly phage (crAssphage), an established viral MST marker, in prevalence across samples. Taken together, these results indicate that ToBRFV is a promising viral human-associated MST marker. IMPORTANCE Human exposure to fecal contamination in the environment can cause transmission of infectious diseases. Microbial source tracking (MST) can identify sources of fecal contamination so that contamination can be remediated and human exposures can be reduced. MST requires the use of host-associated MST markers. Here, we designed and tested novel MST markers from genomes of tomato brown rugose fruit virus (ToBRFV). The markers are sensitive and specific to human stool and highly abundant in human stool and wastewater samples.


Assuntos
Solanum lycopersicum , Águas Residuárias , Animais , Frutas , Biomarcadores , Fezes/microbiologia , Monitoramento Ambiental/métodos
3.
bioRxiv ; 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36712100

RESUMO

Microbial source tracking (MST) identifies sources of fecal contamination in the environment using fecal host-associated markers. While there are numerous bacterial MST markers, there are few viral markers. Here we design and test novel viral MST markers based on tomato brown rugose fruit virus (ToBRFV) genomes. We assembled eight nearly complete genomes of ToBRFV from wastewater and stool samples from the San Francisco Bay Area in the United States of America. Next, we developed two novel probe-based RT-PCR assays based on conserved regions of the ToBRFV genome, and tested the markers’ sensitivities and specificities using human and non-human animal stool as well as wastewater. TheToBRFV markers are sensitive and specific; in human stool and wastewater, they are more prevalent and abundant than a currently used marker, the pepper mild mottle virus (PMMoV) coat protein (CP) gene. We applied the assays to detect fecal contamination in urban stormwater samples and found that the ToBRFV markers matched cross-assembly phage (crAssphage), an established viral MST marker, in prevalence across samples. Taken together, ToBRFV is a promising viral human-associated MST marker. Importance: Human exposure to fecal contamination in the environment can cause transmission of infectious diseases. Microbial source tracking (MST) can identify sources of fecal contamination so that contamination can be remediated and human exposures can be reduced. MST requires the use of fecal host-associated MST markers. Here we design and test novel MST markers from genomes of tomato brown rugose fruit virus (ToBRFV). The markers are sensitive and specific to human stool, and highly abundant in human stool and wastewater samples.

4.
Cell Host Microbe ; 30(4): 420-422, 2022 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-35421334

RESUMO

Modulation of the microbiota to improve clinical outcomes remains challenging partially because of the large variability in biotherapeutic composition. In this issue of Cell Host & Microbe, Dsouza and colleagues present the phase 1 study results of a defined microbial consortia developed for the prevention of recurrent Clostridioides difficile infection (CDI).


Assuntos
Clostridioides difficile , Infecções por Clostridium , Microbiota , Infecções por Clostridium/prevenção & controle , Transplante de Microbiota Fecal , Amigos , Humanos
5.
JCI Insight ; 7(7)2022 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-35239511

RESUMO

BACKGROUNDGut decontamination (GD) can decrease the incidence and severity of acute graft-versus-host disease (aGVHD) in murine models of allogeneic hematopoietic cell transplantation (HCT). In this pilot study, we examined the impact of GD on gut microbiome composition and the incidence of aGVHD in HCT patients.METHODSWe randomized 20 patients undergoing allogeneic HCT to receive (GD) or not receive (no-GD) oral vancomycin-polymyxin B from day -5 through neutrophil engraftment. We evaluated shotgun metagenomic sequencing of serial stool samples to compare the composition and diversity of the gut microbiome between study arms. We assessed clinical outcomes in the 2 arms and performed strain-specific analyses of pathogens that caused bloodstream infections (BSI).RESULTSThe 2 arms did not differ in the predefined primary outcome of Shannon diversity of the gut microbiome at 2 weeks post-HCT (genus, P = 0.8; species, P = 0.44) or aGVHD incidence (P = 0.58). Immune reconstitution of T cell and B cell subsets was similar between groups. Five patients in the no-GD arm had 8 BSI episodes versus 1 episode in the GD arm (P = 0.09). The BSI-causing pathogens were traceable to the gut in 7 of 8 BSI episodes in the no-GD arm, including Staphylococcus species.CONCLUSIONWhile GD did not differentially affect Shannon diversity or clinical outcomes, our findings suggest that GD may protect against gut-derived BSI in HCT patients by decreasing the prevalence or abundance of gut pathogens.TRIAL REGISTRATIONClinicalTrials.gov NCT02641236.FUNDINGNIH, Damon Runyon Cancer Research Foundation, V Foundation, Sloan Foundation, Emerson Collective, and Stanford Maternal & Child Health Research Institute.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Microbiota , Animais , Criança , Descontaminação , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Camundongos , Projetos Piloto
6.
Hematology Am Soc Hematol Educ Program ; 2019(1): 303-314, 2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31808861

RESUMO

Growing evidence suggests that human microbiota likely influence diverse processes including hematopoiesis, chemotherapy metabolism, and efficacy, as well as overall survival in patients with hematologic malignancies and other cancers. Both host genetic susceptibility and host-microbiota interactions may impact cancer risk and response to treatment; however, microbiota have the potential to be uniquely modifiable and accessible targets for treatment. Here, we focus on strategies to modify microbiota composition and function in patients with cancer. First, we evaluate the use of fecal microbiota transplant to restore microbial equilibrium following perturbation by antibiotics and chemotherapy, and as a treatment of complications of hematopoietic stem cell transplantation (HSCT), such as graft-versus-host disease and colonization with multidrug-resistant organisms. We then address the potential use of both probiotics and dietary prebiotic compounds in targeted modulation of the microbiota intended to improve outcomes in hematologic diseases. With each type of therapy, we highlight the role that abnormal, or dysbiotic, microbiota play in disease, treatment efficacy, and toxicity and evaluate their potential promise as emerging strategies for microbiota manipulation in patients with hematologic malignancies and in those undergoing HSCT.


Assuntos
Hematologia , Microbiota , Pesquisa Translacional Biomédica , Transplante de Microbiota Fecal , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Pessoa de Meia-Idade , Probióticos/uso terapêutico , Resultado do Tratamento
7.
Blood Adv ; 3(21): 3461-3472, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31714965

RESUMO

Growing evidence suggests that human microbiota likely influence diverse processes including hematopoiesis, chemotherapy metabolism, and efficacy, as well as overall survival in patients with hematologic malignancies and other cancers. Both host genetic susceptibility and host-microbiota interactions may impact cancer risk and response to treatment; however, microbiota have the potential to be uniquely modifiable and accessible targets for treatment. Here, we focus on strategies to modify microbiota composition and function in patients with cancer. First, we evaluate the use of fecal microbiota transplant to restore microbial equilibrium following perturbation by antibiotics and chemotherapy, and as a treatment of complications of hematopoietic stem cell transplantation (HSCT), such as graft-versus-host disease and colonization with multidrug-resistant organisms. We then address the potential use of both probiotics and dietary prebiotic compounds in targeted modulation of the microbiota intended to improve outcomes in hematologic diseases. With each type of therapy, we highlight the role that abnormal, or dysbiotic, microbiota play in disease, treatment efficacy, and toxicity and evaluate their potential promise as emerging strategies for microbiota manipulation in patients with hematologic malignancies and in those undergoing HSCT.


Assuntos
Microbiota , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Tomada de Decisão Clínica , Terapia Combinada , Gerenciamento Clínico , Suscetibilidade a Doenças , Transplante de Microbiota Fecal , Feminino , Microbioma Gastrointestinal , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/etiologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Interações Hospedeiro-Patógeno , Humanos , Infecções/diagnóstico , Infecções/etiologia , Infecções/terapia , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Probióticos/uso terapêutico , Pesquisa Translacional Biomédica , Transplante Homólogo
8.
Biol Blood Marrow Transplant ; 25(11): 2274-2280, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31326608

RESUMO

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 (n = 5), Enterococcus faecium (n = 2), Enterobacter cloacae (n = 1), and Rothia mucilaginosa (n = 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.


Assuntos
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 Prospectivos
9.
Cell Host Microbe ; 24(3): 334-336, 2018 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-30212646

RESUMO

Probiotics and other bacteriotherapies are actively being explored and applied as symptom- and disease-modifying agents. In a recent issue of Cell, two papers contribute to our understanding of how live bacterial therapies variably affect individuals and the short- and longer-term impact of these therapies on colonization and host response.


Assuntos
Fenômenos Fisiológicos Bacterianos , Probióticos/uso terapêutico , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Bactérias/crescimento & desenvolvimento , Disbiose/microbiologia , Disbiose/terapia , Gastroenteropatias/terapia , Microbioma Gastrointestinal/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos
10.
Genomics ; 96(6): 342-51, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20858542

RESUMO

Repulsive guidance molecule c (RGMc; gene symbol: Hfe2) plays a critical role in iron metabolism. Inactivating mutations cause juvenile hemochromatosis, a severe iron overload disorder. Understanding mechanisms controlling RGMc biosynthesis has been hampered by minimal information about the RGMc gene. Here we define the structure, examine the evolution, and establish mechanisms of regulation of the mouse RGMc gene. RGMc is a 4-exon gene that undergoes alternative RNA splicing to yield 3 mRNAs with 5' different untranslated regions. Gene transcription is induced during myoblast differentiation, producing all 3 mRNAs. We identify 3 critical promoter elements responsible for transcriptional activation in skeletal muscle, comprising paired E-boxes, a putative Stat and/or Ets element, and a MEF2 site, and muscle transcription factors myogenin and MEF2C stimulate RGMc promoter function in non-muscle cells. As these elements are conserved in RGMc genes from multiple species, our results suggest that RGMc has been a muscle-enriched gene throughout its evolutionary history.


Assuntos
Sequência Conservada/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Membrana/metabolismo , Músculo Esquelético/metabolismo , Regiões Promotoras Genéticas/genética , Animais , Sequência de Bases , Diferenciação Celular , Evolução Molecular , Feminino , Proteínas Ligadas por GPI , Proteína da Hemocromatose , Ferro/metabolismo , Masculino , Proteínas de Membrana/química , Proteínas de Membrana/genética , Camundongos , Dados de Sequência Molecular , Músculo Esquelético/citologia , Splicing de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição
11.
Biochem J ; 422(3): 393-403, 2009 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-19698085

RESUMO

RGMs (repulsive guidance molecules) comprise a recently discovered family of GPI (glycosylphosphatidylinositol)-linked cell-membrane-associated proteins found in most vertebrate species. The three proteins, RGMa, RGMb and RGMc, products of distinct single-copy genes that arose early in vertebrate evolution, are approximately 40-50% identical to each other in primary amino acid sequence, and share similarities in predicted protein domains and overall structure, as inferred by ab initio molecular modelling; yet the respective proteins appear to undergo distinct biosynthetic and processing steps, whose regulation has not been characterized to date. Each RGM also displays a discrete tissue-specific pattern of gene and protein expression, and each is proposed to have unique biological functions, ranging from axonal guidance during development (RGMa) to regulation of systemic iron metabolism (RGMc). All three RGM proteins appear capable of binding selected BMPs (bone morphogenetic proteins), and interactions with BMPs mediate at least some of the biological effects of RGMc on iron metabolism, but to date no role for BMPs has been defined in the actions of RGMa or RGMb. RGMa and RGMc have been shown to bind to the transmembrane protein neogenin, which acts as a critical receptor to mediate the biological effects of RGMa on repulsive axonal guidance and on neuronal survival, but its role in the actions of RGMc remains to be elucidated. Similarly, the full spectrum of biological functions of the three RGMs has not been completely characterized yet, and will remain an active topic of ongoing investigation.


Assuntos
Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Animais , Moléculas de Adesão Celular Neuronais , Proteínas Ligadas por GPI , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Modelos Genéticos , Proteínas Musculares/química , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Filogenia , Estrutura Secundária de Proteína
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