The Complexity of Microbial Diversity in Bacterial Vaginosis
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《新英格兰医药杂志》
From the time that Robert Koch prepared stained smears of biologic samples from humans, scientists have been engaged in describing the microbiologic flora of the human vagina. In 1882, D?derlein described the lactic acid–producing lactobacilli from the vaginas of healthy women, and he was the first to report the treatment of gonococcal infections in women with human-derived strains of lactobacillus. In 1921, Schr?der published detailed drawings of vaginal smears from women with the condition now known as bacterial vaginosis, and these drawings portended the incredible microbiologic diversity present in the female reproductive tract.
The microbiologic cause of bacterial vaginosis has long eluded scientists, and newly described vaginal microbes are often considered pathogens. In 1955, Gardnerella vaginalis was described by Gardner and Dukes as the primary bacterial agent responsible for bacterial vaginosis, and the syndrome was retermed G. vaginalis vaginitis. However, nearly 30 years later, British researchers attached great importance to the presence of anaerobic bacteria and proposed that the syndrome be renamed anaerobic vaginosis. The subsequent "discoveries" of other newly described bacteria in the female reproductive tract resulted in transient consideration of their role as possible etiologic agents of bacterial vaginosis. Examples include mobiluncus in the 1980s and atopobium during the present decade. The ecology of the vaginal microflora is influenced by several forces, such as endogenous and exogenous hormones, sexual intercourse, and douching, all of which complicate the vaginal microenvironment, thus challenging our understanding of the normal diversity of vaginal flora and making elusive the identification of a specific etiologic agent of bacterial vaginosis.
As noted by Fredricks et al. in this issue of the Journal (pages 1899–1911), bacterial vaginosis is a common condition among women of reproductive age. In addition to its causing such symptoms as discharge, odor, and irritation, pregnant women with this syndrome have been shown to have an increased risk of preterm delivery. The syndrome has also been linked with the increased acquisition of a variety of sexually transmitted infections, including gonorrhea, herpes simplex virus infection, human papillomavirus infection, and human immunodeficiency virus infection. Recently, subgroups of microorganisms related to bacterial vaginosis, particularly the black-pigmented, anaerobic, gram-negative rods, have been associated with an increased risk of pelvic inflammatory disease. Antimicrobial agents that act against anaerobes are the current treatment for bacterial vaginosis recommended by the Centers for Disease Control and Prevention. However, recurrence is common and there is a poor understanding of how to optimally target treatment against specific pathogens, which is a failure related primarily to our limited understanding of the microbiologic cause of this syndrome according to traditional culture-based techniques.
Fredricks and colleagues have performed a molecular analysis of the microbiota of the vaginal fluid based on the use of broad-range polymerase-chain-reaction (PCR) assays of 16S ribosomal DNA and bacterium-specific PCR testing. These methods permit the detection of microorganisms that are not easily cultured and thus provide a more comprehensive description of the vaginal microflora. The major finding of this study is the description of a cluster of new organisms related to clostridium that were detected in 27 women with bacterial vaginosis and absent in the 46 women in the control group. A particular strength of the study is the use of fluorescence in situ hybridization to show that some of the curved-rod morphotypes that are often visible with the use of Gram's staining of vaginal smears from women with bacterial vaginosis (see images) represent these new organisms. The study also provides molecular confirmation of the culture-based observations showing that lactobacillus species are the dominant bacteria in women without bacterial vaginosis, whereas women with bacterial vaginosis have considerable microbial diversity, with a mean of 13 phylotypes per subject.
Gram's Staining of Vaginal-Fluid Smears from a Woman with Lactobacillus-Predominant Microflora (Panel A) and from a Woman with Bacterial Vaginosis (Panel B).
The vaginal squamous cell on the right in Panel B is a clue cell.
There are important limitations to the study, many of which have been recognized by the authors. On the basis of culture techniques, the density of bacteria in the vaginal microflora has been estimated to range from 106 to 108 bacteria per gram of vaginal fluid. Characterization of 100 clones from each subject means that microorganisms present at concentrations of 106 or fewer colony-forming units per gram of vaginal fluid are unlikely to be detected by the PCR approach. Thus, the present study provides a better understanding of the numerically dominant microbial populations than is achievable with the use of culture-based methods. Bacteria of known pathogenic potential that are present at concentrations of 103 to 106 colony-forming units per gram of vaginal fluid would not be detected (e.g., group B streptococcus, which is known to be present in the vagina of one in three women, although at a low density, as compared with other microbes). Group B streptococcus, even at low concentrations, can cause catastrophic infections in peripartum women and their newborns. In the context of bacterial vaginosis, high microbial density may not denote pathogenicity.
Bacterial vaginosis is common among women of reproductive age, and vaginal discharge is the symptom most frequently cited by women who seek health care. In addition to the direct health care costs associated with the management of this syndrome are the costs associated with the adverse reproductive health sequelae. As we gain a better appreciation of the changes in the microflora that occur with bacterial vaginosis, it will be important to assess whether these newly described organisms are linked with an increased risk of preterm labor or susceptibility to sexually transmitted infections and whether there is evidence of host response to these organisms. The study by Fredricks et al. provides important new insights regarding the great variety of dominant microbes present in the ecosystems of women with bacterial vaginosis, but we do not know whether these microorganisms represent innocent colonizers or possible pathogens.
Dr. Hillier reports having received consulting or lecture fees from 3M Pharmaceuticals, Pfizer, KV Pharmaceuticals, Presutti Laboratories, and Becton Dickinson Microbiology Systems.(Sharon L. Hillier, Ph.D.)
The microbiologic cause of bacterial vaginosis has long eluded scientists, and newly described vaginal microbes are often considered pathogens. In 1955, Gardnerella vaginalis was described by Gardner and Dukes as the primary bacterial agent responsible for bacterial vaginosis, and the syndrome was retermed G. vaginalis vaginitis. However, nearly 30 years later, British researchers attached great importance to the presence of anaerobic bacteria and proposed that the syndrome be renamed anaerobic vaginosis. The subsequent "discoveries" of other newly described bacteria in the female reproductive tract resulted in transient consideration of their role as possible etiologic agents of bacterial vaginosis. Examples include mobiluncus in the 1980s and atopobium during the present decade. The ecology of the vaginal microflora is influenced by several forces, such as endogenous and exogenous hormones, sexual intercourse, and douching, all of which complicate the vaginal microenvironment, thus challenging our understanding of the normal diversity of vaginal flora and making elusive the identification of a specific etiologic agent of bacterial vaginosis.
As noted by Fredricks et al. in this issue of the Journal (pages 1899–1911), bacterial vaginosis is a common condition among women of reproductive age. In addition to its causing such symptoms as discharge, odor, and irritation, pregnant women with this syndrome have been shown to have an increased risk of preterm delivery. The syndrome has also been linked with the increased acquisition of a variety of sexually transmitted infections, including gonorrhea, herpes simplex virus infection, human papillomavirus infection, and human immunodeficiency virus infection. Recently, subgroups of microorganisms related to bacterial vaginosis, particularly the black-pigmented, anaerobic, gram-negative rods, have been associated with an increased risk of pelvic inflammatory disease. Antimicrobial agents that act against anaerobes are the current treatment for bacterial vaginosis recommended by the Centers for Disease Control and Prevention. However, recurrence is common and there is a poor understanding of how to optimally target treatment against specific pathogens, which is a failure related primarily to our limited understanding of the microbiologic cause of this syndrome according to traditional culture-based techniques.
Fredricks and colleagues have performed a molecular analysis of the microbiota of the vaginal fluid based on the use of broad-range polymerase-chain-reaction (PCR) assays of 16S ribosomal DNA and bacterium-specific PCR testing. These methods permit the detection of microorganisms that are not easily cultured and thus provide a more comprehensive description of the vaginal microflora. The major finding of this study is the description of a cluster of new organisms related to clostridium that were detected in 27 women with bacterial vaginosis and absent in the 46 women in the control group. A particular strength of the study is the use of fluorescence in situ hybridization to show that some of the curved-rod morphotypes that are often visible with the use of Gram's staining of vaginal smears from women with bacterial vaginosis (see images) represent these new organisms. The study also provides molecular confirmation of the culture-based observations showing that lactobacillus species are the dominant bacteria in women without bacterial vaginosis, whereas women with bacterial vaginosis have considerable microbial diversity, with a mean of 13 phylotypes per subject.
Gram's Staining of Vaginal-Fluid Smears from a Woman with Lactobacillus-Predominant Microflora (Panel A) and from a Woman with Bacterial Vaginosis (Panel B).
The vaginal squamous cell on the right in Panel B is a clue cell.
There are important limitations to the study, many of which have been recognized by the authors. On the basis of culture techniques, the density of bacteria in the vaginal microflora has been estimated to range from 106 to 108 bacteria per gram of vaginal fluid. Characterization of 100 clones from each subject means that microorganisms present at concentrations of 106 or fewer colony-forming units per gram of vaginal fluid are unlikely to be detected by the PCR approach. Thus, the present study provides a better understanding of the numerically dominant microbial populations than is achievable with the use of culture-based methods. Bacteria of known pathogenic potential that are present at concentrations of 103 to 106 colony-forming units per gram of vaginal fluid would not be detected (e.g., group B streptococcus, which is known to be present in the vagina of one in three women, although at a low density, as compared with other microbes). Group B streptococcus, even at low concentrations, can cause catastrophic infections in peripartum women and their newborns. In the context of bacterial vaginosis, high microbial density may not denote pathogenicity.
Bacterial vaginosis is common among women of reproductive age, and vaginal discharge is the symptom most frequently cited by women who seek health care. In addition to the direct health care costs associated with the management of this syndrome are the costs associated with the adverse reproductive health sequelae. As we gain a better appreciation of the changes in the microflora that occur with bacterial vaginosis, it will be important to assess whether these newly described organisms are linked with an increased risk of preterm labor or susceptibility to sexually transmitted infections and whether there is evidence of host response to these organisms. The study by Fredricks et al. provides important new insights regarding the great variety of dominant microbes present in the ecosystems of women with bacterial vaginosis, but we do not know whether these microorganisms represent innocent colonizers or possible pathogens.
Dr. Hillier reports having received consulting or lecture fees from 3M Pharmaceuticals, Pfizer, KV Pharmaceuticals, Presutti Laboratories, and Becton Dickinson Microbiology Systems.(Sharon L. Hillier, Ph.D.)