Vagina flora and its influence on women's health and disease

Explorations of the vaginal flora started over 150 years ago. Using light microscopy and bacterial cultures, the concept of normal versus abnormal flora in women began to emerge. The latter became known by the term "bacterial vaginosis" . Bacterial vaginosis flora is dominated by Gardnerella vaginalis and includes a number of anaerobic organisms. In contrast, normal flora is dominated by various Lactobacilli. Bacterial vaginosis flora is associated with vaginal discharge, poor pregnancy outcomes, pelvic inflammatory disease, postoperative wound infections and endometritis after elective abortions. In addition, bacterial vaginosis flora predisposes women to infection by human immunodeficiency virus (HIV) and sexually transmitted diseases.  

The small and short Gram-negative rodes are clustered onto the squamous epithelium forming        “clue cells”, typical of Garderella vaginalis infection

The application of molecular techniques over the past decade has significantly advanced the understanding of the vaginal flora. It is much more complex than previously recognized and is composed of many previously unknown organisms in addition to those already identified by culture. Analyses using high-throughput sequencing techniques have lead to the discovery of unique microbial communities not previously recognized within the older, established vaginal flora categories. These new findings will inform the design of future clinical investigations of the role of the vaginal flora in health and disease.

                                                       Lactobacillus species 

The possible role of anaerobes in inflammatory bowel disease ( ulcerative colitis and Crohn's disease)

The distal ileum and colon harbors very high concentrations of bacteria. These may include potential pathogens that could initiate inflammatory bowel disease (IBD). Increased underlying genetic predisposition due to genetic mucosal or immune defect may enhance IBD in some individuals. As study by sutton et al provided support for this hypothesis in finding of an immune response directed against a particular bacterial DNA segment (I2) in affected mucosa from 54 % of patients with Crohn's disease compared to 4 to 10 % of normal individuals. However, no specific organism has been shown to have a consistent relationship to IBD.

Because of the high number of anaerobic bacteria within the intestinal flora, any disturbance of the intestinal epithelium could generate an inflammatory response. This can be due to the effects of microbial products that effect  the underlying epithelium, or from defects in the epithelium which permits bacterial and food antigens to stimulate the mucosal immune system. Studies in genetically engineered mice support the importance of an intact epithelium as an altered gut epithelium lead to the development of spontaneous colitis. Genetic studies have described susceptibility loci that regulate innate responses to the microbial flora and provide support for the role of microbes in the pathogenesis of IBD.

 The ability of the microbial flora to induce disease has been demonstrated in murine models of IBD. A genetically engineered mice that was deficient in cytokines IL-2 and IL-10 or rats containing the HLA-B27 transgene develop inflammatory bowel disease in the presence of a normal microflora but not in germ-free conditions. Mow et al found that immunoreactivity to microbial antigens correlates with complications of small bowel Crohn's disease in humans.

A Link Between Fusobacterium species and Colon Cancer

The possibility that are associated of Fusobacterium species with colonic cancer was suggested in two studies published in Genome Research. The organism was detected in colon cancer cells by both Meyerson et al from the Dana Farber Cancer Institute and Holt et al from the British Columbia Cancer Agency Genome Sciences Center. The two research groups used genetic probes to identify the bacteria found in the tumor tissues.  

Fusobacterium species are mostly found in the mouth and are linked to periodontal disease and oral infections. It is rarely found among the usual gastrointestinal bacteria, but it appears to the only type of bacteria inside colonic cancer cells.  

Gram staining of Fusobacterium nucleatum 

Meyerson et al looked for bacterial DNA, comparing tumor tissue and healthy colon samples from nine patients with colonic cancer. They found Fusobacteria DNA mostly in the cancer tissue. In further studies these investigators found Fusobacterium species in 95 other colon cancer patients.  

Holt et al. focused on RNA instead of DNA. These investigators studied colon cancer biopsies and normal tissues of 11 patients and found that Fusobacteria were more likely to be in cancer tissue than in normal cells. In some specimens, the number of Fusobacteria was hundreds of time higher in cancer cells than in normal tissues.   The investigators also found that other types of bacteria that commonly reside in the gut are depleted in colon cancer tissues. Whether the Fusobacteria are crowding out these more common bugs, or whether they tend to die off in the presence of malignant cells isn't known.  

Currently it is unclear whether or how Fusobacteria might be contributing to the development of cancer. These organisms may promote inflammation, which can contribute to malignant transformation in normal cells. Alternatively, the tumor environment may be more hospitable to Fusobacterial growth, and the high number of this bacterium would be a consequence, not the cause, of the cancer.

Colonic cancer

A link between colonization of the gastrointerstinal tract with Desulfovibrio species and autism

Autism is a complex disorder with no specific diagnostic test so the disease is defined by its characteristics including cognitive defects, social, communication and behavioral problems, repetitive behaviors, unusual sensitivity to stimuli such as noise, restricted interests, and self stimulation. The incidence of this disease has increased remarkably in recent years and was 110/10,000 children (∼1%) in multiple areas of the US in 2007. The financial burden on families and communities is enormous. In terms of predisposing factors, heredity plays a role in some subjects, but it is clear that environmental factors are also important.

Environmental toxins can affect the immune system adversely. Intestinal bacteria are recognized by a few investigators as potentially important and we have proposed that certain antimicrobial drugs may be a key factor in modifying the intestinal bacterial flora adversely, selecting out potentially harmful bacteria that are normally suppressed by an intact normal intestinal flora.

Finegold  et al hypothesis that clostridia in the gut might be involved in autism because they are virulent organisms and spore-formers; spores would resist antibacterial agents so that when antibiotics were discontinued the spores would germinate and by toxin production or another mechanism lead to autism. A recent study by Finegold et al. employing the powerful pyrosequencing technique on stools of subjects with regressive autism showed that Desulfovibrio was more common in autistic subjects than in controls. The investigators  subsequently confirmed this with pilot cultural and real-time PCR studies and found siblings of autistic children had counts of Desulfovibrio that were intermediate, suggesting possible spread of the organism in the family environment.

Desulfovibrio is an anaerobic bacillus that does not produce spores but is nevertheless resistant to aerobic and other adverse conditions by other mechanisms and is commonly resistant to certain antimicrobial agents (such as cephalosporins) often used to treat ear and other infections that are relatively common in childhood. This bacterium also produces important virulence factors and its physiology and metabolism position it uniquely to account for much of the pathophysiology seen in autism. If these results on Desulfovibrio are confirmed and extended in other studies, including treatment trials with appropriate agents and careful clinical and laboratory studies, this could lead to more reliable classification of autism, a diagnostic test and therapy for regressive autism, development of a vaccine for prevention and treatment of regressive autism, tailored probiotics/prebiotics, and important epidemiologic information.

Propionibacterium species as pathogens

Propionibacterium species are part of the normal bacterial flora that colonize the skin, conjunctiva, oropharynx, and gastrointestinal tract. These non-spore-forming, anaerobic, gram-positive bacilli are frequent contaminants of specimens of blood and other sterile body fluids and have been generally considered to play little or no pathogenic role in humans.

Propionibacterium acnes and other Propionibacterium species have, however, been recovered with or without other aerobic or anaerobic organisms as etiologic agents of multiple infection sites. These include conjunctivitis, intracranial abscesses, mycotic aneurysm, peritonitis, and dental, parotid, pulmonary, and other serious infections. They have often been recovered as a sole isolate in specimens obtained from patients with infections associated with a foreign body (such as joint infection, an artificial valve), endocarditis, and central nervous system shunt and post surgical intracranial infections.  Some P. acnes strains possess synergistic capabilities with facultative and aerobic bacteria. The possible role of P. acnes in the pathogenesis of acne vulgaris was suggested. The data that support this are based on the recovery of this organism in large numbers from sebaceous follicles, especially in patients with acne, on its ability to elaborate enzymes such as lipase, protease, and hyaluronidase, and on its ability to activate the complement system and enhance chemotactic activity of neutrophils.