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.

Anaerobic beta-lactamase-producing-bacteria in mixed infections

Aerobic and anaerobic beta-lactamase-producing bacteria (BLPB) can play an important role in polymicrobial infections. They can have a direct pathogenic impact in causing the infection as well as an indirect effect through their ability to produce the enzyme beta-lactamase. BLPB may not only survive penicillins therapy but can also, as was demonstrated in in vitro and in vivo studies, protect other penicillin-susceptible bacteria from penicillins by releasing the free enzyme into their environment ( see figure ). This phenomenon occurs in upper respiratory tract, skin, soft tissue, abdominal, surgical and other infections.

Many Gram negative anaerobic bacteria can produce the enzyme beta-lactamse (BL). Bacteroides fragilis group has been known as a BL producer. However recent studies illustrated that other anaerobes have also become BL producers. These include up to 50% of pigmented Prevotella and Porphyromonas and Fusobacterium spp. that predominate in respiratory and head and neck infections, and Prevotella bivia, and Prevotella disiens important in female pelvic infections).

The presence of free BL in clinical specimens was reported in abscesses and mixed infections. These include abdominal infections, empyema, cerebrospinal specimens, abscesses, ear aspirates of acute and chronic ear infections, and aspirates of acutely and chronically inflamed sinuses. Many of these infections had failed beta-lactam therapies and required surgical drainage to enhance cure.

The isolation of penicillin-susceptible bacteria mixed with BLPB in patients who have failed to respond to beta-actam therapy suggests the ability of BLPB to protect a susceptible organism from the activity of those drugs.

Aerobic and anaerobic BLPB may play a role in penicillin failure to eradicate Group A beta hemolytic streptococci tonsillitis (GABHS). BLPB were recovered in over 2/3 of tonsils removed from those who failed penicillin therapy.

The presence of BLPB in mixed infection warrants administration of drugs that will be effective in eradication of BLPB as well as the other pathogens. Antimicrobials active against aerobic and anaerobic BLPB as well as GABHS were more effective in the eradication of this infection and even prevented elective tonsillectomy compared to penicillin. These include lincomycin, clindamycin , and amoxicillin/clavulanate.

Other infections where this approach was superior to penicillins therapy were acute and chronic otitis media and sinusitis, aspiration and tracheostomy-associated pneumonia, and lung abscesses.

The management of polymicrobial infections is enhanced by directing antimicrobial therapy at the eradication of both aerobic and anaerobic BLPB. Although beta lactam antibiotics are still the mainstay in treatment of numerous infections, agents effective against BLPB should be considered in the treatment of those who failed these agents.

Bacterial Interference by anaerobes in ear, sinus, and tonsillar infections

Interactions between bacteria that include antagonism (interference) and synergism maintain balance between members of the normal endogenous flora and play a role in preventing colonization by potential pathogens.  Bacterial interference can assist in the recovery from infections, in promotion of health and prevention of upper respiratory tract infection. Bacteria capable of interfering with the growth of potential respiratory pathogens include alpha- hemolytic streptococci, non-hemolytic streptococci, and the anaerobic bacteria Prevotella and Peptostreptococcus spp.

Bacterial Interference in colonization by pathogens

Bacterial interference plays a role in the emergence of upper respiratory tract infections and their eradication. These infections include recurrent pharyngo-tonsillitis, otitis media , and sinusitis. The tonsils, and nasopharyngeal flora of patients with these infections harbor less interfering bacteria than those without that history. The presence of interfering bacteria may therefore play a role in preventing pharyngo-tonsillitis, otitis media, and sinusitis.

Treatment with antimicrobials and smoking can affect the balance between the interfering organisms and potential pathogens.  Antimicrobials that spare the normal flora, can assist in preserving the interfering flora.

Balance between interfering bacteria and pathogens

Introduction into the indigenous microflora of low virulence bacteria that are capable of interfering with colonization and infection with virulent organisms has been used as a means of preventing the failure of antimicrobials in the treatment of pharyngo-tonsillitis and otitis media.