For over a century the view as to how microbes played a causative role in disease has been influenced by the concepts proposed by Robert Koch. Koch’s postulates gives rise to the impression that infection with a single pathogenic microbe is sufficient to cause disease. Recently, many investigators are beginning to re-examine this dogma and are investigating how the tripartite interaction between pathogen, host and the indigenous microbiota influences the development of disease.
Gastroenteritis due to Salmonella has been well studied in terms of the genetic adaptations the pathogen has evolved and the role of the host immune system in determining disease outcome. Two recent studies have examined how interactions with the intestinal microbiota influences resultant Salmonella infection. One group employed antibiotic treatment to alter the indigenous microbiota and then experimentally infected these antibiotic-treated mice with S. Typhimurium (29*). All 3 antibiotics employed (streptomycin, vancomycin and metronidazole) altered the indigenous microbiota and increased the ability of S. Typhimurium to colonize the intestine. However while greater inflammation was seen in the intestinal tract of streptomycin or vancomycin-treated animals infected with S. Typhimurium compared to infected animals that did not receive any antibiotics, no significant pathology was seen in metronidazole-treated animals that were similarly challenged with S. Typhimurium. This indicates that specific subsets of the intestinal microbiota may mediate protection against the development of colitis. Culture-independent comparison of the microbiota remaining in animals treated with the various antibiotics was performed but the significance of these differences needs to be directly tested in follow-up experiments. Another elegant study examined how salmonella is able to take advantage of the inflammatory response generated by the host to promote its own survival within the gut microbial community (30**). It had been known for many decades that salmonella is able to use the compound tetrathionate as a terminal electron acceptor. This fact is used in the clinical microbiology lab to perform culture enrichment of salmonella from fecal samples. These investigators determined that hydrogen sulfide, which is produced in relatively large quantities by certain members of the indigenous gut microbiota is detoxified by the intestinal mucosa by conversion to thiosulfate. Thiosulfate is in turn oxidized by products produced by infiltrating neutrophils, which characterize the acute inflammatory response to salmonella infection. These findings highlight another example of the intricate interactions that take place in the gut. In this case, the pathogen takes advantage of the hosts inflammatory response to its presence to create an environment that allows it to outcompete per resident microbes.
Competition between potential pathogens and the indigenous microbiota is a common theme that is emerging in the study of infectious colitis. Similar to the situation described above for salmonella, vancomycin-resistant enterococcus has been shown to trigger post production of antimicrobial peptides that decreases the resistance of the mouse intestine to VRE colonization presumably by altering the community structure of the resident microbiota (31
). In a follow-up study, these investigators used culture independent profiling of the intestinal microbiota to determine the specific changes that antibiotic treatment triggered (32*). They noted that changes triggered by specific antibiotics could persist following cessation of the drug and these altered communities remained susceptible to VRE colonization. In susceptible communities VRE would become the dominant organism in the gut. Most interestingly, they extended these animal studies by examining patients who developed VRE bacteremia following bone marrow transplant. Patients who developed VRE bacteremia were found to have domination of their gut microbiota by the organism prior to the development of bloodstream infection. This result suggests that profiling the intestinal microbiota of patients may have a future role in guiding subsequent therapy.
Our group as investigated the role of the indigenous microbiota in protecting the host against infection with the toxin-producing bacterium Clostridium difficile
. We recently published a study where we related specific changes in the indigenous microbiota, brought on by antibiotic administration, with susceptibility to colonization with C. difficile
and the severity of subsequent disease (33
). Again, are findings support the idea that there is a dynamic interplay between potential pathogens and the indigenous microbiota. Patients with C. difficile
infection are generally treated with in antibiotic regimen targeting the pathogen. Recently however, is been noted that a greater proportion of patients with C. difficile
infection will develop recurrent disease with symptoms returning after specific C. difficile
antibiotic therapy is stopped. Several groups including our own have reported that recurrent C. difficile
is in at least part due to abnormal diversity of the remaining indigenous microbiota. Such results underscore the rationale behind a seemingly unpalatable yet relatively successful treatment for refractory C. difficile
infection, the transplantation of fecal material from a healthy individual to the patient with recurrent infection. Two recent reports have shown that treatment with donor feces results in long-term changes in the microbial community present in the intestine of the recipient (34*, 35*).