Brendan Kelly, MD
In a new clinical trial [NCT05632315] researchers at PennMedicine are homing in on natural methods to promote the growth of intestinal commensal bacteria that have the capacity to displace drug-resistant pathogens elsewhere in the body. Leading the study is Brendan Kelly, MD, of the Penn Infectious Diseases Program.
In recent years, much research has focused on the microbiota of the intestine as a potential source of both health and disease. A collection of bacteria and other microbial communities, the microbiota bind to the intestinal mucosal epithelium to provide a barrier to pathogen colonization.
In healthy persons, the relationship between the host and the gut microbiota is commensal. The host provides a home for the microbiota and they in turn regulate gut immunity, contribute to digestion, synthesize amino acids, and maintain homeostasis within the intestine. This balance is achieved through a series of direct and indirect mechanisms known collectively as colonization resistance.
Organic Bactericide by Colonization Resistance
Colonization resistance describes territorial activity by one community of bacteria to resist the expansion or overgrowth of others. These efforts can involve forthright efforts to kill competitors through the production of bacteriocins and or antimicrobial peptides (AMPs), or passive nutrient hoarding and depletion of oxygen concentrations to starve or suffocate invaders. Regulation of gut barrier integrity to prevent penetration and translocation of pathogens offers another avenue of resistance.
“The gut microbiota constitute an important part of human defense against infection,” says Dr. Kelly. “Antibiotics prescribed for an initial infection can diminish the colonization resistance provided by the gut microbiota and increase the risk of secondary infections”.
The intestinal microbiota can be home to a host of infectious pathogens normally held in check by colonization resistance. These include multi-drug-resistant organisms, or MDROs, and other resistant microbials that are together the source of a reservoir of antimicrobial resistant genes within the collective genome of the microbiota (or microbiome) known as the resistome.
MDROS are defined as bacteria resistant to more than three classes of antibiotics. In the gut, MDROs become a concern when colonization resistance is compromised by dysbiosis, a disturbance in the equipoise of the gut microbial communities. The prevailing consequence of dysbiosis is destruction of the microbial homeostasis of the gut. Typically, when this occurs, a single bacterial species acquires territory throughout the intestine by overwhelming the tools of commensal colonization resistance. Because regulation of the gut barrier is among these, bacteria normally confined to the gut may translocate to the bloodstream to foster life-threatening, systemic infections and can contaminate the healthcare environment, increasing the risk of infection for others. MDRO infections are uniquely distressing when they involve nosocomial infection of immunocompromised patients, who may be precluded from treatment with certain classes of antibiotics, and who usually have worse outcomes as a result of poorer efficacy with second- and third-line therapy.
Natural Restoration of Microbial Homeostasis
The act of restoring balance to the gut ecosystem is termed eubiosis. Attempts to achieve eubiosis have evolved in recent years in the hospital setting to include decolonization therapy with fecal microbiota transplantation.
Decolonization has the intention of reducing colonizing pathogens within a specific environment by using select bacteria against targeted strains known to be vulnerable to their mechanisms of colonization resistance. The theory of using the armamentarium of commensal bacterial colonization to combat infectious pathogens had its origin with the successful use of microbiota transplantation (~87–90% cure rate) to treat recurrent antibiotic-resistant Clostridium difficile (C diff). It is thought that in such use, the infused microbiota deprive C diff of nutrients, encourage the recovery of normal host-microbiota interactions, and increase the presence of secondary bile acids and other byproducts of healthy microbiota to which C diff is averse.
Inspired by this success, the use of microbiota transplantation for the treatment of antibiotic-resistant pathogens and as a restorative for the body’s own protection against invasive infection is an area of active research.
At Penn Medicine, microbial decolonization is being explored in a clinical investigation of Penn Microbiome Therapy (PMT) products [ClinicalTrials.gov ID NCT05632315] in MDRO infections of the bloodstream, respiratory tract, and urinary tract by bacterial pathogens, including Enterobacterales, Staphylococcus aureus, Pseudomonas aeruginosa, and Enterococcus. PMT products are comprised of microbiota obtained from healthy individuals for transplantation.
“We’re excited that this novel treatment strategy has the potential to restore colonization resistance and reduce the risk of recurrent or new infections,” Dr. Kelly notes.
The use of microbiota transplantation to treat the aforementioned MDROs elsewhere in the body has been widely studied, with the suggestion that the therapy is effective versus bloodstream infections and recurrent urinary tract infections, and has a regulatory effect on pulmonary flora.
The Penn Microbiome Therapy clinical trial will take place at the Hospital of the University of Pennsylvania.