Community Research and Development Information Service - CORDIS



Project ID: 293894
Funded under: FP7-PEOPLE
Country: Spain


Antibiotic resistant pathogens (ARPs), such as Vancomycin-resistant Enterococcus (VRE) or carbapenem-resistant Klebsiella pneumoniae (KPC) are an increasing problem in hospitalized patients. Infections with these opportunistic pathogens generally begin by colonization of the intestinal epithelium. Our intestinal tract is inhabited by hundreds of commensal bacterial species that suppress intestinal colonization by ARPs. Commensal microbes might prevent infection by releasing inhibitory molecules, by competing for nutrients or by inducing the immune response. Disruption of the microbiota after antibiotic administration enhances intestinal colonization by ARPs. However, not much is known about (i) how antibiotic-induced changes in the microbiota increase the risk of infection, (ii) which commensal bacterial species are key in conferring protection and (iii) the mechanism by which specific commensal microbes inhibit pathogen colonization. To answer these questions we have used a multidisciplinary approach combining microbiology, immunology and high-throughput sequencing techniques with mouse models of infection and analysis of human samples.
We have used a mouse model to understand how different antibiotics of different spectrum promote different changes in the microbiota composition, which enable to a different extent VRE and KPC colonization. Using this model we have demonstrated that antibiotics such as ampicillin, vancomycin or clindamycin promote drastic changes in the microbiota composition, which enable the pathogen to reach very high levels in the intestinal tract. However, antibiotics such as neomycin produce fewer microbiota changes, which do not allow intestinal colonization by these pathogens. Importantly, ampicillin, clindamycin and vancomycin produce persistent changes in the composition of the microbiota. Indeed, some of the commensal bacteria eliminated by the antibiotic never recovered after antibiotic cessation. These persistent microbiota changes allowed the pathogen to persist in the intestinal tract. Importantly, similar results were obtained in humans. Indeed, subjects treated with vancomycin, develop strikingly similar changes in their microbiota composition, as compare to mice, including persistent changes in their microbiota composition. Indeed, in some of the analyzed subjects, the majority of most abundant commensal bacteria identified at baseline, could not be detected even 22 weeks after antibiotic cessation. These results are clinically very relevant, since they indicate that at least some of the individuals that are treated with certain antibiotics could have permanent changes in their microbiota, which could subsequently predispose to disease (e.g. infections by antibiotic resistant pathogens). Importantly, we observed a great variability in the microbiota recovery in humans upon vancomycin administration, with some individuals recovering a similar microbiota as the one identified at baseline. This variability in the recovery upon vancomycin treatment was also observed in mice and correlated with the ability of the pathogen to colonize the intestinal tract. These results suggest that patient’s microbiota should be monitorized, upon antibiotic treatment, to identify those “low microbiota recovery” individuals that will have a higher predisposition to develop infections.
Subsequently, we have utilized different statistical approaches in order to correlate the changes in the microbiota composition observed in mice with the capacity of the pathogen to colonize the intestine. These analyses have allowed us to identify certain commensal bacterial species that associate with resistance against infection (i.e. when they are present, the pathogen is not able to colonize the intestinal tract). Importantly, administration of a mix containing the identified bacteria (cocktail of 5 different bacterial species) to mice that received antibiotic treatment, considerably diminished the capacity of the pathogen to colonize the intestinal tract. This last result indicates that the identified bacteria play a key role in conferring resistance to VRE or KPC. This information is clinically relevant because it could allow in the future the development of novel probiotics in order to combat infections in hospitalized patients.
Using the mouse model of infection, we have also investigated the mechanisms by which commensal bacteria confer resistance against antibiotic resistant pathogens. Importantly, using mice defective in different components of the immune system we were able to demonstrate that the microbiota can confer resistance to ARPs (i.e. VRE) in the absence of a proper innate immune response (Toll like and NOD receptors) or adaptive response (B and T cells). These last results suggest that other mechanisms not dependent on the immune response may be crucial for the defense against ARPs. These mechanisms may include the production of molecules by commensal microbes that could inhibit the growth of the pathogen or interfere with its behavior, or nutrient competition between commensals and pathogens. A new research line in the laboratory is now trying to investigate direct mechanisms by which the microbiota may promote resistance against pathogens.
Finally, in collaboration with Dr. Xavier in Gulbenkian Institute (Portugal), we were able to demonstrate the role of quorum sensing molecules in shaping the composition of the microbiota during antibiotic treatment. Importantly, we showed that manipulation of bacterial quorum sensing could restore some of the microbiota changes induced by antibiotics. This last result opens new therapeutic possibilities in order to diminish the detrimental effects promoted by antibiotic treatment.

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