We study the responses of microbial communities and isolated microbes to external stressors such as antimicrobial agents. This work is particularly pressing because unlike at any other time in human history, we are currently exposed to a wide array of natural and artificial antimicrobial agents in the form of antibiotics, chemical disinfectants, and chemotherapeutic agents among others. In the past killing all bacteria – no matter the type – was a logical goal, but now that we understand the critical role that bacteria play in the host and the environment we must take a more nuanced view. We now understand that optimal antimicrobial therapy must effectively kill the target pathogen while maintaining microbial homeostasis. In addition, each exposure of a microbial community to an antimicrobial or another stressor has the potential to promote the evolution or selection of resistance genes that will further exacerbate the current antibiotic resistance crisis.

To tackle the dual problem of antimicrobial resistance and microbiome disruption, we must develop a more complete understanding of how and why bacteria respond to and die from antibiotics in their natural environment. To develop this understanding, we employ multi-omic systems-biology approach to study host and environmental microbial communities. This approach combines high-throughput DNA and RNA sequencing, metabolomics, proteomics, and traditional microbiology techniques. This holistic methodology allows us to go beyond the descriptive paradigm of many microbiome studies and ask the critical mechanistic questions described below.  

Questions

How does the microbiome respond to antibiotics? Why do some bacteria survive while others do not? 

For the most part, broad-spectrum antibiotics are prescribed to target specific pathogenic bacteria. However, these agents are also toxic to many of the benign and beneficial bacteria that make up the human microbiome. As a result, numerous studies have correlated antibiotic treatment with the development of dysbiosis and associated disorders. To formulate therapies that do not induce these complications, we need to understand how core microbiome members respond to antibiotics. Currently, our understanding of how antimicrobial agents impact the microbiome is limited by the difficulty of isolating and culturing the bacteria that make up this complicated community. To avoid this problem, we study the microbial community as a whole in the setting of the human and murine gut. We utilize metagenomics and metatranscriptomics to profile the microbial response to antibiotics in previously unstudied and unculturable organisms. These results have the potential to identify and profile bacteria that are negatively impacted by these drugs and provide insights for the development of less toxic therapeutic options. 

Can we protect the microbiome from broad-spectrum antibiotics?

Developing a clear understanding of why specific bacteria in the microbiome die from antibiotics and which conditions contribute to this death has given us insight into ways that we can protect this community from antibiotic-induced dysbiosis. We are now parlaying this insight into developing interventions that can be combined with traditional antibiotics to preserve microbiome homeostasis.

How do antibiotics impact the evolution and horizontal transfer of resistance genes?

Exposure to antibiotics has been proposed to induce various forms of genome instability in bacteria. At the same time we are beginning to understand the important role that horizontal gene transfer plays in the spread of antibiotic resistance. Thus, understanding how antibiotic treatment impacts genome instability and horizontal gene transfer in the microbiome will provide critical insight into the mechanisms underlying the spread of resistance. To address this question, we are utilizing engineered transfer elements to track the movement of genetic information in microbial communities. We are also defining how this genetic instability contributes to de novo resistance evolution.

How do antibiotic resistance genes spread, accumulate, and persist in the environment? 

The upper portion of the Narragansett Bay near Providence has a long history of industrial pollution, as well as current problems with surface water runoff and human waste management. It is well-established that contaminants such as metals and antibiotics promote the selection and accumulation of resistance genes. By utilizing microbiota samples from organisms throughout the food web of the Narragansett Bay, we are working to describe local microbial reservoirs of antibiotic resistance. This work has strong potential to promote our understanding of how our activities contribute to dissemination of resistance. This is important because marine bacteria can serve as reservoirs to maintain antibiotic resistance genes and return them to us through water exposure or consumption of seafood from the bay.

How are microbial communities established and maintained during food production by fermentation?

I have a keen personal interest in the microbial modification of food. Fermentation produces thousands of foods including pickles, cheese, and even coffee. This microbial modification of food is also a commercially and culturally important practice that feeds billions around the world. Just like the human microbiome, the food microbiome established during fermentation is a complex community with a large web of microbial interactions. Modulating these interactions has the potential to improve industrial efficiency and food safety. We are applying the systems-biology approaches developed for the study of the gut microbiome to define the structure and function of the food-fermenting community.