Investigating how xenobiotics interact with phages to shift energy balance

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Project Summary Obesity is a major public health concern associated with several co-morbidities, such as metabolic syndrome, type 2 diabetes, and cardiovascular disease. Many prescription medications, including second-generation antipsychotics (SGAs), increase obesity risk by causing significant weight gain. Our lab studies the widely prescribed SGA, risperidone, and has shown that weight gain associated with this drug is mediated by the gut microbiome. Bacteriophages, or phages, are highly abundant in the gut and are important mediators of the gut microbial community composition. Thus, we investigated how risperidone treatment influences phages in the gut and found that risperidone treatment leads to the release of phages from bacterial genomes; these phages are sufficient to drive weight gain and shifts in microbiome composition, and they also have an increased potential to influence their bacterial hosts’ metabolic state compared to control phages. While we know that phages are important contributors to risperidone-induced weight gain (RIWG), we have yet to determine mechanistically how these phages are induced by the presence of risperidone. Temperate phages are often induced through activation of the bacterial SOS response, leading to the hypothesis that risperidone is acting as a bacterial stressor that induces the SOS response in gut bacteria, ultimately leading to the release of phages from the bacterial genomes. This hypothesis will be investigated in Aim 1. One bacterial species that we found to release phages in response to risperidone is Limosilactobacillus reuteri. Further, bioinformatics analysis revealed that L. reuteri is significantly depleted in risperidone-treated animals, suggesting that it may be an important contributor to a lean phenotype. Co-treatment of mice with risperidone and L. reuteri prevented RIWG and generated a microbiome distinct from that of control animals. Additionally, reutericyclin (Rtc), a specialized metabolite produced by some strains of L. reuteri, was sufficient to deflect RIWG, suggesting that L. reuteri deflects RIWG through the release of Rtc. Rtc has known antimicrobial properties and, like risperidone, is a small molecular xenobiotic leading to the hypothesis that Rtc deflects RIWG by differentially altering the phageome. This hypothesis will be investigated in Aim 2. The overall goal of this project is to understand how the presence of xenobiotics can catalyze alterations in the phageome and determine how these alterations can contribute to changes in energy flux. This work will take place in the laboratory of Dr. John Kirby in the Department of Microbiology & Immunology at the Medical College of Wisconsin, a highly collaborative and stimulating environment that is well equipped to perform the proposed aims. We have designed a training plan that will be beneficial for my scientific and professional growth and ultimately will position me to reach my goal of becoming an independent biomedical scientist. Altogether, this project is fundamental for my advancement as an autistic woman in biomedical research, the field of obesity research, and the generation of microbiome-based therapeutics for xenobiotic-induced weight gain.