Role of nitrate in microbiota ecology

/ABSTRACT The diverse microbial communities, or microbiota, that colonize our barrier sites (e.g., gut, skin, and oral cavity) broadly impact human health. Whether these impacts are positive or negative depends on the microbiota’s composition, particularly its ecological balance between health- and disease-promoting microbes (“symbionts” and “pathobionts,” respectively). Strategies to directly manipulate this balance could therefore unlock the microbiota’s immense therapeutic potential. Yet, this remains a challenge due to the overwhelming complexity of microbe-microbe interactions. For host-associated microbiota, polymicrobial interactions are largely driven by competition and/or cooperation for limited host-derived nutrients, which, depending on their identity/source, can select for symbionts or pathobionts. In turn, microbiota-derived metabolites can affect the integrity of host barriers. Due to the central role of metabolites in mediating both microbe-microbe and microbe-host interactions, the overall goal of my research program is to advance our fundamental understanding of how metabolites shape microbiota ecology and its varied impacts on host health. Over the next 5 years, my laboratory will work towards this goal by focusing on the host-derived metabolite nitrate, a microbe-specific nutrient that can selectively induce the expansion of symbionts and, as a result, promote numerous systemic health benefits (e.g., lowered blood pressure). Because nitrate is consistently abundant within the host, diverse nitrate-utilizing symbionts persistently co-colonize individual barrier sites across the body. Despite this, we lack basic knowledge of how these symbionts interact with each other, with co-residing pathobionts, and with the host to ultimately maintain local homeostasis at nitrate-rich barrier sites. My future research program will aim to decipher these complex interactions using the oral microbiota as a tractable model. We will employ microbial genetics (in both oral symbionts and pathobionts), genomic tools (most notably, high-throughput transposon mutant growth profiling, or Tn-seq), both simplified (2-species) and complex microbial communities (ex vivo oral microbiota cultures), and both in vitro (biofilm) and in vivo (mouse) models to define key mechanisms by which nitrate governs microbiota ecology and its reciprocal impacts on the host. Long-term, our vision is that this research will lay the groundwork for the development of novel microbiota-directed therapies that can precisely control the microbiota’s composition to promote human health. Project Number: 1R35GM160210-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Apollo Stacy | Institution: CLEVELAND CLINIC LERNER COM-CWRU, CLEVELAND, OH | Award Amount: $442,750 | Activity Code: R35 | Study Section: Special Emphasis Panel[ZRG1 CDB-E (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11201440