Small molecule signaling in regulation of GUT microbiota structure and colonization resistance

The National Institute of General Medical Sciences (NIGMS) awarded UC Riverside a $2.06 million Project Grant under the Biomedical Research and Research Training program (CFDA 93.859) on September 1, 2025, with a completion date of August 31, 2029. This award funds fundamental research to elucidate the molecular mechanisms by which small molecule signaling factors—including bacterial quorum sensing autoinducers and microbial bile and diet metabolites—regulate gut microbiota structure and colonization resistance against pathogenic bacteria, particularly Vibrio cholerae. The research employs V. cholerae as a genetically tractable model organism to examine microbial invasion, inter-bacterial competition, and biochemical interactions within the gastrointestinal tract.

The primary deliverables include mechanistic understanding of how diverse human gut microbial communities establish biochemical conditions that confer colonization-resistant or susceptible states, along with identification of novel molecular targets for prophylactic and therapeutic microbiota manipulation. This research addresses interpersonal differences in microbiota composition and their critical role in infection outcomes, with direct applications to controlling infectious disease and enabling targeted microbiota interventions. The award supports UC Riverside's research infrastructure and positions the institution to advance foundational knowledge of microbial ecology relevant to both pathogen prevention and controlled microbiota assembly strategies.

Abstract

The community of commensal microbes in the GUT, the GUT microbiota, participates in numerous processes key for human health, including protection against foreign microorganisms. A greater mechanistic understanding of how the GUT microbiota resists the invasion of foreign bacteria, from pathogens to new commensal microorganisms, is essential both for the control of infection and in targeted approaches for microbiota manipulation. Our work has shown that interpersonal differences in the GUT microbiota are an important driver of outcome of infection by vibrio cholerae, the etiologic agent of cholera, a devastating diarrhea affecting millions of people each year worldwide. As a genetically tractable model organism for examining invasion of the GUT microbial community, studies with v. Cholerae allow for mechanistic examination of microbial colonization and inter-bacterial interaction and competition in the gastrointestinal tract. We have shown that small molecule signaling factors, including bacterial quorum sensing autoinducers, and microbial bile and diet metabolites, modulates microbiota structure and in turn multiple pathways of colonization resistance against v. Cholerae. This proposal aims to define molecular mechanisms underpinning the ability of diverse human GUT communities to drive the biochemical milieu of the GUT into colonization-resistant or susceptible states, thus shaping resistance against colonization of both pathogens such as v. Cholerae and new commensals. The proposed studies aim to provide mechanistic understanding for the processes driving assembly of GUT microbial communities and identify new targets for prophylactic and therapeutic manipulations of the GUT microbiota to combat invading microorganisms.