Of Mice and Metabolites: Microbial Metabolites their effects on the body and a story of a little dairy bug, Lactococcus lactis subspecies cremoris Restricted; Files & ToC
Gacasan, Camilo Anthony (Spring 2026)
Abstract
Abstract
Of Mice and Metabolites: Microbial Metabolites their effects on the body and a story of a little dairy bug, Lactococcus lactis subspecies cremoris
By Camilo Anthony Gallarde Gacasan
The gut microbiome functions as a dynamic interface between environmental exposures and host physiology, generating chemical signals that extend beyond the intestinal lumen to influence systemic metabolic and immune states. This dissertation was guided by two central hypotheses: first, that microbial metabolic activity can reprogram host transcriptional and biochemical networks in distal organs through coordinated metabolite-mediated signaling; and second, that both beneficial microbial interventions and pharmacologic perturbations reshape host physiology in-part through alterations in microbial metabolic function rather than taxonomic composition alone.
Using integrative approaches that combine gnotobiotic models, high-resolution untargeted metabolomics, and network-based systems analysis, this work interrogates host–microbe interactions across multiple physiological contexts. Supplementation with the defined beneficial microbe Lactococcus lactis subsp. cremoris was associated with improved tissue resilience following injury and activation of cytoprotective transcriptional programs, including redox- and nuclear receptor–associated pathways. These phenotypic changes were accompanied by coordinated remodeling of metabolic networks involving glutathione metabolism, fatty acid utilization, purine turnover, and bile acid signaling. Together, these findings support the concept that targeted microbial supplementation can bias systemic metabolic organization toward protective states through structured chemical signaling.
In parallel, pharmacologic exposure to antipsychotic therapeutics induced drug-specific restructuring of gut microbial communities and metabolomic profiles, with measurable effects on susceptibility to enteric infection. These results demonstrate that non-antibiotic medications can act as ecological perturbations of the microbiome, altering microbial metabolic output in ways that influence host physiology and disease susceptibility.
Across contexts, bile acids and other gut-derived metabolites emerged as key mediators linking microbial enzymatic capacity to host receptor signaling and transcriptional regulation. Network-level consistency reinforced the interpretation that coordinated metabolic programs, rather than isolated molecular shifts underlie microbiome-associated phenotypes. At the same time, the probabilistic nature of untargeted metabolomics and the context-dependence of microbial effects underscore the need for mechanistic validation and cautious translation.
Collectively, this dissertation supports a systems-level model in which the gut microbiome operates as a modifiable regulator of distal organ biology through chemical signaling and metabolic network organization. By prioritizing functional capacity and metabolite flux over taxonomy alone, this work advances a more mechanistically grounded framework for understanding how microbial ecology shapes resilience and vulnerability in health and disease.
Table of Contents
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About this Dissertation
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File download under embargo until 27 May 2028 | 2026-04-09 08:23:56 -0400 | File download under embargo until 27 May 2028 |
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