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Open Access Publications from the University of California

Scholarly Works (2 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2024)

Over the last few years, there has been increasing recognition that the healthy gut microbiome is dynamic. It is also well known that the microbiome plays a crucial role in gastrointestinal health. Disruptions to the gut microbiome can cause or exacerbate various metabolic diseases, including obesity, type 2 diabetes, liver disease, gastrointestinal cancer, and inflammatory bowel disease. Additionally, a loss in the cycling of bacterial populations has been linked to some of these metabolic diseases. Microbes significantly influence host metabolism through the breakdown and production of metabolites. For example, short-chain fatty acids (SCFAs) and bile acids (BAs) are microbially produced metabolites that modulate metabolism and reduce inflammation. However, until recently, most microbial studies have focused on investigating changes in microbial populations rather than microbial functions. In this thesis, I explore the impact of time on microbial functions and how these functions modulate the development of metabolic diseases.

In the first part of the thesis, I explore how the blood metabolite pool changes before and after Transjugular Intrahepatic Portosystemic Shunt (TIPS) placement which showed there is compensatory shunting in the liver even before TIPS that affects the susceptibility to hepatic encephalopathy (HE). Additionally, we identified some microbial metabolites affected by TIPS that may be protective against HE. In the second part of the thesis, I describe how the dietary intervention time-restricted feeding (TRF) does not prevent the development of Metabolic dysfunction-associated steatohepatitis (MASH) in a streptozotocin/high fat diet (STAM/HFD)-induced MASH model. Moreover, we found a Lachnospiraceae and Oscillospiraceae microbe that may be protective against MASH through the modulation of fatty acids. Finally, the last chapter demonstrates that metatranscriptomics is a useful method for understanding time-dependent changes in microbial activity induced by TRF. This chapter also introduces a new bacterial therapeutic we engineered based on our metatranscriptomics results. These three chapters demonstrate how accounting for time and microbial functions provide new insights into microbe-host relationships and their role in mediating or protecting against diseases.

    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2024)
    As the microbiome field moves from descriptive and associative research to mechanistic and interventional studies, being able to account for all confounding variables in the experimental design, which includes the maternal effect1, cage effect2, facility differences3, as well as laboratory and sample handling protocols4, is critical for interpretability of results. Despite significant procedural and bioinformatic improvements, unexplained variability and lack of replicability still occur. One underexplored factor is that the microbiome is dynamic and exhibits diurnal oscillations that can change microbiome composition5-7. In this retrospective analysis of 16S amplicon sequencing studies in male mice, we show that sample collection time affects the conclusions drawn from microbiome studies and its effect size is larger than those of a daily experimental intervention or dietary changes. The timing of divergence of the microbiome composition between experimental and control groups is unique to each experiment. Sample collection times as short as only 4 hours apart can lead to vastly different conclusions. Lack of consistency in the time of sample collection may explain poor cross-study replicability in microbiome research. The impact of diurnal rhythms on the outcomes and study design of other fields is unknown but likely significant.
      Cover page: Time of sample collection is critical for the replicability of microbiome analyses
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