UC San Diego

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.