The Effects of Early-Life Drug and Dietary Interventions on Late-Life Disease Development

Abstract

This dissertation is a culmination of several projects that each explore how early-life diet or drug can impact later-life health outcomes. The first chapter is an introduction to provide important context or supplementary information (in addition to the introduction in each chapter).

Chapter 2 is a collaborative project testing the adipose-tissue specific effect of three Interventions Testing Program (ITP) drugs that extend median lifespan in mice: acarbose (ACA), 17α-estradiol (17aE2), and rapamycin (Rapa). We hypothesized these three ITP drugs may extend life through the reduction of adipose tissue inflammation. We found ACA and 17aE2 do not alter adipose tissue inflammation. Rapa-treated HET3 mice have increased M1 adipose tissue macrophages. We conclude that Rapa’s lifespan extension benefits occur in the context of exacerbated adipose tissue inflammation.

Chapter 3 documents the spontaneous outbreak of C. difficile infection (CDI) in our mouse colony. During this outbreak, methyl-donor supplementation (MS) diet F1 mice had higher mortality than control diet F1 mice. We hypothesized the MS diet alters F1 gut microbiota in a way that increases CDI susceptibility. In Chapter 4, we tested if MS diet affects gut microbiota, and if so, whether these changes affect colonization resistance. We found the MS diet F1 mice gut microbiota is enriched with Lactobacillus, Porphyromonadaceae, and Bacteroides and decreased abundance of certain types of Bacteroides, Akkermansia, and Alistipes. We show that F0 diet can lead to an altered F1 gut microbiota. Interestingly, the altered gut microbiota does not compromise F1 colonization resistance to the 16N203 C. difficile spore dosage we tested.

The MS diet is modeled after the diet, epigenetic, and obesity link established in the agouti viable yellow (Avy) mice. In Chapter 5, we hypothesized the MS diet can protect C57BL/6J F1 mice from diet-induced obesity in adult life through reduction of adipose tissue inflammation. We found that the MS diet generally does not alter obesity susceptibility nor metabolic inflammation outcomes in C57BL/6J F1 mice.