Management of Mitochondrial Disorders Through Increased Intestinal Fermentation and Reduced Metabolic Burden
Abstract
This proposal addresses the Peer Reviewed Medical Research Program (PRMRP) portfolio category of nutrition and metabolism, topic area concerning Mitochondrial Disease, with the strategic goal of understanding correlations between nutrition and disease susceptibility. Mitochondrial disease is a term describing several illnesses characterized by loss of function of mitochondria, cellular organelles that oversee multiple aspects of energy and nutrient metabolism. Examples of mitochondrial diseases are severe conditions such as MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes) syndrome and Leigh syndrome, one of the most common pediatric mitochondrial disorders that is often fatal in the first 3 years of life. These diseases are caused by mutations in genes involved in multiple aspects of mitochondrial function. Mutations in mitochondrial genes can also alter the composition of the intestinal flora, the diverse set of bacteria residing inside the intestines, also known as the microbiome. Certain species of bacteria in the microbiome can ferment dietary fibers and other nutrient into small metabolites known as short-chain fatty acids (SCFAs.) These SCFAs can in turn improve mitochondrial function and energy metabolism both in the intestine and in other organs, including the brain, with known benefits in metabolic pathologies such as obesity and diabetes. Despite the obvious connection between mitochondrial function and the microbiome, to date no study has determined whether mitochondrial disease can alter the composition of the intestinal flora or whether increasing the abundance of intestinal bacteria that produce SCFAs can improve the symptoms and progression of mitochondrial disease. To test this hypothesis, we plan to determine which bacteria and in what amounts are present in the intestines of mutant mice at different stages of the disease and whether they produce higher levels of SCFAs. To do this, we will sequence a unique portion of the bacterial genome that will allow us to identify different bacterial species. In parallel, we will measure the abundance of SCFAs in ceca, sera, and brains of mutant mice via mass spectrometry. In the second aim, we will transfer the bacteria from the intestines of acarbose-treated animals into germ-free mutant mice via feces transplantation. We will follow survival and disease progression in these mutant animals. In addition, we will promote proliferation of a fermenting microbiome and its activity via dietary interventions. Our work will be the first to establish a role for the intestinal microbiome in the onset, treatment, and progression of severe mitochondrial disease and create the opportunity to further study the relationship between the two in greater detail. We will also potentially determine the mechanism of action of a well-characterized, U.S. Food and Drug Administration (FDA)-approved drug in mitochondrial disease, as well as identify novel diagnostic tools and therapies for these life-threatening disorders.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310016
Entities
People
- Alessandro Bitto
Organizations
- United States Army
- University of Washington