The gut microbiome as a therapeutic target in systemic disease

Abstract

The gut microbiome is a contributing factor in inflammatory diseases. It has been demonstrated, largely through fecal microbiota transplants, that restoration of the gut microbiome can ameliorate disease. As such, this dissertation explores using the gut microbiome as a therapeutic target in systemic inflammatory diseases. Here, we first investigate the gut and skin microbiomes of patients with post-treatment Lyme disease syndrome (PTLDS). Acute Lyme disease, caused by an infection with the tick-borne spirochete Borreliella burgdorferi, affects approximately 300,000 people in the United States annually. Most patients return to health following antibiotic treatment, but 10-20% of patients develop PTLDS which presents similarly to an autoimmune disease and is characterized by debilitating fatigue, pain, and cognitive difficulties. We identify a signature of dysbiosis in the gut and skin microbiomes of patients with PTLDS. While correlational, this investigative study suggests that the microbiome could be contributing to symptomology or etiology in PTLDS, and that the microbiome could thus serve as a therapeutic target and a diagnostic tool in PTLDS.In addition, this dissertation evaluates therapeutic strategies to restore the gut microbiota composition. We investigate components of the American cranberry for prebiotic potential and find that some components shift the microbiome towards a less dysbiotic state. Furthermore, we develop strategies to reduce Enterobacteriaceae, a family of pro-inflammatory bacteria implicated in many diseases, in the gut microbiome. The present work aims to remove advantages that Enterobacteriaceae gain in an inflamed colon by using a defined consortium of commensal bacteria that inhibits Escherichia coli. These investigations of therapeutic strategies serve as a proof-of-concept that suggest that prebiotics and rationally designed live bacterial therapeutics might ameliorate systemic disease associated with a dysbiotic microbiome. Lastly, this dissertation evaluates the use of a narrow-spectrum antibiotic, hygromycin A, to prevent antibiotic-associated microbiome dysbiosis. Hygromycin A has selective activity against spirochetes and weak activity against normal gut microbiome bacteria. Indeed, we found that it caused less disturbance to the microbiome than broad spectrum antibiotics, which might prevent antibiotic-associated microbiome dysbiosis and subsequent diseases, including PTLDS. Taken together, this dissertation evaluates therapeutic strategies targeting the microbiome to alleviate and prevent systemic inflammatory diseases.--Author's abstract