The Intestinal Gut Microbiome as a Biomarker and Driver of Obesity and Non-Alcoholic Fatty Liver Disease
- Author(s): Dong, Tien Sy
- Advisor(s): Pisegna, Joseph R;
- Jacobs, Jonathan P
- et al.
Nonalcoholic fatty liver disease (NAFLD) affects almost 1 out of every 5 Americans. The development of NAFLD increases an individual’s risk for cardiovascular disease, cirrhosis, and cancer. Given that there are few treatments available for NALFD, it is imperative to understand the features that can prognosticate and alter the progression of NAFLD. One area of research that has gained significant traction is the role of the gut microbiome in the development and progression of NAFLD. By utilizing a multi’omics approach, we discovered that the gut microbiome can affect obesity through alterations of the brain-gut axis. In a study of over 100 patients, we saw that the gut microbiome was highly associated to food addiction. Patients with food addiction had significantly lower abundances of Bacteroides, Akkermansia, and Eubacterium, and a higher abundance of Megamonas. This was associated with a reduction in a neuroprotective tryptophan-related metabolite, indolepropionate, and altered connectivity in the brain’s reward regions. This data suggests that the gut microbiome plays a role in eating behavior and is likely a modifiable risk factor for obesity. Furthermore, research has shown that the microbiome and metabolite profile of patients with NAFLD differs at each stage of the disease. Using a machine learning algorithm, we created and validated a classifier based on the gut microbiome that highly predicts advanced fibrosis in patients with NAFLD. To explore the causal effects of the gut microbiome on the development of NAFLD, we utilized the microbiome of bariatric surgery patients and transplanted them into antibiotic treated mice. Through this model, we see that an obese phenotype microbiome is able to induce significant weight gain and hepatic steatosis. Associated with these changes we see a significant alteration of the expression levels of natural killer T-cells, cytotoxic T-cells, Kupffer cells, and monocyte-derived macrophages. The data shows that not only can the gut microbiome prognosticate NAFLD, it can also alter the progression of NAFLD through changes of the innate immune system of the liver. This work shows the feasibility of the gut microbiome both as a biomarker but also as a source for potential novel therapeutics against obesity and NAFLD.