Deciphering the relationship among nutrition, host and microbe

Abstract

Within the human gastrointestinal tract, there are trillions of resident microbes collectively known as the gut microbiota. These organisms have a profound impact on host physiology, particularly the immune system. Upon birth, the gut microbiota begins to take shape with input from various influences including genetics and environmental factors such as dietary habits, antibiotic use, and stress. While the gut microbiota has been shown to be necessary for proper development and immunity, it has also been implicated in the development of several environment linked diseases including non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD) and colorectal cancer (CRC). The consequences of the changing microbiota in these disease states and how the microbiota can be used therapeutically has yet to be fully explored. In this body of research, alterations to the microbiota due to diet (Chapter 2) and host genetics (Chapter 5 and 6) in the context of disease are analyzed. Environmental factors that influence the gut microbiota are also explored in the context of individual species (Chapter 3 and 4). One of the key players in shaping the gut microbiota is diet. To study how dietary fats could alter host microbiota and liver pathology, various diets were used in a model of NAFLD. A NAFLD-inducing diet high in cholesterol and sucrose was used to induced steatosis and liver inflammation while two intervention diets of either low fat and low fiber or a high fish oil diet were developed. While switching from the NAFLD-inducing diet to either of the intervention diets drastically reduced the steatosis and improved liver pathology, the corresponding microbiotas from the intervention diets were not sufficient to resolve hepatic steatosis and may even exacerbate the liver inflammation in the absence of dietary change (Chapter 2). To study the effects of dietary factors directly on the microbes, dietary fatty acids were applied directly to the enteric pathogen, Yersinia enterocolitica. Arachidonic acid is an omega-6 fatty acid that is found in high concentrations in the Western diet and has been associated with inflammation. Therefore, this study analyzed how arachidonic acid altered the protein signature using a technique of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) (Chapter 3) and virulence through both in vitro and in vivo assays. Following exposure to physiological levels of arachidonic acid, Y. enterocolitica became highly virulent with increased invasion into colonic epithelial cells and rapid systemic infection of mice (Chapter 4). Another factor influencing the gut microbiota and, therefore the host immune response, is genetics. Development of the human immune system depends on various receptors capable of recognizing and responding to pathogens and commensals. These receptors include toll-like receptors (TLRs) found on macrophages, dendritic cells, and intestinal epithelial cells. Using TLR1 and TLR6 knockout mice, these studies aim to understand how disruption in host recognition of the microbiota can exacerbate disease. In Chapter 5, aberrant TLR1 signaling led to increased mucosal-adherent microbes and defective mucosal immunity. These changes consequently exacerbated the host response to a model of colonic injury and recovery. On the other hand, defective TLR6 signaling worsens the host susceptibility to inflammation associated colorectal cancer (Chapter 6). Within the same study, analyze of the microbiota revealed a potential therapeutic by restoring microbial ecology. By investigating the various influences on the microbiota and the host in the context of nutrition and disease we can begin to understand the complexity of the microbiome and develop therapeutics. The diverse studies in this body of research ultimately reveal how environmental stimuli and disrupted sensing of the microbiota can have prolonged immunological impact.