Gut-brain Axis Regulation of Food Intake and Visceral Illness

Abstract

Body weight and feeding regulation are carefully governed by complex homeostatic neural networks that respond to a myriad of peripheral signals that reflect both short- and long-term energy status. A critical component of that regulation involves communication between the gut and the brain. This “gut-brain” axis delicately coordinates ingestive behaviors with physiological systems that must process and absorb what gets ingested. The gastrointestinal tract maintains two predominant but contrasting functions. One is nutrient absorption and the other is to act as a barrier to protect against toxic compounds and bacteria. The gut-brain axis plays a crucial role in an organism’s ability to regulate energy balance and maintain an appropriate body weight. A negative energy balance will stimulate hunger and food seeking and vice-versa to maintain a set-point of body weight and adiposity. In doing so, energy input and expenditure are carefully matched to maintain fuel availability and prevent shifts in long-term body weight. Under various conditions, this set-point can become too high and the resultant increase in body mass can have a myriad of detrimental effects. Similarly, under particular stress conditions, intestinal and neural signaling are altered to maintain a pathologically low set-point, resulting in maladaptive feeding and illness responses. Central networks that regulate illness symptoms of anorexia in pathophysiological states are still yet to be completely identified and understood. Deciphering the key gut-brain signals that regulate feeding related disorders will open opportunities for critically needed therapeutics. For example, obesity has become one of the world’s largest health threats. Obesity and the associated comorbidities can decrease the quality of life and substantially increase susceptibility to pathologies such as cancer and infection. This dissertation examines the role of various peripheral signals in regulating feeding networks, weight patterns and illness in pathophysiological states of infection and obesity. Studies in Chapter 2 examined growth differentiation factor 15 (GDF15) and GDNF family receptor alpha-like neuronal signaling in a model of bacterial sepsis. We demonstrated that GDF15 secretion was highly induced with exposure to lipopolysaccharide (LPS) in mice, rats, and humans. Because infection responses are influenced by housing temperatures, we examined mice at several temperatures to increase the translational relevance of rodent to human thermoregulatory responses. We then tested the necessity of GDF15 in body weight regulation, feeding behavior, and illness outcomes in response to LPS. As physiological responses vary for differing microorganisms, we investigated a model of trichothecene infection in Chapter 3. Using genetically altered mouse models of GDF15 and glucagon-like peptide 1 (GLP-1) ligand and receptor, we determined that these gut-brain signals are not necessary for the illness and feeding responses to deoxynivalenol and LPS. Chapter 4 focuses on gut signals that are highly altered in gastro-intestinal restructuring surgeries. Bariatric surgeries result in long-term weight loss demonstrating the importance of the gastro-intestinal tract in regulating overall energy balance. One important goal is identifying the signals that are altered that account for the potent effects of bariatric surgeries. After surgery, there is a prominent increase of the hormone glucagon-like-peptide 2 (GLP-2). We used a loss-of-function mouse model to test the role of GLP-2 in the effects of surgery to reduce weight, improve glucose regulation and alter levels and composition of bile acids. We demonstrated that while GLP-2 is required for changes in bile acids, it is not necessary for the benefits of bariatric surgery.