Gut Feelings - From Brain to Gut and from Lumen to Gut

Abstract: Part 1: From Brain to GutThe brain is an organ with a high energy requirement. To meet this demand, the brain needs a continuous and well-regulated blood supply. In situations where the brain, or parts of the brain, does not receive sufficient blood flow injury arise. This condition, commonly known as cerebral ischemia, is prevalent in today's society. In 2015, more than 6 million people died from stroke worldwide. In parallel to the central injury, more than half of the affected patients report gut dysfunctions such as constipation, dysmotility and incontinence after the ischemic event. In recent years an increased awareness and focus on the gut-brain axis has emerged. This bidirectional axis of communications has been showed to be involved in several conditions including anxiety, depression, Parkinson's disease and stroke.A key player in gut regulation is the enteric nervous system (ENS), which sometimes is referred to as the "second brain". It is suggested that gut dysfunctions are rooted in an imbalanced ENS, since this system regulates motility, secretion, local blood flow and also interacts with the immune and endocrine systems. In part 1 of this thesis the effects of different types of cerebral ischemia on the ENS in regards to survival and neuroplasticity are investigated in mouse. From this research, we are able to show that one type, focal ischemia, induces a significant of loss of enteric neurons as well as neurotransmitter plasticity. The underlying mechanisms are suggested to involve neuroimmune actions, including galectin-3 activation of toll like receptor 4. We further show that models of global cerebral ischemia and cerebral hypertension elicit a non-neurotoxic response on enteric neurons, suggesting that each type of ischemia triggers unique peripheral responses.Part 2: From Lumen to GutIn addition to taste thrills on the tongue, food also triggers sensations in the gastrointestinal (GI) tract. Similar to taste buds and taste receptors, specialized "intestinal sensor cells" in the GI epithelium are able to sense and mediate intestinal chemosensation. This includes sensing nutrients as well as harmful components in the luminal environment. One of the epithelial cells possessing chemosensory potential is the tuft cell, recognized by its fusiform shape and distinct apical "tuft" of microvilli extending into the lumen. Tuft cells are able to sense bitter, sweet and umami substances in lumen by expressing taste cell transduction proteins, α-gustducin, and activating taste related cation channel, transient receptor potential channel 5. They also contribute to the protection of the gut barrier and trigger type 2 immune reactions. Tuft cells are a rare cell type in the gut, its role in health and disease is just starting to be investigated. In part 2 of this thesis we study the tuft cell, their distribution and proximity to endocrine cells and nerve fibers in the mouse intestine. From this research we are able to show that tuft cells have a specific distribution throughout the intestine, with a decreasing gradient from upper small intestine to distal small intestine and large intestine. We further describe a high degree of contacts with mucosal sensory nerve fibers and appetite associated endocrine cells. From this we suggest that tuft cells act as an interface between signals in the intestinal lumen and the host. In part 2 of the thesis we also identify a novel subset of tuft cells which harbor serotonin (5HT) apically. This 5HT containing tuft cell, accounts for up to 80% of all tuft cells in mouse small intestine but are rare in the large intestine. We have not, yet, been able to discern the source of 5HT since neither the synthesizing enzyme tryptophan hydroxylase nor the 5HT transporter are found in tuft cells. However, we believe this subset cells have the possibility to play unique roles in gut regulation.