Handy Glia

Speaker: Dr. Anthony Blikslager, DVM, PhD, DACVS, from NC State

Title: "Do enteric glial cells play a role in age dependent mucosal repair?"

 

Summary: Dr. Anthony Blikslager is a Professor of Equine Surgery and Gastroenterology at NC State University. His lab’s focus is gastrointestinal physiology, specifically studying repair of the intestinal barrier and its role in healing in diseases like strangulating obstruction in animals and necrotizing enterocolitis in human newborns. In studying this intestinal barrier, Dr. Blikslager and his team found that prostaglandins stimulate the recovery of tight junctions in injured juvenile intestine. In the presence of a prostaglandin inhibitor, epithelial cells can repair but the tight junctions cannot, resulting in a leaky barrier. They also found an age dependence in barrier repair; younger mammals have greater difficult repairing their intestinal barrier. In newborns, epithelial restitution is arrested after ischemic injury. Using scanning electron microscopy, they have observed a different morphology in newborn and juvenile epithelial tissue. Neonatal epithelial tissue is rounded whereas juvenile tissue flattens out. The reason behind this remains unknown. To help answer this question, the lab has started to investigate the role of enteric glial cells in the healing process. They hypothesize that glial cells signal epithelial restitution. Further, they hypothesize that oligosaccharides feed the microbiota which in turns signals glial cells to support this restitution. Initial studies suggest that the enteric glial cell network is underdeveloped in neonates. Additionally, data show that feeding oligosaccharides results in both a maturation of the enteric glial cell network and a positive shift in the microbiome. These preliminary results suggest a temporal link to development of enteric glial cells, and define them as a potential target in intestinal barrier repair.

Mood and bugs and guts

Speaker: Dr. Alban Gaultier, Ph.D. from University of Virginia

Title: “Effect of gut microbes on mood and anxiety”

Dr. Alban Gaultier is an Assistant Professor at the University of Virginia. To study the effect of the microbiome on depression and anxiety, Dr. Gaultier’s lab used the unpredictable chronic mild stress (UCMS) protocol to induce a depressive phenotype in mice. In work published in Scientific Reports this year, they showed the UCMS protocol does not change the total amount of microbiota present in the gut. Rather, it drives dysbiosis, reducing the population of Lactobacillus species in the gut across multiple strains of mice. Further, they found that replacing the lost species with Lactobacillus reuteri improved the depressive phenotype. They then delved into the pathogenesis of these findings.

Using metabolomics, they found an increase in products of the tryptophan kynurenine pathway in depressed mice. They reasoned that Lactobacillus generate reactive oxygen species, and these reactive species inhibit the enzyme IDO1, responsible for converting tryptophan to kynurenine. They hypothesized that reduced Lactobacillus species can cause increased levels of kynurenine, which is able to cross the blood brain barrier and contribute to depressive symptoms. To confirm this hypothesis, they found that augmenting kynurenine levels abolished the beneficial effect of Lactobacillus supplementation. Since the publication of their paper this year, Dr. Gaultier’s lab has been asking the question: how does the UCMS protocol change the microbiome?

Their first hypothesis was that the adaptive immune system could be contributing to this change, but they observed the same decrease in Lactobacillus in mice without an adaptive immune system. Further investigation showed that stressed mice have increased colonic motility; and because Lactobacillus are scavengers, they hypothesized that the reduced transit time in the colon caused the Lactobacillus to be outcompeted. Their data show that not only does administering a laxative reduce Lactobacillus species, but also it drives depressive behavior in mice.

Finally, they have been investigating the effect of the kynurenine pathway on oligodendrocytes, the glial cells of the CNS, as a reduction of glial cells can be found in the brains of depressed patients. Preliminary data shows that increased levels of kynurenine reduces the survival of oligodendrocyte progenitor cells and inhibits their differentiation. In summary, Dr. Gaultier and his lab has revealed a mechanism by which the microbiome, specifically Lactobacillus species, can contribute to anxiety and depression.

The gut, the brain, and addiction

Speaker: Dr. Ivan de Araujo, D.Phil from Yale University

Dr. de Araujo is an Associate Professor from Yale University in the John B. Pierce Laboratory. The goal of his lab is to define the sensorimotor circuitry that controls feeding programs. In 2008 work published in Neuron, Dr. de Araujo showed that taste alone is not enough to communicate the reward value of sugar; he knocked out the trpm5 taste receptor in mice to create a taste blind mouse, but found that mice still tend to prefer sugar after a few hours.

From there, he studied the brain regions that encode for this reward. He found that reward behavior can be abolished by inhibiting the mesolimbic and nigrostriatal brain dopamine pathways. He found that intake of sweeteners activates the ventral striatum while D-glucose activates the dorsal striatum, and that the infusion of nutrients into the gut increases dopamine levels proportional to the amount of calories infused. He then went about delineating the neural circuit driving this response.

Initially, he found that energy is transmitted to the substantia nigra pars compacta to the dorsal striatum to the substantia nigra. Meanwhile, sweetness, in the form of non-nutritive sweeteners, takes a different pathway; it is transmitted to the ventral tegmental area to the ventral striatum to the ventral pallidum. In summary, Dr. Ivan de Araujo has greatly impacted the way we understand the neurobiology of feeding and the reward pathways it elicits.

Biliary stem cells

Speaker: Dr. Adam Gracz, Ph.D from UNC Chapel Hill

Title: “Stem Cell Dynamics in Intestinal and Biliary Epithelia.”

Dr. Gracz is an Assistant Professor at UNC Chapel Hill and started his independent laboratory in July 2016 after completing his postdoctoral fellowship in intestinal stem cell biology in Dr. Scott Magness’s lab at UNC Chapel Hill. His collective work has explored how cells pattern to form functional tissues.

In his post-doctoral work, Dr. Gracz studied how stemness is regulated in the intestine. He and his colleagues found that SOX9 EGFP is expressed in variable levels in intestinal crypts, specifically finding that the level of expression marks distinct cell populations including progenitor cells, intestinal stem cells, and enteroendocrine cells. They used various novel and state-of-the-art techniques in their work; specifically, they collaborated with biomedical engineers to use microraft arrays (MRAs) to facilitate genetic screening of organoids. After his successful postdoctoral fellowship, Dr. Gracz started his independent laboratory based on the central question “How does epigenetic regulation drive functional outcomes in cell and tissue biology?”

His lab focuses on two areas of research: the chromatin structure of intestinal stem cell biology and the cellular dynamics of biliary epithelium. In his talk, Dr. Gracz focused on his lab’s work in biliary epithelial populations. He is using SOX9 EGFP to study the sub-populations of biliary epithelial cells and to identify potential biliary stem cells. In summary, Dr. Gracz is continuing to further the field’s understanding of stem cell dynamics in GI epithelial tissues.

Stem cells

Glad to announce the kickoff of our Gastronauts series 2017/18. We are on our 3rd year! and this would have not been possible without your attendance and support to the monthly meetings. This year we have a vibrant list of speakers, a new venue (GSRBI 4002), and a Gastronauts symposium that goes global (more coming soon).
On Tuesday September 5th, at 4p, we will have our first speaker. This time Dr. Chris Dekaney from the NCSU School of Veterinary Medicine is visiting us. Chris is a stem cell biologist and will be sharing his work –Life Within the Intestinal Stem Cell Niche During Damage and Repair – Friends and Enemies
The primary focus of Chris’s research is unlocking how intestinal stem cells proliferate after injury.
Also over the summer, there have been a few great articles, resources, and announcements that have come online. Please see them below. If you have something worth spreading please send it my way, I am sure a group member will be excited to read it too.

Gut-brain axis collection of articles – click here

Piglets and infant formulas

Jack Odle, Ph.D.
William Neal Reynolds Distinguished Professor
Department of Nutrition
North Carolina State University

Dr. Odle Lab studies lipid metabolism, specifically of long chain fatty acids found in milk, and intestinal disorders, specifically ischemic or infectious insults. His group uses piglets as a pediatric nutrition model and has discovered the mechanisms by which several fatty acids, like arachachidonic acids, stimulate the repair of the intestinal epithelium to maintain intestinal health. These findings have served as a foundation to develop human infant formulas.

GLP1 and metabolism

Jonathan Campbell, Ph.D.
Assistant Professor of Medicine
Duke University

Dr. Campbell studies glucose-dependent insulinotropic peptide (GIP), an incretin hormone released from the proximal small intestine that stimulates insulin release after a meal.

The field of incretin biology has long focused on the other incretin, glucagon-like peptide-1 (GLP-1), and utilized this hormone as a pharmaceutical target for diabetes and obesity. GIP, however, is less well understood; previous studies demonstrate that GIP resistance and receptor loss is associated with decline in pancreatic beta cell function, as seen in type II diabetes. Dr. Campbell’s laboratory is working to uncover the mechanism and effects of GIP.

Using global GIP receptor knockouts, he has shown that beta cells without GIPR are more sensitive to the other incretin, GLP-1, and maintain the ability to secrete insulin. Dr. Campbell is creating tissue-specific knockout models to describe beta cell defects seen in his transcription factor  knockout experiments. His goal is that these experiments may serve as a target for diabetes pharmaceuticals.

Neuroimmune interactions and behavior

Staci Bilbo, Ph.D.
Associate Professor of Psychology and Neuroscience
Duke University

Dr. Bilbo’s laboratory explores the interactions between the nervous and immune systems. In particular, their interest is how nerves and immune cells join forces to influence behaviors such as cognition and emotion. Recent studies have linked the immune system with a number of neurodevelopmental disorders, such as schizophrenia, anxiety/depression, and autism.

Dr. Bilbo’s research focuses on how early challenges in life, such as infections, prime the immune system to influence brain development and affective behaviors. She is now the Director of the Lurie Center for Autism at Harvard Medical School.

https://www.hms.harvard.edu/dms/neuroscience/fac/Bilbo.php

 

MicroRNAs… MicroRNAs… gut MicroRNAs.

Praveen Sethupathy, Ph.D.
Assistant Professor of Genetics
UNC-Chapel Hill

Dr. Praveen Sethupathy studies microRNAs and how they respond to gut microbes.

Here is a short recap from his talk:

  • Non-coding RNA encompasses a large class of RNA, including microRNA. The Sethupathy lab in interested in how miRNA regulate diseases, can act as biomarkers of disease, and how they respond to changes in environment. 
  • Sethupathy lab has studied how miRNA is related to Diabetes and Obesity, but recent RNA sequencing data has turned their attention to miRNA in the GI system and their  relationship to Microbiota 
  • Their hypothesis is that miRNA respond to the microbiota, this response is cell-type specific and that miRNA can control Enteroendocrine cells
  • They have mapped miRNA in intestinal epithelial cells and have seen that in GI stem cells, there is increased miR-30d, miR-92, miR-7, miR-375, and let-7, while miRNA-375 is increased in microbiota-sensitive stem cells
    • An ex vivo knockout of miR-375 using LNA 375 led to proliferation of EECs
  • In conclusion, miRNA are specific to cell types in the GI epithelium, miRNA are more sensitive in stem cells than in other GI cells, and a sub-population analysis of miRNA is needed to check response to microbiota. 
You can see more of Dr. Sethupathy’s work at www.med.unc.edu/genetics/sethupathylab.

Window to the gut… literally

Xiling Shen, Ph.D.
Associate Professor of Biomedical Engineering
Duke University

Dr. Shen’s laboratory recently moved from Cornell University and has developed a unique 3D printed scaffold to image the gut in awake behaving animals. The device can be used to image from stem cells, to bacteria, to neurons. His team is also working on peripheral nerve stimulation and recording devices for nerves innervating the gut.

This story was highlighted as one of the top 100 stories by Discovery Magazine in 2016
http://discovermagazine.com/2017/janfeb/60-first-glance–into-the-gut