Adult enteric neurogenesis: Implications for gut and brain health and disease
Dr. Subhash Kulkarni, M.S., Ph.D., is an Assistant Professor of Medicine at the Johns Hopkins University School of Medicine. His research focuses on the origin and development of the enteric nervous system (ENS). The ENS is maintained despite significant and continuous insults, and chronic dysmotility can result from dysregulation of the ENS. However, there is significant conflicting data on the stability of the ENS over a lifetime, with research disputing the occurrence of apoptosis and neurogenesis of enteric neurons. Dr. Kulkarni’s laboratory’s research has focused on investigating three central hypotheses: 1) the ENS is maintained by a balance of apoptosis and neurogenesis, 2) ENS turnover contributes to recovery from insult, and 3) issues with the autocorrect mechanisms regulating the ENS can cause adult onset dysmotility. In work published in PNAS in 2017, Dr. Kulkarni and colleagues showed that apoptosis and neurogenesis occur in balance to maintain a steady number of enteric neurons over time. Further, they showed that Nestin+ cells are the enteric neuron precursor cells that proliferate and generate adult neurons, replacing 88% of the adult ENS in two weeks. To address their second hypothesis, Dr. Kulkarni and his laboratory considered the intestinal insult of antibiotics. After exposure to the antibiotic ampicillin, intestinal dysbiosis changes ganglionic diversity, and over time, increased neurogenesis restores neuronal numbers to pre-ampicillin levels in a TLR2 mediated mechanism. Finally, Dr. Kulkarni and colleagues studied how ENS neurogenesis from precursor cells could contribute to disease. Knocking out PTEN in enteric neuron precursor cells caused unchecked proliferation and significantly increased neuronal numbers, size, and whole-gut transit time— an intestinal phenotype that resembled ganglioneuromatosis, a disorder of adult onset dysmotility. Dr. Kulkarni and his lab will continue to study how the ENS originates and develops and how it affects diseases of dysmotility.
Dr. Robert Heuckeroth, M.D. Ph.D. is a Professor of Pediatrics and practicing pediatric gastroenterologist at The Children’s Hospital of Philadelphia- Research Institute. His research aims to better understand enteric nervous system anatomy and development to translate into clinical pathology. One of the diseases he studies is Hirschsprung’s disease, a disease in which the distal portion of the bowel is aganglionic due to defective nerve cell migration. This lack of nerve cells prevents the bowel from working correctly causing significant obstruction. Dr. Heuckeroth has provided insight into how the enteric nervous system develops and what external factors affect its development. Hirschsprung’s disease is commonly associated with RET mutations, as RET signaling is critical for enteric nervous system proliferation, migration, and network formation. Dr. Heuckeroth’s work has identified glial cell line-derived neurotrophic factor (GDNF) as an important molecule in establishing enteric nervous system structure and function. His lab has also identified external, prenatal factors that promote proper enteric nervous system development. Vitamin A is essential for enteric nervous system development. Additionally, they have shown that maternal usage of ibuprofen slows migration of enteric nervous system precursor cells and predisposes for Hirschsprung’s disease. They will continue to investigate the internal and external factors that contribute to enteric nervous system development with hopes of both preventing childhood bowel motility disorders.
Metabolomics and xenometabolomics: Applications to study metabolic health
Dr. Sean Adams is the Director of the Arkansas Children’s Nutrition Center where his research aims to understand the molecular processes that underlie metabolic disease and obesity. Although it is well known that health status affects the microbiome and that the microbiome affects health status, molecular signals linking gut microbes and host pathophysiology remain largely unknown. His lab applies metabolomics to gut microbiome metabolism, which they call xenometabolomics. During his talk, Dr. Adams focused on two topics. Firstly, how does microbial metabolism impact host physiology? To investigate this question, they have studied nitrogen, kidney, and liver metabolism in the context of an altered microbiome. They have found that dietary manipulation of the gut microbiome alters the host liver metabolome; there are reduced hepatic amino acids and urea cycle metabolites in mice feed a high starch diet. The same diet fed to experimental mice in a chronic kidney disease model ameliorates the kidney disease. They believe that the high starch diet increases the density of beneficial bacteria which then act as a nitrogen sink to reduce the nitrogen load on the kidney. Further, they reason that the changed metabolites from the changed microbiome reduces uremic solutes. Second, Dr. Adams discussed how host physiological states impact the microbe population and biochemistry. In a study of adult human women, they found that xenometabolites—specifically, cis-3,4-methylene heptanoyl carnitine and aminomalonic acid— change with both acute exercise and with weight loss. They have also found the microbiome and xenometabolomics distinctively change during diabetes progression in a rat model. In fact, performing a “xenoscan” of the cecal metabolites can discriminate severity of disease in a rat model. Knowing this, his group hopes to investigate how we can use these altered metabolites to treat or identify disease. In summary, Dr. Adam’s group has shown that host microbiome cross talk involves a two-way street. They will continue to investigate the molecular factors involved in this communication and work towards improving our metabolic health by studying microbiota ecology and xenometabolism.
Dr. Liberles is a Professor of Cell Biology at Harvard University. His lab is interested in understanding how the brain processes external sensory and internal homeostatic signals to initiate behavioral and physiological responses. They study how our senses of smell and taste process different environmental cues (like pheromones, food cues, predator odors) to elicit innate mating, foraging, and avoidance responses. In recent efforts, they are also investigating internal sensory modalities of the vagus nerve.
See more of Dr. Liberles's work: Liberles Lab
Dr. Parker is an Associate Professor of Surgery at Duke University. The primary focus of his laboratory deals with the concept of “evolutionary mismatch” and how that affects immune function in the modern world. An evolutionary mismatch is simply described as a condition in which an organism’s current environment leads to disease because it does not match the environment which drove the evolution of that organism’s genes. Evolutionary mismatches in Western countries lead to a variety of consequences, including sedentary lifestyles, vitamin D deficiency, chronic psychological stress, and inflammatory diets, which in turn lead to inflammatory diseases. We are interested in normalizing immune function in Western society, in particular by dealing with one of the most profound and impactful consequences of evolutionary mismatch, “biome depletion”. Their lab was instrumental in understanding the role of the human appendix.
See more of Dr. Parker’s work: Parker Lab
Dr. Van Landeghem is an Assistant Professor at NC State College of Veterinary Medicine. Her laboratory focuses on understanding how signals emanating from the microenvironment impact normal and cancer intestinal stem cells with an emphasis on enteric glia. Her group aims to define the molecular crosstalk between intestinal stem cells and their neighboring cells such as enteric glial cells in healthy intestines, and to assess whether alterations of this crosstalk induced by chronic stress occurring during intestinal pathologies may lead to the malignant transformation of normal stem cells into cancer stem cells and promote tumor development using genetic mouse models and primary co-culture systems.
See more of Dr. Lendeghem’s work: Van Landeghem
Dr. Rao is a pediatric gastroenterologist at Columbia University. Her research interest is in the enteric nervous system (ENS). Specifically, she is utilizing mouse genetic models in the laboratory to investigate the role of glial cells in the ENS and determine how they regulate normal digestive function. In addition, she is studying how enteric glial cells participate in ENS neurogenesis, which may have important implications for intestinal injury and repair.
See more of Dr. Raos work here: Rao Scholar
Dr. Kravitz is an Investigator in the Eating and Addiction Section, Diabetes, Endocrinology, and Obesity Branch of the National Institute of Diabetes and Digestive and Kidney Diseases. His work focuses on the study of basal ganglia circuits and how their function changes in disease states such as obesity, addiction, and depression. Under normal conditions, the basal ganglia drives animals toward the selection of specific behavioral outcomes. Learning can bias this selection process toward specific behavior by altering synapses within and outside the basal ganglia. In extreme cases, these synaptic alterations can produce pathological behavioral selection, as in obesity or addiction. Using behavioral testing, optogenetics, and in vivo electrophysiology and optical measurements, the lab characterizes changes in behavior following learning in a feeding context and attempts to understand the neural correlates and causes of these changes in behavior.
See more of his work: Kravitz Lab
Jennifer Kern and Katherine Flynt are two speech-language pathologists at Duke University who work with many autistic children. They shared their insights into autism and its relationship to eating abnormalities!
Lawrence David is an Assistant Professor in GCB and the Department of Molecular Genetics & Microbiology. His Lab is particularly interested in how commensal microbes help resist, and ultimately respond to, colonization by human pathogens. An active area of research is the longitudinal study of cholera infections among residents of Dhaka, Bangladesh. Primary research questions include: Can enteric microbial communities predict an individual’s susceptibility to cholera? Why do bacterial ecological successions follow cholera infection? What long-term effects do infection and treatment have on commensal gut microbes? The David Lab is also broadly interested in developing new modeling and visualization tools for time-series of complex microbial communities, as well as exploring the ecology of human microbiota in the developing world.
See more of his work: David Lab