Sep 2018 – Subhash Kulkarni

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.