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Neurons live long life in the gut of adult mice

Contrary to dogma, new evidence supports how a healthy adult mouse can regenerate a third of its gut nerve cells every week. This refutes a long-held scientific belief that the number of gut nerve cells from birth to death are the same — which may be true for human gut neurons as well.


Publishing in the journal Proceedings of the National Academy of Sciences, this finding by Johns Hopkins researchers' has profound implications for treating disorders of the digestive system.

Pankaj Jay Pasricha MBBS, MD, Professor of Medicine and Director of the Johns Hopkins Center for Neurogastroenterology, along with Subhash Kulkarni, MS, PhD, assistant professor, Johns Hopkins University School of Medicine, led the research. Their discovery challenges all previous  concepts of a birth to death neuronal life cycle in the mouse digestive tract.


Previous studies suggested that a healthy adult gut generates few or no new neurons.

According to Pasricha, their study demonstrates a healthy adult small intestine loses and regenerates about five percent of its nerve cells every day, or a third of them every week.


"Scientific dogma believed that gut neurons don't regenerate and that this 'brain,' known as the enteric nervous system, remained relatively static shortly after birth," Pasricha explains. "We now have proof that, not only do they regenerate, but the whole network turns completely over every few weeks in adult animals."

The enteric nervous system controls and regulates vital gastrointestinal functions such as digestion, immunity and inflammation. After the brain, the digestive tract contains the largest nervous system in the human body.


"The yin and the yang of neuronal loss and birth keeps us going."

Subhash Kulkarni, MS, PhD, Assistant Professor, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.


Pasricha, Kulkarni and their team confined their research to the small intestines of healthy adult mice. Using a variety of techniques, they identified those proteins associated with neural cell death in order to observe the cycle of neuronal processing. Their work provided irrefutable evidence of continual adult gut neuronal death due to apoptosis. The rate of nerve cell loss left one question — how does the gut maintain its rather constant number of neurons?


"There could be only one answer, the high turnover of neurons in the gut could only be reconciled by birth of newborn neurons, or neurogenesis."

Subhash Kulkarni, MS, PhD


Despite years of research, proof of neurogenesis in a healthy digestive system has been elusive. Scientists knew the numbers of enteric neurons in a healthy small intestine remain remarkably constant for most of an adult's life. While previous studies have shown the adult gut contains cells that generate neurons in lab settings outside a living organism, finding whether these cells truly give rise to neurons in healthy adult animals has eluded scientists for years. Pasricha adds the key to finding the process came when they focused on following the behavior of cells expressing Nestin, a protein typically associated with brain stem cells.

After years of "staking out" these Nestin-expressing cells, studying location, behavior and fate in the adult gut tissue, they found that some, called "enteric neural precursor cells," generate new neurons rapidly. Enteric neural precrsor cells shore up and maintain a large neuronal population which would otherwise dwindle quickly with continual neuronal death.


The study also shows how any change in gut cells' birth-and-death balance may lead to disease.


Kulkarni: "Although previous studies have shown that regeneration of adult neurons may happen in an injured gut, by and large, this appeared a relatively isolated and rare phenomenon. We now provide evidence that this happens continually and robustly in the adult healthy gut. It helps explain how this nervous system maintains itself, despite constant exposure to dietary factors, toxins, microbes and mechanical forces."

"We didn't believe it ourselves, at first," says Pasricha, who has been working on these neural stem cells for many years. "It's an extraordinary result; the mice get an entirely new 'brain' in the gut every few weeks."   He cautions that their study was limited to the mouse small intestine and that further research is needed to determine whether other species — including humans — and other regions of the gut experience the same cellular birth and death processes. Such studies are underway in Pasricha's Johns Hopkins lab.

The researchers hope the findings will help identify new regenerative and other therapies for gastrointestinal motility disorders like achalasia, gastroparesis, pseudo-obstruction, colonic inertia and other problems related to the digestive system.


"And as we dig deeper into this research, we will gain new insights into a whole host of other diseases that affect not just the gut, but other organ systems with which this nervous system communicates, such as the brain."

Subhash Kulkarni, MS, PhD


Significance
The demonstration of a robust neurogenesis program in the adult gut and the existence of an enteric neural precursor cell (ENPC) responsible for the same has profound biological and clinical implications. This demonstrates the presence of robust adult neurogenesis outside of the CNS, and indicates the vulnerability of the enteric nervous system to exogenous influences, even in adults. As an example, it is possible that acquired diseases of the enteric nervous system, such as achalasia, may result from a loss of ENPC, analogous to congenital disorders, such as Hirschsprung’s. The ability to identify the adult ENPC will therefore enable a new understanding of the pathogenesis of enteric neuromuscular diseases as well as the development of novel regenerative therapies.

Abstract

Additional authors of the article are Jenna Leser, Ya-Yuan Fu, Liansheng Liu, Qian Li, Monalee Saha, Cuiping Li, Michael Anderson, Xinzhong Dong and Hongjun Song of The Johns Hopkins University School of Medicine; Manish J. Butte of the University of California, Los Angeles; E. Michelle Southard-Smith of Vanderbilt University Medical Center; Raj P. Kapur of Seattle Children's Hospital; Maria-Adelaide Micci of the University of Texas Medical Branch; Changsik Shin and Milena Bogunovic of the Pennsylvania State University; Shiue-Cheng Tang of the National Tsing Hua University; Grigori Enikolopov of Cold Spring Harbor Laboratory; Laren Becker of the Stanford University School of Medicine; Nikolai Rakhilin and Xiling Shen of Duke University.


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Apr 25, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   



TOP - New neurons (green) emerging from their BOTTOM - precursor cells (red).
Image Credit: Pankaj Jay Pasricha lab, Johns Hopkins Division of Gastroenterology

 


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