Finding the Cause of Congenital Diarrhea

Early diagnosis and treatment of infants with deadly congenital diarrheal disease

Each year children are born with deadly diarrheal syndromes with no discrete cause. It is estimated that 5–10 of these infants are cared for each year by every newborn intensive care unit in the United States and likely throughout the world. Because no discrete diagnosis can be discerned, these children often spend months in newborn intensive care units sustained by intravenous nutrition.  Ultimately they often die from sepsis or failure to thrive. Dr. James Goldenring, of Vanderbilt University School of Medicine, is seeking to understand the molecular bases of congenital diarrheal diseases that could be targets for potential treatments and thus, decrease the profound morbidity and mortality observed in these children. Dr. Goldenring’s goal in the case of neonatal diarrheas is to change the standard of care and provide more rapid identification of the genetic causes of congenital diarrheas that can lead to early and effective interventions to ameliorate these often deadly diarrheal syndromes.

Over the past year, Dr. Goldenring led a group of physicians and scientists to impact the care of infants with congenital diarrheal disease without diagnosis. By employing state-of-the-art genomic sequencing analysis of the affected children and their parents, his group has successfully identified the genetic mutations responsible for diarrhea in the first four patients studied. These have led to alterations in diet that have cured one patient, strongly improved the health of two others, and eliminated the need for and risk of intravenous feeding. Unfortunately, insurance companies presently do not pay for whole genome analysis, and therefore there is a great need to establish a new standard of care. As these initiatives are not amenable to traditional funding sources, philanthropy will greatly impact breakthroughs. The team at Vanderbilt led by Dr. Goldenring is now seeking to expand their efforts to accomplish more rapid genetic analysis and then subsequent studies to determine the effects of genetic mutations and how they may be overcome.

Current research includes:

  • Diarrhea in Infants with Microvillus Inclusion Disease: Infants with loss of function mutations in myosin Vb develop a syndrome known as Microvillus Inclusion Disease (MVID), which is manifested in unremitting diarrhea beginning in the first two weeks of life. Dr. Goldenring has developed new mouse models of MVID and is studying the  physiology of culture enteroids to elucidate strategies for amelioration of the disease.
  • Identification of Genes Causing Undiagnosed Neonatal Diarrhea: Due to the startling number of infants affected by neonatal diarrheal diseases, Dr. Goldenring has initiated an IRB-approved protocol to perform whole genome sequencing on infants with undiagnosed congenital diarrhea at Vanderbilt and from other institutions. Analysis of identified mutations is leading to interventions that can ameliorate symptoms in the infants. Dr. Goldenring is also creating cellular models of identified mutations that can lead to insights into the molecular pathology of specific mutations.
  • Membrane Trafficking: Dr. Goldenring has led the way on the concept that alterations in trafficking may be key factors in the development of both diarrheal disease and cancer. He and his team are now studying these mouse models of diarrheal syndromes and cancer that accrue from alterations in membrane trafficking and intestinal cell polarity.
  • Gastric Cancer: Dr. Goldenring's studies have made paradigm shifting recognition that the precancerous metaplasias that lead to gastric cancer do not arise from normal stem cells that go bad, but rather come from transdifferentiation of mature chief cells (protease-secreting cells) into a mucous cell metaplasia that then can further evolve into a more proliferative precancerous lesion that can then progress to cancer. These studies have changed the way scientists look at the precancerous process. Dr. Goldenring's studies indicate that, in mice who show extensive metaplasia, treatment with inhibitors of Ras effectors can reverse the progression of metaplasia and allow the recrudescence of normal gastric lineages in the stomach. These finding suggest that Ras signaling inhibitor treatment could be an effective adjuvant therapy for patients with extensive precancer and early cancer in the stomach.


Dr. Goldenring has been interested in scientific research since early in college where his focus was on neuroscience. From the start, he was interested in how cells communicate with each other. While he grew up around medicine, with his father being the first pediatrician on the Connecticut shoreline, the idea of doing a dual M.D./Ph.D. degree came only late in college. After finishing his Ph.D., Dr. Goldenring found himself drawn away from the neurosciences and towards surgery. His clinical training in surgery refocused his interest on issues of membrane trafficking in the cells lining the gastrointestinal tract and also spurred his interest first in the regulation of gastric acid secretion and then gastric cancer.

The advent of laparoscopic surgery in the late 1980's changed the practice of surgery radically and the opportunity to be part of a new initiative to form an Institute of Molecular Medicine in Georgia led him away from clinical practice and back to the laboratory. Nevertheless, the questions of how gastrointestinal diseases, both benign and cancerous, arise remain his focus. His more recent studies on diarrheal disorders in infants have taken him back to the interests of his father, who oversaw the newborn well baby nursery at Yale-New Haven Hospital for a decade. As Co-Director of the Epithelial Biology Center at Vanderbilt, Dr. Goldenring leads a team of scientist and clinicians dedicated to coming up with solutions to the problems involved in diagnosing and treating infants with congenital diarrheas.

In his free time, aside from research, Dr. Goldenring enjoys fencing with undergraduates at Vanderbilt.

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American Association for the Advancement of Science Fellow, 2014

Association of American Physicians, 2013

Takeda Distinguished Research Award

American Physiological Society, 2011

American Gastroenterological Association Fellow, 2006

American Society for Clinical Investigation, 2004


Identification of Spasmolytic Polypeptide-Expressing Metaplasia

Dr. Goldenring holds patents on the identification of Spasmolytic Polypeptide-Expressing Metaplasia, the first metaplastic lineage that develops from transdifferentiation of chief cells.