From the AGA Journals

Surgical model to study reflux esophagitis after esophagojejunostomy

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This model may describe human metaplastic columnar-lined esophagus elongation

Agoston et al. reported that metaplastic columnar-lined esophagus develops in a wound-healing process on the distal edge of the ulcer, starting distally at the esophagojejunal anastomosis in the esophagojejunal anastomosed rat model. They also concluded that the columnar-lined esophagus was caused through migration of jejunal cells into the esophagus.

These new findings bring up a couple of issues. One is that metaplastic columnar-lined esophagus originates from jejunal crypt budding over the anastomosis. Some researchers may think this is not metaplasia, as there is no reprogramming of the stem cells. However, the definition of metaplasia is an endpoint such that a normal lineage is placed in an abnormal position, and it can be called metaplasia even it is from budding of jejunal crypt. This new finding is not denying metaplasia.

The second issue is whether these rodent models are really mimicking human metaplastic columnar-lined esophagus or not. In humans, metaplastic columnar-lined esophagus usually accompanies gastroesophageal reflux, but jejunum is not next to esophagus, and jejunal crypt budding is less likely. However, it is common to observe ulcerated lesions in the proximal front of long-segment Barrett’s esophagus in humans. In this process, the model of Agosto et al. is describing the human metaplastic columnar-lined esophagus elongation.

There would be more reprogramming happening in the body of animals under the effect of microenvironment. This is a kind of adaptation, and analyzing key factors for this reprogramming would be the path to clarifying carcinogenesis in the metaplastic field and also a way to advance regenerative medicine.

Sachiyo Nomura MD, PhD, AGAF, FACS, is an investigator in gastrointestinal carcinogenesis and epithelial biology, and a gastrointestinal surgeon, at University of Tokyo Hospital, department of stomach and esophageal surgery, as well as an associate professor, department of gastrointestinal surgery, graduate school of medicine, at the university. She has no conflicts.



During a wound repair process in rats, metaplastic columnar-lined esophagus was produced and increased in length following esophagojejunostomy, which may be independent of stem cell reprogramming, according to results from an anastomosed rodent study.

The investigators studied esophageal and tissue sections of 52 rats at different time points after esophagojejunostomy and samples were analyzed for length, type, and location of columnar lining. In addition, the sections were examined immunophenotypically to elucidate the molecular changes that occur during ulceration. Agoston T. Agoston, MD, PhD, of Brigham and Women’s Hospital and the department of pathology at Harvard Medical School, Boston, and colleagues reported the findings in Cellular and Molecular Gastroenterology and Hepatology.

“This rodent columnar-lined esophagus has been proposed to develop from cellular reprogramming of progenitor cells, but studies on early columnar-lined esophagus development are lacking,” the researchers wrote.

In the model, ulceration was seen 2 weeks after surgery, which began distally at the esophagojejunal anastomosis. Representative of wound healing, reepithelialization of the ulcer region took place through formation of immature glands, which were found to bud directly from jejunal crypts.

After immunophenotypic analysis, the researchers reported that “immunohistochemical characterization of neoglandular epithelium located immediately proximal to the anastomosis showed features similar to those of the native nonproliferating jejunal epithelium located immediately distal to the anastomosis.” They further reported that “the columnar-lined esophagus’s immunoprofile was similar to jejunal crypt epithelium.”

Upon further examination of the ulcer segment, Dr. Agoston and colleagues found that columnar-lined esophagus elongated from 0.15 mm (standard error of the mean, ± 0.1) to 5.22 mm (SEM, ± 0.37) at 2 and 32 weeks post esophagojejunostomy, respectively.

“There was a highly significant linear relationship between the length of the neoglandular epithelium in the distal esophagus and the number of weeks after surgery (correlation coefficient, 0.94; P less than .0001),” the investigators stated.

Locational analysis revealed epithelial-mesenchymal transition markers being expressed by spindle-shaped cells at the leading edge of the columnar-lined esophagus. In addition, neoglands were identified within esophageal ulcer beds and actively dividing squamous epithelium was seen exclusively at the proximal ulcer border.

Following the systematic analysis, the authors noted that the columnar-lined esophagus was most likely the result of jejunal cell migration into the esophagus. They suggested that if compared, jejunal cells may competitively dominate squamous cells in the context of chronic gastroesophageal reflux disease. Furthermore, they observed that the region of ulceration following esophagojejunostomy in their model was more expansive than that reported in other comparable rodent models of reflux esophagitis.

“The reason for this difference is not clear, but we speculate that it is the result of technical aspects of our reflux-inducing surgery,” the researchers wrote. They further explained that “we intentionally fashioned a large anastomotic orifice between the esophagus and jejunum, perhaps larger than that fashioned by other investigators.” And they concluded, “we suspect that this larger orifice resulted in esophageal exposure to larger volumes of refluxate and, consequently, larger areas of ulceration.”

The authors acknowledged their results may not be fully applicable in the context of human Barrett’s esophagus, given the rodent model. However, they do believe the findings may provide a basis to help understand the wound repair process, particularly the distal edge of ulcers that border the columnar epithelium.

“Using a rat model of reflux esophagitis via surgical esophagojejunostomy, we have shown that a metaplastic, columnar-lined esophagus develops via a wound healing process, and not via genetic reprogramming of progenitor cells,” the researchers concluded.

The study was supported by grant funding from the National Institutes of Health and the Baylor Scott and White Research Institute. The authors reported no conflicts of interest.

SOURCE: Agoston AT et al. Cell Mol Gastroenterol Hepatol. 2018 Jun 26. doi: 10.1016/j.jcmgh.2018.06.007.

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