A technology with roots dating back to the 19th Century is showing potential to offer new advantages for modern-day medicine. In findings published this month in the journal Nature Communications, scientists at Case Western Reserve University School of Medicine in Cleveland, Ohio, describe how stereomicroscopy can provide physicians with a valuable diagnostic tool for assessing issues within the gastrointestinal tract.
Originally used by 19th-century photographers to create the illusion of depth of field in their viewed images, stereomicroscopy since has evolved to become a staple of the film and videogame industries. Only recently has medicine been giving it another look, a factor that makes these findings particularly important.
Using 3-D pattern stereomicroscopy with mouse models, School of Medicine researchers report being able to develop entire topographical views of the inside of the intestinal system, rather than just two-dimensional visuals of individual sections or of tissue or cell samples. Stereomicroscopy’s more expansive and detailed imagery allows them to identify distinct patterns related both to health and disease within those structures — patterns they could not see using traditional approaches.
The Nature Communications paper, entitled Stereomicroscopic 3D-pattern profiling of murine and human intestinal inflammation reveals unique structural phenotypes (Nature Communications 6, Article number: 7577 doi:10.1038/ncomms8577), is coauthored by Case Western Reserve professors Fabio Cominelli and Alex Rodriguez-Palacios, with Tomohiro Kodani, Lindsey Kaydo, Davide Pietropaoli, Daniele Corridoni, Jeffry Katz, and Theresa T. Pizarro, all of the Division of Gastroenterology and Liver Disease in Department of Medicine at Case Western Reserve University School of Medicine, and Wei Xin, of the School of Medicine’s Department of Pathology, and the Digestive Health Institute at University Hospital’s Case Medical Center.
The coauthors note that histology is fundamental to the assessment of two-dimensional intestinal inflammation, but inflammatory bowel diseases (IBDs) are often indistinguishable microscopically on the basis of mucosal biopsies. In this study the researchers used stereomicroscopy (SM) to rapidly profile the entire intestinal topography and assess levels of inflammation. They examined the mucosal surfaces of more than 800 mice (encompassing >16 strains and various IBD-models), creating a profiling catalogue of 3D-stereomicroscopic abnormalities and demonstrating that mice with comparable histological scores display unique sub-clusters of 3D-structure-patterns of IBD pathology, which they call “3D-stereoenterotypes” that are otherwise indiscernible histologically.
The researchers also show that two ileal IBD-stereoenterotypes (cobblestones versus villous mini-aggregation) cluster separately within two distinct mouse lines of spontaneous ileitis, suggesting that host genetics drive unique and divergent inflammatory 3D-structural patterns in the gut. In humans, stereomicroscopy reveals liquefaction lesions and hierarchical fistulous complexes, enriched with clostridia/segmented filamentous bacteria, running under healthy mucosa in Crohn’s disease.
As part of the study, the researchers developed a catalogue of specific profiles for abnormalities in persons with inflammatory bowel diseases (IBD), which not only provide a depth of information not attainable by other means, but can also accelerate the process of determining the condition or illness that is troubling the patient. The coauthors conclude that stereomicroscopic (3D-SMAPgut) profiling can be easily implemented and enable the comprehensive study of inflammatory 3D structures, genetics and flora in IBD.
“This is really exciting for us because for the first time, we have a technique that provides a better way to examine these lesions,” says senior author Fabio Cominelli, chief of the Division of Gastroenterology and Liver Disease and the Hermann Menges, Jr. Chair in Internal Medicine at Case Reserve. “The traditional, two-dimensional histology views do not tell us what is going on in the entire tissue. The precision of this 3-D technology will allow us to visualize the location of lesions along the entire intestinal tract to learn the exact cause of the inflammation.”
Dr. Cominelli, who is also director of the Digestive Health Institute at University Hospital’s Case Medical Center, has assembled a team of investigators to focus research on inflammatory diseases of the digestive tract, particularly Crohn’s disease, inflammatory bowel disease and ulcerative colitis. One of the team members, Dr. Alexander Rodriguez-Palacios, instructor of medicine, made the breakthrough possible by identifying a novel way to use a stereomicroscope, a device often used in microsurgery.
Typically physicians have been limited to endoscopy or histology in studying inflammatory bowel diseases. Recognizing the shortcomings of these techniques, the research team sought other means of gaining better understanding of the nature of different bowel diseases, reasoning that the more they knew about different conditions, the more effective they could be in helping patients.
“Currently, we have treatments that can make the patient feel better, but we are not able to achieve a sustained positive response in patients,” Dr. Cominelli observes in a Case Western release. “The goal for developing new therapies now is to have lesions disappear, or possibly prevent lesions from appearing in the first place.”
Drs. Cominelli, Rodriguez-Palacios, and their colleagues set out to test the efficacy of this alternative approach by studying the inflammatory-diseased intestinal tracts of more than 800 mice from 16 strains of the animals. During the course of their study, the scientists were able to identify distinct patterns of lesions as they developed in the different kinds of mice — the different patterns observed pointing to the genetic origins of various inflammatory intestinal diseases.
“What we saw were unique structural characteristics in inflamed tissue and in normal tissue,” Dr. Rodriguez-Palacios explains. “Before, a lesion was just a lesion. We found that these lesions had a particular configuration. Now we can tell the different kinds of lesions and patterns of lesions that make a difference in the disease. Nobody has ever done that before.”
Using 3-D microscopy, the investigators found two mouse model most closely resembling inflammatory bowel disease in humans. The SAMP mouse has cobblestone lesions typical of human Crohn’s disease, and the TNF mouse has enlarged and distorted intestinal villa typical of inflammatory bowel disease. (Villa being the finger-like projections protruding from the intestinal wall that aid in nutrient absorption.)
By studying both mouse models using 3-D stereoscopy, the CAse Western investigators hope to be better able to make informed predictions about how inflammatory bowel diseases develop and progress in humans. They also plan to observe the natural history of the illness, from early onset through end stages, and hopefully to discover what causes these intestinal diseases, what genes are expressed, underexpressed or overexpressed, and what intricacies are involved in the microbial environment of the gut.
“We will use the 3-D stereoscopy to study these mouse models extensively to understand what causes the disease in mice,” says Dr. Cominelli, “[and then] correlate that understanding to human patients and then develop new therapies.”
This work received funding support from the National Institutes of Health grants DK091222, DK055812, and DK042191 and the Crohn’s and Colitis Foundation of America via a Career Development Award.
Founded in 1843, Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and is among the nation’s top medical schools for research funding from the National Institutes of Health. The School’s innovative and pioneering curriculum interweaves four themes — research and scholarship, clinical mastery, leadership, and civic professionalism — to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century. Nine Nobel Laureates have been affiliated with the School of Medicine, which annually trains more than 800 MD and MD/PhD students, and ranks in the top 25 among U.S. research-oriented medical schools as designated by U.S. News & World Report’s “Guide to Graduate Education.”
Case Western Reserve University School of Medicine
Case Western Reserve University School of Medicine