RESEARCH ALERT: The New Geography of the Gut
Study Uses Genomic Sequencing for the First Time to Redefine the Regions of the Small Intestine
BACKGROUND
Investigators from Cedars-Sinai; the University of California, San Francisco (UCSF); Harvard University; and the Weizmann Institute of Science in Israel conducted a study to determine where individual nutrients are absorbed in the small intestine. For the first time, they identified the molecular markers that define five distinct intestinal regions.
The human small intestine measures more than 20 feet long. Scientists have long sought to understand the biological patterns along the length of the small intestine that allow it to function efficiently. The ancient Greeks loosely organized the organ into three portions they called the duodenum, the jejunum and the ileum. These areas have served as the common basis of scientific knowledge—until now. This study provides evidence for a modern paradigm for the regional organization of the intestine, which is critical to understanding how it absorbs nutrients and performs other processes.
The research was published today in Nature Cell Biology.
IMPACT
“As far as we know, this is the first study to molecularly define the regions of the small intestine,” said Ophir Klein, MD, PhD, executive director of Cedars-Sinai Guerin Children’s, the David and Meredith Kaplan Distinguished Chair in Children’s Health and corresponding author of the study. “This is information scientists can use to understand the cellular and molecular processes that occur in the small intestine and what goes wrong in gastrointestinal diseases.”
“We’re excited because this groundwork identifies different cellular ‘neighborhoods’ within the small intestine that not only execute different intestinal functions, but also show major differences in the likelihood to develop gastrointestinal diseases, such as intestinal cancers, ileitis [a common type of inflammatory bowel disease], and celiac disease,” said Rachel Zwick, PhD, an American Cancer Society Postdoctoral Fellow at UCSF and first author of the study. “These regional molecular and cellular differences help us better understand these diseases.”
The study may also lead to technological advances in regenerative medicine by providing information that can be used to regenerate regional nutrient absorption in portions of the intestine damaged by bowel resection surgeries and disease.
METHODS
In contrast to the three portions typically sampled, in this study investigators examined 30 portions of the small intestine in multiple species. This allowed for a view of intestinal geography at an unprecedented spatial resolution. Investigators used genomic sequencing technology to determine the precise locations where genes involved in nutrient absorption were expressed along the length of the small intestine. From the resulting sequencing data, computational and experimental approaches were used to determine the number of intestinal regions that span the tissue and the unique properties of each region.
FINDINGS
With a high degree of precision, investigators were able to define five regions within the mouse and human small intestine, distinct from the three that scientists had previously described. Each domain is associated with different aspects of nutrient absorption, and each exhibits distinct responses to changes in diet.
The study authors also identified three regional groups of intestinal stem cells, the cell type that regenerates new cells in the gut throughout life, with important implications for regenerative medicine.
The cellular composition of the small intestine is constantly regenerating, and yet, somehow, intricate regional organization is maintained throughout adult life. To show how this is achieved, the study investigators generated a predictive model of key factors that may maintain regional expression of nutrient absorption genes. They generated cell cultures from different newly defined regions and found that cells “remembered” key aspects of the molecular signature of individual regions even after more than a month in culture. Using CRISPR-Cas9 technology, researchers manipulated these long-maintained regional signatures, validating several factors that they had predicted might control regional aspects of metabolism.
AUTHORS
Rachel Zwick, UCSF; Petr Kasparek, UCSF; Brisa Palikuqi, UCSF; Sara Viragova, UCSF; Laura Weichselbaum, UCSF; Christopher McGinnis, UCSF; Kara McKinley, Harvard University; Asoka Rathnayake, UCSF; Dedeepya Vaka, Cedars-Sinai; Vinh Nguyen, UCSF; Coralie Trentesaux, UCSF; Efren Reyes, UCSF; Alexander Gupta, UCSF; Zev Gartner, UCSF; Richard Locksley, UCSF; James Gardner, UCSF; Shalev Itzkovitz, Weizmann Institute of Science, Rehovot, Israel; Dario Boffelli, Cedars-Sinai; Ophir Klein, Cedars-Sinai.
FUNDING
This work was funded by the Intestinal Stem Cell Consortium, a collaborative research project funded by the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institute of Allergy and Infectious Diseases; the National Institute of Dental and Craniofacial Research; a Ruth L. Kirschstein Postdoctoral Individual National Research Service Award; and an American Cancer Society–South Florida Research Council Postdoctoral Fellowship.
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