Knocking out a single gene reprograms part of the large intestine to function like the nutrient-absorbing small intestine. In a preclinical study, Weill Cornell Medicine investigators showed that the technique reversed the malnutrition that results when most of the small intestine is removed.
The successful demonstration suggests that a similar strategy could be used to treat short bowel syndrome, a life-threatening disorder that can occur when very little of the small intestine remains after surgery to address chronic inflammation, cancer, trauma or congenital conditions.
Because the small intestine is the principal nutrient absorber in the gastrointestinal system - the large intestine, or colon, mostly absorbs water - patients with short bowel syndrome may need to receive all their nutrition intravenously. In the new study, published April 3 in Gastroenterology, the investigators showed that in a preclinical model of short bowel syndrome, deleting the colon gene SATB2 prompts cells of the upper colon to change their identity to small intestine-like cells, restoring nutrient absorption and reversing weight loss.
"Our demonstration may help pave the way for a future gene therapy for short bowel syndrome," said study senior author Xiaofeng Steve Huang, an assistant professor of molecular biology research in medicine and a member of the Hartman Institute for Therapeutic Organ Regeneration at Weill Cornell Medicine.
The study's co-first authors were postdoctoral associate Tao Liu, and Shiri Li, a research associate in Dr. Alessio Pigazzi's laboratory. During the study, Liu and Huang, who are also co-corresponding authors of the paper, were members of the laboratory of Qiao Zhou, professor of regenerative medicine at Weill Cornell Medicine, who helped initiate and guide the study; Zhou died in June 2024.
Zhou and Huang and their colleagues discovered SATB2's key role in maintaining colon cells' "identity" in research published in 2021. They found that deleting this gene either in mouse or human colon cells causes the cells to start functioning like cells of the lowest portion of the small intestine, called the ileum, which normally is adjacent to the upper colon.
In the new study, they tested whether deleting the gene could improve nutrient absorption in preclinical models of short bowel syndrome, which affects an estimated 10,000 to 20,000 people in the United States. They found that mice that lost the gene quickly recovered their normal weights, and 80% survived for longer than 60 days - in contrast to the control mice that retained the gene, which had only 10% survival at 60 days. The investigators found that the tissue structure and the presence of blood and lymph vessels in the upper colons of the treated mice resembled that found in ileal tissue and supported ileum-like nutrient absorption.
Moving a further step toward human gene therapy, the researchers tested their strategy in small, organ-like tissue clumps called "organoids," which were derived from human colon cells. They used an adenovirus-associated virus (AAV) to deliver a gene editor for deleting SATB2 and showed that the treated colon organoids became ileum-like and were able to survive when transplanted into mice.
The team is continuing to develop its therapeutic strategy, and plans to test it on more advanced preclinical models of short bowel syndrome in the future, Huang said.
This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health, as well as Weill Cornell Medicine, a Tri-Institutional Stem Cell grant, and a grant from Sanofi.
Jim Schnabel is a freelance writer for Weill Cornell Medicine.
