Gastric bypass surgery is one of the most commonly performed weight-loss procedures in the U.S. and globally. As well as enabling patients to lose significant amounts of weight, the procedure is also better than drug treatment at managing type 2 diabetes (T2D), independently of weight loss. However, while the surgery results in multiple benefits to patients, and improved quality of life, relatively few patients will go under the knife.
A team headed by researchers at Brigham and Women’s Hospital (BWH), Harvard Medical School, has now developed a material that effectively mimics the effects of the Roux-en-Y gastric bypass (RYGB) procedure. Formulated as an oral pill, the substance—which they called LuCI, or luminal coating of the intestine—is designed to temporarily coat the intestine and act as a barrier that blocks dietary nutrients from contacting the lining in the small intestine. Tests in rats showed that oral administration of LuCI prevented the spikes in blood sugar levels that otherwise result after eating a meal, and suggest that the treatment could feasibly help to treat type 2 diabetes.
“What we've developed here is essentially, 'surgery in a pill,'” says Yuhan Lee, Ph.D., a materials scientist in the BWH Division of Engineering in Medicine. “We've used a bioengineering approach to formulate a pill that has good adhesion properties and can attach nicely to the gut in a preclinical model. And after a couple of hours, its effects dissipate.” Dr. Lee is co-senior author of the team’s paper, entitled, “Therapeutic Luminal Coating of the Intestine,” which is published today in Nature Materials.
RYGB surgery effectively bypasses a significant portion of the stomach and small intestine, and obese T2D patients who undergo the procedure experience “an early and weight-independent improvement or complete resolution of their T2D,” the researchers write. “In fact, 80% of the patients who have RYGB experience early remission of their T2D.”
However, as the team points out, the risks of surgery, combined with the fact that the procedure makes permanent changes to gastrointestinal anatomy, have held back widespread acceptance, and only 1% to 2% of eligible patients will have the surgery.
As an alternative approach, the researchers set out to develop a material that could coat the small intestine as a barrier, but then dissolve after a few hours. “Gastric bypass is one of the best-studied surgeries in the world, and we know that it can lead to many benefits, including positive effects for blood pressure, sleep apnea, and certain forms of cancer, and a remarkably fast and weight-independent improvement in diabetes,” comments Ali Tavakkoli, M.D., co-director of the Center for Weight Management and Metabolic Surgery at BWH. “Having a transient coating that could mimic the effects of surgery would be a tremendous asset for patients and their care providers.”
The team screened potential candidates that are either on the FDA’s generally recognized as safe list, or that are components in FDA-approved orally administered products. Their search identified sucralfate, a drug that is used to treat gastrointestinal ulcers, as a top candidate. Sucralfate creates a sticky paste in acidic environments, such as the stomach, and binds to ulcerated areas of the gastric lining where the pH is particularly low because the gut’s own bicarbonate secreting machinery is malfunctioning.
However, in vitro and in vivo tests in rats showed that sucralfate wasn’t as effective at coating healthy gastric mucosa, where the pH is higher than it would be in ulcerated gastric environments. The researchers had to make some modifications to the sticky LuCI compound to make it less dependent on pH, so that it would coat all areas of the gastrointestinal tract, without the need for stomach acid. Initial tests with the modified compound were encouraging, and showed that “unlike sucralfate, the barrier property of LuCI is retained in higher pH environments similar to the environment at different locations in the gastrointestinal tract.”
The team then used a variety of techniques to dry the LuCI pastes into a powder that could be packaged into a pill format. When mixed with water or other simulated body fluids, the powder simply reconstituted into the sticky, water-immiscible pastes that coated the gastric lining. Initial tests in healthy rats showed that the LuCI paste formed a layer in the stomach and small intestine, and was stable over the 5-hour period of study, but dissipated within 24 hours. Histological analyses showed that the coating had no adverse effect on the lining of the small intestine, and the treatment didn’t cause the animals to develop diarrhea or lose weight, “which suggests a favorable biocompatibility of LuCI on the gastrointestinal mucosa.”
Further in vivo tests demonstrated that the LuCI coating acted as a nutrient barrier in the small intestine, lowering glucose response following glucose administration using a standard oral glucose tolerance test (OGTT). Interestingly, low-viscosity LuCI pastes resulted in much higher reduction in blood glucose responses than higher viscosity pastes, and the effects on glucose response reduction were more marked when the glucose was administered just one hour after the LuCI treatment than when given three hours after LuCI administration. In a separate set of tests, the team also showed how the LuCI formulations can also act as a delivery vehicle for therapeutic proteins, protecting the biologic molecules from degradation by stomach acid and other intestinal fluids.
“We showed that LuCI forms a transient physical barrier on the luminal surface of the gastrointestinal tract and, in essence, emulates a critical part of bariatric surgery in a non-invasive way,” the authors conclude. “…in addition to controlling nutrient absorption, LuCI may find clinical use as a protein delivery vehicle.”
“We envision a pill that a patient can take before a meal that transiently coats the gut to replicate the effects of surgery,” comments co-senior author Jeff Karp, Ph.D., a bioengineer and principal investigator at BWH. “Over the last several years, we've been working with our surgical colleagues on this idea and have developed a material that meets an important clinical need.”