Short bowel syndrome: how can gene and cell therapy help?

Adults and infants that have Short Bowel Syndrome (SBS) are unable to absorb enough water and nutrients. This is because they often have dysfunctional or atypically short small intestines. SBS can be serious, sometimes requiring nutrients and water to be supplied directly into the blood stream to avoid malnutrition and dehydration. Many medical advances have improved the survival of those affected by SBS, but this remains a debilitating disorder that is both difficult and costly to treat.

About SBS

Short Bowel Syndrome (SBS) is a group of conditions caused by the failure of the small intestine to absorb enough water, nutrients and minerals to sustain normal health and growth of the individual. SBS is often due to the small intestine being half the length (or less) of a normal small intestine. SBS can be diagnosed through physical exams, blood tests, x-rays and faecal fat tests, a test that indicates if the body is able to digest and absorb fats.

The small intestine

The small intestine is important for absorbing most of the nutrients and water that we consume, but there’s a lot going on in the intestine that most people don’t realise. Our intestines are part of a symbiotic relationship, creating an ideal growing chamber for bacteria to live in. Bacteria get food to grow on, a protected environment and an ideal temperature for growth. In turn, those bacteria help break down foods into molecules that our intestines can absorb or indeed that keep the intestinal lining healthy.

The small intestine also has many complex components that allow it to push food and waste and collect nutrients; a nervous system, muscles, a complex vascular (blood vessel) network, many types of specialized cells and, perhaps most importantly, stem cells. These ‘Tissue Stem Cells’ are critical for maintaining and repairing the intestine and are constantly making new cells. This is particularly important for the inner lining of the small intestine (the epithelium), which has many crevasses and extensions, called crypts and villi. The villi extend into the centre of the intestine and greatly increase the speed and ability of nutrient absorption. However, the cells that make up the villi are exposed to very harsh conditions, so they don’t live very long and need to be constantly replaced.

Stem cells that remain in the crypts (crevasses) have to replace ALL the villi cells in the small intestine every 3 to 5 days! These and other stem cells also help repair minor to moderate damage to the intestine. However, when major damage occurs stem cells might not be able to repair everything. This can lead to intestine failure, which is a very serious health concern and can be life threatening. To save lives, doctors may remove regions of failed or dead bowels in individuals. If these sections are large, it may lead to short bowel syndrome.

Finding stem cells

Stem cells are unique in their ability to both self-renew and generate cells that can become specialised. However, stem cells don’t always look very unique; under a microscope their size and shape may be the same as other cells around them. So how do researchers know which cells are which?

Researchers answer this puzzle by identifying genes that are specifically turned on in stem cells but not in other cells. These genes code for proteins that are needed to make the cells behave like the specific stem cells researchers are interested in studying. Because these proteins are unique to the cells, researchers call them “molecular markers”. Some researchers, like Kim Jensen at the University of Copenhagen, dedicate their labs to studying and looking for molecular markers of cells and stem cells. As for the small intestine, a major advancement was the identification of the protein “Lgr5” by Hans Clevers’ research group at the Hubrecht Institute in Utrecht as a unique molecular marker for the subset of stem cells responsible for making the intestinal epithelium (the inner most layer of cells).

Types of SBS

SBS is often discussed in the context of infants and adult cases. The majority of adult and infant SBS cases occur after damaged sections of the small intestine are surgically removed.

In adults, SBS can occur when a different medical problem requires the removal of half or more of the small intestine. Medical problems that may require removing parts of the intestine include things such as severe cases of Crohn’s disease, blood clots, death of neurons controlling the intestine, physical damage (like a serious wound to the abdomen) or ,very rarely, intestinal cancer.

In infants, developmental problems can cause parts of the small intestine to be severely damaged or start to die. One specific example of this is necrotizing enterocolitis, which is an infective/inflammatory process that causes parts of an infant’s intestine (including the intestinal lining layer, muscles and nerves) to die making the intestine non-functional. Surgical removal of these regions can greatly shorten the small intestine and lead to SBS. Alternatively, some infants suffering from SBS are born missing large parts of the small intestine, but this is less common.

Current treatment for SBS

Most treatments for SBS (for both infants and adults) begin with supplying nutrients and water directly to the blood stream (parenteral nutrition). This gives the intestine time to recover from any surgical treatments and then adapt to being shorter in length. However, even if the intestine does manage to adapt and parenteral nutrition is stopped, special diets and dietary supplements for individuals are often a permanent requirement.

Treatments may include the use of drugs (such as anti-diarrhoeals) to slow the digestive process and allow more time for nutrient absorption. Hormones are also commonly prescribed to promote the growth and adaptation of intestinal cells. In severe cases, small intestine transplants are performed. Transplants are challenging because the intestines normally hold bacteria, which can lead to infections. Also, intestine donors are limited. It’s important to realise that there are different sections of the small intestine, each with varying importance. Often transplants are only done if critical sections of the small intestine have been removed and need to be replaced.

Current research and clinical trials

From drugs to surgical methods and stem cells to growing synthetic intestines in a lab, all aspects and methods for treating SBS are being examined. Many researchers, such as Dr Simon Eaton who studies biochemistry and metabolism of the gut at University College London (UCL), focus on understanding how cells in the intestine change due to disease and surgical treatments, which is the first important step to addressing how to treat diseases and complications like SBS. Some research aims to prevent SBS, by exploring treatments (including stem cell treatments) for intestinal diseases before removing sections of intestine is required.

Clinicians are also examining what surgical strategies can be used to minimise the impact of removing sections of the small intestine. Surgical methods to treat SBS are being explored, such as introducing valves to the small intestine to slow down the passage of food. Methods for treating SBS include research into drugs and hormones such as Teduglutide, which promote intestinal cells to absorb more water and nutrients.

Some research groups are focused on small intestine bioengineering, the process of artificially building or growing segments of the small intestine for transplantation. One example of groups working to bioengineer segments of small intestine is the Intestinal Tissue ENgineering Solution (INTENS) collaborative research program (more on this below). However, advanced technologies like this are many years away from being used for treatment. Research takes years to develop into medical treatments, pass clinical trials and be approved as safe and effective for use in clinics.

If you are keen to know the latest news on SBS treatments, you can find many of the latest treatments being examined in clinical trials at clinicaltrials.gov. Please be aware that listing a trial on a database does not guarantee that it has been through a regulatory process. Please read any disclaimers, speak to trusted healthcare providers and learn about the risks and potential benefits.

How could regenerative medicine help?

Many of the research areas surrounding the treatment of SBS are actively interested in stem cells. Stem cells offer opportunities to repair, heal and regrow sections of the small intestine, but using them requires years of research to understand the basics of how stem cells work as well as how they might help treat diseases. Here are just a few ways that stem cells are being used.

One area of stem cell research is looking at treating medical problems of the small intestine before surgery is needed to remove damaged parts. For example, Nikhil Thapar’s laboratory at UCL has looked at ways to use stem cells to rebuild parts of the intestinal nervous system, which could treat individuals suffering from an “enteric neuropathy” (failure of the gut nervous system, sometimes also called “Intestinal pseudoobstruction”). Treatments that rebuild the intestine’s nervous system would greatly help prevent surgeries that lead to SBS.

Researchers are also using stem cells and patient tissue to grow small intestine ‘organoids’ (meaning organ-resembling). These tiny groups of cells arrange into a layer of cells with folds that mimic the structure and function of the inner lining of the small intestine (the epithelium). Organoids may be a cheaper and faster way to study how the intestine works, grows, heals from damage and replaces cells. They might also be useful to study diseases, drugs and new medical treatments in laboratories before trials are tested on animals or people. A key study from the INTENS project combined tissue engineering and the intrinsic ability of cells to self-organise to form mini-gut tubes that retained key features of the intestine, including specialised cell types and the capacity to regenerate. This demonstrates a way to guide stem cells to form organoids that more closely match the physiology of the real tissue, and such advances in organoid technology enable the next stages of research that are necessary before safe and effective treatment can be made available.

In cases where surgeries to remove the small intestine are unavoidable, stem cell transplants may be able to help repair the intestine after surgery and regrow some of the cells and tissue that has been lost. Alternatively, researchers part of the international collaborative INTENS project are examining how stem cells might be used to grow new segments of intestine on biological scaffolds that can be transplanted. This is an ambitious project because the intestine has many different types of cells that make the whole organ work. However, researchers are making progress, with the long-term aim being to deliver a functional small bowel.

One of the complex issues with building intestinal tissue in the lab is having stem cells correctly form the intestine’s shape. Research in Paolo de Coppi’s laboratory at UCL has shown that protein scaffolds, made from donor tissue stripped of all its original cells, provides a good starting structure for stem cells to adhere to and grow. Alongside, researchers in Vivian Li’s laboratory at The Francis Crick Institute have engineered small intestinal lining (mucosal) grafts using scaffolds and intestinal stem cells. By comparing scaffolds, researchers found that the small intestine and colon could be used interchangeably to reconstruct transplantable grafts. This opens up the possibility that colon tissue could be used for children who have lost their entire small bowel.

Other aspects of bioengineering new intestines, such as making the gut’s muscles and nervous system, are still underway and may take many years to develop into safe and reliable treatment options, but in the end the results could be well worth the work. Using an individual’s own stem cells to grow a bioengineered intestine would greatly reduce the chances of transplant rejection and avoids searches for compatible donors.

Acknowledgements and credits

This factsheet was created by Ryan Lewis in June 2017 and reviewed by Nikhil Thapar, University College London.

Updated in 2021 by Lucinda Tullie, Francis Crick Institute, and Amanda Waite. Reviewed by Vivian Li, Francis Crick Institute, and Brendan Jones, University College London.