The Role of Growth Factors and Glutamine in Enhancing Gut Adaptation

Alan L. Buchman, MD, MSPH

Over the past 15 years several growth factors and amino acids have been researched to see whether they can enhance bowel adaptability and therefore reduce parenteral nutrition (PN) dependency in patients with short bowel syndrome (SBS). Some of these therapies have shown modest improvements, which has led to the Federal Drug Administration’s (FDA) approval of growth hormone in the treatment of SBS; however most therapies are still in the research stages. This article will cover the factors that influence bowel adaptation and lower PN dependence; as well as some of the therapies being researched to enhance these efforts.

The potential for decreasing or eliminating the need for parenteral nutrition (PN) in a patient who has a shortened bowel depends on several variables. These include the length as well as the absorptive capacity of the remaining intestine, age, the absence of continuing disease in the remaining bowel (such as Crohn’s), the presence of the ileocecal valve (this joins the small bowel to the colon and acts as a break for fluid and nutrients), and the degree to which the small intestine adapts following a resection.
 

Adaptation is the process during which the intestine “grows.” It may become slightly longer, but more importantly, it increases in diameter; total surface area increases and absorption improves. Animal studies, and limited studies in humans, suggest this occurs when the villi (frond-like projections from the lining of the intestine) increase in size and number, and the crypts (where absorption occurs) increase in number and depth. This process occurs naturally, is thought to be most active in the first six months following resection, and is generally considered to be completed by one or two years.
 

One of the most important factors necessary to enhance this adaptive process is to eat. Eating helps release an intestinal growth factor from the salivary glands called epidermal growth factor (EGF). EGF is useful in simulating the intestinal cells to multiply and grow thereby increasing absorptive capacity. Other hormones produced in the intestine such as cholecystokinin, secretin and glucagon-like peptide, may also play a significant role in the adaptive process. Having adequate blood flow to the remaining intestine is important as well.
 

Fluid Losses

Normally the small intestine absorbs about 6 to 9 liters of fluid daily. The colon absorbs about 1 to 2 liters daily. These organs have the capacity to increase absorption to up to 12 liters and 4 to 5 liters daily, respectively. In patients with a jejunostomy from whom all of the ileum has been removed, and perhaps even part of the jejunum, a state exists where the secretion from the intestine is greater than the amount of fluid consumed by mouth. In other words, these patients are losing more fluid from their bowels each day than they are drinking.
 

In addition, the stomach secretes a lot of fluid during the first six months following a massive resection of the small intestine. The reason for this is unclear, but may relate to the loss of some hormonal block. This may result in further fat malabsorption because the stomach acid breaks down the enzyme lipase, which is necessary to digest fat, and may also break down bile salts which are necessary for fat absorption. Typically, for the first six months or so, this gastric hypersecretion is treated with intravenous or high dose oral proton pump inhibitors such as Nexium®, omeprazole, Protonix®, or Prevacid®. Older medications such as H2 blockers (Tagamet®, Pepcid®, etc.) may also be useful if used in sufficiently high doses. Somatostatin (octreotide) is rarely used because some experimental evidence in animals suggests its use may decrease the adaptation process.
 

Fluid losses should be replaced by drinking oral rehydration solutions. Such solutions were designed knowing that when the intestine absorbs salt, it absorbs sugar, and vice versa. When either salt or sugar is absorbed, water is absorbed as well. When the concentration of salt in a solution taken by mouth is too low (lower than the concentration in blood, for example), the intestine secretes salt in order to bring the concentration of the ingested solution up to that of blood. That results in the secretion of salt and water. Therefore, drinking water may be worse than drinking nothing at all, as it may worsen dehydration. Similarly drinking fluids with high sugar, but no salt, like soda and juice can actually make the patient more dehydrated. Ideally the amount of salt in the solution should be at least 90meg/liter. Solutions such as the World Health Organization rehydration solution, CeraLyte®, or Pedialyte® (with an extra teaspoon of salt added per liter) can be used.
 

The World Health Organization formula is available in prepackaged form from Jianas Brother Packaging Co. (2533 Southwest Blvd., Kansas City, MO 64108; 816-421-2880).  If you choose to make the rehydration fluid yourself, the recipe is as follows: 1 liter water, 3/4 tsp. table salt, 1/2 tsp. baking soda, 1 cup orange juice, and 4 tbs. table sugar. Flavoring may be added by using sugar-free Kool-aid® or Crystal Light®. CeraLyte is available either on their website, www.ceraproductsinc.com or by contacting the company (9017 Mendenhall Court, Columbia, MD 21045;888-ceralyte). Indicate that you are an Oley member to receive a 15% discount.”

Nutrient Absorption

The length and absorptive capacity of the remaining bowel is critical in determining a patient’s level of PN dependency. To some degree, what’s left of the intestine, jejunum (proximal) or ileum (distal), can pick up the slack left from where the other has been removed. The exceptions are that vitamin B12 and bile salts are absorbed only by specialized cells in the terminal or end part of the ileum. When the bile salts cannot be re-absorbed, they pass into the colon. In the colon they can cause the secretion of fluid, which results in increased diarrhea. In addition, bile salt deficiency may develop and the malabsorption of fat and fat-soluble vitamins A, D and E may worsen.
 

The colon also plays an important role. It is critical to make use of whatever portion of the colon is available to digest certain nutrients including carbohydrates, fatty acids, electrolytes and some amino acids. Complex carbohydrates that are not absorbed by the small intestine pass into the colon. Bacteria normally present in the colon ferment these carbohydrates and soluble fibers to short chain fatty acids. These fatty acids (butyrate, acetate, propionate) are fuel for cells of the colon  and their absorption by the colon’s cells results in net energy absorption. Thus it is important to have the colon connected to the remaining small intestine whenever possible. Those individuals with the most remaining colon generally have the least fluid loss and need the least PN.
 

Finally, age and disease effect nutrient absorption. Younger patients generally do better, but there isn’t much one can do about age. However, diseases like Crohn’s, recurring in even a small segment of intestine can reduce absorption, and must be aggressively treated.
 

Artificial Enhancements

There is a limit to the natural adaptation process. In an attempt to artificially enhance the normal adaptive process, several studies have researched the effects of growth hormone, and/or glutamine.
 

An early study by Dr. Douglas Wilmore and Theresa Byrne suggested providing growth hormone and glutamine, together with a modified diet, would lead to a decrease in the amount of PN patients required. However, the majority of the patients studied had a colon and could decrease their fluid losses simply by changing their diet. Similarly, the progress made by other patients in the study could be attributed to an increase in their overall food intake and consumption of oral rehydration solutions, rather than the growth hormone or glutamine. In addition, there may have been a placebo effect or biased results since the patients, as well as the investigators, knew the patients were receiving a treatment that was supposed to work. Subsequent studies, where the patients did not know whether they received treatment or a placebo yielded little or no decrease in PN dependence. Since then a study in France of patients given only growth hormone, showed a modest improvement in both fluid and nutrient absorption.
 

Most recently, a study was undertaken that included 41 patients. This four-week study had three groups of patients: those that received only a specialized oral diet and glutamine, those that received the diet and growth hormone, and those who received the diet, growth hormone and glutamine. PN was able to be decreased in all patient groups, but more so in those patients that received growth hormone than in those that received the new diet alone. Patients that received growth hormone were able to reduce their PN by an extra day per week. The addition of glutamine had a modest, but not significant, effect on reducing PN requirements. Unfortunately absorption of fluid and nutrients was not measured. This study led to the Food and Drug Administration (FDA) approval of growth hormone for the treatment of short bowel syndrome. Side effects from growth hormone were reported, although these were generally mild. Some patients developed swelling because of the fluid retention induced by the growth hormone, and painful joints (most likely related to fluid accumulation in the joints). The joint pains resolved with growth hormone dose reduction and/or Tylenol®. Other studies have reported the rare development of carpal tunnel syndrome and high blood sugar.
 

Glucagon-like peptide-2 or GLP-2 is a growth factor that is released in healthy individuals from specialized cells in the distal small intestine and beginning part of the colon in response to eating a meal. Investigators in Denmark found GLP-2 levels did not increase in SBS patients after eating because they were missing the cells that normally produce the hormone. When GLP-2 was administered to SBS patients over a six-week period, fluid absorption improved to a modest degree. The problem is this growth factor is very rapidly metabolized by enzymes in the intestine. Subsequently, Dan Drucker at the University of Toronto, found a way to alter GLP-2 so that it still had the same effects, but lasted longer in the intestines. The resultant teduglutide is currently undergoing investigation across the U.S. and in Europe to determine how it can be used to reduce PN volume and frequency. Initial results have indicated this new growth factor may have some efficacy in decreasing PN.
 

There are various other growth factors that are just starting to be evaluated for potential therapeutic use. These include neurotensin, transforming growth factor, hepatocyte growth factor (which, interestingly, has greater effects on the intestine than on the liver), keratinocyte growth factor and others. They may be useful in decreasing the frequency of intravenous fluid and PN use in those that require a significant amount, such as 5 to 7 nights a week, but will likely be of greatest use in the individual that requires a minimal amount of PN or perhaps only intravenous hydration fluids.
 

Information regarding these issues is a “work in progress” and more research is continuing. If you are interested in finding out more about growth hormones, or participating in a study of GLP-2 or any other growth hormone, be sure to discuss it with your physician. More information is also available by calling the Oley office (800-776-OLEY).
 

Dr. Buchman is an Associate Professor of Medicine and Surgery in the Division of Gastroenterology at the Feinberg School of Medicine, at Northwestern University, in Chicago, Illinois.