September 20, 2010

That Queasy Feeling

John Y. Kao, M.D., Nirmal Kaur, M.D., and Vincent B. Young M.D.,Ph.D.
Gastro-intestinal distress? Could be an imbalance among the billions of microbes in your GI tract. Probiotics may help.
John Y. Kao, M. D, is Assistant Professor, Nirmal Kaur, M.D., is Fellow and Vincent B. Young, M.D., Ph.D., is Assistant Professor, Department of Internal Medicine, Infectious Diseases Division, Department of Microbiology & Immunology, University of Michigan Medical School, Ann Arbor, Michigan.

It’s a subject that many of us are not typically wildly excited to discuss: our gastrointestinal system, or GI tracts. The interworkings of our bowels present somewhat of a mystery to most, and talking about them and understanding just how they function can make people feel uneasy, queasy, or just plain grossed out. However, the functioning of our GI systems is central to our health and well-being, and the complexity of their operation is actually rather astounding. Not only is the system responsible for absorbing the vital nutrients that we eat to nourish our bodies, but it also has the hefty task of ridding the body of all the things that we don’t want in it, like waste matter and harmful toxins.

When it comes to our GI tracts "we’re not alone", so to speak. There are billions and billions of organisms, known as microbes, that live in our GI system.

The GI tract technically consists of everything from where food enters your body to where it exits. So the GI tract is made up of the mouth, esophagus, stomach, small intestine, large intestine (including colon and rectum), and anus. Food is moved through the digestive system with a rhythmic, wavelike motion called peristalsis. To coordinate the many actions and responsibilities of the GI tract, a nervous system, known as the enteric nervous system controls how the gut works. In fact, there are as many neurons on the enteric nervous system as there are in our spinal cords.[A]

But even given this complexity, there’s still more to the story than just this. Many people may be aware that when it comes to our GI tracts "we’re not alone", so to speak. There are billions and billions of organisms, known as microbes, living in our GI system. Once upon a time, the medical community assumed that these tiny organisms were just hitching a ride on unsuspecting hosts (us), without actually contributing anything to our general well-being.

Now, however, there’s overwhelming evidence to suggest that these microorganisms are actually extremely beneficial, and that they play key roles both in maintaining the health of our GI systems (and, in many ways, the rest of our bodies) and in the development of disorders and diseases of the GI tract.

Under normal conditions, these microbes interact with and affect the cellular lining of the GI tract as well as with the immune systems of the human (or animal) in which they’re living. The relationship, known as "symbiosis", is complicated one — but in its normal state, symbiosis provides a benefit to all parties involved. But if the normal balance is upset for any reason, disease can result. This article will go over how microbes in the gut function overall, and what can occur if the natural balance of these interesting organisms gets out of whack.

Just What Do The Microbes of the Gut Do?

The number of microorganisms living in the intestines is staggering. There aren’t just a few different types, but rather there are at least 10,000 different species of microorganisms that dwell in the gut. Researchers have had to design clever methods (mostly using complicated RNA and DNA techniques) to determine the likely number of these organisms, because many of them won’t grow in culture, which makes them difficult to study.

Changes in the makeup of the microorganism population are related to obesity, inflammatory bowel disease (IBD), and diarrhea that may be a side-effect of antibiotic use.

A variety of factors affects the balance of species, like a person’s nutrition, one’s physiology in general, his or her immune system and general health. The makeup of the population of microbes can vary quite a lot among people and even within a single person over a period of time, as the factors mentioned above can change considerably throughout the years.

The Human Microbiome Project is a large and ongoing set of studies to understand exactly how these little critters affect human health and well-being.

The variety of functions that microbes play is almost as impressive as their number. Functions range from helping us metabolize nutrients in the food we eat to helping the gut develop. What’s more, changes in the makeup of the microorganism population are related to obesity, inflammatory bowel disease (IBD), and diarrhea that may be a side-effect of antibiotic use. All these changes that we feel on our end are thought to be related to changes in the metabolic activity of the microorganisms in our guts, or how they interact with our immune systems. All these reasons are why the makeup of the microbe population can have such strong effects on our overall health.

Changes in Microbe Makeup Can Lead to Intestinal Diseases and Distress

Since it is clear that the microbes that inhabit our G.I. tract can help keep us healthy, disturbances in this complex community can lead to a variety of illnesses. In some ways, this is quite different from what we think of when we consider how microbes might make us ill. We are used to thinking about a microbe causing an "infection" by invading our body, but it’s a different way of thinking to consider that the lack of particular microbes or perhaps a change in the community of microbes can make us sick. In the following sections we will discuss a number of illnesses where changes in the G.I. microbes are thought to contribute to the disease process.

Inflammatory Bowel Disease (IBD)
Inflammatory Bowel Disease is thought to develop at least partially from problems in the balance of the normal microbes in the gut. (IBD actually includes two different subtypes: Crohn’s disease and ulcerative colitis, both of which can cause chronic inflammation and pain in the gut.) Changes in the makeup of the microbes in the intestines have been shown in patients with IBD (specifically lower concentrations of Bacteroides fragilis and Bacteroides vulgates). Administering the Bacteroides fragilis to mice has actually been shown to protect them from developing ulcerative colitis. Studies in children with IBD (both Crohn’s disease and ulcerative colitis) have also shown lower levels of certain types of bacteria, as well as differences in the way the bacteria are distributed throughout the small intestines and colon, compared to healthy kids.

More evidence for the IBD-bacteria connection comes from the fact that the body seems to be making antibodies to certain bacteria in IBD patients.

We’ve all heard horror stories about people getting sick from ingestion of a particular strain of Escherichia coli (E. coli), but some studies have actually linked the bacteria to the presence of Crohn’s disease. One study found that E. coli were more abundant in people with Crohn’s disease, but less common in people with ulcerative colitis and healthy individuals. In another study, E. coli was present in 22% of patients with Crohn’s disease but only 6% of healthy controls, and others have found similar variations in people with both forms of IBD.

More evidence for the IBD-bacteria connection comes from the fact that the body seems to be making antibodies to certain bacteria in IBD patients. However, it is unclear whether these immune system changes are actually due to the presence of bacteria in certain parts of the gut, or whether the bacteria may actually be relocating because of a leaky lining in the gut. More research will obviously be needed to tease apart the IBD-microbe connection, but what’s known so far looks promising.

Irritable Bowel Syndrome
Irritable Bowel Syndrome (IBS) is another syndrome that may be linked to changes in the microbes of the gut. IBS is characterized by bloating, cramping, abdominal discomfort, and diarrhea and/or constipation. It is considered a syndrome rather than a disease partly because the gut appears normal under close inspection, but the way it functions (and passes matter along) seems to present the problem. Though the medical community does not fully understand just how and why IBS originates, more and more evidence is pointing to a gut-microbe link. For example, people with IBS seem to have lower concentrations of the bacteria lactobacilli and bifidobacteria in their intestines. As techniques become more advanced, the connection between IBS and both lactobacilli and bifidobacteria has become more clear, and more studies are able to arrive at the same results. If these strains of bacteria seem familiar to you, they probably are: they are found in many yogurts and nutritional supplements, and are often touted for their intestinal health benefits. Perhaps it’s not so far a stretch to think that they may also play a role in more serious disorders of the intestinal tract.

Diarrhea from Antibiotics? Gut Microbes May Be the Culprit
As mentioned earlier the vast array of microbes that lives in the intestines of humans and other animals coexist peaceably with their hosts under normal conditions. Though we hardly notice their existence, we depend on it greatly. As they metabolize their own food they actually participate in our own digestion by helping us break down nutrients. However, they also release other chemicals and antigens that can affect our metabolism and immune systems. For these reasons, changes in the microbial "community" can have significant effects on our overall health.

For example, changes in the gut’s microbe population have been linked to obesity, inflammatory bowel disease, and the diarrhea that comes with the use of antibiotics. All of these conditions are probably the results of changes in the metabolism of the gut microbes or in how they interact with our immune systems. It is very likely that this is what is going on with antibiotic-associated diarrhea (AAD), which is simply diarrhea that is with a side-effect of the administration of antibiotics without another obvious cause. The frequency of AAD varies among different antibiotics but it may occur in as many as 25% of people who take antibiotics, which is a fairly high proportion.

The bacterium Clostridium difficile is thought to be linked to AAD, partly because it has occurred in hospital outbreaks. Administering the antibiotic clindamycin has often been linked to an increased risk of developing C. difficile-associated diarrhea (CDAD). There are other antibiotics that are also connected to CDAD, which include are ampicillin, amoxicillin and the cephalosporins. Although C. difficile probably only causes about 15-25% of all AAD cases, it is thought to be responsible for other gastrointestinal diseases as well. Hospital-related C. difficile infections in the United States are thought to cost us over $1.1 billion per year.

Changes in the gut’s microbe population have been linked to obesity, inflammatory bowel disease, and the diarrhea that comes with the use of antibiotics. All of these conditions are probably the results of changes in the metabolism of the gut microbes or in how they interact with our immune systems.

How do these harmful bacteria sneak in to a healthy gut? It is thought that a normal intestine can resist invasion by harmful bacteria like C. difficile because of the natural balance of microorganisms that is established under healthy conditions (this idea is known as "colonization resistance"). When people are infected by the bacterium, however, it is believed that this can only happen because the natural equilibrium has already been disrupted (such as by the use of antibiotics). Some studies have actually explored this idea using hamsters, and found that the natural balance of microbes in the gut does seem to ward off invasion by harmful intruders like C. difficile. However, because the little critters are so resistant to being cultured, it has been very difficult to study exactly which members of the microbe community play the largest roles in resisting invasion.

But there are other causes for diarrhea besides C. difficile. Researchers believe that in the other 75% of AAD cases, changes in the normal population of microbes actually interferes with the way we digest carbohydrates, and it is this that brings about the diarrhea. One study looked at how the population changes in one person who was on two common antibiotics (amoxicillin and clavulanic acid), and found that one type of bacteria (in the Clostridiaceae family) was dramatically reduced. And, interestingly, this is bacterium that helps us break down complex carbs into the end products that the cells of the colon use for energy. After this patient stopped taking the antibiotics, the levels of this beneficial bacterium returned to normal.

This case illustrates beautifully how what we put in our bodies can affect the microbes in our guts, which in turn affect the well-being of our own bodies. Other studies have shown how the diversity of the gut’s normal microbe population is drastically reduced after recurring C. difficile infections, and underline just how important the delicate microbial balance is to our intestinal health.

Probiotics May Help

Given the fact that gut microbes help us maintain our health as well as lead to disease, administering them in various ways may help prevent and treat certain conditions and diseases. Antibiotics use is one way that we have done this, but it also has its drawbacks, such as, infections of damaging bacteria like C. difficile mentioned above. On the other hand, antibiotics have been used successfully in treating diseases like IBD and possibly others. But there are other ways in which we can harness the power of microbes in order to boost our overall health and fight off disease.

The use of probiotics has gained much attention in recent years. The two mentioned above, lactobacillus and bifidobacterium, have gotten particular attention. Probiotics are usually defined as "live microorganisms, which when administered in adequate amounts, confer a health benefit on the host." Although the potential advantages of using probiotics to shift the makeup of the gut’s microbe population seem very promising, the research to back this up is just getting underway. Below are some of the conditions that do appear to be helped by the use of probiotics.

Irritable Bowel Syndrome
Since standard treatments for IBS are either less-than-effective or come with side effects, probiotics may offer an attractive alternative to IBS sufferers. One of the most promising probiotics for the treatment of IBS is Bifidobacterium infantis, which several studies have shown to be quite effective in reducing IBS symptoms. Other studies have found other probiotics to be promising as well, but they will need larger follow-up studies to confirm their results.

Ulcerative Colitis
There’s also some nice evidence that probiotics may also help with ulcerative colitis (UC). In one study, patients were given milk that had been fermented with Bifidobacteria, and showed significant improvements in symptoms, compared to people who were given regular milk. Another study looked at how the supplement known as VSL#3 might help patients with UC. VSL#3 is a mixture of eight different probiotic strains, including Lactobacillus and Bifidobacterium, and can be purchased at many drug and health food stores. When UC patients were given the supplement for six weeks, 53% experienced remission of their symptoms. Some studies in children have also found that VSL#3 can be used to help maintain remission of UC following initial treatment methods. VSL#3 may also be used to treat other conditions (see pouchitis, below).

Crohn’s Disease
There is less evidence that probiotics help Crohn’s disease patients, possibly because of the presumption that probiotics may only help microbe imbalances in the colon and may have less influence on the bugs in the small bowel where we commonly find Crohn’s disease. However, [A1] one study has found that VSL#3 was about twice as effective as placebo in preventing Crohn’s disease from recurring after surgery. More studies are required to see if probiotics are helpful in Crohn's patients.

There is less evidence that probiotics help Crohn’s disease patients, possibly because practitioners support the theory of colonic dysbiosis as a contributing factor of UC and pouchitis, and because of the regional ileal distribution of Crohn’s disease. Some studies have found that VSL#3 was about twice as effective as placebo in preventing Crohn’s disease from recurring after surgery.

Antibiotic-Associated Diarrhea (AAD) and C. difficile
According to some studies, there seems to be great promise for using probiotics to help treat AAD and our "difficult" bug C. difficile. But because others have not reached the same conclusions, the medical community has been reserved about recommending probiotics for this purpose. But it’s generally agreed that follow-up studies are very much needed to determine whether — and which — probiotics might be an effective treatment for AAD.

Pouchitis is a condition in which the surgical pouch, a reservoir created to store stool before a bowel movement, becomes inflamed. Some studies have found that taking the supplement after the surgery resulted in a much lower rate of developing pouchitis than people who took placebo. Others have also found that VSL#3 lowers incidents of remission and helps maintain health after the initial surgery. These types of studies show that probiotics can be extremely useful in both preventing and treating certain gastrointestinal conditions.


Medical researchers now appreciate that the microbes that normally inhabit the gut are more than mere "freeloaders" looking for an easy meal. Instead, these microorganisms play a key role in maintaining our gastrointestinal health. Developing more sophisticated techniques has allowed researcher to understand just how these microorganisms function in both health and diseased states. As researchers continue to study these beneficial beings, it is likely that we will learn more about how to harness their powers, so to speak — as with probiotics — to treat a variety of gastrointestinal diseases and maintain good intestinal and overall health.

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