Researchers Identify Gene Mutations Underlying Risk for Most Common Form of Parkinson's Disease

Two genes containing mutations known to cause rare familial forms of parkinsonism are also associated with the more common, sporadic form of the disease where there is no family history, researchers have found.
The finding came in the largest genome-wide association study (GWAS) reported to date involving Parkinson's disease. GWAS studies look in the DNA on all of the chromosomes in a specific population of individuals for common genetic associations with a disease. To date, such studies have been done on relatively small numbers of samples and have not been able to identify genetic variations of smaller effect in Parkinson's disease. But now, GWAS studies in very large sample sets are able to identify these elusive genetic variations.

Collaborating scientists in the United States and Europe pooled nearly 14,000 DNA samples and data to confirm that mutations in the alpha-synuclein (SNCA) gene and microtubule associated protein tau (MAPT), both present in the general population, are risk factors for sporadic Parkinson's disease.

In an independent study from Japan, researchers also identified a different combination of genetic variants as risk factors in people of Japanese descent, a finding that highlights the power of GWAS in comparing risk factors among different populations.

The findings presented in the Nov. 15, 2009, online issue of  were supported in Nature Genetics part by the National Institute on Aging (NIA), National Institute of Neurological Disorders and Stroke, National Cancer Institute, and the National Institute of Environmental Health Sciences, all components of the National Institutes of Health.

Parkinson's disease, which affects about 1.5 million Americans, is a progressive neurologic disorder caused by the degeneration of nerve cells in the portion of the brain that controls movement. The likelihood of developing the disorder increases with age and involves a combination of environmental risk factors and genetic susceptibility. GWAS studies require large numbers of DNA samples — a hurdle the international team of researchers overcame through collaboration.

"Because previous Parkinson's GWAS were too small and lacked power, we worked together to compile and analyze the large data sets needed to identify the elusive genetic variations that play a role in this complex disease," said Andrew B. Singleton, Ph.D., chief of the NIA Laboratory of Neurogenetics, who co-led the study with Thomas Gasser, M.D., of the Hertie Institute for Clinical Brain Research, University of Tubingen, and the German Center for Neurodegenerative Disease, of Tubingen, Germany. "With this better understanding of the underlying genetic variants involved in the progress of this disorder, we have more insight into the causes and underlying biology of this disease. We hope this new understanding will one day provide us with strategies to delay, or even prevent, the development of Parkinson's disease."

The two-phase GWAS first analyzed DNA samples of 1,713 people with the disease and 3,978 free of the disorder, all of whom were Europeans. The findings were then replicated in a similar group of 3,361 people with Parkinson's disease and 4,573 without the disorder. Following the initial findings implicating SNCA and MAPT variants as risk factors for typical Parkinson's disease, the team then compared results with researchers performing a GWAS study in a group of Japanese people (2,816 with Parkinson's disease and 3,401 free of the disorder). This second GWAS also strong association for SNCA but not for MAPT.

Additionally, both GWAS studies found evidence for two additional risk variants; the first, which was strongest in the Japanese population, was namerevealed the d Park16; the second is close to a gene, LRRK2, which Dr. Singleton's and Dr. Gasser's groups previously found contains mutations that cause an inherited form of Parkinson's disease.

"These findings support the notion that the sporadic and rare familial forms of the disease are related and that common genetic variability plays a role in developing the disorder," said NIA Director Richard J. Hodes, M.D. "Future GWAS involving greater numbers of DNA samples will likely reveal additional common genetic risk factors. As we continue to use these and other novel approaches to understand complex diseases, we move closer to a complete understanding of the genetic basis of Parkinson's disease."

Source : National Institutes of Health

Smart phones allow quick diagnosis of acute appendicitis

Radiologists can accurately diagnose acute appendicitis from a remote location with the use of a handheld device or mobile phone equipped with special software, according to a study presented today at the annual meeting of the Radiological Society of North America (RSNA).

"The goal is to improve the speed and accuracy of medical diagnoses, as well as to improve communications among different consulting physicians," said the study's lead author, Asim F. Choudhri, M.D., fellow physician in the Division of Neuroradiology at Johns Hopkins University in Baltimore. "When we can make these determinations earlier, the appropriate surgical teams and equipment can be assembled before the surgeon even has the chance to examine the patient." 

Appendicitis, or inflammation and infection of the appendix, is a medical emergency requiring surgical removal of the organ. Undiagnosed or left untreated, the inflamed appendix will rupture, causing toxins to spill into the abdominal cavity and potentially causing a life-threatening infection.

Appendicitis can occur at any age but is most common in people between the ages of 10 and 30, according to the National Institutes of Health.

Typically, a patient arriving at the emergency room with suspected appendicitis will undergo computed tomography (CT) and a physical examination. If a radiologist is not immediately available to interpret the CT images or if consultation with a specialist is needed, diagnosis is delayed, increasing the risk of rupture. Transmitting the images over a mobile device allows for instant consultation and diagnosis from a remote location. It can also aid in surgical planning.

"This new technology can expedite diagnosis and, therefore, treatment," Dr. Choudhri said.

For the study performed at the University of Virginia in Charlottesville, CT examinations of the abdomen and pelvis of 25 patients with pain in the right lower abdomen were reviewed over an encrypted wireless network by five radiologists using an iPhone G3 equipped with OsiriX Mobile medical image viewing software. All of the patients had surgical confirmation or follow-up evaluations to confirm whether or not they had appendicitis.

"The scans can be read in full resolution with very little panning, and the software allows the reader to zoom and adjust the contrast and brightness of the image," Dr. Choudhri said. "The radiologist is evaluating actual raw image data, not snapshots." 

Fifteen of the 25 patients were correctly identified as having acute appendicitis on 74 (99 percent) of 75 interpretations, with one false negative. There were no false positive readings. In eight of the 15 patients who had appendicitis, calcified deposits within the appendix were correctly identified in 88 percent of the interpretations. All 15 patients had signs of inflammation near the appendix that were correctly identified in 96 percent of interpretations, and 10 of the 15 had fluid near the appendix, which was correctly identified in 94 percent of the interpretations. Three abscesses were correctly identified by all five readers. 

"The iPhone interpretations of the CT scans were as accurate as the interpretations viewed on dedicated picture archiving and communication system (PACS) workstations," Dr. Choudhri said. 

Dr. Choudhri pointed out that patient privacy concerns would have to be addressed before any handheld mobile device could be considered practical for clinical use, but noted that this technique has great potential for improving emergency room care. 

"We hope that this will result in improved patient outcomes, as evidenced by decreased rates of ruptured appendicitis, shorter hospital stays and fewer complications," he said.

Source: Radiological Society of North America

New stem cell technology leads to better treatment for complicated bone fractures

    A novel technology involving use of stem cells, developed by Hebrew University of Jerusalem researchers, has been applied to provide better and rapid healing for patients suffering from complicated bone fractures.

The technology, involving isolation of the stem cells from bone marrow, was developed by Dr. Zulma Gazit, Dr. Gadi Pelled, Prof. Dan Gazit and their research team at the Skeletal Biotechnology Laboratory at the Hebrew University Faculty of Dental Medicine and was given public exposure in an article that appeared in the prestigious journal Stem Cells. The technology has now successfully been used to treat complicated fractures in seven patients at the Hadassah University Hospital in Ein Kerem, Jerusalem.

To date, in clinical orthopedics, standard treatment for severe bone loss has involved either amputation or a prolonged period of disability. The use of prosthetic implants tends to fail in the long term. Excessive bone loss may result in non-uniting fractures, which are observed in more than one million new cases per year in the US alone.

In recent years, the use of mesenchymal stem cells (MSCs, or multipotent stem cells that can differentiate into a variety of cell types) has been claimed to be a promising biological therapy that could be used to treat complicated fractures and other disorders in the skeleton. These cells constitute a unique population of adult stem cells that can readily be isolated from various sites in the human body, especially from bone marrow and adipose (fat) tissues. Following isolation, MSCs can be utilized to repair a variety of injured tissues including bone, cartilage, tendon, intervertebral discs and even the heart muscle.

The conventional method of MSC isolation, using prolonged periods of growth in designated incubators, has proved to be laborious, costly and also possibly injurious to the therapeutic quality of the cells. Therefore, an alternative method involving the immediate use of these stem cells was an unmet need in the field of regenerative medicine.

Now, the Hebrew University group has developed a technology called immuno-isolation in which MSCs are sorted out from the other cells residing in a bone marrow sample, using a specific antibody. In the Stem Cell paper it was shown that the immuno-isolated cells could be immediately used to form new bone tissue when implanted in laboratory animals, without having to undergo a prolonged incubator growth period.



Following this breakthrough, a unique and close collaboration was established among clinicians (Prof. Meir Liebergall, head of orthopedics, Hadassah University Hospital), the Good Manufacturing Practice (GMP) facility at Hadassah (Headed by Prof. Eithan Galun) and the Gazit group at the Faculty of Dental Medicine.
Within this collaborative effort, a clinical-grade protocol for the use of immuno-isolated MSCs was established. Subsequently a clinical trial was initiated at Hadassah, aimed at establishing the foundation for the use of immuno-isolated MSCs in orthopedic surgery. 

To date, seven patients suffering from complicated fractures have been treated successfully with a combination of their own immuno-isolated MSCs and blood products. The entire procedure lasted a few hours and without any need to grow the cells for weeks in a laboratory.


It is anticipated that future development of the current endeavor will extend to treat other injuries in the skeleton, such as degenerated intervertebral discs or torn tendons. The Gazit group believes that further clinical trials will demonstrate that the immuno-isolation technology is useful in overcoming morbidity in patients suffering from skeletal fractures and diseases, and might restore function and quality of life to sick and injured people.

In this regard, Yissum Research Development Company of the Hebrew University of Jerusalem, the technology transfer arm of the university, licensed the immuno-isolation technology to TheraCell Inc. of California in July 2009. TheraCell aims to further develop and commercialize the technology for advanced regenerative medicine procedures such as spinal fusion.

New genetic cause of cardiac failure discovered

Over the course of a lifetime, the heart pumps some 250 million liters of blood through the body. In the order to do this, the muscle fibers of the heart have to be extremely durable. The research group headed by Dr. Wolfgang Rottbauer, vice chair of the Department of Medicine III at Heidelberg University Hospital (Germany), has discovered a protein that is responsible for the stability of the smallest muscular unit, the sarcomere.

In cooperation with other researchers within the National Genome Research Network they proved that mutations of this protein are the cause of a new type of heart failure. The results have been published in the November issue of Nature Medicine.
Primary heart muscle disease with decreased cardiac pump function leading to enlargement of the heart chambers (dilated cardiomyopathy) is one of the most frequent causes of chronic heart failure. Six new cases per 100,000 people occur each year; 20 percent of these cases are genetic. The heart disease weakens cardiac cells and the heart can no longer pump efficiently which leads to dilation of the cardiac chambers.

Muscle activity takes place in the smallest unit of muscle fiber, the sarcomere. In the presence of an appropriate stimulus, actin and myosin filaments interact and contract the muscle. These movable elements are anchored in what are known as Z-disks. With every heartbeat, enormous forces act on the Z-disks.
Torn Z disks weaken the heart.


"In our studies of zebrafish, we discovered a protein that is needed to stabilize the Z-disk. If this protein (nexilin) is mutated, the movable muscle elements are no longer anchored firmly enough. The muscles then lose strength and the heart is weakened," explains Dr. Tillman Dahme, resident and co-author of the study. The researchers examined the genetic material of affected patients and verified a mutated Z-disk protein in 9 of 1000 participants. They showed that in these patients, the defective nexilin was the major cause of heart disease. "The nexilin dilated cardiomyopathy allowed us for the first time to describe a new form of heart muscle dilatation and define the mechanism causing it, namely destabilization of the Z-disk," says Dahme.
The studies also showed that the extent of the damage to the Z-disk is directly related to the workload. This insight has an influence on clinical therapy. "Patients with a nexilin mutation might benefit from early treatment with medications that reduce cardiac stress. This could lower the mechanical stress on the Z-disks and prevent progressive damage to the heart," said Dr. Rottbauer.

Genome advances promise personalized medical treatment

A whirlwind of activity is under way to apply the findings of the $3 billion Human Genome Project to improve health care in the United States and around the world.

Six years after scientists finished decoding the human genome -- the genetic instruction book for life -- they're starting to take their new knowledge from the research laboratory to the doctor's office and the patient's bedside.

"We hope all this knowledge of the genome will lead to more kinds of therapies," said Francis Collins, who ran the federal government's Human Genome Project from 1993 to 2008.

Researchers are seeking ways to tailor treatments to individuals -- they call it "personalized medicine" -- in order to improve patient outcomes and to lower costs in the overburdened U.S. health care system.

The goal is to deliver the right drug at the right time in the right dose to the right person, and eliminate treatments that don't work.

"Already some of these personalized treatments are finding their way into practice," Collins told a recent seminar in Washington. "We want to optimize the way we practice medicine, diagnosis and risk prediction."

For example, instead of a standard therapy to treat breast cancer, personalized medicine allows doctors to employ a treatment precisely designed to fit one woman's specific needs. If a gene test shows that her tumor overproduces a substance called HER-2, she's considered to be a good candidate for the drug Herceptin, which cuts her chance of a recurrence nearly in half. If the test is negative, using the drug could be wasteful.

Advocates say that personalized medicine also can reduce unnecessary suffering and expense by minimizing the chance of adverse drug reactions. According to the Food and Drug Administration, there were 319,741 serious illnesses and 49,958 deaths due to unexpected reactions to drugs last year in the United States alone. A British study estimated the cost of such reactions at $847 million per year in the United Kingdom.

For instance, heart patients who have two tiny mutations in their genomes have an increased risk of serious problems, even death, if they take the popular anti-clotting drug Plavix, according to Rick Hockett, the chief medical officer of Affymetrix, a genetics firm in Santa Clara, Calif.

Experts caution, however, that it's premature to say that an era of individually customized medicine has arrived. Major scientific and policy hurdles remain before patients can benefit widely from the promises of personalized medicine. Issues of insurance coverage, medical training, privacy and safety remain to be resolved.

"It is not ready for moving into the clinic. It is not ready for prime time," Pamela Sankar, a medical ethicist at the University of Pennsylvania, told the seminar.

Nevertheless, advances in genomic medicine are accelerating, thanks to new, high-speed sequencing machines. Unlike the slow, painstaking methods used to decode the first sample genome, second-generation robotic machines can analyze hundreds of thousands of units of DNA in minutes.

Collins said the improvement in speed of sequencing had been "breathtaking." Costs have come down proportionately.

In 2003, it cost an estimated $300 million to decode the first genome of an individual human. By 2007, the cost per person had come down to $100 million, and by 2008, it was $60,000. The current cost is about $20,000, according to Clifford Reid, the chief executive of Complete Genomics Inc., a gene-processing company in Mountain View, Calif.

Radoje Drmanac, the chief scientist at Complete Genomics, predicted that it soon will be possible to sequence a person's genome in one day. "For the first time, this will enable large numbers of patients to be sequenced to get to the bottom of thousands of genetically controlled diseases," Drmanac said.

Collins said the goal was to be able to sequence a complete human genome for $1,000 by five years from now, making it a staple of medical practice. People routinely will have their genomes sequenced to predict their individual risks of disease and responses to drugs, he predicted.

So far, fewer than two dozen complete human genomes have been published in scientific journals, but more are being sequenced rapidly. Larger efforts are also under way.

Last year, an international consortium launched a "1000 Genomes Project" to sequence the genomes of at least a thousand people from around the world by 2012. The goal is to produce a catalog of all the genetic variations that exist in at least 1 percent of the human population. The cost is estimated to be $30 million to $50 million.

"This will change the way we carry out studies of genetic disease," Collins said.

Already, studies of variant genes have provided clues to hundreds of diseases, he said.

Scientists are beginning to apply a new idea to cut the cost dramatically and speed the process of reading a person's genome. It's based on the fact that only about 1 percent of the 3 billion units of DNA in a person's genome contain the genetic code to produce proteins, the chemical building blocks of an organism. The rest used to be called "junk DNA", but some of it's now known to perform important functions, such as turning genes on or off.

So, instead of sifting through a "vast ocean of stuff", as one researcher called the complete genome, only the coding bits, known as the "exome", need to be read. The faster, simpler, cheaper exome process is sometimes called the "One Percent Solution."

Scientists at the University of Washington in Seattle reported in the journal Nature last week that they've sequenced 12 human exomes and have identified the cause of Miller syndrome, a rare disease that causes terrible facial and limb abnormalities in children.

Trying last-ditch lung bypass for worst swine flu

A technology originally developed for premature babies may be helping to save some of the sickest swine flu patients by rerouting their blood so their lungs can rest.

Cancer Ablation Center - Lung, Liver, Bone, Adrenal, Kidney & Breast Cancer Treatment - www.cancerablation.com

It's a risky approach using equipment that only certain specialized hospitals have. But faced with children and young adults struggling to breathe despite ventilators has intensive-care doctors dusting off these machines, named ECMO, that they often consider last-ditch and almost never use for influenza.

"It was pretty scary knowing that was his blood flowing through those tubes in and out of his body," says Susie Damm of Omaha, Neb., whose 19-year-old son Ryan survived a life-threatening bout after 10 days on ECMO.

"I was one of the people sick and tired of hearing about the swine flu, thinking people were making a big deal of it," she adds. "Now I've had a different look, and I'm very, very thankful" he survived.

No one knows which patients are most likely to benefit - not everyone does. But ECMO is gaining attention after Australian researchers reported that the machines helped during that country's outbreak of what scientists call the 2009 H1N1 flu strain. A voluntary U.S.-based registry counts 107 critically ill swine flu patients recently treated with ECMO, most from this country.

In Omaha, Dr. Jeff DeMare credits the technique with saving Ryan Damm and 7-year-old Tania Romero-Oropeza after both patients' lungs went from clogged to nearly useless in a stunning matter of hours. Tania's care was complicated by a drug-resistant staph infection.

"You wonder, 'OK, we've got a lot of folks who get this disease and why is it so bad in some cases?' We don't have a real good handle on that," says DeMare, a critical care specialist at Children's Hospital & Medical Center.

Whatever the reason, "your body needs time to fight the infection," he adds, and he gambled that the pricey equipment could buy that time.

Estimates from the federal Centers for Disease Control and Prevention suggest that swine flu has hospitalized 98,000 Americans in the past six months, and killed nearly 4,000. For most, standard treatment works.

But the sickest often need ventilators to pump their lungs, and ventilators damage lung tissue, especially as they're turned up to higher pressures as patients worsen.

Hospitals are "exhausting all measures" on those patients, says Dr. Pauline Park, a University of Michigan ICU co-director who's helping to analyze the ECMO registry in hopes of determining best candidates. "Physicians don't want to give false hope to families, but also don't want to stand by if a life can be saved."

Enter ECMO, decades-old technology that essentially offers a temporary lung bypass. Tubes carry blood out of the body so a filter can remove carbon dioxide and reinfuse oxygen, and then dump the blood back.

It's a twist on the heart-lung machine used for open-heart surgery, modified so that patients can stay on the machine for weeks instead of just hours and, key here, so that blood doesn't have to bypass the heart if only the lungs need a rest. 

 

There are many cautions. It's risky, requiring blood thinners to avoid clots and posing the potential for additional infection. It can double the cost of ICU care. Only about 120 hospitals in the U.S. offer it, most just a few times a year for newborns with respiratory failure, its primary use.

ECMO in adults is hugely controversial because past research couldn't prove that it significantly increased survival.

Here's what's new: 

-Australian researchers reported last month that they used ECMO in 68 critically ill swine flu patients who failed standard care, and about 71 percent survived. That research predicted some 800 people might be ECMO candidates if the U.S. experienced similar rates of swine flu. 

-Coincidentally, a British study also published last month found that nearly two-thirds of adults randomly assigned to ECMO survived other types of respiratory failure - before swine flu hit - while just 47 percent survived with regular ICU care. It's the most rigorous study of ECMO performed in adults and one that has lung specialists debating wider use.

-Preliminary data from the Michigan-run ECMO registry suggests survival can reach 72 percent if recipients get it within six days of using a ventilator. With longer ventilator use, the survival rate plummets. 

Back in Omaha, DeMare agrees ECMO shouldn't be last-ditch, noting his own patients were on ventilators for just hours before getting it. Still, Tania had a monthlong hospital stay, including her eight days on ECMO. 

 

"Thank God the doctor took that decision to use this machine," said Tania's mother, Antonieta Oropeza, speaking in Spanish through an interpreter.

Irritable Bowel Syndrome (IBS)

What is irritable bowel syndrome (IBS)?

Irritable bowel syndrome (IBS) is one of the most common ailments of the bowel (intestines) and affects an estimated 15% of persons in the US. The term, irritable bowel, is not a particularly accurate one since it implies that the bowel is responding irritably to normal stimuli, and this may or may not be the case. The several names for IBS, including spastic colon, spastic colitis, and mucous colitis, attest to the difficulty of getting a descriptive handle on the ailment. 
IBS is best described as a functional disease. The concept of functional disease is particularly useful when discussing diseases of the gastrointestinal tract. The concept applies to the muscular organs of the gastrointestinal tract; the esophagus, stomach, small intestine, gallbladder, and colon. What is meant by the term, functional, is that either the muscles of the organs or the nerves that control the organs are not working normally, and, as a result, the organs do not function normally. The nerves that control the organs include not only the nerves that lie within the muscles of the organs but also the nerves of the spinal cord and brain to which they connect.
Some gastrointestinal diseases can be seen and diagnosed with the naked eye, such as ulcers of the stomach when visualized with certain methods. Thus, ulcers can be seen at surgery, on X-rays, and at endoscopy. Other diseases cannot be seen with the naked eye but can be seen and diagnosed with the microscope. For example,celiac disease and collagenous colitis are diagnosed by microscopic examination of biopsies of the small intestine and colon, respectively. In contrast, gastrointestinal functional diseases cannot be seen with the naked eye or with the microscope. In some instances, the abnormal function can be demonstrated by tests, for example, gastric emptying studies or antro-duodenal motility studies. However, these tests often are complex, are not widely available, and do not reliably detect the functional abnormalities. Accordingly, by default, functional gastrointestinal diseases are those involving the abnormal function of gastrointestinal organs in which abnormalities cannot be seen in the organs with either the naked eye or the microscope.
Occasionally, diseases that are thought to be functional are ultimately found to be associated with abnormalities that can be seen. Then, the disease moves out of the functional category. An example of this would be Helicobacter pylori infection of the stomach. Many patients with mild upper intestinal symptoms who were thought to have functional abnormal function of the stomach or intestines have been found to have an infection of the stomach with Helicobacter pylori. This infection can be diagnosed by seeing the bacterium and the inflammation (gastritis) it causes under the microscope . When the patients are treated with antibiotics, the Helicobacter pylori, gastritis, and symptoms disappear. Thus, recognition of Helicobacter pylori infection removed some patients' diseases from the functional category.
Functional diseases of the stomach and intestines may be shown ultimately to be caused by reduced levels of normal chemicals within the gastrointestinal organs, the spinal cord, or the brain. Should a disease that is demonstrated to be due to a reduced chemical still be considered a functional disease? I think not. In this theoretical situation, we can't see the abnormality with the naked eye or the microscope, but we can measure it. If we can measure an associated or causative abnormality, the disease probably should no longer be considered functional.
While IBS is a major functional disease, it is important to mention a second major functional disease referred to as dyspepsia, or functional dyspepsia. The symptoms of dyspepsia are thought to originate from the upper gastrointestinal tract; the esophagus, stomach, and the first part of the small intestine. The symptoms include upper abdominal discomfort, bloating (the subjective sense of abdominal fullness without objective distension), or objective distension (swelling, or enlargement). The symptoms may or may not be related to meals. There may be nausea with or without vomiting and early satiety (a sense of fullness after eating only a small amount of food).
The study of functional disorders of the gastrointestinal tract often is categorized by the organ of involvement. Thus, there are functional disorders of the esophagus, stomach, small intestine, colon, and gallbladder. The amount of research on functional disorders has been focused mostly on the esophagus and stomach (such as dyspepsia), perhaps because these organs are easiest to reach and study. Research into functional disorders affecting the small intestine and colon (for example, IBS) is more difficult to conduct and there is less agreement among the research studies. This probably is a reflection of the complexity of the activities of the small intestine and colon and the difficulty in studying these activities. Functional diseases of the gallbladder, like those of the small intestine and colon, also are more difficult to study.

What causes IBS?

As described previously, IBS is believed to be due to the abnormal function (dysfunction) of the muscles of the organs of the gastrointestinal tract or the nerves controlling the organs. The nervous control of the gastrointestinal tract, however, is complex. A system of nerves runs the entire length of the gastrointestinal tract from the esophagus to the anus in the muscular walls of the organs. These nerves communicate with other nerves that travel to and from the spinal cord. Nerves within the spinal cord, in turn, travel to and from the brain. Thus, the abnormal function of the nervous system in IBS may occur in a gastrointestinal muscular organ, the spinal cord, or the brain.
The nervous system that controls the gastrointestinal organs, as with most other organs, contains both sensory and motor nerves. The sensory nerves continuously sense what is happening within the organ and relay this information to nerves in the organ's wall. From there, information can be relayed to the spinal cord and brain. The information is received and processed in the organ's wall, the spinal cord, or the brain. Then, based on this sensory input and the way the input is processed, commands (responses) are sent to the organ over the motor nerves. Two of the most common motor responses in the intestine are contraction or relaxation of the muscle of the organ and secretion of fluid and/or mucus into the organ.
As already mentioned, abnormal function of the nerves of the gastrointestinal organs, at least theoretically, might occur in the organ, spinal cord, or brain. Moreover, the abnormalities might occur in the sensory nerves, the motor nerves, or at processing centers in the intestine, spinal cord, or brain. Some researchers argue that the cause of functional diseases is abnormalities in the function of the sensory nerves. For example, normal activities, such as stretching of the small intestine by food, may give rise to abnormal sensory signals that are sent to the spinal cord and brain, where they are perceived as pain.
Other researchers argue that the cause of functional diseases is abnormalities in the function of the motor nerves. For example, abnormal commands through the motor nerves might produce a painful spasm (contraction) of the muscles. Still others argue that abnormally functioning processing centers are responsible for functional diseases because they misinterpret normal sensations or send abnormal commands to the organ. In fact, some functional diseases may be due to sensory dysfunction, motor dysfunction, or both sensory and motor dysfunction. One area that is receiving a great deal of scientific attention is the potential role of gas produced by intestinal bacteria in patients with IBS. Studies have demonstrated that some patients with IBS produce larger amounts of gas than individuals without IBS, and the gas may be retained longer in the small intestine. Among patients with IBS, abdominal size increases over the day, reaching a maximum in the evening and returning to baseline by the following morning. In individuals without IBS, there is no increase in abdominal size during the day.
There has been a great deal of controversy over the role that poor digestion and/or absorption of dietary sugars may play in aggravating the symptoms of IBS. Poor digestion of lactose, the sugar in milk, is very common as is poor absorption of fructose, a sweetener found in many processed foods. Poor digestion or absorption of these sugars could aggravate the symptoms of IBS since unabsorbed sugars often cause increased formation of gas.
Although these abnormalities in production and transport of gas could give rise to some of the symptoms of IBS, much more work will need to be done before the role of intestinal gas in IBS is clear.
Dietary fat in healthy individuals causes food as well as gas to move more slowly through the stomach and small intestine. Some patients with IBS may even respond to dietary fat in an exaggerated fashion with greater slowing. Thus, dietary fat could--and probably does--aggravate the symptoms of IBS.

What are IBS symptoms?

The primary purpose of the gastrointestinal tract is to digest (break down) and absorb (take into the blood stream) food. In order to fulfill this purpose, food must be ground, mixed, and transported through the intestines, where it is digested and absorbed. In addition, undigested and unabsorbed portions of the food must be eliminated from the body.
In functional diseases of the gastrointestinal tract, the grinding, mixing, digestion, and absorption functions are disturbed to only a minor degree. These functions are essentially maintained, perhaps because of a built-in over-capacity of the gastrointestinal tract to perform these functions. The most commonly affected function in these diseases is transportation. In the stomach and small intestine, the symptoms of slowed transportation are nausea, vomiting, abdominal bloating (the sensation of abdominal fullness), and abdominal distention (enlargement). The symptom of rapid transportation usually is diarrhea. The interpretation of symptoms, however, may be more complicated than this. For example, let's say that a person has abnormally rapid emptying of the stomach. The sensing of this rapid emptying by the intestinal sensory nerves normally brings about a motor nerve response to slow emptying of the stomach and transportation through the small intestine. Thus, rapid emptying of the stomach may give rise to symptoms of slowed transportation.
In the colon, abnormally slowed or rapid transportation results in constipation or diarrhea, respectively. In addition, there may be increased amounts of mucus coating the stool or a sense of incomplete evacuation after a bowel movement.
As discussed previously, normal sensations may be abnormally processed and perceived. Such an abnormality could result in abdominal bloating and pain. Abnormally processed sensations from the gastrointestinal organs also might lead to motor responses that cause symptoms of slowed or rapid transportation.
Slowed transportation of digesting food through the small intestine may be complicated, for example, by bacterial overgrowth. In bacterial overgrowth, gas-producing bacteria that are normally restricted to the colon move up into the small intestine. There, they are exposed to greater amounts of undigested food than in the colon, which they turn into gas. This formation of gas can aggravate bloating and/or abdominal distention and result in increased amounts of flatus (passing gas, or flatulence) and diarrhea.
The gastrointestinal tract has only a few ways of responding to diseases. Therefore, the symptoms often are similar regardless of whether the diseases are functional or non-functional. Thus, the symptoms of both functional and non-functional gastrointestinal diseases are nausea, vomiting, bloating, abdominal distention, diarrhea, constipation, and pain. For this reason, when functional disease is being considered as a cause of symptoms, it is important that the presence of non-functional diseases be excluded (ruled out). In fact, the exclusion of non-functional diseases usually is more important in evaluating patients who are suspected of having functional disease. This is so, in large part, because the tests for diagnosing functional disease are complex, not readily available, and often not very reliable. In contrast, the tests for diagnosing non-functional diseases are widely available and sensitive (able to diagnose most cases).

What are the complications of IBS?

The complications of functional diseases of the gastrointestinal tract are relatively limited. Since symptoms are most often provoked by eating, patients who alter their diets and reduce their intake of calories may lose weight. Fortunately, loss of weight is unusual in functional diseases, and it should suggest the presence of a non-functional disease. Symptoms that awaken patients from sleep also are more likely to be due to non-functional than functional diseases.
Most commonly, functional diseases interfere with the patients' comfort and their daily activities. For example, patients who suffer from morning diarrhea may not leave their home until the diarrhea stops. If the diarrhea is constant, they may go only to places where they know that a toilet is readily available. Patients who develop pain after eating may skip lunch. Very commonly, patients associate symptoms with specific foods, such as milk, fat, vegetables, etc. Whether or not these associations are real, these patients will restrict their diets accordingly. Milk is the food that is most commonly eliminated, often unnecessarily and to the detriment of adequate calcium intake. The interference with daily activities also can lead to problems with interpersonal relationships, especially with spouses. However, most patients with functional disease tend to just live with their symptoms and infrequently visit physicians for diagnosis and treatment.

How is IBS diagnosed?

The Rome Criteria

The symptoms of IBS are varied and inconsistent among patients. Moreover, there are no characteristically abnormal tests that can be used to diagnose IBS. All of this has made it difficult to define IBS and identify patients, especially for research studies. In 1999, a group of international investigators met in Rome for a second time (Rome II). There, they developed a set of criteria for symptoms to be used for diagnosing IBS.
The Rome II Criteria state that in order to be diagnosed with IBS, a patient should have suffered abdominal pain or discomfort for 12 weeks or more (not necessarily consecutive weeks) in the previous 12 months. The pain or discomfort should have two out of the three following features:

• Relief with defecation
• Onset associated with a change in the frequency of stool
• Onset associated with a change in the form of stool

Other symptoms that are not essential, but support a diagnosis of IBS, are: (1) abnormal frequency of stools (more than 3/day or less than 3/week); (2) abnormal stool form (lumpy and hard, or loose and watery); (3) abnormal stool passage (straining, urgency, or feeling of incomplete evacuation); (4) passage of mucus; and (5) bloating (feeling of abdominal distention, or enlargement).
The Rome II criteria are rather specific for a diagnosis of IBS. In essence, they require the presence of prolonged abdominal pain or discomfort that is in some way related to an alteration in the pattern of bowel movements. Symptoms of dyspepsia (nausea or abdominal discomfort following meals), abdominal distention, and increased flatus (passing gas, or flatulence) alone do not fall within this definition. Nevertheless, many patients have these symptoms along with the symptoms of IBS. It is not clear if these patients have one problem (IBS) or more than one problem.
In 2006, the group of international investigators met for the third time in Rome and developed the Rome III criteria. A system of classification of gastrointestinal functional disorders came out of this meeting that was much more comprehensive and detailed than prior classifications. The definition of the subcategory, IBS, remained essentially unchanged, however, except for a requirement that the abdominal pain occur at a frequency of at least three times per month. The classification also clearly set apart from IBS three other functional bowel disorders - functional bloating, functional constipation, functional diarrhea, and unspecified functional bowel disorder.

Exclusion of non-functional gastrointestinal disease

As mentioned previously, the exclusion of non-functional disease in patients with suspected IBS is an important concern. There are many tests to exclude non-functional diseases. The primary issue, however, is to decide which tests are reasonable to perform. Since each case is individual, different tests may be reasonable for different patients. Nevertheless, there are some basic tests that are often performed to exclude non-functional gastrointestinal disease. These tests identify anatomic (structural) and histological (microscopic) diseases of the intestines. As always, a detailed history from the patient and a physical examination frequently will suggest the cause of symptoms. Routine screening blood tests often are performed looking for clues to unsuspected diseases. Examinations of stool also are a part of the evaluation since they may reveal infection, signs of inflammation, or blood and direct further diagnostic testing. Sensitive stool testing (antigen/antibody) for Giardia lamblia would be reasonable because this parasitic infection is common and can be acute or chronic. Some physicians do blood testing for celiac disease (sprue), but the value of doing this is unclear. Moreover, if an EGD is planned, biopsies of the duodenum usually will make the diagnosis of celiac disease. Both X-rays and endoscopies can identify anatomic diseases. Only endoscopies, however, can diagnose histological diseases because biopsies (taking samples of tissue) can be taken during the procedure. The X-ray tests include:

• The esophagram and video-fluoroscopic swallowing study for examining the esophagus
• The upper gastrointestinal series for examining the stomach and duodenum
• The small bowel series for examining the small intestine
• The barium enema for examining the colon and terminal ileum.

The endoscopic tests include:

• Upper gastrointestinal endoscopy (esophago-gastro-duodenoscopy, or EGD) to examine the esophagus, stomach, and duodenum
• Colonoscopy to examine the colon and terminal ileum
• Endoscopy also is available to examine the small intestine, but this type of endoscopy is complex, not widely available, and of unproven value in suspected IBS.

For examination of the small intestine, there is also a capsule containing a tiny camera that can be swallowed. As the capsule travels through the intestines, it sends pictures of the inside of the intestines to an external recorder for later review. However, the capsule is not widely available and its value in IBS has not yet been proven.
X-rays are easier to perform and are less costly than endoscopies. The skills necessary to perform X-rays, however, are becoming rarer among radiologists because they are doing them less often. Therefore, the quality of the X-rays often is not as high as it used to be. As noted above, endoscopies have an advantage over X-rays because at the time of endoscopies, biopsies can be taken to diagnose or exclude histological diseases, something that X-rays cannot do.

Exclusion of non-intestinal disease

Patients with suspected IBS often undergo abdominal ultrasonography (US), computerized tomography (CT or CAT scans), or magnetic resonance imaging (MRI). These tests are used primarily to diagnose non-intestinal diseases. (Although these tests also may diagnose intestinal diseases, their value for this purpose is limited. As described above, X-ray and endoscopy are better tests.) It also is important to realize that US, CT, and MRI are powerful tests and will uncover abnormalities that are unrelated to IBS. The most common example is the finding of gallstones that, in fact, often cause no symptoms. This finding can cause a problem if the gallstones are assumed to be the source of the IBS symptoms. The problem is that surgical removal of the gallbladder with its gallstones (cholecystectomy) is unlikely to relieve the symptoms of IBS. (Cholecystectomy would be expected to relieve only the characteristic symptoms that gallstones sometimes can cause.) Tests to exclude non-intestinal diseases may be appropriate in specific situations, although certainly not in most patients.

Evaluation of intestinal transportation

If abnormal function of the muscles of the small intestine is suspected, tests to evaluate transportation through the small intestine or the colon (small intestinal and colonic transit studies, respectively) are available. These studies are done with either radioactive compounds or markers that can be seen on X-rays of the abdomen. It also is possible to pass catheters into the stomach and small intestine or the colon to determine if the muscles of these organs are working normally (antro-duodenal and colonic motility studies, respectively). Finally, constipation due to malfunction of the anal muscles can be diagnosed by ano-rectal motility studies.

Psychiatric illness

The possibility of psychiatric (psychosomatic) illness often arises in patients with IBS because the symptoms frequently are subjective, and no objective abnormalities can be identified. Psychiatric illness may complicate IBS, but it is unclear if psychiatric illness causes IBS. If there is a possibility of psychiatric illness, a psychiatric evaluation is appropriate.

How is IBS treated?

The treatment of IBS is a difficult and unsatisfying topic because so few drugs have been studied or have been shown to be effective in treating IBS. Moreover, the drugs that have been shown to be useful have not been substantially effective. This difficult situation exists for many reasons, as follows:

• Life-threatening illnesses (for example, cancer, heart disease , and high blood pressure), are the diseases that capture the public's interest and, more importantly, research funding. IBS is not a life-threatening illness and has received little research funding. Because of the lack of research, an understanding of the physiologic processes (mechanisms) that are responsible for IBS has been slow to develop. Effective drugs cannot be developed until there is an understanding of these mechanisms.

• Research in IBS is difficult. IBS is defined by subjective symptoms, (such as pain), rather than objective signs (for instance, the presence of an ulcer). Subjective symptoms are more unreliable than objective signs in identifying homogenous groups of patients. As a result, groups of patients with IBS who are undergoing treatment are likely to contain some patients who do not have IBS, and this may negatively affect the results of the treatment. Moreover, the results of treatment must be evaluated on the basis of subjective responses (such as improvement of pain). In addition to being more unreliable, subjective responses are more difficult to measure than objective responses (such as the healing of an ulcer).

• Different subtypes of IBS (for example, diarrhea-predominant, constipation-predominant, etc.) are likely to be caused by different physiologic processes (mechanisms). It also is possible, however, that the same subtype may be caused by several different mechanisms in different people. What's more, any drug is likely to affect only one mechanism. Therefore, it is unlikely that any one medication can be effective in all-even most-patients with IBS, even patients with similar symptoms. This inconsistent effectiveness makes the testing of drugs difficult. Indeed, it can easily result in drug trials that demonstrate no efficacy (usefulness) when, in fact, the drug is helping a subgroup of patients.

• Subjective symptoms are particularly prone to responding to placebos (inactive drugs, or sugar pills). In fact, in most studies, 20% to 40% of patients with IBS will improve if they receive inactive drugs. Now, all clinical trials of drugs for IBS require a placebo-treated group for comparison with the drug-treated group. So, the placebo response means that these clinical trials must utilize large numbers of patients to detect meaningful (significant) differences in improvement between the placebo and drug groups. Therefore, such trials are expensive to conduct.

The lack of understanding of the physiologic processes (mechanisms) that cause IBS has meant that treatment cannot be directed at these mechanisms. Instead, treatment usually is directed at the symptoms, which are primarily constipation, diarrhea, and abdominal pain. These symptoms are not mutually exclusive since patients may have abdominal pain with either constipation or diarrhea. Moreover, periods of constipation may alternate with periods of diarrhea. This variation in symptoms over time can make the treatment of symptoms complex. The psychotropic drugs (antidepressants) and psychological treatments (for example, cognitive behavioral therapy) treat hypothetical causes of IBS (such as abnormal function of sensory nerves and the psyche) rather than the symptoms.

Constipation

Constipation is due to the slow transport (transit) of intestinal contents through the intestines, primarily the colon. This slow transit may be due to either abnormal function of the muscles of the entire colon or just the muscles of the anus and rectum.
The treatment of constipation in IBS usually begins with a trial of the supplements and medications that are used to treat constipation of any cause. In 2002, the FDA approved tegaserod (Zelnorm), the first drug specifically for the treatment of abdominal pain and constipation in women with IBS. However, in March of 2007, the FDA asked Novartis to suspend sales of tegaserod (Zelnorm) in the United States because a retrospective analysis of data by Novartis from more than 18,000 patients showed a slight difference in the incidence of cardiovascular events (heart attacks, strokes and angina) among patients on Zelnorm compared to placebo. The data showed that cardiovascular events occurred in 13 out of 11,614 patients treated with Zelnorm (.11%), compared to one cardiovascular event in 7,031 (.01%) placebo-treated patients. However, it is unclear whether Zelnorm actually causes heart attacks and strokes. Doctors and scientists will be scrutinizing the data to determine the long-term safety of Zelnorm.
The mechanism whereby tegaserod reduces constipation is interesting. It is the contractions of the intestinal muscles that controls transit of digesting food through the intestine. More contractions speed transit, fewer contractions slow transit. In constipated patients, contractions are fewer. One important factor in the control of the contractions is serotonin. Serotonin is a chemical manufactured by nerves in the intestine. It is released by the nerves and then travels to other nerves where it binds to receptors on the nerves. It is, in scientific terms, a "neurotransmitter" that allows nerves to communicate with each other. When it binds to receptors on nerves that control the contractions of intestinal muscles, serotonin can either promote or prevent contractions depending on the type of receptor it binds to. Binding to some types of receptors causes contractions, and binding to other types of receptors prevents contractions. The serotonin 5-HT4 receptor is a receptor that prevents contractions when serotonin binds to it. Tegaserod blocks the 5-HT4 receptor, prevents serotonin from binding to it, and thereby increases contractions of the intestinal muscles. The increased contractions speed the transit of digesting food. In addition, tegaserod reduces the sensitivity of the intestinal pain-sensing nerves and can thereby reduce the perception of pain.
In a randomized, double blind, placebo-controlled, study involving more than 1000 patients (80% women) with constipation-predominant IBS, tegaserod was found to be more effective than placebo in increasing the frequency of stools, relieving abdominal pain and discomfort, and decreasing the sensations of bloating among women. (There was an insufficient number of men in the study to draw conclusions about the effectiveness of treatment in men.) The beneficial effects of treatment started during the first week of treatment and were sustained throughout the 12-week period of study.
Diarrhea was the only side effect in the tegaserod study. Diarrhea usually occurred early during treatment and resolved quickly even if the treatment was continued. There was no effect of tegaserod on blood counts, liver and kidney tests, electrocardiograms, blood pressure, pulse, and body weight. (A medication similar to tegaserod, called cisapride or Propulsid, which also promoted intestinal muscle contractions, was withdrawn from the market due to rare but potentially fatal effects on the electrical rhythm of the heart. So far, there have been no reports of rhythm disturbances related to tegaserod.) Patients with major liver or kidney disease should not take tegaserod. The safety of tegaserod to the fetus or nursing infants has not been studied and is unknown. Therefore, pregnant or nursing women should avoid tegaserod.

Diarrhea

The most widely studied drug for the treatment of diarrhea in IBS is loperamide (Imodium). Loperamide appears to work by inhibiting (slowing down) the contractions of the muscles of the small intestine and colon. Loperamide is approximately 30% more effective than a placebo in improving symptoms among patients who have diarrhea as the predominant manifestation of their IBS. It is not clear if loperamide reduces abdominal pain. Loperamide can be potent and itself can cause constipation. Therefore, the dose must be carefully adjusted and individualized for each patient. Alosetron (Lotronex) is used to treat diarrhea and abdominal discomfort that occurs in women with severe IBS that does not respond to other simpler treatments.
Alosetron, like tegaserod, affects the serotonin receptors. (See the discussion above of tegaserod.) Alosetron blocks the 5-HT3 receptor, a receptor that causes contractions when serotonin binds to it. Alosetron, by blocking 5-HT3 receptors, prevents serotonin from binding and thereby prevents contractions.
Alosetron was approved by the FDA in February, 2000, but was withdrawn from the market in November, 2000, because of serious, life-threatening, gastrointestinal side effects. In June 2002, it was approved again by the FDA for marketing but in a restricted manner as part of a drug company-sponsored program for managing the risks associated with treatment. Use of alosetron is allowed only among women with severe, diarrhea-predominant, IBS who have failed to respond to conventional treatment for IBS.
The most common side effect with alosetron is constipation. One-quarter to one-third of patients may develop this side effect, but in only 10% (10 out of every 100 patients) will the drug need to be stopped temporarily or permanently.
A rare side effect that has occurred with alosetron is severe intestinal inflammation caused by poor circulation of blood ( ischemic colitis). This complication is life-threatening, may require surgery, and has even caused death in a small number of patients. Therefore, immediate medical attention should be sought if the signs of ischemic colitis (rectal bleeding or a sudden worsening of abdominal pain) occur.

Abdominal pain

The most widely studied drugs for the treatment of abdominal pain are a group of drugs called smooth-muscle relaxants.
The gastrointestinal tract muscle is composed of a type of muscle called smooth muscle. (By contrast, skeletal muscles, such as the biceps, are composed of a type of muscle called striated muscle.) Smooth muscle relaxant drugs reduce the strength of contraction of the smooth muscles but do not affect the contraction of other types of muscles. They are used in IBS with the assumption (not proved) that strong or prolonged contractions of smooth muscles in the intestine-spasms-are the cause of pain in IBS. There are even smooth muscle relaxants that are placed under the tongue, like nitroglycerin for angina, so that they may be absorbed rapidly. Smooth muscle relaxants are approximately 20% more effective than a placebo in reducing abdominal pain. It is not clear if smooth muscle relaxants have a beneficial effect on constipation or diarrhea.
Commonly used smooth muscle relaxants are hyoscyamine (for example, Levsin) and methscopolamine (for example, Pamine). Other drugs combine smooth muscle relaxants with a sedative (for example, Donnatal), but there is no evidence that the addition of sedatives adds to the efficacy (effectiveness) of the treatment.

Psychotropic drugs

Patients with IBS are frequently found to be suffering from depression, but it is unclear if the depression is the cause of IBS, the result of the IBS, or unrelated to the IBS. Several trials have shown that antidepressants are effective in IBS in relieving abdominal pain and, perhaps, diarrhea. The antidepressants work in IBS, however, at relatively low doses that have little or no effect on depression. It is believed therefore, that they are working not by combating depression, but in different ways (through different mechanisms). For example, these drugs have been shown to adjust (modulate) the activity of nerves and to have analgesic (pain-relieving) effects as well. Commonly used psychotropic drugs include the tricyclic antidepressants, amitriptyline (Elavil, Endep), desipramine (Norpramine), and trimipramine (Surmontil). Although studies are encouraging, it is not yet clear whether the newer class of antidepressants, the serotonin-reuptake inhibitors, such as fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil) are effective.

Psychological treatments

Psychological treatments include cognitive-behavioral therapy, hypnosis, psychodynamic or interpersonal psychotherapy, and relaxation/stress management. They have been used in patients with IBS who are psychologically distressed to the point that their quality of life is being impaired. A few studies have shown that psychological treatments can reduce anxiety and other psychological symptoms in addition to reducing IBS symptoms, particularly pain and diarrhea.

Diet

It is unclear if diet has much effect on the symptoms of IBS. Nevertheless, patients often associate their symptoms with specific foods (such as salads, fats, etc.). Although specific foods might worsen IBS, it is clear that they are not the cause of IBS. The common placebo response in IBS also may explain the improvement of symptoms in some people with the elimination of specific foods.
Dietary fiber often is recommended for patients with IBS. Fiber probably is of benefit to IBS patients with constipation, but it does not reduce abdominal pain. Lactose (milk sugar) intolerance often is blamed for diarrhea-predominant IBS, but it does not cause IBS. Because they are both common, lactose intolerance and IBS may coexist. In this situation, restricting lactose will improve, but not eliminate the symptoms. Lactose intolerance is easily determined by testing the effect of lactose (hydrogen breath testing) or trying a strict lactose elimination diet. Intolerance to sugars other than lactose, specifically, fructose, sucrose, and sorbitol, may cause symptoms that are similar to IBS or make IBS worse. It is unlikely, however, that these sugars cause IBS.

Is there a relationship between IBS and small intestinal bacterial overgrowth?

IBS and small intestinal bacterial overgrowth (SIBO)

There is a striking similarity between the symptoms of IBS and a condition known as small intestinal bacterial overgrowth (SIBO).
The entire gastrointestinal tract, including the small intestine, normally contains bacteria. The number of bacteria is greatest in the colon (at least 1,000,000,000 bacteria per ml of fluid) and much lower in the small intestine (less than 10,000 bacteria per ml of fluid). Moreover, the types of bacteria within the small intestine are different than the types of bacteria within the colon. SIBO refers to a condition in which abnormally large numbers of bacteria (at least 100,000 bacteria per ml of fluid) are present in the small intestine, and the types of bacteria in the small intestine resemble more the bacteria of the colon than the small intestine.
The symptoms of SIBO include excess gas, abdominal bloating and distension, diarrhea, and abdominal pain. A small number of patients with SIBO have chronic constipation rather than diarrhea. When the overgrowth is severe and prolonged, the bacteria may interfere with the digestion and/or absorption of food, and deficiencies of vitamins and minerals may develop. Loss of weight also may occur. The symptoms of SIBO tend to be chronic; a typical patient with SIBO can have symptoms that fluctuate in intensity over months, years, or even decades before the diagnosis is made.
It has been theorized that SIBO may be responsible for the symptoms in at least some patients with IBS. The estimates run as high as 50% of patients with IBS. Support for the SIBO theory of IBS comes from the observation that many patients with IBS are found to have an abnormal hydrogen breath test, a test used for diagnosing SIBO. In addition, some patients with IBS have improvement of their symptoms after treatment with antibiotics, the primary treatment for SIBO. Moreover, small, scientifically sound studies have shown that treatment with probiotics ("good" bacteria) improves the symptoms of IBS. Although there are several ways in which probiotics may be having their beneficial effect, one way is by affecting the existing bacteria in the small intestine. If this is indeed the mechanism of action, it would support the theory that SIBO is a cause of IBS. Nevertheless, it has not been determined if this is the mechanism of action of probiotics in IBS.
Although the theory that SIBO causes IBS is tantalizing and there is much anecdotal information that supports it, the rigorous scientific studies that are necessary to prove or disprove the theory have just begun. Nevertheless, many physicians have already begun to treat patients with IBS for SIBO. In addition, a lack of rigorous scientific studies demonstrating benefit from antibiotics and probiotics has not stopped physicians from using them for treating patients.

Treatment of IBS based on the theory of small intestinal bacterial overgrowth.

The two most common treatments for SIBO among patients with IBS are oral antibiotics and probiotics. Probiotics are live bacteria that when ingested by an individual, result in a health benefit to the individual. The most common probiotic bacteria are lactobacilli (also used in the production of yoghurt) and bifidobacteria, both of which are found in the intestine of normal individuals. There are numerous explanations for how probiotic bacteria might benefit individuals; however, the beneficial mechanism of action has not been identified clearly. It may be that the probiotic bacteria inhibit other bacteria in the intestine that may be causing symptoms, or it may be that the probiotic bacteria act on the host's intestinal immune system to suppress inflammation.
Several antibiotics either alone or in combination are reported to be successful in treating SIBO in patients with IBS. Treatment success, when measured by either improvements in symptoms or by normalization of the hydrogen breath test, ranges from 40-70%. When one antibiotic fails, doctors may add another antibiotic or change to a different antibiotic, but the doses of antibiotic, the duration of treatment, and the need for maintenance treatment to prevent recurrence of SIBO have not been adequately studied. Most physicians use standard doses of antibiotics for one to two weeks. Probiotics may be used alone, in combination with antibiotics, or for prolonged maintenance. When probiotics are used, it probably is best to use one of the several probiotics that have been studied in medical trials and shown to have effects on the small intestine, (though not necessarily in SIBO). The commonly-sold probiotics in health-food stores may not be effective. Moreover, they often do not contain the stated bacteria or the bacteria are dead. Following are some options for treatment:

• neomycin orally for 10 days (One observation that has been made is that neomycin eradicates methane-producing bacteria and alleviates constipation.)

• levofloxacin (Levaquin) or ciprofloxacin (Cipro) for 7 days

• metronidazole (Flagyl) for 7 days

• levofloxacin (Levaquin) combined with metronidazole (Flagyl) for 7 days

• rifaximin (Xifaxan) for 7 days. Rifaximin is a unique antibiotic that is not absorbed from the intestine, and, therefore, acts only within the intestine. Because very little rifaximin is absorbed into the body, it has few important side effects. Higher-than-normal doses of rifaximin (1200 mg/day for 7 days) were superior to standard lower doses (400 or 800 mg/day) in normalizing the hydrogen breath test in patients with SIBO and IBS; however, it is not yet known whether the larger dose is any better at suppressing symptoms.

• Commercially available probiotics such as VSL#3 or Flora-Q which are mixtures of several different bacterial species have been used for treating small intestinal bacterial overgrowth and IBS, but their effectiveness is not known. Bifidobacterium infantis 35624 is the only probiotic that has been demonstrated to be effective for treating patients with IBS.

Treatment with antibiotic versus probiotic.

There are no trials of treatment comparing antibiotics and probiotics; however, antibiotics have certain disadvantages. Specifically, symptoms tend to recur after treatment is discontinued, and prolonged or repeated courses of treatment may be necessary in some patients. Physicians are reluctant to prescribe prolonged or repeated courses of antibiotics because of concern over long-term side effects of the antibiotics and emergence of bacteria that are resistant to the antibiotics. Physicians have less concern over long-term side effects or emergence of resistant bacteria with probiotics and, therefore, are more willing to prescribe probiotics repeatedly and for prolonged periods. One option is to treat initially with a short course of antibiotics and then long-term with probiotics. Long-term studies comparing antibiotics, probiotics, and combinations of antibiotics and probiotics are badly needed.

What is a reasonable approach to IBS?

The initial approach to IBS-treatment or testing--depends on the patient's symptoms and their duration. If the symptoms clearly fit the definition for IBS and have been present for years without change, then there is less need for extensive testing to exclude other intestinal and non-intestinal diseases. Rather, treatment that is directed at specific symptoms, as discussed previously, can begin. The role of antibiotics and/or probiotics is currently being studied.
On the other hand, if the symptoms are of recent onset (such as weeks or months), progressively worsening, severe, or associated with "warning" signs, then early testing is appropriate. Warning signs include loss of weight, nighttime awakening, rectal bleeding, and signs of inflammation, such as fever or abdominal tenderness. Testing also is appropriate if, in addition to symptoms of IBS, there are other prominent symptoms that are not part of IBS (for example, abdominal distention, increased flatus, or vomiting). Finally, testing is warranted if attempts at treating the symptoms of IBS are unsuccessful.
If there are symptoms that suggest non-IBS diseases, tests that are specific for these conditions should be done first. The reason is that if these other tests disclose disease other than IBS, it may not be necessary to do additional testing. Examples of symptoms and possible testing include:

• Vomiting: upper gastrointestinal endoscopies to diagnose inflammatory or obstructing diseases; and gastric emptying studies and/or electrogastrography to diagnose impaired emptying of the stomach.

• Abdominal distention with or without increased flatulence: upper gastrointestinal and small intestinal X-rays to diagnose obstructing diseases; and hydrogen breath testing to diagnose SIBO.

• Constipation without pain: colonoscopy or barium enema to exclude colonic cancer; marker studies to diagnose slow colonic transit; and ano-rectal motility studies to diagnose rectal muscle disorders

For a patient with typical symptoms of IBS who requires testing to exclude other diseases, the testing might reasonably include a standard screening panel of blood tests and stool specimens for examination for parasites, pus, and blood. A plain X-ray of the abdomen might be done during an episode of abdominal pain (to look for intestinal blockage or obstruction). Testing for lactose intolerance or a trial of a strict lactose-free diet should be done. Colonoscopy (and, possibly, esophago-gastro-duodenoscopy, or EGD) would be the next test, probably with multiple biopsies of the colon (and stomach and duodenum if EGD is done). Finally, small intestinal X-rays might be done.
If all of the above appropriate testing reveals no disease that could be causing the symptoms, other tests should be considered. These tests include hydrogen breath testing to diagnose SIBO and antro-duodenal and colonic motility studies to diagnose intestinal muscle or nerve disorders. These studies probably should be done at centers that have experience and expertise in diagnosing and treating these diseases.