Pathophysiology of IBS
 

Why don't we start with you, Lin? IBS is seen as a multifactorial disease. We keep hearing about the "integrated model of IBS" in the literature. What is that?

Lin Chang MD: It interrelates several mechanisms that are thought to play key roles in the pathophysiology of IBS. One mechanism is altered gut motility and secretion leading to altered bowel habits. Another is enhanced visceral perception. The patients are more sensitive to luminal contents like gas and stool, so they'll present with bloating and pain. And then there's the dysregulated brain-gut axis. The bidirectional brain-gut communications are very important for gut function and when they becomes dysregulated, as in IBS, patients will develop these symptoms. These three different factors actually interrelate and can influence each other.

Peter Salgo MD: That sounds pretty complicated. Larry, what kind of motility disturbances do you see in IBS?

Lawrence Schiller MD: There are a number that have been described over the years. People talk about excessive contractions in response to distention of the gut. People also have described problems with the transit time through the intestine being either too slow, as in the case of constipation, or too fast, as in the case of diarrhea.

Peter Salgo MD: Are there any IBS-specific motor disturbances that you can point your finger at and say, "Ah, that's IBS?"

Lawrence Schiller MD: Not really. You can't do a motility study and say, "You have IBS," on the basis of that motility study.

Susan Lucak MD: That's why earlier studies that focused on motility in irritable bowel syndrome were looking for any specific motility patterns. But none have been found that we can use specifically and diagnostically for irritable bowel syndrome.

Peter Salgo MD: That surprises me.

Lin Chang MD: I would make a comment on that. One of the findings is enhanced sigmoid contractions following a meal. That is something fairly common in IBS, but you don't see it in every patient. For constipation, patients will have slow transit and the patients with diarrhea will have rapid transit.

Patients with diarrhea will have increased high-amplitude, propagating contractions, which can be associated with the sensation of pain, along with their enhanced visceral perception. In combination with these altered motility markers, they will have more pain.

Peter Salgo MD: Help me out on this, as I'm a non-specialist here. You're talking about transit times.

Lin Chang MD: Right.

Peter Salgo MD: You are saying there are disordered transit times which do seem to be consistent with the diarrheal phase or the constipated phase of the illness, but that this is distinct from motility. How do you make that distinction?

Peter Salgo MD

Lin Chang MD

Lin Chang MD: Well, for the diarrhea type, you would have these increased high-amplitude, propagating contractions. So enhanced motility will lead to rapid transit. These two things go hand-in-hand more easily than constipation and the degree of motility. In constipation, if, for example, you had decreased motility, you would have decreased contractions, and thus slow transit. But potentially you could also have constipation and increased contractions, but not in a propagating way, so the stool doesn't move through as normally as it should.

Peter Salgo MD: Why don't you lead us through the other part of this, which is the so-called visceral hypersensitivity. It's the second part of this integrated model, right? What do you mean by it? How do you measure it?

Lawrence Schiller MD: People have been fascinated by this for a long time. A series of old observations have been made and confirmed in recent years that people who have irritable bowel syndrome are more sensitive to distending stimuli in the lower intestine. This curve shows that.

On the horizontal axis is the volume that's placed in a balloon that's put up into the rectosigmoid colon versus the percent of patients reporting pain with that degree of distention.

And you can see on the lower part of the curve, the healthy non-IBS population feels the balloon rather early. The typical sensation threshold is only 10 or 20 cc of air, so it's a very sensitive area. But it's not perceived as painful until the distending volume gets quite large: in the range of 180 or so.

In contrast, the upper curve shows you the percent of the IBS patients that are experiencing pain at the different distending volumes. And as you can see, by the time you get to 180 milliliters of distention, about half of the IBS patients are reporting pain. So they're more sensitive to distention of the rectosigmoid colon than the healthy controls.

Peter Salgo MD: Is this something that you could use as a diagnostic test in clinical practice?

Lawrence Schiller MD: It probably wouldn't work very well in clinical practice, because only half of the IBS patients have the excessive pain perception. And that's a difficulty when you're dealing with a syndrome which may have many separate diseases as its cause.

Peter Salgo MD: Here comes the most dangerous question in medicine. You've described something, now tell me why it occurs.

Lawrence Schiller MD: There are several theories that have been developed. For example, we know that irritable bowel syndrome occurs after people have a gastroenteritis. The thought is that somehow the enteric nervous system becomes sensitized to some stimuli that come from the gut and that this results in the excessive perception of pain. But we don't know why that occurs in the vast majority of these people.

Peter Salgo MD: Do you think this a local phenomenon as opposed to a central phenomenon?

Lawrence Schiller MD: Again, we're not absolutely sure about that. There's some evidence on both sides that it can occur both in the periphery and in the central nervous system - in the spinal cord and perhaps in the brain as well.

Peter Salgo MD: Lin, there are some observable differences centrally, right?

Lin Chang MD: There have been brain activation studies, both in the form of positron emission tomography or PET and functional MRI. The studies are showing that areas of brain activation differ between IBS patients and controls, even when they're given the same stimulus, and that stimulus is usually a balloon distention in the colorectal region.

Peter Salgo MD: What is the reason for this central difference in patients with and without irritable bowel syndrome? Do we have any reason at all?

Lin Chang MD: No, it's not really completely understood. I think it may have to do with the way that the brain responds to stressors. And over a period of time, it may be different in certain individuals than others. Whether or not there are any genetic factors isn't really well-known.

Peter Salgo MD: I want to come back to something else, Susan. Although we may not be able to demonstrate drastic motility differences, there may be some symptomatic differences in people with observed motility disorders. Is that right?

Susan Lucak MD: Right. We see the different motility patterns that were described by Lin and by Larry, but we do not really see the motility patterns coupled to symptoms. We can observe motility patterns, but at the same time patients don't experience pain, for example, or they don't have the urge to defecate or they don't feel particularly constipated.

Peter Salgo MD: Susan, in the past, people with IBS were often told, "Well, you know, this is all in your head." Is what we know about this disease today causing a change in thinking, and are we looking at these patients differently today than we used to?

Susan Lucak MD: Patients who have irritable bowel syndrome certainly have increased sensitivity in the gut. They may have some motility patterns that are different in comparison to patients who don't have irritable bowel syndrome. And then they have different central processing, different brain processing of pain.

Peter Salgo MD: Where do these patients normally present?

Susan Lucak MD: Most commonly, they will present to their primary care physicians, and then approximately 5% of patients with irritable bowel syndrome who have more severe symptoms will present to gastroenterologists

Lin Chang MD: I do want to make a comment about psychosocial factors and symptoms. I think the way that research is moving now, we're trying to find the biologic mechanisms underlying psychosocial or psychological distress and GI symptoms. Those are probably linked hand-in-hand. Psychophysiologic disturbances are seen in these patients.

Peter Salgo MD: It's very complicated, isn't it?

Lin Chang MD: Right.

Peter Salgo MD: We're looking at the central nervous system, but the more we look down at the enteric nervous system, the more interesting this thing gets. So Larry, perhaps you could lead us through this a little bit. What is the ENS; what does it do?

Lawrence Schiller MD: The enteric nervous system is probably best thought of as the little brain in the gut. It has all the components of a full-fledged neurological system that you might find in a worm or some other simple creature. There is a sensory arm to it, there is an integrative arm, interneurons, and then there's a motor, or effector, arm. So it can do a whole panoply of different programmed behaviors, depending on what the inputs are.

Peter Salgo MD: And it's semiautonomous, right? You don't need the CNS for the ENS to be working.

Lawrence Schiller MD: Absolutely.

Peter Salgo MD: The more you look at the structure there, the more it looks like the CNS than the other peripheral nervous systems.

Lawrence Schiller MD: It does. There are lots of connections between the CNS and the enteric nervous system. But in every sense of the word, it's its own creature.

Peter Salgo MD: Lin, help me out here a little bit. What role does serotonin play in the motility of the gut?

Lin Chang MD: It regulates peristalsis, secretomotor function and intestinal reflexes.

Peter Salgo MD: And how does that affect transmitters?

Lin Chang MD: The release of serotonin acts on the enteric nervous system within these interneurons, acts on sensory and motor neurons. It'll cause a contraction proximally and relaxation distally so that youl get peristalsis.

Peter Salgo MD: Susan, where is this ENS located?

Susan Lucak MD: The enteric nervous system consists of two ganglionated plexuses. The first one is located under the mucosa; it's called the submucosal plexus. And the myenteric plexus is located between the circular and the longitudinal muscles of the bowel.

Serotonin is stored in enterochromaffin cells, which are in the lining of the gastrointestinal tract. So upon either chemical or physical stimulation, serotonin is released from these enterochromaffin cells into the submucosa. There it acts on receptors and the submucosal plexus and then through interneurons. The neurological information is then passed down to the myenteric plexus.

Peter Salgo MD: But the serotonin's not the only thing in there, right?

Susan Lucak MD: No. There are many other chemical messengers, neurotransmitters, peptides, hormones that may mediate the functioning of the enteric nervous system.

Peter Salgo MD: For example?

Susan Lucak MD: Serotonin is the one that has been studied most recently, because it has both effect on sensory as well as motor function. But there are other neurotransmitters; there's substance P, there are neurokinins and there are other neurotransmitters that may play a very important role - including acetylcholine, of course.

Lin Chang MD: Yes, for example, acetylcholine and substance P are thought to play a role in the contraction that you see proximally. And vasointestinal peptide and nitric oxide are thought to play a role in the relaxation.

Peter Salgo MD: Larry, in which enteric cells is serotonin located?

Lawrence Schiller MD: Well, serotonin is mainly in the enterochromaffin cells, as has been pointed out. So there are receptors on the sensory neurons, the interneurons and the motor neurons for serotonin.

Peter Salgo MD: Lin, can you link us to serotonin and its activity and the symptoms that it produces?

Lin Chang MD: The serotonin interacting in the enteric nervous system, where you have serotonin release acting on the 5-HT3 and the 5-HT4 subtype receptors, will stimulate peristalsis. So if you block that, you would inhibit peristalsis. Its actions on enteric nervous system can also increase or decrease secretion, depending on the presence of a receptor agonist or antagonist.

It's not really clear what role the enteric nervous system plays in pain. There are 5-HT3 and 5-HT4 receptors on the extrinsic neurons, the visceral afferents. Serotonin may modulate visceral pain through those mechanisms.

Peter Salgo MD: What about the epiphenomenon? The nausea, the bloating: are these symptoms serotonin-related, as well?

Lin Chang MD: Possibly. I think the cause of bloating is a little more complicated, but it probably has to do with two factors. One is slow transit of gas through the GI tract, which has been shown in IBS patients. And it's also partly visceral hypersensitivity, where patients have this enhanced perception of gas. The combination of those two make the patient have bloating.

Nausea is more of an upper gut symptom and that may be linked to not the enteric nervous system so much as maybe to the vagal nervous system.

Peter Salgo MD: Now, of course, when a doctor hears that we've got a substance, we've got a receptor and it is in some way, however indistinctly, linked to disorders in peristalsis or other motility, the first thing most docs think of is, "Let's block it", or, "Let's push it." We see if we can fix things by doing that mechanistically. So, if you blocked some of these serotonin receptors pharmacologically, what might you expect?

Susan Lucak MD: Well, if one blocks serotonin type 3 receptor, as was done with a medication called alosetron, the effect is that the stool frequency of patients with diarrhea will decrease. It may also diminish their sense of urgency. Their stool consistency may change, and that is an effect that it may have on secretion. And also their abdominal discomfort may improve.

With regard to serotonin type 4 receptor, in terms of an agonistic action, as has been seen with tegaserod, the effect is to speed up gut motility. It increases gut secretion, so that the stools are more hydrated. It also helps with bloating and sensations. So these mechanisms and receptors have been explored with these medications.

Peter Salgo MD: Now, we've got a chemical, we've got receptors, we've got explorations into blocking the effects of this chemical on the various receptors. But, Larry, the $64,000 question is, has anybody linked disorders in serotonin production to this kind of illness? Where's the clinical correlation here?

Lawrence Schiller MD: Certainly, the theory is that patients who tend to have diarrhea might have more available serotonin and those who have constipation might tend to have less. There are studies that suggest that the numbers and kinds of enterochromaffin cells may be altered in those states and that there may be some changes in receptors as well. But that's all very preliminary information.

Peter Salgo MD: But there's enough there, you think, to justify this, this agitation in the serotonin pathway and looking for ways to block or influence its effect?

Lawrence Schiller MD: I think that since we know serotonin is so central to many of these gut effects, manipulating it may have beneficial effects in patients who have problems.

Susan Lucak MD: One thing that's important to recognize is that there's a tremendous amount of serotonin in the gut. 95% of serotonin in the body is in the gut, and only about 5% is localized in the brain.

Peter Salgo MD: Before we finish this segment, Lin, I wonder if you can take us through a little bit about gastroenteritis, other sources of GI infection and inflammation. Can these lead to IBS?

Lin Chang MD: There's evidence that between 7 and 30% of those with a proven bacterial gastroenteritis will develop irritable bowel syndrome. It's called postinfectious IBS. There are some risk factors; typically the female gender, the duration of the acute illness and the presence of chronic life stressors at the time they get the illness. These can lead to postinfectious IBS.

Peter Salgo MD: What's the mechanism here, do we know? Are cytokines floating around in here in some bizarre way? What's happening?

Lin Chang MD: It's not well-known at this point. Studies are investigating the immune cellularity and also the presence of cytokines. Cytokines can feed back from the gut to the brain and stimulate, for example, corticotropin-releasing factor.

Lin Chang MD