In the past, the predominant pathophysiologic mechanisms in IBS were thought to be abnormalities in the gut smooth muscle function, visceral hypersensitivity, and central nervous system (CNS) hypervigilance.
We now recognize the existence of peripheral mechanisms that initiate perturbation of gastrointestinal (GI) motor and sensory functions that lead to IBS symptoms. These irritants include the products of digestion, neurotransmitters, transporters, a history of gastroenteritis, changes in the microbiome, mucosal immune activation, and increased mucosal permeability. In addition, it is recognized that disorders of rectal evacuation mimic the symptoms of constipation-predominant irritable bowel syndrome (IBS-C).
The symptoms of evacuation disorder -- constipation, straining, a sense of incomplete evacuation, bloating, left-sided abdominal pain that are relieved by bowel movements -- are very similar to those of IBS-C. In clinical practice, we recognize spastic disorders of the pelvic floor or the anal sphincter that prevent evacuation. Women who have had multiple vaginal deliveries, forceps delivery, or injury to the perineum can have descending perineum syndrome, in which the pelvic floor does not function normally; in contrast to spastic disorders, it results in a flaccid pelvic floor.
During normal evacuation, the puborectalis muscle relaxes and the rectoanal angle opens up in order to facilitate defecation. In the spastic disorders, the anal sphincter and puborectalis contract spastically, preventing the opening of the rectoanal angle. In descending perineum syndrome, the entire perineum balloons out with straining, but the angle between the rectum and the anal canal remains acute, preventing expulsion of stool.
Prokinetic and stimulant agents will have limited or no benefit in evacuation disorders mimicking IBS-C, and can worsen pain without overcoming the problem of rectal evacuation. The diagnosis of an evacuation disorder requires history, examination, evaluation of perineal descent, anorectal manometry, and balloon expulsion test.
Among the peripheral mechanisms associated with IBS is disturbance of colonic motility, which may be accelerated or delayed, and may be secondary to an abnormality in secretion in the intestine or colon.
Several factors may be involved, including neuromuscular dysfunction, products of the enteroendocrine cells, production of organic acids within the lumen, and sometimes even genetic predisposition, as has been described in patients who have a disturbance in either bile acid synthesis or a rare mutation involving the guanylate cyclase C receptor. As a result of this abnormality of motility or transit, approximately 45% of patients with diarrhea-predominant IBS (IBS-D) have accelerated transit, and about 25% of those with IBS-C have delayed transit.
Approximately 35% of the patients with IBS-D had accelerated transit and the same proportion of patients who had IBS-C had delayed transit.
Recent research suggests that excess hepatic synthesis and excretion of bile acids may contribute to IBS-D; and that decreased production and excretion may contribute to IBS-C
We know that certain types of bile acids have at least 2 α-hydroxy groups at the 3, 7, and 12 positions are natural secretory agents; they are natural laxatives that facilitate movement of contents through the colon. There is now evidence that a deficiency in these secretory bile acids contributes to the slow transit in patients who have constipation or IBS-C. This is relevant as it may provide a rationale for new approaches to treatment of both diarrhea and constipation in IBS.
A second major peripheral mechanism pertains to the sensing of the small bowel and colon, and responses to those sensations. Activation of local secretory and motor reflexes and sensory mechanisms may result from ingestion of foods that stimulate enteroendocrine cells or the organic acids, such as short-chain fatty acids (SCFAs) that are produced by the breakdown of complex carbohydrates in the colon by the resident microflora. As mentioned earlier, it may also be related to the presence of bile acids that bypass the ileal reabsorptive mechanism and reach the colon, causing symptoms such as diarrhea, bloating, and abdominal pain.
Important cellular mechanisms present in the small intestine and colon -- goblet cells, enterocytes, and enteroendocrine cells -- work in unison to change fluid and electrolyte movement through the epithelium. For example, goblet cells produce not only mucins, but also secrete guanylin, and uroguanylin which activate the guanylate cyclase C receptor to induce chloride secretion from the enterocytes. Similarly, enteroendocrine cells produce transmitters, such as 5-hydroxytryptamine, which then stimulate either the submucosal neuron to evoke secretion, or directly stimulate the enterocytes to produce chloride secretion and thereby drag water and sodium into the lumen.
Different mechanisms may be involved in the pathophysiology of IBS, but more importantly, perhaps, is that these mechanisms provide a means to treat IBS-C. For example, drugs that activate the chloride channel directly, and drugs that bind to the guanylate cyclase C receptor to induce chloride secretion, help to manage constipation in IBS-C.
Rectal hypersensitivity had previously been thought to be associated with IBS, but it is now apparent that not all patients with IBS have evidence of hypersensitivity of the rectum or the intestines. IBS is not all about sensation, and we need to consider other mechanisms for IBS.
One of those mechanisms is a change in the barrier function in the small intestine and in the colon, which we term mucosal permeability. Increased permeability with alteration of the expression of the tight junction proteins may occur as the result of prior gastroenteritis, atopy, or food intolerance. These may occur, for example, with gluten intake or ingestion of fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs), the sugar entities that alter barrier function of the intestine. Stress also is known to make the mucosa leaky (more permeable) and allow antigens or other chemicals in the lumen access to the surface epithelial cells and to nerve cells below that level. Typically, changes in permeability results in IBS-D, with fluid secretion or activation of those sensory mechanisms that ultimately become expressed as pain.
It is not only the epithelial cells that constitute the barrier. Within the lumen, there is degradation of bacteria and antigens by bile, gastric acid, and pancreatic juice. There are commensal bacteria that inhibit the colonization of pathogens by producing antimicrobial substances. The microclimate provides an unstirred water layer, the glycocalyces from the epithelial cells, and the mucus layer, which, along with secretion of immunoglobulin-A (IgA) within the intestine, prevents bacterial adhesion.
Those 3 layers prevent entry of antigens, or attack by microorganisms, even before we get to the epithelial cells, which are connected by junctional complexes that have the ability to transport luminal content and react to noxious stimuli by secretion of chloride and antimicrobial peptides. This secretion can wash away those antigens so that they cannot gain ground within the lining of the intestine.
Below the epithelial cells, we have a number of other mechanisms. Within the lamina propria, we have immune cells that bring innate and acquired immunity, secretion of immunoglobulin cytokines to protect the intestine from attack. We also have other endocrine and enteric nervous systems that induce intestinal propulsion and move that attacking organism or antigen, preventing it from gaining ground within the intestinal wall.
Just as there is a mucosal barrier in the small intestine, there is also a low permeability in the normal state in the colon. The barrier in the colon may be broken, however, when malabsorption of either carbohydrates or fat results in the production of SCFAs, when there is bile acid malabsorption or immune activation, in the presence of genetic predisposition to inflammation or immune activation or bile acid synthesis. Typically, this is going to be associated with IBS-D, increased fluid secretion and activation of sensory mechanisms.
Research has documented an increased intestinal permeability in IBS; this is relevant because 1 of the agents used in the treatment of IBS, lubiprostone, has been shown in a porcine ischemia model to restore tight junction function and normalize permeability of the intestine. This may be advantageous if permeability is indeed a significant mechanism causing the patient's diarrhea.
The cumulative excretion of a sugar molecule such as mannitol has been shown to be a fairly good noninvasive marker of permeability, as has been demonstrated in patients who have IBS-D. Although the increase in permeability is lower than that which is observed in patients with inactive or microscopic or ulcerative colitis, changes in permeability and tight junction proteins appear to be quite relevant in IBS. There is a relationship among duration of disease, body mass index, and, importantly, the expression of the tight junction protein occludin and pain in IBS.
Another mechanism relevant in IBS is the activation of mucosal immune mechanisms. This activation has a secondary effect of increasing permeability as well as switching on reflexes and sensory mechanisms that result in manifestations of IBS. The factors involved in mucosal immune activation are a history of gastroenteritis, and inflammatory cells such as mast cells and T lymphocytes. Increased circulating cytokines can also result from mucosal immune activation. The T lymphocytes and mast cells appear to be activated among patients who have IBS-D, rather than IBS-C.
This leads to the question of whether IBS-D may be an inflammatory disease, and if so, what is its cause? At the present time 2 of the mechanisms thought to be causally related to this mucosal inflammation or immune activation are the bile acid malabsorption and the presence of dietary antigens, such as gluten, to which some patients may be sensitive, even in the absence of overt celiac disease.
The last mechanism to be discussed is the colonic microbiome and production of SCFAs. Even people without IBS pass about 10% of those complex carbohydrates from the ileum to the colon. Because of the interaction between the microbes in the colon and the complex carbohydrates that reach the colon, the production of SCFAs results in the stimulation of motor, secretory, and sensory mechanisms.
This is identified primarily by an increase in Firmicutes spp, or the ratio of Firmicutes spp to Bacteroidetes spp. Clearly, the microbiome in the colon can be modified by antibiotics and probably also by probiotics. Bile acids influence the microbial species in the colon. The consequences of these changes in the microbiome are abdominal bloating, pain, and diarrhea.
Studies have examined the microbiota and the feces from patients with IBS. The most straightforward summary of those findings is that, in general, the number of Firmicutes spp is increased and the number of Bacteroidetes spp is decreased. As examples, Clostridia spp and Veillonella spp are increased, whereas Bacteroides spp and Prevotella spp are decreased in patients with IBS. More work is being done in this area.
In summary, there are a number of pathophysiologic mechanisms that result in the symptoms of IBS. It is also important to recognize there is a potential role of genetics in altered sensing and stimulation of secretion and motility, permeability, immune activation, colonic transit. These include changes in serotonergic control, inflammation, bile acid synthesis, and the guanylate cyclase C receptor on the enterocytes.
At present, management is guided by the symptom criteria, such as the Rome III criteria. Commonly used treatments for IBS-C include fiber, osmotic laxatives, bisacodyl, lubiprostone, and linaclotide; loperamide and alosetron are available for patients with functional diarrhea or IBS-D. We also use antispasmodics for colic, and antidepressants for pain.
We recognize that constipation and bloating may arise in the presence of pelvic floor dysfunction, or normal transit constipation, or slow transit constipation. We recognize that diarrhea may be the result of altered motility and secretion. Beyond that, we know that factors such as increased permeability, mucosal inflammation, and activation of sensory fibers that induce those changes in motility and secretion may have a role and may, in part, explain the pain associated with IBS.
A number of treatments for IBS are under development. While they focus on central pain perception, altered sensation, and altered motility and secretion, novel approaches appear very promising as they will be directed at specific mechanisms that can be identified through tests that are either available or will be in future. For example, in patients who have mucosal immune activation or evidence of inflammation, these treatments may include probiotics, antibiotics, mast-cell stabilizers, or 5-aminosalicylic acid compounds. Similarly, alterations of motility and secretion may be targeted with new classes of medications that include serotonin synthesis inhibitors, chloride channel openers, guanylate cyclase C agonists, and ileal bile acid transporter inhibitors, as well as other agents directed at the specific mechanisms occurring in the GI tract.
We now recognize the existence of peripheral mechanisms that initiate perturbation of gastrointestinal (GI) motor and sensory functions that lead to IBS symptoms. These irritants include the products of digestion, neurotransmitters, transporters, a history of gastroenteritis, changes in the microbiome, mucosal immune activation, and increased mucosal permeability. In addition, it is recognized that disorders of rectal evacuation mimic the symptoms of constipation-predominant irritable bowel syndrome (IBS-C).
The symptoms of evacuation disorder -- constipation, straining, a sense of incomplete evacuation, bloating, left-sided abdominal pain that are relieved by bowel movements -- are very similar to those of IBS-C. In clinical practice, we recognize spastic disorders of the pelvic floor or the anal sphincter that prevent evacuation. Women who have had multiple vaginal deliveries, forceps delivery, or injury to the perineum can have descending perineum syndrome, in which the pelvic floor does not function normally; in contrast to spastic disorders, it results in a flaccid pelvic floor.
During normal evacuation, the puborectalis muscle relaxes and the rectoanal angle opens up in order to facilitate defecation. In the spastic disorders, the anal sphincter and puborectalis contract spastically, preventing the opening of the rectoanal angle. In descending perineum syndrome, the entire perineum balloons out with straining, but the angle between the rectum and the anal canal remains acute, preventing expulsion of stool.
Prokinetic and stimulant agents will have limited or no benefit in evacuation disorders mimicking IBS-C, and can worsen pain without overcoming the problem of rectal evacuation. The diagnosis of an evacuation disorder requires history, examination, evaluation of perineal descent, anorectal manometry, and balloon expulsion test.
Among the peripheral mechanisms associated with IBS is disturbance of colonic motility, which may be accelerated or delayed, and may be secondary to an abnormality in secretion in the intestine or colon.
Several factors may be involved, including neuromuscular dysfunction, products of the enteroendocrine cells, production of organic acids within the lumen, and sometimes even genetic predisposition, as has been described in patients who have a disturbance in either bile acid synthesis or a rare mutation involving the guanylate cyclase C receptor. As a result of this abnormality of motility or transit, approximately 45% of patients with diarrhea-predominant IBS (IBS-D) have accelerated transit, and about 25% of those with IBS-C have delayed transit.
Approximately 35% of the patients with IBS-D had accelerated transit and the same proportion of patients who had IBS-C had delayed transit.
Recent research suggests that excess hepatic synthesis and excretion of bile acids may contribute to IBS-D; and that decreased production and excretion may contribute to IBS-C
We know that certain types of bile acids have at least 2 α-hydroxy groups at the 3, 7, and 12 positions are natural secretory agents; they are natural laxatives that facilitate movement of contents through the colon. There is now evidence that a deficiency in these secretory bile acids contributes to the slow transit in patients who have constipation or IBS-C. This is relevant as it may provide a rationale for new approaches to treatment of both diarrhea and constipation in IBS.
A second major peripheral mechanism pertains to the sensing of the small bowel and colon, and responses to those sensations. Activation of local secretory and motor reflexes and sensory mechanisms may result from ingestion of foods that stimulate enteroendocrine cells or the organic acids, such as short-chain fatty acids (SCFAs) that are produced by the breakdown of complex carbohydrates in the colon by the resident microflora. As mentioned earlier, it may also be related to the presence of bile acids that bypass the ileal reabsorptive mechanism and reach the colon, causing symptoms such as diarrhea, bloating, and abdominal pain.
Important cellular mechanisms present in the small intestine and colon -- goblet cells, enterocytes, and enteroendocrine cells -- work in unison to change fluid and electrolyte movement through the epithelium. For example, goblet cells produce not only mucins, but also secrete guanylin, and uroguanylin which activate the guanylate cyclase C receptor to induce chloride secretion from the enterocytes. Similarly, enteroendocrine cells produce transmitters, such as 5-hydroxytryptamine, which then stimulate either the submucosal neuron to evoke secretion, or directly stimulate the enterocytes to produce chloride secretion and thereby drag water and sodium into the lumen.
Different mechanisms may be involved in the pathophysiology of IBS, but more importantly, perhaps, is that these mechanisms provide a means to treat IBS-C. For example, drugs that activate the chloride channel directly, and drugs that bind to the guanylate cyclase C receptor to induce chloride secretion, help to manage constipation in IBS-C.
Rectal hypersensitivity had previously been thought to be associated with IBS, but it is now apparent that not all patients with IBS have evidence of hypersensitivity of the rectum or the intestines. IBS is not all about sensation, and we need to consider other mechanisms for IBS.
One of those mechanisms is a change in the barrier function in the small intestine and in the colon, which we term mucosal permeability. Increased permeability with alteration of the expression of the tight junction proteins may occur as the result of prior gastroenteritis, atopy, or food intolerance. These may occur, for example, with gluten intake or ingestion of fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs), the sugar entities that alter barrier function of the intestine. Stress also is known to make the mucosa leaky (more permeable) and allow antigens or other chemicals in the lumen access to the surface epithelial cells and to nerve cells below that level. Typically, changes in permeability results in IBS-D, with fluid secretion or activation of those sensory mechanisms that ultimately become expressed as pain.
It is not only the epithelial cells that constitute the barrier. Within the lumen, there is degradation of bacteria and antigens by bile, gastric acid, and pancreatic juice. There are commensal bacteria that inhibit the colonization of pathogens by producing antimicrobial substances. The microclimate provides an unstirred water layer, the glycocalyces from the epithelial cells, and the mucus layer, which, along with secretion of immunoglobulin-A (IgA) within the intestine, prevents bacterial adhesion.
Those 3 layers prevent entry of antigens, or attack by microorganisms, even before we get to the epithelial cells, which are connected by junctional complexes that have the ability to transport luminal content and react to noxious stimuli by secretion of chloride and antimicrobial peptides. This secretion can wash away those antigens so that they cannot gain ground within the lining of the intestine.
Below the epithelial cells, we have a number of other mechanisms. Within the lamina propria, we have immune cells that bring innate and acquired immunity, secretion of immunoglobulin cytokines to protect the intestine from attack. We also have other endocrine and enteric nervous systems that induce intestinal propulsion and move that attacking organism or antigen, preventing it from gaining ground within the intestinal wall.
Just as there is a mucosal barrier in the small intestine, there is also a low permeability in the normal state in the colon. The barrier in the colon may be broken, however, when malabsorption of either carbohydrates or fat results in the production of SCFAs, when there is bile acid malabsorption or immune activation, in the presence of genetic predisposition to inflammation or immune activation or bile acid synthesis. Typically, this is going to be associated with IBS-D, increased fluid secretion and activation of sensory mechanisms.
Research has documented an increased intestinal permeability in IBS; this is relevant because 1 of the agents used in the treatment of IBS, lubiprostone, has been shown in a porcine ischemia model to restore tight junction function and normalize permeability of the intestine. This may be advantageous if permeability is indeed a significant mechanism causing the patient's diarrhea.
The cumulative excretion of a sugar molecule such as mannitol has been shown to be a fairly good noninvasive marker of permeability, as has been demonstrated in patients who have IBS-D. Although the increase in permeability is lower than that which is observed in patients with inactive or microscopic or ulcerative colitis, changes in permeability and tight junction proteins appear to be quite relevant in IBS. There is a relationship among duration of disease, body mass index, and, importantly, the expression of the tight junction protein occludin and pain in IBS.
Another mechanism relevant in IBS is the activation of mucosal immune mechanisms. This activation has a secondary effect of increasing permeability as well as switching on reflexes and sensory mechanisms that result in manifestations of IBS. The factors involved in mucosal immune activation are a history of gastroenteritis, and inflammatory cells such as mast cells and T lymphocytes. Increased circulating cytokines can also result from mucosal immune activation. The T lymphocytes and mast cells appear to be activated among patients who have IBS-D, rather than IBS-C.
This leads to the question of whether IBS-D may be an inflammatory disease, and if so, what is its cause? At the present time 2 of the mechanisms thought to be causally related to this mucosal inflammation or immune activation are the bile acid malabsorption and the presence of dietary antigens, such as gluten, to which some patients may be sensitive, even in the absence of overt celiac disease.
The last mechanism to be discussed is the colonic microbiome and production of SCFAs. Even people without IBS pass about 10% of those complex carbohydrates from the ileum to the colon. Because of the interaction between the microbes in the colon and the complex carbohydrates that reach the colon, the production of SCFAs results in the stimulation of motor, secretory, and sensory mechanisms.
This is identified primarily by an increase in Firmicutes spp, or the ratio of Firmicutes spp to Bacteroidetes spp. Clearly, the microbiome in the colon can be modified by antibiotics and probably also by probiotics. Bile acids influence the microbial species in the colon. The consequences of these changes in the microbiome are abdominal bloating, pain, and diarrhea.
Studies have examined the microbiota and the feces from patients with IBS. The most straightforward summary of those findings is that, in general, the number of Firmicutes spp is increased and the number of Bacteroidetes spp is decreased. As examples, Clostridia spp and Veillonella spp are increased, whereas Bacteroides spp and Prevotella spp are decreased in patients with IBS. More work is being done in this area.
In summary, there are a number of pathophysiologic mechanisms that result in the symptoms of IBS. It is also important to recognize there is a potential role of genetics in altered sensing and stimulation of secretion and motility, permeability, immune activation, colonic transit. These include changes in serotonergic control, inflammation, bile acid synthesis, and the guanylate cyclase C receptor on the enterocytes.
At present, management is guided by the symptom criteria, such as the Rome III criteria. Commonly used treatments for IBS-C include fiber, osmotic laxatives, bisacodyl, lubiprostone, and linaclotide; loperamide and alosetron are available for patients with functional diarrhea or IBS-D. We also use antispasmodics for colic, and antidepressants for pain.
We recognize that constipation and bloating may arise in the presence of pelvic floor dysfunction, or normal transit constipation, or slow transit constipation. We recognize that diarrhea may be the result of altered motility and secretion. Beyond that, we know that factors such as increased permeability, mucosal inflammation, and activation of sensory fibers that induce those changes in motility and secretion may have a role and may, in part, explain the pain associated with IBS.
A number of treatments for IBS are under development. While they focus on central pain perception, altered sensation, and altered motility and secretion, novel approaches appear very promising as they will be directed at specific mechanisms that can be identified through tests that are either available or will be in future. For example, in patients who have mucosal immune activation or evidence of inflammation, these treatments may include probiotics, antibiotics, mast-cell stabilizers, or 5-aminosalicylic acid compounds. Similarly, alterations of motility and secretion may be targeted with new classes of medications that include serotonin synthesis inhibitors, chloride channel openers, guanylate cyclase C agonists, and ileal bile acid transporter inhibitors, as well as other agents directed at the specific mechanisms occurring in the GI tract.
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