Irritable bowel syndrome (IBS) is the most frequent reason for consulting a gastroenterologist and the second reason, after the flu, for absenteeism from work. It is estimated to affect around 15% of the general population, with studies even reporting more than 45%.
Generally, women are more affected than men, in a ratio of 2:1, with peak incidence occurring in early adulthood. In general, patients are divided into 3 subtypes: predominantly diarrhea (IBS-D), predominantly constipation (IBS-C) or mixed (IBS-M). Women commonly suffer from IBS-C, while men mostly suffer from IBS-D.
Pathophysiology
One of the most common conditions that cause symptoms in IBS patients is food intolerance. IBS patients understand that specific types of foods trigger their symptoms. These usually include legumes, vegetables, foods with lactose, fatty foods, stone fruits and artificial sweeteners.
One category of foods recognized for triggering worsening of IBS due to their osmotic and fermentative effects are those containing oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs).
The problem with a low FODMAP diet is that it is very restrictive. Therefore, monitoring by an experienced nutritionist is necessary to prevent any nutritional deficit or unintentional weight loss.
Other researchers have reported an improvement in symptoms after eliminating gluten from their patients’ diets and a relapse when it was reintroduced. These patients were neither diagnosed nor suspected of having celiac disease. Gluten could influence the pathogenesis of IBS through changes in the function of the epithelial barrier, having a role in the pathogenesis that is still unknown.
enteric infection
Patients sometimes complain of IBS symptoms after an infection. This is generally known as post-infectious IBS and usually occurs after bacterial, viral or protozoal gastroenteritis, when around 20% of patients develop IBS symptoms. Risk factors include prolonged infection, prolonged fever, young age, depression and anxiety.
In a study of almost 20,000 people, drinking water from a source contaminated with pathogens such as Giardia lamblia, novovirus and Campylobacter jejuni, researchers showed that the risk for IBS symptoms was higher in subjects with anxiety, depression or young age, reinforcing theories of a brain-gut connection.
Inflammation-immunology
Many of the patients who report IBS symptoms have inflammatory diseases. Celiac disease, inflammatory bowel disease, and severe acute gastroenteritis are just examples. Inflammation could be a predisposing factor for IBS symptoms, but the pathophysiology behind this is still unclear.
Greater activity of innate and adaptive immunity was observed in the enteric mucosa of some patients with IBS.
Visceral hypersensitivity has also been associated with mucosal inflammation in a study in rats and with increased colonic and small intestine permeability in patients with IBS-D.
One study reported that patients with IBS have a 15-50% increase in intestinal permeability. This could be because patients with IBS seem to have increased levels of interleukin-10, interleukin-6, TNF-α and other cytokines, and their concentration is associated with the frequency and severity of pain, but also with the presence of anxiety.
In a study with patients with IBS, after exposure to food antigens to which they were intolerant, mucosal alterations were observed. These alterations included an increase in intraepithelial lymphocytes, widening of intervillous spaces, and formation of epithelial gaps.
Gut-brain axis
IBS is a good example of dysregulation between the gut and the brain.
The gut-brain axis includes the central nervous system, the hypothalamic-pituitary axis, the autonomic nervous system, and the enteric nervous system. The triggers come from the intestine through the vagus, spinal and enteric nerves.
Signals to the intestine are transmitted by neuroendocrine neurotransmitters produced in the intestine by immune cells and enterochromaffins to alter the behavior of the microbiota. This is possible because bacteria also have some receptors for neurotransmitters and are influenced by these signals.
Serotonin
The enteric nervous system has been described as a “second brain” and contains 5 times more neurons than the spinal cord. In the gastrointestinal tract, 90% of serotonin (5-HT) and 50% of dopamine are produced by enterochromaffin cells. Serotonin production is further stimulated by sporulating bacteria, modifying the immune response, secretion and gastrointestinal motility.
It is also stimulated by the microbiota after exposure to short-chain fatty acids that come from foods and the FODMAP diet, or from short-chain fatty acid-producing bacteria. These fatty acids increase intestinal transit and could be a possible causal factor of IBS symptoms.
The role of serotonin in the pathogenesis of IBS has been confirmed by studies that examined different drugs that act at the level of the 5-HT receptor with beneficial effects on IBS symptoms. Another study concluded that those patients with IBS-D have a lower reuptake of serotonin, while those with IBS-C have a lower release of it.
Stress-depression
More than 75% of patients with IBS symptoms usually have concomitant anxiety or depression. One study found that patients exposed to stressful life events tended to have greater IBS symptoms.
An interesting study, which compared levels of anxiety and depression in IBS patients and healthy individuals, found that the activity of the dorsolateral prefrontal cortex of IBS patients was dysregulated in behavioral selection tasks. This indicates that patients with IBS can experience alterations in brain function even without suffering from anxiety or depression.
On the other hand, the production of noradrenaline by stressful stimuli appears to increase the growth of many intestinal pathogens, including C. jejuni and E. Coli.
GABA
GABA is an important inhibitory neurotransmitter that prevents abnormal firing of CNS neurons. Dysregulation of GABA leads to diseases such as epilepsy and anxiety disorders. GABA-b receptors are also thought to be involved in the gastrointestinal tract, affecting visceral sensation, pain, and intestinal motility.
Genetics
IBS is more common in monozygotic than dizygotic twins, suggesting a possible genetic background for the disease. This is plausible since a specific mutation was found to be common in 2% of IBS patients in one study and the majority of them had IBS-C
Bile acid metabolism
Idiopathic bile acid diarrhea is estimated to affect up to 20% of IBS-D patients, while IBS-C patients have altered bile acid metabolism. De-conjugation occurs in the intestine and is carried out by bacteria.
Therefore, if the intestine is exposed to large amounts of bile acids, diarrhea may occur. Conversely, if there is an insufficient amount of bile acids in the stool, constipation may occur.
The association between bile acid metabolism and IBS can also be confirmed by the improvement of IBS-D symptoms observed in patients taking the bile acid sequestrant colestipol.
Microbiota
It is assumed that patients with IBS have altered microbiota in their intestines. Observations from a study in 110 IBS patients show that IBS patients have a different intestinal microbiota, with a lower microbial variety and a lower number of Methanobacteriales and Prevotella species.
Lactobacillus and Bacteroides species, known beneficial bacteria, are also reduced, while the number of pathogenic bacteria, such as Streptococcus spp., increases. One of the most common symptoms in IBS is bloating, and gas-producing bacteria may be responsible for this.
Presentation Patients with IBS are classified into subtypes according to their predominant bowel habit. These include IBS-D, IBS-C, and mixed IBS (IBS-M). Generally, IBS -D and IBS -C have a similar prevalence. Common signs and symptoms of IBS are:
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Differential diagnosis
It includes many diseases, not only of the gastrointestinal tract, but also due to extra-intestinal causes. Diseases that commonly present with diarrhea and should be excluded first are microscopic colitis, inflammatory bowel disease, celiac disease, infections, hyperthyroidism, carbohydrate malabsorption, and bile acid diarrhea.
On the other hand, disorders that present with constipation and must be excluded are colorectal cancer or anal neoplasia that obstructs the lumen, dyssynergic defecation, and hypothyroidism. Other causes of abdominal pain should also be excluded: endometriosis, diverticulitis, pelvic inflammatory disease and ovarian cancer are just a few examples.
Assessment
The clinical history and physical examination are very important in the evaluation of patients with IBS. Generally, if there are no warning signs or symptoms or other risk factors for organic disease , the diagnosis of IBS can be made with confidence, especially in the case of IBS-C.
Warning signs and symptoms include :
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Inspection of the perianal area should be performed in search of fissures or fistulas, as well as a digital rectal examination in search of anal pathology.
A complete blood count and a C-reactive protein test are usually sufficient to reassure the patient that there is no organic disease, provided that other risk factors or the warning signs and symptoms mentioned above are absent.
In patients with IBS-D, investigation should also include:
- serology for celiac disease
- thyroid function evaluation
- fecal calprotectin
- analysis of feces for infectious microorganisms
Invasive procedures should only be performed if there is a specific indication for them, such as the presence of blood in stool.
Diagnosis: Rome IV Criteria
They replaced the Rome III criteria in 2016. The main difference between the two is that abdominal discomfort, a vague term, was withdrawn and currently only patients with abdominal pain can be diagnosed with IBS.
Furthermore, in the Rome IV criteria abdominal pain must be present on at least one day a week for three months, while in Rome III it must be present on at least three days a month.
Aside from IBS, the Rome IV criteria include several functional disorders. Some examples are functional diarrhea, functional constipation, functional dyspepsia, etc. Additionally, the presence of other functional disorders, including fibromyalgia, chronic fatigue, and other gastrointestinal or extraintestinal functional disorders, makes IBS more likely as a diagnosis.
Treatment
Treatment for IBS is usually based on the predominant symptoms. However, treatment of the pathophysiological causative agent responsible for the symptoms is an emerging approach.
An acceptable initial therapy, especially for patients with mild disease, is lifestyle modification and education.
This starts with eliminating gas-producing foods and following a low FODMAP diet. If this is helpful, reintroducing foods, one at a time, is recommended. Otherwise, these specific foods should be avoided in the long term.
Avoiding milk is also an option in some patients, both lactose-intolerant and lactose-intolerant, as an ingredient in milk other than lactose may trigger symptoms.
Similarly, a gluten- containing diet has also been reported to cause IBS symptoms in patients with non-celiac disease, but this may be due to fructans, which are also found in wheat, and not gluten.
Constipation
Treatment for IBS-C should be aimed at relieving constipation. A higher fiber consumption is recommended. A first initial drug treatment could include osmotic laxatives, such as polyethylene glycol, but this may not help with the pain. Among these , lactulose should be avoided because it produces a lot of gas and bloating.
Linaclotide or lubiprostone , which improve colonic transit time and abdominal pain, can be used instead . Also plecanatide is a recent promising option for IBS-C, which has been shown to improve overall IBS symptoms.
Diarrhea
Likewise, treatment for IBS-D should be aimed at relieving diarrhea. Loperamide may help with diarrhea by inhibiting peristalsis and increasing colonic transit time, but it does not resolve abdominal pain . Its effectiveness in patients with IBS-D was not statistically significant. Cholestyramine, a bile acid sequestrant, could be tried as a first-line treatment if bile acid diarrhea is suspected.
Abdominal pain
Regardless of the predominant type, all patients with IBS suffer from abdominal pain , according to the Rome IV criteria. Antispasmodics are the treatment of choice to relieve pain. However, they should be used with caution in IBS-C due to their anticholinergic effects.
Tricyclic antidepressants are the most tested category of antidepressants for IBS, with many studies finding that they relieve abdominal pain and diarrhea symptoms, and improve slow colonic transit times. However, its use is limited by its numerous side effects, including drowsiness, dry mouth, fatigue, and constipation.
On the other hand, serotonin reuptake inhibitors have a safer profile and improve symptoms overall compared to placebo. Interestingly, cognitive behavioral therapies, hypnotherapy and psychotherapy appear to be helpful in reducing overall symptoms, probably due to the connection between the gut and the brain. Likewise, regular, gentle exercise appears to reduce bloating and gas production.
Lastly, probiotics appear to be helpful in reducing symptoms, but it is still unclear which strains of bacteria are most effective. They are thought to improve symptoms such as abdominal pain and bloating by altering the gut microbiota, which may play an important role in the pathogenesis of IBS. On the other hand, prebiotics or synbiotics are not recommended.
Fecal microbiota transplant
It is a relatively new and promising procedure for the treatment of IBS. It has been well studied in patients with C. difficile infection and is already considered an effective option.
Studies reported that response to treatment was successful and patients had significant improvement in abdominal pain, bloating and flatulence. Symptom relief was 70-85% in the first 3 months and 45-60% in 6 months, suggesting that it is a procedure that should be repeated.
Conclusions IBS is a very common disease, however, its pathophysiology is not yet fully understood. Treatment for IBS is usually based on the predominant symptoms, with many options for each subtype. Fecal microbiota transplantation is a promising new option for patients with IBS and appears to have a beneficial effect. However, treatment of the pathophysiological causative agent responsible for the symptoms is an emerging approach. Therefore, before choosing the appropriate therapeutic option to treat IBS, a clinical judgment must be made about its pathophysiology. |
