New insights into the pathophysiology of IBS: intestinal microflora, gas production and gut motility
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European Review for Medical and Pharmacological Sciences 2008; 12(Suppl 1): 111-117
New insights into the pathophysiology
of IBS: intestinal microflora, gas production
and gut motility
A. GASBARRINI, E.C. LAURITANO, M. GARCOVICH, L. SPARANO, G. GASBARRINI
Internal Medicine Department, Gemelli Hospital, Catholic University of Sacred Heart, Rome (Italy)
Abstract. – Irritable bowel syndrome (IBS) onset associated with a change in stool form.
is a complex disorder clinically characterized by These clinical criteria need to be fulfilled for the
abdominal pain and altered bowel habit. Its last 3 months with symptom onset at least 6
pathogenetic mechanisms are still incompletely
known; genes, psychosocial factors, changes in
months prior to diagnosis1.
gastrointestinal motility and visceral hypersensi- Supportive symptoms include abnormal stool
tivity are traditionally thought to play a crucial frequency, abnormal stool form, defecation
role in symptom generation. Recent studies have straining, urgency, a feeling of incomplete bowel
identified new additional factors that can interact movement, passing mucus and bloating.
with the established mechanisms. Dysregulation Different IBS subtypes may be distinguished
of brain–gut axis, gastrointestinal infection, low- according to the predominant stool pattern: IBS
grade infiltration and activation of mast cells in
the intestinal mucosa with consequent release of with constipation (IBS-C); IBS with diarrhea
bioactive substances, and altered serotonin me- (IBS-D); mixed IBS (IBS-M); unsubtyped IBS
tabolism are the emerging factors of IBS patho- (IBS-U) and alternating IBS (IBS-A).
genesis. Finally, modification of small bowel and Traditionally several factors have been consid-
colonic microflora and altered gas balance may ered to play a role in the pathophysiology of IBS,
be of relevance in at least some subgroups of including psychosocial factors, altered gastroin-
IBS patients. New therapies can be developed
only on the basis of a better understanding of
testinal motility and visceral hypersensitivity.
the heterogeneous picture of the pathophysiolo- However, recent studies have focused on alter-
gy of IBS. ations of the brain–gut axis, activation of the
lamina propria immune system and dysregula-
Key Words: tion of intestinal microflora and gases2.
Intestinal microflora, Irritable bowel syndrome,
Small intestinal bacterial overgrowth.
Epidemiology
Throughout the world, about 10-20% of adults
and adolescents have symptoms consistent with
IBS and the prevalence is relatively similar
Introduction across Europe and the USA3.
The IBS frequency peaks in the 3 th and 4 th
IBS is the most common chronic functional decade, with a female predominance of approxi-
gastrointestinal disorder and characterized by ab- mately 2:1 in the 20s and 30s, although this dif-
dominal pain and altered bowel habit not accom- ference is less apparent in older patients. IBS
panied by underlying structural or biochemical symptoms persist beyond middle life and contin-
diseases. Diagnosis of IBS is currently based on ue to be reported by a substantial proportion of
Rome III criteria, including recurrent abdominal individuals in their 7th and 8th decades4. IBS is
pain or discomfort at least 3 days per month in frequently associated with other chronic diseases
the last 3 months associated with 2 or more of such as heartburn, fybromyalgia, headache, back-
the following: improvement with defecation; on- ache, genitourinary symptoms and pelvic pain in
set associated with a change in stool frequency; women5.
Corresponding Author: Antonio Gasbarrini, MD; e-mail: agasbarrini@rm.unicatt.it 111A. Gasbarrini, E.C. Lauritano, M. Garcovich, L. Sparano, G. Gasbarrini
IBS symptoms come and go over time and motor responses to emotional stress, corti-
have a significant negative impact on quality of cotropin-releasing hormone, cholecystokinin
life and social functioning6. Moreover, IBS is a and meal ingestion (particularly in patients
very expensive disorder and it consumes a dis- with diarrhea) and a reduced postprandial distal
proportionate amount of resources, both directly colonic tone (in patients with both constipation
because of health care costs and, indirectly, be- and diarrhea)16.
cause of time off work7. Moreover, the number of propagating high
amplitude contractions (HAPCs) seem to be
higher in IBS-D patients while IBS-C patients
Pathophysiological Mechanisms in IBS show reduced number of HAPCs and delayed
transit17.
IBS has been traditionally considered as a In conclusion, motor abnormalities are clearly
complex and only partially understood disorder detectable in subgroups of IBS patients, and they
where psychological factors, altered gastroin- are probably important for bowel habit. Their rel-
testinal motility and visceral hypersensitivity are evance for other gastrointestinal symptoms is still
the most important pathophysiological factors. uncertain.
Over the last years, new research has focused on
the role of the brain-gut axis, low-grade intestinal Visceral Hypersensitivity
inflammation, alterations in intestinal microflora Visceral hypersensitivity represents a frequent
and abnormal gas handling8. finding in IBS patients and probably can explain
at least in part their symptoms. It is caused by
Genetic Factors different factors involving both the peripheral
Many data suggest a role of genetic factors in and central nervous system.
IBS. Members of IBS patient families often re- Visceral sensations arising from the gastroin-
port similar gastrointestinal symptoms and recent testinal tract are transmitted via afferent nerves to
studies seem to show that IBS clearly aggregates the spinal cord and the brain, where pain and dis-
within families9. However, twin studies found comfort are perceived. These signals could be
controversial results restricting the genetic con- amplified at different levels (gut, spinal cord or
tribution to IBS symptoms10. Associations be- brain) leading to a significant increase of the
tween various genes and IBS have also been in- brain response observed in IBS patients. On the
vestigated such as polymorphism of genes con- other hand, descending inhibitory mechanisms
trolling down-regulation of inflammation (e.g. controlling visceral signal transmission from the
IL-10, TNF-α)11 and serotonin metabolism12. periphery to the central nervous system can be
Although these findings seem to support a ge- altered18.
netic susceptibility in at least subgroups of IBS To support a role of peripheral mechanisms, it
patients, genetic factors alone cannot explain IBS has been demonstrated that (i) IBS occurs more
onset but can interact with environmental factors frequently after irritation of the gut by infectious
for the full clinical expression of the disease. agents19, (ii) infiltration of inflammatory cells
takes place near the enteric plexuses20, (iii) pain
Gastrointestinal Motility hypersensitivity is found only in the visceral but
A number of motility alterations have been de- not somatic system of IBS patients21, and (iv) lo-
scribed in IBS patients but a specific relationship cal administration of lidocaine is able to reduce
with gastrointestinal symptoms is quite difficult rectal sensitivity to barostat distension22.
to show. On the other hand, a significant component of
Abnormalities observed in small bowel motili- the enhanced perception may also be due to
ty include: exaggerated intestinal motor respons- central factors23. In particular, the anterior cin-
es to stress, meal ingestion, mechanical stimula- gulate cortex, a region of the prefrontal cortex,
tion, cholecystokinin and corticotropin-releasing is considered to be essential for the central pro-
factor13; increased frequency and duration of dis- cessing of noxious stimuli originating from the
crete cluster contractions14; increased frequency gut 24. An activation of the anterior cingulate
of migrating motor complex and more retrograde cortex as demonstrated by functional brain
duodenal and jejunal contractions15. imaging has been found in IBS patients both
As concerns colonic motility, the most im- during actual exposure to and anticipation of
portant motor alterations include exaggerated painful stimuli25.
112New insights into the pathophysiology of IBS: intestinal microflora, gas production and gut motility
Intestinal Inflammation cumstances gas transit and evacuation are modu-
Recent evidence suggests that transient or lated by several intraluminal and extra-abdomi-
chronic gastrointestinal inflammation may play a nal factors. In healthy individuals gas transit is an
role in IBS pathogenesis26. In fact, IBS symp- active process that requires a normal intestinal
toms frequently develop after an acute episode of motor activity; this is achieved by gut
infectious gastroenteritis (post-infectious IBS, mechanoreceptors which can promote gas transit
PI-IBS). The incidence of PI-IBS has been re- even after mild stimulation. Stimulation of
ported to vary between 3% and approximatively chemoreceptors by nutrients modulates transit
35%27. Risk factors for PI-IBS development in- depending on their composition, caloric load and
clude the virulence of the pathogen, younger age, site of action. Lipids and proteins, but not carbo-
female sex, the long duration of the initial illness hydrates, have been shown to slow down gas
and the presence of psychological disorders such transit and evacuation, when infused into the
as hypochondriasis, anxiety, depression and ad- proximal duodenum35. Physical activity and pos-
verse life events28. Histologically, PI-IBS is char- ture have also been shown to modulate intestinal
acterized by an increased number of inflammato- transit of gas: mild physical activity and an up-
ry cells such as mast cells, T lymphocytes and right position might promote gas transit and
macrophages in various compartments of the evacuation, whereas a supine position has the op-
small bowel and colon8. These cells are activated posite effect36-37.
and release several mediators (interleukins, nitric Patients reporting IBS-like symptoms have
oxide, histamine and proteases) capable of stimu- been studied in order to explore possible alter-
lating the enteric nervous system and conse- ations in the mechanisms responsible for in-
quently abnormal secreto-motor responses within testinal gas homeostasis. King et al. reported an
the gut29. increased production of colonic gas, particular-
An increased number of mast cells has also ly of hydrogen, in patients with IBS compared
been found in the terminal ileum and colon of to healthy controls. Both symptoms and gas
IBS patients and in the jejunum of IBS-D pa- production were reduced by an exclusion diet,
tients30. Mast cells are localized in close proximi- supporting the hypothesis that fermentation and
ty to mucosal nerves and their degranulation rate higher gas production associated with alter-
and vicinity to nerves are significantly related to ations in the activity of hydrogen-consuming
both severity and frequency of abdominal pain31. bacteria may be an important factor in IBS
pathogenesis38. In addition, altered transit of in-
Intestinal Gas testinal gas seems to be implicated in gas reten-
Despite the large capacity of the gastrointesti- tion and symptoms of IBS patients. Infusion of
nal tract, the total volume of intraluminal gas gas into the small intestine (jejunum) can cause a
amounts only to 100-200 ml32. The volume and markedly delayed transit, lead to gas retention
composition of intestinal gases result from a and reproduce IBS-related symptoms. It seems
complex balance involving different mecha- that the proximal bowel may act as a sensitive
nisms. Swallowing of air, bacterial production trigger-zone capable of inducing conscious sen-
and chemical reactions are mainly responsible sation, whereas the distal colon appears to be ca-
for gastrointestinal gas input; eructation, absorp- pable of accommodating large masses of gas
tion, bacterial consumption and flatus ensure gas without discomfort39-40.
output33.
Gas production and composition are extremely Gut Microflora
variable depending on the nature of ingested food Beginning with its colonization by the mi-
and the metabolic characteristics of the intestinal croflora shortly after birth, the human gastroin-
flora. During basal conditions, nitrogen is the testinal tract is a complex ecosystem whose
most important content of flatus, but ingestion of maintenance depends on the physiological func-
food (especially carbohydrates) leads to a preva- tions of the host, particularly the cooperation be-
lent production of hydrogen, oxygen, carbon tween the mucosal barrier and local immune sys-
dioxide and methane (in producers); various oth- tem. The symbiosis between microbes and host
er gases such as sulphur-containing gases are al- involves approximately 100 trillion bacteria, a
so present in small quantities34. number that is about 10 times that of eukaryotic
An important factor in the management of a cells in the human body. In other terms, over
gas surplus is intestinal transit. Under normal cir- 300,000 bacterial genes circulate in human gut41.
113A. Gasbarrini, E.C. Lauritano, M. Garcovich, L. Sparano, G. Gasbarrini The stomach and the proximal small bowel malabsorption syndrome due to an increase in contain normally only a few species of bacteria, microrganisms within the small intestine (pres- particularly Lactobacilli and Enterococci. Bacter- ence of more than 105 CFU per ml of intestinal ial density rises towards the colon, reaching con- aspirate and/or of colonic-type species)46. Bacte- centrations up to 10 12 Colony-Forming Units ria in excess can interfere with the metabolism (CFU) per ml (Enterobacteria, Bacteriodes, and absorption of many substances such as car- Clostridia, Lactobacilli and others)42. bohydrates, proteins, lipids and vitamins. The The symbiotic relationship between microbio- loss of activity of brush-border disaccharidases ta and gut is important for the integrity and func- due to mucosal injury and the bacterial fermenta- tion of the gastrointestinal tract and involves a tion of sugars such as sorbitol, fructose and lac- continuous and dynamic effect on the host. In tose could be responsible for carbohydrate mal- fact, the intestinal microflora plays a role in the absorption47. Injury of enterocytes may alter gut defense against pathogenic organisms, in the reg- permeability, predisposing to the development of ulation of metabolic and trophic functions of ep- a protein-losing enteropathy. Moreover, bacteria ithelial cells and in the synthesis of vitamins and may compete with the host for protein and lead nutrients. It also exerts remarkable effects on the to the production of ammonia48. Deconjugation development and maintenance of gut sensory and of bile acids in the proximal gut causes malab- motor functions, including the promotion of in- sorption of fat and lipophilic vitamins (A, D, E) testinal propulsive activity. and leads to the production of lithocholic acid, In healthy subjects, the main mechanisms con- which is poorly absorbed and may be directly trolling the intestinal microflora are the gastric toxic to enterocytes49. Cobalamin (vitamin B12) acid barrier, mucosal and systemic immunity and deficiency can occur in SIBO as a result of the intestinal clearance. When these mechanisms use of the vitamin by anaerobic bacteria. fail, an imbalance in the microbiota develops. Clinical signs and symptoms of SIBO are ane- Failure of the gastric acid barrier is observed in mia, megaloblastic anemia, osteomalacia, neu- drug-induced inhibition of acid secretion; failure ropathy, weight loss and edema. However, an of mucosal and systemic immunity could be due overt malabsorption syndrome is uncommon and to immunoglobulin deficiencies; and failure of typical of older and hospitalized patients50. SIBO intestinal clearance is associated with anatomical is more frequently characterized by symptoms abnormalities (gastrointestinal surgery, intestinal such as abdominal pain, bloating, flatulence and diverticula or fistula) or conditions impairing in- diarrhea, symptoms that are similar to those re- testinal peristalsis (myopathic, neuropathic, au- ported by IBS patients. toimmune, metabolic and endocrine diseases)43. Several studies have addressed the prevalence An imbalance in the intestinal microflora can of SIBO in IBS patients, reporting contrasting re- lead to both gastrointestinal and extra-gastroin- sults. Pimentel et al.51 found a high prevalence of testinal diseases. Two recent studies have shown SIBO as tested by the lactulose breath test in IBS that gastrointestinal microbiota are significantly subjects, and in a successive therapy-aimed study altered in IBS and their composition varies with antibiotic decontamination was associated with a the main symptoms of the patients44,45. As the significant improvement in 35% of patients ver- majority of the gastrointestinal bacterial species sus 11% patients treated with placebo52. The high cannot be cultivated, culture-independent molec- prevalence of SIBO in IBS patients was be ex- ular methods such as PCR analysis of faeces plained by an abnormal intestinal motor pattern, have shown that the bacterial counts of Clostridi- particularly in phase III of interdigestive motility um coccoides and Bifidobacterium catenulatum which is responsible for clearing the lumen dur- are significantly lower in IBS patients than in the ing the fasting state. Specifically, IBS subjects healthy control group. On the other hand, Lacto- affected by SIBO showed few or no phase III bacillus counts are lower in the samples from events and a significant abbreviation of this IBS-D patients, whereas Veillonella counts are motility complex53. Another study confirmed that higher in IBS-C patients. SIBO evaluated by the glucose breath test has a Over the last years, research has focused on higher prevalence in IBS patients, relative to a the role of small intestinal bacterial overgrowth consistent control group. In addition, SIBO was (SIBO) in IBS pathogenesis. SIBO is a particular more prevalent in the IBS-D subtype than in the qualitative and quantitative alteration of the in- IBS-C and IBS-A subgroups, although this dif- testinal microflora. It is generally defined as a ference did not reach statistical significance54. 114
New insights into the pathophysiology of IBS: intestinal microflora, gas production and gut motility
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