The latest data indicate that the main mechanism inducing abdominal pain is the visceral hypersensitivity 5 . The primary afferent neuron terminals of enteric nervous system (ENS) which are localized in submucosal tunica of gastrointestinal tract (Meissner plexus) and between smooth muscle fibers (Auerbach plexus) transmit stimuli to central nervous system (CNS) through sympathetic and parasympathetic autonomic nervous system (SANS and PANS). SNS transmits stimuli which are recognized as abdominal pain, whereas PNS transmits stimuli initiating a variety of reflexes. The pain stimuli through thalamus stimulate the cerebral cortex and permit the recognition of visceral pain. On the other hand, for the integration of visceral reflexes, the afferent stimuli through hypothalamus stimulate efferent neural fibers which through PNS stimulate or inhibit the contraction of smooth muscle fibers and the secretion of enterocytes in the gastrointestinal tract modifying the gut motility and secretion 5 .

It is known that visceral sensitivity is regulated in many levels. Specifically this regulation is mediated at the level of enteric mucosa and submucosa, the level of spinal cord, the level of thalamus and the level of cerebral cortex.

It is known that autonomic nervous system (ANS) regulates visceral sensitivity and modulates and coordinates GI motility and secretion 32 . New studies support that sections of ANS are implicated in the immunological regulation and inflammatory reaction at the level of enteric mucosa 33 .

It is also reported that most of IBS symptoms are directly related to specific abnormalities of ANS. It seems that the main characteristic of IBS patients is the increased activity of SANS and the decreased activity of PANS 34 . There are differences between patients with diarrhea and constipation as predominant symptoms and between men and women. It is believed that vagal dysfunction is associated with constipation as a predominant symptom whereas adrenergic sympathetic dysfunction is associated with diarrhea as a predominant symptom 35 . Other studies reported that IBS diarrhea-predominant patients were shown to have cortisol hyper-responsiveness unlike that of constipation-predominant IBS patients and controls 36 . Robert et al. 37 and Tillish et al. 38 , on the other hand, observed elevated sympathetic dominance and vagal withdrawal during non-REM and REM sleep in diarrhea-predominant IBS patients, but not in those with an alternating type of IBS. However, constipation-predominant IBS patients could not be distinguished from diarrhea-predominant IBS patients or alternating type IBS with regard to autonomic nervous system. It is reported that there might be a continuum of autonomic dysfunction among these symptom-specific subgroups 39 .

Concerning sex-specific alterations in autonomic function among IBS patients, it is believed that there are differences in visceral sensitivity both at the level of mucosa, and at the level of central pain sensation 40 . Recent evidence has confirmed that sex differences exist among IBS patients in term of colonic transit response to pharmacological treatment 41 . These observations may justify the different IBS incidence between male and female. It is also found that male IBS patients had significantly higher sympathovagal balance than healthy male controls, whereas no differences were noted between IBS females and female controls. However, differences in autonomic nervous system responses to specific stimuli may also play a role in producing sex-based variations in IBS symptom patterns and in differential responses to some pharmacological agents 42 .

Increased SNS activity and decreased PNS activity are the most frequent noted signs in IBS patients. We often observed cutaneous hyperalgia in IBS patients. Mayer et al. 43 reported that patients with IBS also exhibited a number of extraintestinal manifestations such as migraine headache, back pain, heartburn, dyspareunia and muscle pain, consistent with the central hyperalgesic mechanism.

About 65-84% of IBS patients present with small intestine bacterial overgrowth, that is, presence of more than 10⁵ cfu/ml of bacteria, resembles the bacterial composition of the colon, in the proximal small bowel 44 . The colonization of gastrointestinal tract differs according to the type of bacteria. Particularly, bacteria from the upper respiratory tract and anaerobic bacteria from oral cavity via the slobber swallowing, colonize the upper gastrointestinal tract with a density of < 10⁵ cfu/ml. The stomach is colonized by bacteria with a density of < 10³ cfu/ml because the acidic pH does not permit the colonization and proliferation of bacteria coming from the oral cavity. In the small intestine, there is a progressive colonization of gram positive aerobic and facultative anaerobic bacteria, like staphylococcus, streptococcus, lactobacillus and some types of fungi. The presence of gram-negative and anaerobic bacteria in the proximal jejunum is abnormal. Strains of Prevotella disiens and P. divia are recognized in the small intestine. Normally, small intestinal microflora is believed to be exogenous and not endogenous 45 . Anaerobic strains and mainly Bacteroides fragilis are usually restricted in the distal jejunum and large intestine (Table 1). The ecology of small intestine's content is constant due to normal bowel motility, acidic pH and IgA secretion from small intestine mucosa.

It has been documented that in pathological cases of small intestine bacterial overgrowth, there are excessive bacterial counts in the proximal small bowel, commonly with bacterial species including Streptococci, Bacteroides, Escherichia, and Lactobacilli.

Bacterial overgrowth implies abnormal colonization of the upper gastrointestinal tract, arising from failure of specific defense mechanisms restricting colonization under physiological conditions. These defense mechanisms are the gastric acid barrier and the intestinal clearance. H. pylori induced-gastritis is the main cause of acquired failure of the gastric acid barrier. Failure of intestinal clearance may come as a result of impaired intestinal persistalsis, in case of myopathic, neuropathic, autoimmune, infectious, metabolic, endocrine or neoplastic diseases. Anatomical abnormalities that alter luminal flow may as well cause failure of intestinal clearance. This may be the result of gastrointestinal surgery, intestinal diverticula, or fistula 46 .

The bacterial content of oral cavity, host's general condition, immunological disorders and bad nutrition play important role in the development of bacterial overgrowth syndrome.

Post infectious IBS (PI IBS) represents a subtype of IBS. It affects 6-17% of IBS patients, who had undergone a previous episode of infectious gastroenteritis 47 . While most patients rapidly recover from bacterial gastroenteritis, about a quarter show persistent disturbance of bowel habit at 6 months and most commonly increased stool frequency. A smaller number develop persistent symptoms that meet the Rome III criteria. Clinical features include bloating, loose and watery stools, urgency for defacation and the passage of mucus per rectum 48 .

There are indications that an episode of acute gastroenteritis is capable to induce small intestine sensitization and symptoms of IBS, only if there are other factors mainly psychosocial, which can stimulate through psychical, neuronal and endocrinal mechanisms, the presence of mast cells and other inflammatory cells in the gastrointestinal tract 49 .

PI IBS has been reported after Campylobacter, Salmonella and Shigella infections 50 . Those patients, who later on develop IBS, show increased numbers of enterochromaffin (EC) cells and lymphocyte cell counts at 3 months compared to those who do not develop IBS. Interleukin-1β (IL-1β) mRNA levels are increased in the mucosa of those who develop PI IBS and show also increased gut permeability. Recent studies suggest an increase in peripheral blood mononuclear cell cytokine production in unselected patients, an abnormality that may be ameliorated by probiotic treatment. Recovery from PI IBS may be slow, with approximately 50% of patients manifesting symptoms at 5 years.

One measure to estimate the probability to develop PI IBS, is the duration of the initial diarrheal illness. Diarrhea lasting more that 3 weeks gives a relative risk of 11.4 compared with diarrhea lasting less than 7 days. Changes in the epithelium, during the healing process, are also predictive of the development of PI IBS. Age above 60 gives a protective effect. It seems that older subjects have fewer immunocytes in their rectal mucosa and may be less reactive to infection. Depression and the presence of adverse life events double the relative risk of persistent symptoms 51 .

Acute hypersensitivity reactions are rare causes of IBS. Patients often present with atopic conditions, such as eczema, asthma, angioedema, while they respond well to elimination diets 52 . Those hypersensitivity reactions are mediated by degranulation of mast cells.

The degranulation of mast cells leads to the production of local and systemic mediators, such as leucotriens LTC4 and histamine, which act upon adjacent smooth muscle cells and nerve endings.

Lactose intolerance, as well as intolerance to sorbitol or fructose, has been implicated in IBS. It is likely that the specific enzyme deficiency is not the cause of IBS, but that the hypersensitive guts of patients with IBS show exaggerated responses to the gaseous and fluid distention caused by incomplete absorption of carbohydrate.

The correlation between emotion and gut motility has now been established. Many physiology studies have shown that anger is closely associated with enhanced contractile activity in the sigmoid-rectum area, whereas reduced motility is documented in case of fear. Anxiety can induce rapid small bowel transit and enhanced stool frequency. Moreover, depression is associated with delayed small bowel and colonic transit.

The effects of emotion on gastrointestinal function are mediated by the autonomic nervous system. The normal physiologic response to acute stress involves the linked activation of the hypothalamo-pituitary axis and the sympathetic nervous system. The brain may influence the transmission of nociceptive information from the gut and the activation of visceral reflexes through descending inhibitory and excitatory pathways that terminate within the dorsal horn at the secondary sensory neuron.

Common characteristics of IBS patients are the pathologic gradation of visceral perception, the endogenous pain facilitation and the reduced threshold for pain. Abuse history is common in their past, exaggerated conscientiousness, perfectionism and neuroticism have been detected among their personality features 53 .

Although the family clustering of IBS has been noticed in medical practice for several years, Whorwell et al. 56 found that 33% of patients with IBS reported a family history of IBS compared with only 2% of the control group. Newer studies showed relation between having a first degree relative with bowel problems and presenting with IBS, concluding that these results may represent exposure to similar environmental factors 57 , although some limitations of these studies included the fact that only abdominal symptoms in first degree relatives were assessed and that the IBS diagnosis was not confirmed by a specialist.

An Australian study by Morris-Yates et al. 58 , showed a higher concordance rate for IBS in monozygotic twins than in dizygotic twins (33.3% vs 13.3%). Interestingly, an American study conducted in 2001 showed that the concordance rate in monozygotic twins was twice as high as that in dizygotic twins (17.2% vs 8.4%) 59 . However, the number of dizygotic twins with IBS who have mothers with IBS was greater than the number of dizygotic twins with IBS who have co-twins with IBS; data also showed that having a mother or a father with IBS are both independent predictors of irritable bowel status and are stronger predictors than having a twin with IBS. These results support also that social learning has an important influence 59 . However a Norwegian study published in 2006 showed a concordance for IBS significantly greater in monozygotic than in dizygotic twins. The same study, showed, that low birth weight also influences significantly the development of IBS 60 . Finally, another twin study published in 2007 concluded that the genetic factors are involved in IBS, possibly by the hereditability of anxiety and depression 61 .

The delineation of the regulation of the fut-brain axis at the level of sensation and motility by mediators like 5HT, cholecystokinin (CCK) and substance P, has lead to the investigation of a variety of polymorphisms. Gene polymorphisms involve the serotonergic and adrenergic systems and genes encoding proteins with immunomodulatory and/or neuromodulatory features 62 . One candidate gene is the serotonin transporter gene (SERT). The serotonin transporter protein is responsible for reuptake of serotonin from the synaptic cleft. Within this gene, there is a 44 bp insertion/deletion of repeat elements in the promoter region. This polymorphism results in a long (l), and a sort (s) allele. The s allele is associated with lower transcriptional efficiency and therefore lower serotonin transporter expression, and decreased cellular uptake of serotonin. Recent studies showed relation between the presence of l/l genotype and IBS with constipation as the predominant symptom and decreased response to tegaserod 63 . Other studies revealed that the presence of the s/s genotype is related to IBS with diarrhea as the predominant symptom, particularly in women 63 . A recent Indian study showed that the presence of the s/s genotype is related to IBS with constipation as the predominant symptom 64 .

Association studies of polymorphisms in genes encoding CCK 65 , adrenergic receptors 66 and cytokines like TNF-a and IL-10 investigating the relation between IBS and inflammation 67 have been also reported.

Finally, IBS is a multifactorial functional disorder which is related to genetic, environmental and psychological factors. Due to the important influence of environmental and psychological factors in the development of IBS many studies are required to confirm the genetic base of the syndrome.