Great attention is currently revolving around the pathogenic bases and pathophysiological mechanisms accounting for the clinical manifestations of IBS, 
and there is consistent evidence suggesting an influence of genetic factors on this disorder. 
In this context, our study provides the first evidence that 5HTTLPR impacts on the severity of IBS symptoms. In particular, our findings point out a higher degree of symptom severity in patients with at least one S allele, and suggest that the S variant affects mainly the severity of abdominal pain and bowel dissatisfaction. Of note, our exploratory analysis showed that IBS-SSS values did not differ significantly when comparing subgroups with LS and SS genotypes, thus suggesting that the group of patients with pooled LS/SS genotypes was a homogeneous population.
The contention that the LS/SS genotypes can increase the severity of IBS symptoms, with particular regard for abdominal pain, is supported by previous investigations. In particular our findings are in line with data from Camilleri et al. 
who found that the LS/SS genotypes are associated with increased pain sensation at rectal distension. Taken together, these observations 
and our results are consistent with the notion that the S allele is expected to impair the efficiency of 5-HT reuptake with a consequent prolonged and enhanced activation of serotonergic pathways mediating abdominal pain sensation. Therefore, it can be argued that the reduced 5-HT re-uptake could induce an overstimulation of extrinsic nerve afferents resulting in neuronal sensory sensitisation, which might occur at peripheral, spinal, or even higher CNS levels. 
In this regard, an interesting study by Fukudo et al. 
, aimed at evaluating the link between 5HTTLPR and differential activation of brain regions by colorectal distention in humans, displayed that individuals with a weak function of serotonin transporter (i.e. S/S genotype) responded to signals from gut with higher intensity in emotion-regulating brain regions, thus suggesting that this functional gene polymorphism may partly predict the individual effects of selective serotonin reuptake inhibitors on visceral pain. 
Whether the influence of 5HTTLPR on abdominal pain results mainly from peripheral or central mechanisms, or both, is presently unknown and remains open to future investigations. However, some evidence suggests that central mechanisms may contribute to the enhanced pain perception in IBS patients with LS/SS genotypes: 1) specific brain regions of IBS patients and healthy controls are subjected to differential activation upon application of rectal stimuli; 
2) brain regions highly related to pain recognition and emotion (e.g. anterior cingulated cortex) were found to be more activated by distension of descending colon in IBS patients, 
and altered interactions between anterior cingulated cortex and amygdala have been reported in subjects with LS/SS genotypes; 
3) individuals with the SS genotype were more likely to activate these CNS regions, thus suggesting that the S variant can be relevant in brain activation after colorectal distension in IBS patients. 
Further support to the contribution of central nervous mechanisms on the association of 5HTTLPR with symptom severity in IBS comes from the observations that: 1) in IBS patients, the LS/SS genotypes were associated with high values of somatic symptom scores, suggesting that 5-HTTLPR is implicated in the responses of IBS patients to stress; 
2) individuals with the S allele display higher vulnerability to stressful life events and are more prone to develop depressive symptoms. 
. In this respect, to assess whether the influence of S allele on abdominal pain severity, could be related to differences in patients’ psychopathological traits would be of high interest, and this issue deserves future investigations.
In the present study, when the P values were adjusted for multiple comparisons, the analysis for secondary endpoints revealed that the overall symptom severity did not differ in C- and D-IBS patients, while the analysis of single severity items displayed significant differences only for the severity of abdominal distension. Moreover, our analysis showed a lack of significant interaction between bowel habits and 5HTTLPR genotypes. These findings were not completely unexpected, since C-IBS patients are known to complain of abdominal distension more than D-IBS patients. 
In addition, and most importantly, these data argue against the possibility that the differential influences of 5HTTLPR genotypes on abdominal pain severity might result from differences in bowel habit.
The influence of 5HTTLPR on IBS symptom severity and, particularly, on abdominal pain severity, might have interesting implications for the effectiveness and/or safety of drugs proposed for the therapeutic management of this syndrome. SERT is a specific target of ‘selective serotonin reuptake inhibitors’ (SSRIs) and there is evidence linking 5HTTLPR to the efficacy and safety of these drugs in patients with depression. 
It is being also appreciated that SSRIs can exert beneficial effects on IBS, with particular regard for the control of abdominal discomfort or pain, 
but whether SERT polymorphisms may influence such therapeutic responses remains unknown.
To date, most of the studies on the impact of 5-HT genetics on IBS have investigated the associations of 5HTTLPR with its pathogenesis or clinical presentation. In this regard, the present study was conducted also with the secondary objective of evaluating whether any of such associations could be highlighted in our IBS patients. For this purpose, the frequencies of their 5HTTLPR genotypes were compared with those of healthy controls, selected with similar demographic characteristics, and no significant association was found either for the overall IBS group or for the subgroups of C-IBS and D-IBS patients. Our results are consistent with the majority of previous studies 
which failed in finding a link between 5HTTLPR and IBS. Moreover, while most authors did not find specific links of 5HTTLPR with C-IBS or D-IBS, 
others have reported significant associations of SS with D-IBS, 
SS with C-IBS, 
or LL with C-IBS. 
Among the variety of factors which might account for the heterogeneity of these observations, the most relevant relies perhaps in the different distribution of 5HTTLPR genotypes among different populations. In particular, the allele frequencies between Caucasian and Asian populations are different, since S allele is found in 42% of Caucasians and in 79% of Asians. 
Furthermore, significant variations in the frequency of 5HTTLPR genotypes can be found even in populations sharing the same Caucasian origin, but belonging to distinct ethnicities. 
In this respect, both the IBS patients and healthy volunteers evaluated in our study were highly homogeneous, as we enrolled only white Caucasian subjects of Italian origin.
In conclusion, the present study suggests that the LS and SS genotypes are significantly correlated with IBS symptom severity, although their possible direct causal role remains to be proven. In addition, the present findings do not support an association of 5HTTLPR with IBS or its clinical presentation in terms of bowel habit predominance.