Persistent hypersensitivity of sensory pathways innervating the colon is regarded as primary mechanism contributing to the initiation, development, and maintenance of chronic discomfort and abdominal pain in IBS patients (15, 16, 39). Therefore, determining the mechanisms contributing to these processes is crucial. Swan C et.al originally submitted the GSE36701 dataset, performed mRNA expression profiling study of rectal biopsies from donors with healthy volunteers and IBS-D patients. They collected detailed clinical data (including abdominal pain frequency, anxiety and depression scale), using a combination of bioinformatics and experimental approaches to identify candidate genetic polymorphisms in the IBS. While we further filtered for functional associations related to neurotransmitters/mediators of pain. Most notable among those genes were shown in Table 1(upregulated genes) and Table 2(downregulated genes). Interestingly, GRPR ,NPFF ,TRPA1, BDKRB2,MRGPRX3, that commonly regarded as factor also regulating itch signaling pathways were found[15-17]. Finally, three genes including GRPR, NPFF and TRPA1 were considered to play an essential role in abdominal pain in IBS.
In the colon, afferent sensitization occurs via a variety of processes, including histamine-dependent mechanisms and histamine-independent mechanisms [19, 20]; Evidence have been accumulated that activation of receptors associated with the above two itch pathways on colon-innervating afferents induces visceral hypersensitivity[19, 21]. Gastrin-releasing peptide receptor expressing(GRPR)+ neurons have a central role in the spinal transmission of both histaminergic and non-histaminergic itch.In our study, GRPR was significantly upregulated in IBS-D patients and identified as a hub gene by MCODE. GRPR is a G protein-coupled receptor and mediates itch sensation mainly via the PI3Kγ/Akt pathway. At the same time, GRP induces neutrophil chemotaxis through GRPR via p38, ERK1/2 and PI3K activation and p38, ERK and PI3K are important mediators in visceral pain[25-27]. Itch and pain signals are conveyed by distinct yet interacting neuronal pathways: pruritogens at higher doses produce pain to suppress itch[28, 29]; The frequency of abdominal pain in IBS was higher in patients with chronic pruritus than in healthy controls. In addition, Neuropeptide FF (NPFF), the histamine-independent itch receptors agonist, evoking colonic afferent mechanical hypersensitivity[17, 19], was also clustered by Cytoscape module in our study. Therefore, we speculated that altered GRP-GRPR signaling and NPFF in spinal dorsal horn participate in visceral hypersensitivity through sensitization of itch transmission neurons, thereby contributing to abdominal pain or discomfort.
In the present study, another gene related to pain transmission deserve attention. Our results, together with previous studies have indicated significantly up-regulated TRPA1(Transient receptor potential ankyrin 1) mRNA expression in biopsies of IBS patients. TRPA1 has been implicated in mechanical hypersensitivity of colonic aﬀerents and both bradykinin and TNF-α induce visceral hypersensitivity through a TRPA1-dependent mechanism. On the other hand, TRPA1 can also induce the inﬂammatory response via neurogenic inﬂammation: activation and sensitization of TRPA1 and release of substance P contribute to the initiation and development of colitis in mice, which correspondingly re-sensitises nociceptors. TRPA1 expressed by intestinal enterochromaﬃn cells can serves as the primary detector of intestinal irritants prior to direct sub-mucosal damage. These findings further highlight TRPA1 as an important integrator of sensory signals in colonic afferents by inducing mechanical visceral hypersensitivity.
As we known, IBS is a multifactorial disease. Abnormal stress response, psychological distress and infectious or inflammatory response in susceptible population may initiate visceral hypersensitivity that results in the development of IBS symptoms. According to the functional enrichment analyses, two pathways were associated with dysregulation of renin-angiotensin system (RAS), which is a potent target of stress-induced intestinal inflammation in a murine model of IBS . Circadian entrainment and disorder of several synapses such as Glutamatergic synapse, Dopaminergic synapse may be risk factors of IBS. Besides, certain pathways directly involved in pain transmission were enriched, including Morphine addiction and Retrograde endocannabinoid signaling. Endocannabinoids are involved in controlling motility, secretion and intestinal inﬂammation. The endocannabinoid system in DRG neurons mediate stress-induced visceral hypersensitivity in a mouse model of IBS.