What Causes Visceral Hypersensitivity in Patients with Irritable Bowel Syndrome?

Colon tissues from patients with irritable bowel syndrome (IBS) produce increased levels of specific polyunsaturated fatty acid (PUFA) metabolites, which stimulate sensory neurons to generate visceral hypersensitivity. This occurs via activation of transient receptor potential (TRP) cation channels, researchers show in the August issue of Gastroenterology.

IBS is characterized by abdominal discomfort or pain associated with constipation, diarrhea, or mixed bowel habits. It is also associated with low-grade inflammation and increased protease concentrations and activity.

Proteolytic enzymes released from intestinal tissues activate sensory neurons and generate visceral hypersensitivity in mice, via the proteinase-activated receptor-2 (PAR2 or F2RL1). PAR2-induced visceral hypersensitivity requires activation of TRP cation channel, subfamily V, member 4 (TRPV4), which is widely expressed in the gastrointestinal tract and also regulates serotonin- or histamine-induced visceral hypersensitivity. Activation of TRPV1 and transient receptor potential ankyrin-1 (TRPA1) also induce visceral hypersensitivity in mice.

PUFA metabolites can signal through TRPV1, TRPV4, and TRPA19. Although basic research studies have demonstrated roles for TRP channels in general pain responses, little is known about their endogenous agonists human pain-associated diseases.

Nicolas Cenac et al measured the levels of these endogenous agonists intestinal tissues from patients with IBS and investigated their activities in mice.

They found that levels of the TRPV4 agonist 5′, 6′-epoxyeicosatrienoic acid (5,6-EET), but not TRPV1 or TRPA1 agonists, were increased in biopsies from patients with IBS compared to subjects without IBS (controls). Increases correlated with pain and bloating scores.

Supernatants from IBS biopsies, but not from controls, induced visceral hypersensitivity in mice. Small interfering RNA knockdown of TRPV4 in mouse primary afferent neurons inhibited the hypersensitivity caused by supernatants from IBS biopsies.

Levels of 5,6-EET and another PUFA metabolite, 15-HETE, were increased in colons of mice with, but not without, visceral hypersensitivity. PUFA metabolites extracted from IBS biopsies or colons of mice with visceral hypersensitivity activated mouse sensory neurons in vitro, via activation of TRPV4.

Mouse sensory neurons exposed to supernatants from IBS biopsies produced 5,6-EET via a mechanism that involved the PAR2 and cytochrome epoxygenase (see figure).

In human dorsal root ganglia, TPV4 was expressed by 35% of neurons.

Cenac et al conclude that TRPV4 and its endogenous agonist 5,6-EET mediate hypersensitivity-associated IBS. Therapeutic agents might be therefore developed to reduce channel activation. Proteases and TRPV4 have also been associated with inflammatory bowel diseases and arthritis, so the production of endogenous TRPV4 agonists could also be increased in tissues of patients with these inflammatory conditions.

In an editorial that accompanies the article, Sushil K. Sarna and John H. Winston write that the next step will be to block the observed mediators in patients with IBS, and to evaluate any potential side effects that may result from such blockade.