Neurotransmitter Dysfunction in Irritable Bowel Syndrome: Emerging Approaches for Management

Abstract

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder whose aetiology is still unknown. Most hypotheses point out the gut-brain axis as a key factor for IBS. The axis is composed of different anatomic and functional structures intercommunicated through neurotransmitters. However, the implications of key neurotransmitters such as norepinephrine, serotonin, glutamate, GABA or acetylcholine in IBS are poorly studied. The aim of this review is to evaluate the current evidence about neurotransmitter dysfunction in IBS and explore the potential therapeutic approaches. IBS patients with altered colorectal motility show augmented norepinephrine and acetylcholine levels in plasma and an increased sensitivity of central serotonin receptors. A decrease of colonic mucosal serotonin transporter and a downregulation of α2 adrenoceptors are also correlated with visceral hypersensitivity and an increase of 5-hydroxyindole acetic acid levels, enhanced expression of high affinity choline transporter and lower levels of GABA. Given these neurotransmitter dysfunctions, novel pharmacological approaches such as 5-HT3 receptor antagonists and 5-HT4 receptor agonists are being explored for IBS management, for their antiemetic and prokinetic effects. GABA-analogous medications are being considered to reduce visceral pain. Moreover, agonists and antagonists of muscarinic receptors are under clinical trials. Targeting neurotransmitter dysfunction could provide promising new approaches for IBS management.

Enteric Microbiota-Mediated Serotonergic Signaling in Pathogenesis of Irritable Bowel Syndrome

“…Fecal microbiota samples obtained from IBS patients transmitted hypersensitivity to colonic distension in rats, indicating that gut microbial components are responsible for abnormal pain sensation associated with IBS [ 149 ]. In addition, gut-microbiota-mediated neurotransmitters play a significant role in visceral pain sensation [ 18 , 22 ]. Among those neurotransmitters, peripheral 5-HT appears to preferentially act to induce pain by stimulating mesenteric sensory fibers, and vagal and spinal afferent fibers [ 136 ].…”

“…Numerous basic and clinical studies were conducted to clarify the cause of IBS from multiple aspects, including genetic factors, low-grade mucosal inflammation and immune activation following a severe GI infection, increased gut mucosal permeability, alterations in gut microbiota, aberrant bile salt metabolism, hypersensitivity to particular diet components, abnormal neurotransmitter pathways, and altered central nervous system (CNS) processing [ 14 , 15 , 16 , 17 , 18 ]. Although each factor contributes to forming a certain portion of the IBS etiology, clinical features of the disorder are heterogeneous, and likely created by a mixture of genetic and environmental factors [ 15 , 16 ].…”

“…Neurotransmitters are chemical substances that transmit signals between neurons and target cells, such as muscles, glands, and other neurons, throughout the body [ 24 ]. Enteric microbiota play a critical role in regulating a variety of neurotransmitters, including histamine, serotonin (5-hydroxytryptamine, 5-HT), glutamate, γ-aminobutyric acid (GABA), dopamine, acetylcholine, and catecholamines [ 18 , 22 , 24 ], and each biological substance influences the activity of the enteric nervous system (ENS) independently or corporately as part of the pathology of IBS [ 22 , 25 ]. Among those, 5-HT is one of the most well-studied neurotransmitters in IBS research investigations [ 26 , 27 , 28 ].…”

“…Therefore, the determination of and focus on a specific target molecule or pathway related to IBS pathogenies is challenging, though recent progress in omics technologies, including epigenomics, metabolomics, transcriptomics, and proteomics, provided efficient methods for identification of new pathways and potential targets [19][20][21]. These novel approaches provided results suggesting the importance of interactions between enteric microbiota and neurotransmitters, and their pathways in the context of IBS pathogenesis [15,18,22,23].…”

The Multifaceted Role of Serotonin in Intestinal Homeostasis

“…This definition indicates the complex etiology [154] of these disorders, both local intestinal and central nervous system processes are involved. For a discussion of the importance of 5-HT signaling in IBS and the use of drugs that interfere with 5-HT signaling in the treatment of IBS, we, therefore, refer to some excellent recent reviews [155][156][157].…”