Action Mode of Gut Motility, Fluid and Electrolyte Transport in Chronic Constipation

Abstract

Chronic constipation is a common gastrointestinal disorder, with a worldwide incidence of 14-30%. It negatively affects quality of life and is associated with a considerable economic burden. As a disease with multiple etiologies and risk factors, it is important to understand the pathophysiology of chronic constipation. The purpose of this review is to discuss latest findings on the roles of gut motility, fluid, and electrolyte transport that contribute to chronic constipation, and the main drugs available for treating patients. We conducted searches on PubMed and Google Scholar up to 9 February 2021. MeSH keywords "constipation", "gastrointestinal motility", "peristalsis", "electrolytes", "fluid", "aquaporins", and "medicine" were included. The reference lists of searched articles were reviewed to identify further eligible articles. Studies focusing on opioid-induced constipation, evaluation, and clinic management of constipation were excluded. The occurrence of constipation is inherently connected to disorders of gut motility as well as fluid and electrolyte transport, which involve the nervous system, endocrine signaling, the gastrointestinal microbiota, ion channels, and aquaporins. The mechanisms of action and application of the main drugs are summarized; a better understanding of ion channels and aquaporins may be helpful for new drug development. This review aims to provide a scientific basis that can guide future research on the etiology and treatment of constipation.

Keywords: chronic constipation; fluid and electrolyte transport; gut motility; pathophysiology; pharmacological treatment.

FIGURE 1

Factors that control gut motility, fluid and electrolyte. From top to bottom, it encompasses the central nervous system, the sympathetic and parasympathetic branches of the autonomic nervous system, hypothalamus-pituitary-adrenal axis, the enteric nervous system, endocrine signaling, microbiota, aquaporins, and ion channels.

FIGURE 2

Factors that modulate peristalsis. “+” indicate a promoting role, “−” indicate an inhibition role. Enteric nervous system, autonomic nervous system, central nervous system, neurotransmitters, gastrointestinal hormones and microbiota are the main factors to control peristalsis. Some of these factors also involve the secretion of water. 5-HT: 5-hydroxytryptamine; Ach, acetylcholine; ANS, autonomic nervous system; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; CGRP, calcitonin gene-related peptide; ExPANs, extrinsic primary afferent neurons; GPCR, G-protein coupled receptors; HAP axis, hypothalamus–pituitary–adrenal axis; H₂S, hydrogen sulfide; ICCs, interstitial cells of Cajal; LPS, lipopolysaccharide; NK₁, neurokinin 1; NO, nitric oxide; NOs, nitric oxide synthase; PDGFRα⁺, platelet-derived growth factor receptor α-positive; PGD2, prostaglandin D2; SCFAs, short-chain fatty acids; SP, substance P; VIP, vasoactive intestinal peptide.

FIGURE 3

Fluid and electrolyte transport in the intestine. The blue arrow indicates the transport of fluid beside the cells. Lubiprostone, Plecanatide and Linaclotide act through ion transport. CaCC, Ca²⁺-activated Cl⁻ channel; CFTR, cystic fibrosis transmembrane conductance regulator; ENaC, epithelial sodium channel; IBAT, ileal bile acid transporter; KCC1, K⁺/Cl⁻ co-transporter; NHE, Na⁺/H⁺ exchanger; NKCC1, Na⁺/K⁺/Cl⁻ co-transporter; SLC26A3, Cl⁻ anion exchanger; SLC26A6, anion exchange transporter.

FIGURE 4

Distribution of AQPs in intestinal tract and signal transduction mechanism of AQP3. AQP1, AQP3, AQP7, AQP10, and AQP11 are highly expressed in the small intestine, while AQP2, AQP3, AQP4, AQP7, and AQP8 are the main subtypes in the colon. “+” indicate a promoting role, “−” indicate an inhibition role. In AQP3 expression, there are two pathways: AC-mediated short-time regulation and long-term regulation at the transcriptional level. AC, adenylate cyclase; AQP, aquaporin; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-binding protein; PKA, protein kinase A; TNF-α, tumor necrosis factor alpha.