Intestinal Permeability, Irritable Bowel Syndrome with Constipation, and the Role of Sodium-Hydrogen Exchanger Isoform 3 (NHE3)

Figures & data

Figure 1 Schematic diagram of the intestinal epithelium with (A) normal permeability, and (B) increased permeability. (A) In normal intestinal epithelium, nutrients are absorbed from the lumen of the intestine into systemic circulation by passive, or paracellular, transport between the intercellular spaces. Tight junction proteins interconnecting the epithelial cells stop the transport of macromolecules from the lumen into systemic circulation. (B) In intestinal epithelium with increased permeability, the tight junction complex is disrupted and allow paracellular transport of macromolecules. They may activate mucosal mast cells to produce an inflammatory response, which can excite TRPV1-expressing sensory neurons, leading to increased visceral hypersensitivity and abdominal pain.

Abbreviations: H₂O, water; M, macromolecule; N, nutrients; Na⁺, sodium ion; TRPV1, transient receptor potential cation channel subfamily V member 1.

Table 1 Factors Associated with Abnormal Intestinal Permeability

Nutritional factors	Tight junction downregulation Histone deacetylase inhibitors ENS modulators
Infections and toxins	Viral, bacterial, and protozoal intestinal infections Environmental toxins Food poisoning (eg, preformed toxins, Bacillus cereus)
Hygiene hypothesis	Sterile environment Lack of farming
Lifestyle factors	Anxiety, depression, and/or trauma (psychological distress) Impaired function and diversity of the intestinal microbiota Medications (eg, aspirin, NSAIDs)
Endogenous factors	Hypoperfusion of the intestine Chronic inflammation / autoimmunity Bile acid malabsorption Genetics Ischemia

Notes: Adapted from Bischoff SC, Barbara G, Buurman W, et al. Intestinal permeability--a new target for disease prevention and therapy. BMC Gastroenterol. 2014;14:189, adapted with permission from SNCSC.¹⁷

Abbreviations: ENS, enteric nervous system; NSAID, nonsteroidal anti-inflammatory.

Table 2 Methods for Measuring Intestinal Permeability

Means	Hu	An	Test Molecules	Test Site	Material Needed	Disadvantages
Ex vivo
Ussing chamber	x	x	H2O, ions, sugars, etc.	Site specific	Biopsies	Invasive
In vivo—permeability assays
Lactulose/mannitol	x	x	Oligosaccharides of different MW	Small intestine	Urine	Time consuming
Sucralose	x	(x)	Sucralose (comb)*	Colon	Urine	Time consuming
Sucrose	x	(x)	Sucrose (comb)*	Stomach	Urine	Time consuming
PEG4000/400	x	(x)	Polyethylene glycols	Whole intestine	Urine	Time consuming
^51Cr-EDTA	x	x	^51Cr-EDTA	Whole intestine	Urine	Radioactivity
In vivo—bacteria-related
LAL assay	x	x	Endotoxin (LPS)	Whole intestine	Plasma	Assay limitation
EndoCAb	x	x	Anti-LPS antibodies	Whole intestine	Serum	Only in acute phase
D-lactate	x	x	Bacterial lactate	Whole intestine	Plasma	Low specificity
Butyrate production	x	x	BPB (PCR)	Colon	Feces	Special labs, limited data
Hemolysin test	x	x	Pathogens (cell culture)	Colon	Feces	Special labs, limited data
Inner colon mucus	x	x	Quantification of bacteria	Colon	Biopsies	Invasive, limited standardization
Liver steatosis	x	x	Fat content in liver	Whole intestine	MRT, US	Expensive, unspecific
Breath tests	x	x	Fat content in liver	Whole intestine	GC/MS	Unclear specificity

Notes: *In combination with lactulose/mannitol test. Reprinted from Bischoff SC, Barbara G, Buurman W, et al. Intestinal permeability--a new target for disease prevention and therapy. BMC Gastroenterol. 2014;14:189, reprinted with permission from SNCSC.¹⁷

Abbreviations: ⁵¹Cr-EDTA, chromium-labeled EDTA; An, suitable for animal models; BPB, butyrate-producing bacteria; EndoCAb, circulating endotoxin core antibias; GC, gas chromatography; Hu, suitable for the human system; LAL, limulus amebocyte lysate assay; LPS, lipopolysaccharide; MRT, magnetic resonance tomography; MS, mass spectroscopy; MW, molecular weight; PCR, polymerase chain reaction; PEG, polyethylene glycols; US, ultrasound.

Figure 2 Clinical treatment decision guide for IBS-C.

Notes: *Selection of medication should be based on the clinical features and needs of the patient. Tegaserod (5-HT₄ agonist) is FDA-approved and recommended for women younger than age 65 years with one or more cardiovascular risk factors who have not adequately responded to secretagogues^37,40; however, tegaserod has been removed from the US market for commercial reasons⁴¹ and, therefore, is not included in this chart. Reprinted from Gastroenterology. 163(1), AGA Institute, Clinical Decision Support Tool: IBS Treatment. Page No. 152, Copyright 2022, with permission from Elsevier.^42.

Abbreviations: 5-HT₄, 5-hydroxytryptamine receptor 4; FDA, Food and Drug Administration; IBS-C, irritable bowel syndrome with constipation; FODMAP, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols; NHE3, sodium-hydrogen antiporter 3; TCA, tricyclic antidepressant; SNRI, serotonin-norepinephrine reuptake inhibitor; PEG, polyethylene glycol; CBT cognitive behavioral therapy.

Figure 3 Mechanism of action of tenapanor. Tenapanor inhibits NHE3 located on the apical surface of the intestinal epithelial cells. NHE3 inhibition reduces sodium absorption, leading to water retention in the lumen that in turn softens stools and accelerates intestinal transit. NHE3 inhibition also causes retention of intracellular protons in the epithelial cell, which decreases the intracellular pH and increases TEER. This increase is thought to result from a conformational change in the tight junction proteins that decreases intestinal permeability to macromolecules. Tenapanor also normalizes sensory neuronal excitability and TRPV1 currents and reduces visceral hypersensitivity. This figure is published under Creative Commons license CC-BY: King AJ et al. Am J Physiol Gastrointest Liver Physiol. 2024. doi: 10.1152/ajpgi.00233.2023. Copyright © 2024, American Journal of Physiology-Gastrointestinal and Liver Physiology.⁵⁰

Abbreviations: H⁺, proton; H₂O, water; M, macromolecule; Na⁺, sodium ion; NHE3, sodium-hydrogen antiporter 3; TEER, transepithelial resistance; TRPV1, transient receptor potential cation channel subfamily V member 1.

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