Concise reviews
Visualising and quantifying intestinal permeability -where do we stand
a Department of Medicine, Krankenhaus Vilshofen, Krankenhausstrasse 32, 94474 Vislhofen an der Donau, Germany
b Department of Medicine, Marienhausklinik St. Josef Kohlhof, Klinikweg 1-5, 66539 Neunkirchen, Germany
c Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
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array:24 [ "pii" => "S1665268120301812" "issn" => "16652681" "doi" => "10.1016/j.aohep.2020.09.010" "estado" => "S300" "fechaPublicacion" => "2021-07-01" "aid" => "266" "copyright" => "Fundación Clínica Médica Sur, A.C." "copyrightAnyo" => "2020" "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "rev" "cita" => "Ann Hepatol. 2021;23C:" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "itemSiguiente" => array:19 [ "pii" => "S1665268120301708" "issn" => "16652681" "doi" => "10.1016/j.aohep.2020.08.072" "estado" => "S300" "fechaPublicacion" => "2021-07-01" "aid" => "255" "copyright" => "Fundación Clínica Médica Sur, A.C." "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "rev" "cita" => "Ann Hepatol. 2021;23C:" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:11 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Concise reviews</span>" "titulo" => "Silymarin is an ally against insulin resistance: A review" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 3624 "Ancho" => 3175 "Tamanyo" => 1550186 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0050" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Therapeutic targets of silymarin in IR.</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A) Insulin is released by pancreatic beta cells <elsevierMultimedia ident="202212060651026571"></elsevierMultimedia> in response to elevated blood glucose levels to maintain homeostatic blood glucose. Insulin binds to its receptor INSR <elsevierMultimedia ident="202212060651026572"></elsevierMultimedia> and undergoes Tyr phosphorylation which activates multiple signaling pathways, mainly PI3K and MAPK pathways. However, insulin regulates carbohydrate and lipid metabolism principally through activation of the PI3K pathway, initiated by interaction between the active, self-phosphorylated INSR with IRS1 <elsevierMultimedia ident="202212060651026573"></elsevierMultimedia>. Insulin promotes the translocation of GLUT4 from intracellular compartments to the plasma membrane by a pathway dependent on PI3K and Akt activation <elsevierMultimedia ident="202212060651026574"></elsevierMultimedia> promoting the uptake and storage of glucose in muscle and adipose tissues <elsevierMultimedia ident="202212060651026575"></elsevierMultimedia> [<a class="elsevierStyleCrossRef" href="#bib0025">5</a>,<a class="elsevierStyleCrossRef" href="#bib0030">6</a>,<a class="elsevierStyleCrossRef" href="#bib0165">33</a>,<a class="elsevierStyleCrossRef" href="#bib0250">50</a>,<a class="elsevierStyleCrossRef" href="#bib0285">57</a>].</p> <p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">B) In an insulin-resistant state, target cells (myocytes and adipocytes) have a decreased response to insulin action and hyperinsulinemia ensues. Poor insulin signaling is attributable to defects in insulin binding with its receptor and/or post-insulin binding modifications that alter the functionality of downstream proteins, such as phosphorylation at Ser/Thr residues of INSR and IRS1. This in turn decreases PI3K and Akt activity, and GLUT4 transporter expression, function, and translocation, resulting in decreased glucose uptake of the skeletal muscle and impaired glycogen, lipid, and protein synthesis. In adipocytes, increased lipolysis increases FFA release into the liver. Silymarin aids in pancreatic function recovery through increased insulin and glucagon expression <elsevierMultimedia ident="202212060651026576"></elsevierMultimedia>, normoglycemia, and recovery of insulin serum levels. Silymarin also inhibits JNK and IKK phosphorylation <elsevierMultimedia ident="202212060651026577"></elsevierMultimedia> and NfkB expression <elsevierMultimedia ident="202212060651026578"></elsevierMultimedia>, resulting in a decreased production of pro-inflammatory cytokines (TNFα, IL6) <elsevierMultimedia ident="202212060651026579"></elsevierMultimedia>. As inflammation is decreased, IRS-1/PI3K/Akt pathway signaling is favored <elsevierMultimedia ident="2022120606510265710"></elsevierMultimedia>, increasing GLUT4 expression <elsevierMultimedia ident="2022120606510265711"></elsevierMultimedia>, glucose uptake <elsevierMultimedia ident="2022120606510265712"></elsevierMultimedia>, and PTEN expression <elsevierMultimedia ident="2022120606510265713"></elsevierMultimedia> in muscleskeletal cells [<a class="elsevierStyleCrossRef" href="#bib0025">5</a>,<a class="elsevierStyleCrossRef" href="#bib0030">6</a>,<a class="elsevierStyleCrossRef" href="#bib0165">33</a>,<a class="elsevierStyleCrossRef" href="#bib0190">38</a>,<a class="elsevierStyleCrossRef" href="#bib0250">50</a>,<a class="elsevierStyleCrossRef" href="#bib0285">57</a>,<a class="elsevierStyleCrossRef" href="#bib0305">61</a>].</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">C) In an insulin-sensitive state, binding of insulin to INSR <elsevierMultimedia ident="2022120606510265714"></elsevierMultimedia> and phosphorylation or tyrosine residues <elsevierMultimedia ident="2022120606510265715"></elsevierMultimedia> leads to activation of the PI3K-Akt pathway <elsevierMultimedia ident="2022120606510265716"></elsevierMultimedia>, contributes to glycogen synthesis, decreased gluconeogenesis, protection against apoptosis, stimulation of mRNA translation, lipid and protein synthesis through the GSK3, mTOR and FoxO pathways [<a class="elsevierStyleCrossRef" href="#bib0025">5</a>,<a class="elsevierStyleCrossRef" href="#bib0030">6</a>,<a class="elsevierStyleCrossRef" href="#bib0165">33</a>,<a class="elsevierStyleCrossRef" href="#bib0250">50</a>,<a class="elsevierStyleCrossRef" href="#bib0285">57</a>].</p> <p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">D) In an insulin-resistant state, hyperinsulinemia leads to increased gluconeogenesis, uptake of FFAs, accumulation of lipids inside the cell, and decreased glycogen synthesis. This generates ROS in the mitochondrial chain which act on the fatty acids in the cell membrane causing lipid peroxidation. ROS induces pro-inflammatory cytokine synthesis including TNF-α, TGF-β1, and IL-6. Silymarin restores IRS-1/PI3K/Akt pathway signaling <elsevierMultimedia ident="2022120606510265717"></elsevierMultimedia>, increases PTEN expression <elsevierMultimedia ident="2022120606510265718"></elsevierMultimedia>, activates CFLAR expression and inhibits JNK and IKK phosphorylation <elsevierMultimedia ident="2022120606510265719"></elsevierMultimedia>, NfkB expression <elsevierMultimedia ident="2022120606510265720"></elsevierMultimedia>, and proinflammatory cytokine expression (TNFα, IL6) <elsevierMultimedia ident="2022120606510265721"></elsevierMultimedia>, eliminates free radicals resulting from lipid peroxidation <elsevierMultimedia ident="2022120606510265722"></elsevierMultimedia> and increases GSH cell content <elsevierMultimedia ident="2022120606510265723"></elsevierMultimedia> [<a class="elsevierStyleCrossRef" href="#bib0025">5</a>,<a class="elsevierStyleCrossRef" href="#bib0030">6</a>,<a class="elsevierStyleCrossRef" href="#bib0165">33</a>,<a class="elsevierStyleCrossRef" href="#bib0190">38</a>,<a class="elsevierStyleCrossRef" href="#bib0220">44</a>,<a class="elsevierStyleCrossRef" href="#bib0250">50</a>,<a class="elsevierStyleCrossRef" href="#bib0285">57</a>,<a class="elsevierStyleCrossRef" href="#bib0305">61</a>].</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Akt, Protein kinase B; CASP8, Caspase 8; CFLAR, CASP8 and FADD like apoptosis regulator; FADD, Fas associated via death; FFA, free fatty acids; FoxO, Forkhead box O; GLUT4, Glucose transporter 4; GSH, glutathione; GSK3, Glycogen synthase kinase 3; IKK, I kappa B kinase complex; IL-6, Interleukin-6; INSR, Insulin receptor; IRS1, Insulin receptor substrate 1; JNK, c-Jun N-terminal kinase; MAPK, Mitogen-activated kinases; mTOR, Mammalian target of rapamycin; NfkB, nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; ROS, reactive oxygen species; Ser, serine; TGF-β1, transforming growth factor beta-1; Thr, threonine; TNFα, Tumor necrosis factor α; Tyr, tyrosine.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Karla MacDonald-Ramos, Layla Michán, Alejandra Martínez-Ibarra, Marco Cerbón" "autores" => array:4 [ 0 => array:2 [ "nombre" => "Karla" "apellidos" => "MacDonald-Ramos" ] 1 => array:2 [ "nombre" => "Layla" "apellidos" => "Michán" ] 2 => array:2 [ "nombre" => "Alejandra" "apellidos" => "Martínez-Ibarra" ] 3 => array:2 [ "nombre" => "Marco" "apellidos" => "Cerbón" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268120301708?idApp=UINPBA00004N" "url" => "/16652681/000000230000000C/v3_202212060650/S1665268120301708/v3_202212060650/en/main.assets" ] "itemAnterior" => array:18 [ "pii" => "S1665268120301836" "issn" => "16652681" "doi" => "10.1016/j.aohep.2020.09.012" "estado" => "S300" "fechaPublicacion" => "2021-07-01" "aid" => "268" "documento" => "article" "crossmark" => 1 "licencia" => 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"apellidos" => "Li" ] 8 => array:2 [ "nombre" => "Min" "apellidos" => "Quan" ] 9 => array:2 [ "nombre" => "Ying" "apellidos" => "Duan" ] 10 => array:2 [ "nombre" => "Hong" "apellidos" => "Zhao" ] 11 => array:2 [ "nombre" => "Danying" "apellidos" => "Cheng" ] 12 => array:2 [ "nombre" => "Xiaomei" "apellidos" => "Wang" ] 13 => array:2 [ "nombre" => "Weini" "apellidos" => "Ou" ] 14 => array:2 [ "nombre" => "Huichun" "apellidos" => "Xing" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268120301836?idApp=UINPBA00004N" "url" => "/16652681/000000230000000C/v3_202212060650/S1665268120301836/v3_202212060650/en/main.assets" ] "en" => array:17 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Concise reviews</span>" "titulo" => "Visualising and quantifying intestinal permeability -where do we stand" "tieneTextoCompleto" => true "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Monica Rusticeanu, Vincent Zimmer, Frank Lammert" "autores" => array:3 [ 0 => array:4 [ "nombre" => "Monica" "apellidos" => "Rusticeanu" "email" => array:1 [ 0 => "monicarusticeanu@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:4 [ "nombre" => "Vincent" "apellidos" => "Zimmer" "email" => array:1 [ 0 => "vincent.zimmer@gmx.de" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 2 => array:4 [ "nombre" => "Frank" "apellidos" => "Lammert" "email" => array:1 [ 0 => "Frank.Lammert@uks.eu" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Department of Medicine, Krankenhaus Vilshofen, Krankenhausstrasse 32, 94474 Vislhofen an der Donau, Germany" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Medicine, Marienhausklinik St. Josef Kohlhof, Klinikweg 1-5, 66539 Neunkirchen, Germany" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2870 "Ancho" => 2508 "Tamanyo" => 638982 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0050" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">(A): intestinal villi with intraepithelial gap (black arrow) and increased luminal fluorescence (white arrow) as a sign of increased permeability. (B): intestinal villi without gaps, intravascular fluorescence (black arrow), no increased intraluminal fluorescence.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">1</span><span class="elsevierStyleSectionTitle" id="sect0020">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">According to current data, the intestinal barrier's integrity might play a key role in heath and disease. The assessment of the intestinal permeability is insufficiently standardized in clinical practice, and its clinical relevance for specific disease states remains to be delineated further. In this review, we summarize current knowledge on functional imaging tools for the assessment of intestinal permeability and barrier integrity. The latter contribute not only to the protection of the human body against invasion of pathogenic microorganisms and toxins, but also to the absorption of nutrients vital for life. Factors that influence intestinal permeability and barrier integrity are intestinal perfusion, systemic and/or gastrointestinal infections, diet, drugs as well as life-style and environmental factors [<a class="elsevierStyleCrossRef" href="#bib0005">1</a>]. Certain disease states are associated with increased intestinal permeability favoring mucosal inflammation, resulting in the translocation of intraluminal components. Not only primary gastrointestinal diseases such as inflammatory bowel diseases (IBD) and irritable bowel syndrome (IBS) are linked to impaired barrier function, but also a wide array of pathologies originating from other organs. There are data demonstrating an axis between chronic liver diseases and the gut barrier, thus highlighting the critical interplay between systemic and intestinal disease [<a class="elsevierStyleCrossRef" href="#bib0010">2</a>].</p><p id="par0010" class="elsevierStylePara elsevierViewall">The measurable intestinal permeability as function of paracellular intestinal transport capacities reflects the intestinal barrier function, which, in turn, is closely related to intestinal health. The architecture of the gut barrier comprises various physical and cellular components (mucus, epithelial and vascular cells, stroma). In addition, chemical aspects of the barrier function likewise have to be taken into account, such as cellular products, antimicrobial peptides, and gastrointestinal secretions. Last but not least, the critical contribution of intestinal microbiota, the local and the systemic immune system as well as gastrointestinal motility to gut integrity has to be taken into account [<a class="elsevierStyleCrossRef" href="#bib0015">3</a>].</p><p id="par0015" class="elsevierStylePara elsevierViewall">There are various tools and methods to assess intestinal permeability, which measure distinct components of this complex system. Most of the current instruments for (semi-)quantitative assessment, e.g. lactulose and mannitol permeability or blood zonulin measurements, provide information about the increase in permeability and, potentially, the degree of tissue alteration. However, these parameters are not capable of distinguishing functional changes from structural intestinal damage. Likewise, they provide little information about the exact mechanism and/or localization of disrupted gut permeability. In this review, we highlight less well-established imaging tools for intestinal barrier function assessment with emphasis on confocal laser endomicroscopy (CLE). CLE is a novel tool that integrates <span class="elsevierStyleItalic">in vivo</span> microscopic assessment into standard endoscopy [<a class="elsevierStyleCrossRef" href="#bib0020">4</a>,<a class="elsevierStyleCrossRef" href="#bib0025">5</a>]. Furthermore, available options for the quantitation of disturbed permeability as well as causes and localization of these functional changes are described.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2</span><span class="elsevierStyleSectionTitle" id="sect0025">Imaging Tools</span><p id="par0020" class="elsevierStylePara elsevierViewall">There is an increasing number of studies looking at the functional aspect of intestinal permeability, both in vitro and in vivo, in animal models or patients. As we will present further on, most studies visualizing intestinal permeability in vivo are using the technique of confocal endomicroscopy, with inflammatory bowel disease being the most investigated pathology. Other conditions influencing the intestinal permeability studied with CLE to this date in humans are irritable bowel syndrome and allergies. Other in vivo imaging methods revealed by our PubMed-research were magnetic resonance tomography (MRI) and positron emission tomography (PET)</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2.1</span><span class="elsevierStyleSectionTitle" id="sect0030">Magnetic resonance imaging (MRI)</span><p id="par0025" class="elsevierStylePara elsevierViewall">In a study published in 2015, Towner et al. [<a class="elsevierStyleCrossRef" href="#bib0030">6</a>] demonstrated altered permeability in the urine bladder and bowel in an animal model by means of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). In their preliminary study, they used a concentration of contrast media that readily allowed for direct and quantifiable observation of leakage out of the bladder wall. They also observed a secondary contrast-enhancement in the colon, indicating a breakdown of the colonic permeability barrier in histologically undamaged mucosa after exposure of the bladder to protamine sulfate [<a class="elsevierStyleCrossRef" href="#bib0035">7</a>] In a second publication [<a class="elsevierStyleCrossRef" href="#bib0040">8</a>], the same research group looked at the crosstalk between colon and bladder in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis as established method of inducing transmural and segmental colonic inflammation similar to Crohn disease (CD).</p><p id="par0030" class="elsevierStylePara elsevierViewall">Contrast enhanced MRI (CE-MRI) is in routine clinical use to determine sites and degree of intestinal inflammation in IBD. Assessing gastrointestinal, hepatobiliary or urinary tract with this method may be useful in providing information about how intestinal inflammation influences the permeability in histological healthy tissue of other organs in IBD patients.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2.2</span><span class="elsevierStyleSectionTitle" id="sect0035">Positron emission tomography (PET)</span><p id="par0035" class="elsevierStylePara elsevierViewall">The authors of this study [<a class="elsevierStyleCrossRef" href="#bib0045">9</a>], published 2011, used PET-technology to assess intestinal permeability and absorption of orally administrated <span class="elsevierStyleSup">18</span>F-Fluordesoxyglukose (18F-FDG) in rats, concluding that this would be a powerful tool for in vivo investigation of the gastrointestinal drug absorption.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2.3</span><span class="elsevierStyleSectionTitle" id="sect0040">Histology</span><p id="par0040" class="elsevierStylePara elsevierViewall">Another method of assessing gut barrier integrity is, among others, observing the shedding of the intestinal epithelial cells. There are various histological methods of describing a disrupted barrier, like increased intercellular space as a reflection of damaged tight junctions, quantifying the extracellular tight junction (TJ) protein occludin compared to the intracellular Zonula occludens-1 (ZO-1) protein by polymerase chain reaction (PCR), a decrease suggesting a disturbance in the cellular make-up of tight junctions [<a class="elsevierStyleCrossRef" href="#bib0050">10</a>].</p><p id="par0045" class="elsevierStylePara elsevierViewall">As they are held together by tight junctions, any disruption of the equilibrium between epithelial cell shedding at the villus tip and generation of new cells in the crypt can affect the homeostasis and permeability of the gut. It can be assumed that shedding of intestinal cells from the epithelial monolayer, which can be seen under the microscope, causes transient gaps in the barrier with a corresponding impact on intestinal permeability [<a class="elsevierStyleCrossRef" href="#bib0055">11</a>].</p><p id="par0050" class="elsevierStylePara elsevierViewall">The mechanism underlying this phenomenon of pathological cell shedding, observed in animal models of inflammation and human intestinal conditions like IBD remains poorly understood, but there is a sound rationale to believe that it might stem from systemic and intestinal inflammatory disease and a dysfunctional gut barrier [<a class="elsevierStyleCrossRef" href="#bib0060">12</a>].</p><p id="par0055" class="elsevierStylePara elsevierViewall">Studies investigating the light microscopic aspect of the intestinal mucosa in liver cirrhosis have shown signs of physical injury like epithelial cell shortening, nuclear disarray and degenerative changes of the cytoplasm predominantly in cells located at the tip of the villi, as well as pronounced extrusion of dead cells. Furthermore, at a submicroscopic level liver cirrhosis was linked to a widened tight junction complex as well as disruption of the actin cytoskeleton, mitochondrial dysfunction with consecutive swelling and changes in permeability [<a class="elsevierStyleCrossRef" href="#bib0065">13</a>,<a class="elsevierStyleCrossRef" href="#bib0070">14</a>] as well as changes in sugar composition at the brush border [<a class="elsevierStyleCrossRef" href="#bib0075">15</a>]. At the immunohistochemical level, the expression of TJ proteins occludin and claudin-1 was repressed in cirrhosis. Of note, these findings were even more pronounced in patients with decompensated cirrhosis [<a class="elsevierStyleCrossRef" href="#bib0080">16</a>].</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2.4</span><span class="elsevierStyleSectionTitle" id="sect0045">Confocal endomicroscopy (CLE)</span><p id="par0060" class="elsevierStylePara elsevierViewall">This imaging method is based on tissue illumination after systemic application of fluorescein, which highlights the extracellular matrix [<a class="elsevierStyleCrossRef" href="#bib0085">17</a>]. This allows CLE to assess the internal microstructure of tissues within anatomical tracts, i.e. gastrointestinal (but also urinary or respiratory), through an endoscope. Currently, to our knowledge, the only device on the market providing this technology has the trade name Cellvizio is a fibered confocal microscopic system. It uses the so-called probe based CLE (pCLE) where a probe is passed through the working channel of a standard gastroscope or colonoscope [<a class="elsevierStyleCrossRef" href="#bib0090">18</a>].</p><p id="par0065" class="elsevierStylePara elsevierViewall">A 488-nm wavelength laser system is used. There are different probes for different indications available and the confocal images are steamed at a frame rate of 12 frames per second, obtaining real-time videos of the mucosa [<a class="elsevierStyleCrossRef" href="#bib0095">19</a>].</p><p id="par0070" class="elsevierStylePara elsevierViewall">Confocal miniprobes are made of a distal tip, a fiber with a protective sheath and a connector. When connected to the Cellvizio system through their connector, confocal miniprobes transport the scanned laser beam through the sheathed fiber to the site of observation in contact with the distal tip and capture the fluorescent light emitted back from the tissue, in order to provide in-vivo fluorescence imaging of tissues. The parts of the confocal miniprobes that get in contact with the patient consists of biocompatible glass, plastic and metal derivatives.</p><p id="par0075" class="elsevierStylePara elsevierViewall">Here some examples of intestinal images obtained with the Cellvizio pCLE system:</p><p id="par0080" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">The method permits <span class="elsevierStyleItalic">in vivo</span> microscopy of the human gastrointestinal mucosa during endoscopy, providing optical "virtual biopsies". Endomicroscopy has been applied for the study of several diseases, with most studies focusing on inflammation and neoplasia, such as Barrett esophagus, gastric cancer, celiac disease, IBD or colorectal neoplasia. CLE facilitates the study of pathophysiological events in their natural environment (functional imaging) [<a class="elsevierStyleCrossRefs" href="#bib0100">20–24</a>]. To our knowledge, the role of endomicroscopy in patients with hepatobiliary diseases has been confined to imaging the biliary tree [<a class="elsevierStyleCrossRef" href="#bib0125">25</a>] but has not been used so far to evaluate the intestinal mucosa in patients with chronic liver diseases (CLD). Of note, sugar absorption tests (lactulose and mannitol) have been used to assess intestinal permeability and mucosal barrier function in CLD, but there are no data at this point that demonstrate signs of intestinal barrier dysfunction <span class="elsevierStyleItalic">in vivo</span> in human liver disease by CLE.</p><p id="par0090" class="elsevierStylePara elsevierViewall">As stated above, intestinal epithelial cells and tight junctions play a crucial role in maintaining the intact gut barrier. On the one hand, they assure the absorptive character of the intestine, on the other they are necessary to prevent potentially harmful components from entering the systemic circulation [<a class="elsevierStyleCrossRef" href="#bib0130">26</a>,<a class="elsevierStyleCrossRef" href="#bib0135">27</a>]. Representing a high cellular turnover tissue, the intestinal epithelium is constantly regenerated from stem cells originating at the crypt base. They migrate to the top of the villi as they mature and from where they are shed in time [<a class="elsevierStyleCrossRef" href="#bib0135">27</a>]. The cell shedding is responsible for epithelial gaps, which can be directly observed in real-time by CLE in humans [<a class="elsevierStyleCrossRef" href="#bib0140">28</a>,<a class="elsevierStyleCrossRef" href="#bib0145">29</a>]. Several studies confirmed that increased intestinal permeability can be visualized by CLE, especially in patients with IBD, but also in IBS and food allergy.</p><p id="par0095" class="elsevierStylePara elsevierViewall">The epithelial gap density visualized by CLE has been suggested as quantitative parameter for intestinal permeability. It was shown that the epithelial gap density of the terminal ileum is significantly higher that that of controls without IBD, in both CD and ulcerative colitis (UC) patients. Interestingly, gap density did not correlate with disease activity, hence further studies are needed to better understand the potential significance of these obervations in IBD [<a class="elsevierStyleCrossRef" href="#bib0150">30</a>]. Since cell shedding is a physiological regenerative phenomenon, the qualitative observation of epithelial gaps may not be sufficient to distinguish physiological versus pathological gut permeability. In 2011 Liu et al. [<a class="elsevierStyleCrossRef" href="#bib0155">31</a>] described a method of defining gap density by counting the epithelial gaps per 1,000 cells in adequately imaged villi in the terminal ileum of IBD patients. This definition was also used by Turcotte et al. [<a class="elsevierStyleCrossRef" href="#bib0160">32</a>] who described increased gap density in IBS patients compared with controls in a small sample of six versus 32 individuals. Thereby, they were able to achieve a diagnostic accuracy for the diagnosis of IBS with 62% sensitivity, 89% specificity, 83% positive predictive value, and 73% negative predictive value.</p><p id="par0100" class="elsevierStylePara elsevierViewall">Fritscher-Ravens et al. [<a class="elsevierStyleCrossRef" href="#bib0165">33</a>] used CLE technology in IBS patients to assess their response to specific food components by analyzing intraepithelial lymphocytes and fluid extravasation through epithelial leaks. Using this method, they established a diagnosis of (immune-mediated) food allergy in patients with negative immunoglobulin E (IgE) and skin-prick tests. In this study, several CLE criteria for the detection of barrier disruption were suggested: density of intraepithelial lymphocytes, epithelial breaks, luminal fluorescein leakage, presence of fluorescein between enterocytes and widening of the intervillous space.</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3</span><span class="elsevierStyleSectionTitle" id="sect0050">Discussion</span><p id="par0105" class="elsevierStylePara elsevierViewall">Although an emerging field, imaging methods for intestinal permeability assessment remain immature and in evolution. Radiology methods might provide in vivo information about the functional integrity of the intestinal barrier but fail to characterize morphological changes that lead to permeability change. As of now, CLE represents the only imaging method that may provide detailed cellular and anatomic information as well as functional alterations of the intestinal barrier in real time.</p><p id="par0110" class="elsevierStylePara elsevierViewall">This has been pioneered in a potential clinical application by Fritscher-Ravens for diagnosis and monitoring of distinct types of food allergies [<a class="elsevierStyleCrossRef" href="#bib0165">33</a>]. Further potential clinical utility of this innovative technology may lie in prognostication of treatment responses and its fine-tuning in the IBD field [<a class="elsevierStyleCrossRef" href="#bib0170">34</a>].</p><p id="par0115" class="elsevierStylePara elsevierViewall">Functional imaging with the CLE method also allows for testing of emerging therapies in IBS contributing to better understanding the pathophysiologic mechanisms underlying this condition.</p><p id="par0120" class="elsevierStylePara elsevierViewall">Extraintestinal conditions can be influenced by the intestinal permeability and integrity of the gut barrier. It is well known that in individuals with liver cirrhosis and ascites, disturbed intestinal permeability favours the development of spontaneous bacterial peritonitis (SBP) as a potentially deleterious clinical complication. An early diagnosis and risk stratification by quantification of impaired gut barrier may allow for targeted intervention and preventive measures, such as pre-emptive antibiotic prophylaxis.</p><p id="par0125" class="elsevierStylePara elsevierViewall">Several studies confirmed increased intestinal permeability in liver cirrhosis, however, these disturbances have not yet been addressed thoroughly by in vivo functional imaging such as CLE. Among others, increased gut permeability is considered an essential and early factor in the pathophysiology of SBP as well as other infectious cirrhosis complications related to bacterial translocation [<a class="elsevierStyleCrossRef" href="#bib0175">35</a>,<a class="elsevierStyleCrossRef" href="#bib0180">36</a>].</p><p id="par0130" class="elsevierStylePara elsevierViewall">All these changes could not, to our knowledge, be visualized in real time with in vivo imaging methods.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:7 [ 0 => array:3 [ "identificador" => "xres1814964" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1584614" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xpalclavsec1584615" "titulo" => "Abbreviations" ] 3 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 4 => array:3 [ "identificador" => "sec0010" "titulo" => "Imaging Tools" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Magnetic resonance imaging (MRI)" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Positron emission tomography (PET)" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Histology" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Confocal endomicroscopy (CLE)" ] ] ] 5 => array:2 [ "identificador" => "sec0035" "titulo" => "Discussion" ] 6 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-08-30" "fechaAceptado" => "2020-09-20" "PalabrasClave" => array:1 [ "en" => array:2 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1584614" "palabras" => array:5 [ 0 => "intestinal permeability" 1 => "liver cirrhosis" 2 => "intestinal imaging" 3 => "functional imaging" 4 => "CLE" ] ] 1 => array:4 [ "clase" => "abr" "titulo" => "Abbreviations" "identificador" => "xpalclavsec1584615" "palabras" => array:19 [ 0 => "IBD" 1 => "IBS" 2 => "CLE" 3 => "MRI" 4 => "PET" 5 => "DCE-MRI" 6 => "TNBS" 7 => "CD" 8 => "CE-MRI" 9 => "18F-FDG" 10 => "TJ" 11 => "ZO-1" 12 => "PCR" 13 => "CLE" 14 => "pCLE" 15 => "CLD" 16 => "UC" 17 => "IgE" 18 => "SBP" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Intestinal permeability is getting more and more attention in gastrointestinal research. Although well recognized, its exact role in health and disease is yet to be defined. There are many methods of quantifying intestinal permeability, but most of them fail to deliver tangible information about the morphological integrity of the intestinal barrier. In this review we aim to describe imaging options for the assessment of intestinal barrier integrity and their potential relevance for clinical practice. Our focus is on confocal laser endomicroscopy, which is at this time the only method for visualizing not only functional but also morphological aspects of the gut barrier <span class="elsevierStyleItalic">in vivo</span>.</p></span>" ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2870 "Ancho" => 2508 "Tamanyo" => 638982 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0050" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">(A): intestinal villi with intraepithelial gap (black arrow) and increased luminal fluorescence (white arrow) as a sign of increased permeability. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 15 | 1 | 16 |
| 2024 October | 63 | 12 | 75 |
| 2024 September | 78 | 8 | 86 |
| 2024 August | 68 | 4 | 72 |
| 2024 July | 63 | 1 | 64 |
| 2024 June | 53 | 7 | 60 |
| 2024 May | 59 | 3 | 62 |
| 2024 April | 78 | 6 | 84 |
| 2024 March | 73 | 16 | 89 |
| 2024 February | 48 | 5 | 53 |
| 2024 January | 73 | 17 | 90 |
| 2023 December | 45 | 15 | 60 |
| 2023 November | 63 | 10 | 73 |
| 2023 October | 93 | 22 | 115 |
| 2023 September | 102 | 4 | 106 |
| 2023 August | 90 | 6 | 96 |
| 2023 July | 69 | 7 | 76 |
| 2023 June | 111 | 25 | 136 |
| 2023 May | 110 | 18 | 128 |
| 2023 April | 99 | 11 | 110 |
| 2023 March | 89 | 16 | 105 |
| 2023 February | 64 | 8 | 72 |
| 2023 January | 73 | 9 | 82 |
| 2022 December | 63 | 11 | 74 |
| 2022 November | 60 | 9 | 69 |
| 2022 October | 59 | 14 | 73 |
| 2022 September | 86 | 18 | 104 |
| 2022 August | 60 | 16 | 76 |
| 2022 July | 40 | 18 | 58 |
| 2022 June | 47 | 16 | 63 |
| 2022 May | 56 | 24 | 80 |
| 2022 April | 57 | 22 | 79 |
| 2022 March | 39 | 30 | 69 |
| 2022 February | 51 | 16 | 67 |
| 2022 January | 109 | 11 | 120 |
| 2021 December | 60 | 24 | 84 |
| 2021 November | 43 | 19 | 62 |
| 2021 October | 67 | 21 | 88 |
| 2021 September | 240 | 13 | 253 |
| 2021 August | 200 | 10 | 210 |
| 2021 July | 122 | 14 | 136 |
| 2021 June | 18 | 3 | 21 |
| 2021 May | 23 | 3 | 26 |
| 2021 April | 93 | 6 | 99 |
| 2021 March | 48 | 7 | 55 |
| 2021 February | 33 | 8 | 41 |
| 2021 January | 18 | 3 | 21 |
| 2020 December | 21 | 11 | 32 |
| 2020 November | 13 | 4 | 17 |
| 2020 October | 3 | 3 | 6 |
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