Microbiota-related Changes in Bile Acid & Tryptophan Metabolism are Associated with Gastrointestinal Dysfunction in a Mouse Model of Autism

EBioMedicine

Volumn 24, Issue , 2017, Pages 166-178

  Golubeva, Anna V ^a   Joyce, Susan A ^a,b   Moloney, Gerard ^b   Burokas, Aurelijus ^a   Sherwin, Eoin ^a   Arboleya, Silvia ^a,c   Flynn, Ian ^b   Khochanskiy, Dmitry ^d   Moya Pérez, Angela ^a   Peterson, Veronica ^a   Rea, Kieran ^a   Murphy, Kiera ^c   Makarova, Olga ^d,e   Buravkov, Sergey ^d,e   Hyland, Niall P ^a,b   Stanton, Catherine ^a,b,c   Clarke, Gerard ^a,b   Gahan, Cormac G M ^a,b   Dinan, Timothy G ^a,b   Cryan, John F ^a,b  

^a UNIVERSITY COLLEGE CORK   (Ireland)

^b UNIVERSITY COLLEGE CORK   (Ireland)

^c TEAGASC FOOD RESEARCH CENTRE   (Ireland)

^d RESEARCH INSTITUTE OF HUMAN MORPHOLOGY   (Russian Federation)

^e MOSCOW STATE UNIVERSITY   (Russian Federation)

Author keywords

Autism; Bile acids; BTBR mouse; Gut microbiota; Intestinal permeability; Intestinal transit; Serotonin; Tryptophan

Indexed keywords

CHENODEOXYCHOLIC ACID; CHOLIC ACID; CHOLINE ACETYLTRANSFERASE; DEOXYCHOLIC ACID; KYNURENINE; LITHOCHOLIC ACID; NEURONAL NITRIC OXIDE SYNTHASE; RNA 16S; SEROTONIN; TRYPTOPHAN; URSODEOXYCHOLIC ACID; BILE ACID;

ADULT; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; AUTISM; BIFIDOBACTERIUM; BILE ACID METABOLISM; BLAUTIA; CONTROLLED STUDY; CORTICOSTERONE BLOOD LEVEL; DIGESTIVE SYSTEM FUNCTION DISORDER; DOWN REGULATION; ELECTROLYTE TRANSPORT; ELEVATED PLUS MAZE TEST; FECES ANALYSIS; FIRMICUTES; FORCED SWIM TEST; GAS CHROMATOGRAPHY; GENE EXPRESSION; GENE SEQUENCE; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HIPPOCAMPUS; IMMUNOFLUORESCENCE TEST; INTESTINE FLORA; INTESTINE INNERVATION; INTESTINE TISSUE; INTRACELLULAR SIGNALING; LATENT PERIOD; MALE; MASS SPECTROMETRY; MICROBIAL COMMUNITY; MOTONEURON; MOUSE; MYENTERIC PLEXUS; NONHUMAN; NOVEL OBJECT RECOGNITION TEST; OPEN FIELD TEST; PERMEABILITY; PRIORITY JOURNAL; PROTEIN EXPRESSION; REAL TIME POLYMERASE CHAIN REACTION; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; RNA EXTRACTION; SOCIAL BEHAVIOR; TRYPTOPHAN METABOLISM; WATER CONTENT; ANIMAL; BACTERIUM; CLASSIFICATION; COMPLICATION; DISEASE MODEL; GASTROINTESTINAL DISEASE; GASTROINTESTINAL TRACT; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION; GENE REGULATORY NETWORK; GENETICS; ISOLATION AND PURIFICATION; METABOLISM; MICROBIOLOGY; MICROFLORA;

ANIMALS; AUTISM SPECTRUM DISORDER; BACTERIA; BIFIDOBACTERIUM; BILE ACIDS AND SALTS; DISEASE MODELS, ANIMAL; GASTROINTESTINAL DISEASES; GASTROINTESTINAL TRACT; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION; GENE REGULATORY NETWORKS; MALE; MICE; MICROBIOTA; TRYPTOPHAN;

EID: 85030708733     PISSN: None     EISSN: 23523964     Source Type: Journal    
DOI: 10.1016/j.ebiom.2017.09.020     Document Type: Article

References (76)

1. Alemi, F., Poole, D.P., Chiu, J., Schoonjans, K., Cattaruzza, F., Grider, J.R., Bunnett, N.W., Corvera, C.U., The receptor TGR5 mediates the prokinetic actions of intestinal bile acids and is required for normal defecation in mice. Gastroenterology 144 (2013), 145–154.
2. Angelis, M., Piccolo, M., Vannini, L., Siragusa, S., Giacomo, A., Serrazzanetti, D.I., Cristofori, F., Guerzoni, M.E., Gobbetti, M., Francavilla, R., Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS One, 2013, 8.
3. Association, A.P, Diagnostic and Statistical Manual of Mental Disorders (DSM-5®). 2013, American Psychiatric Pub.
4. Balda, M.S., Whitney, J.A., Flores, C., González, S., Cereijido, M., Matter, K., Functional dissociation of paracellular permeability and transepithelial electrical resistance and disruption of the apical-basolateral intramembrane diffusion barrier by expression of a mutant tight junction membrane protein. J. Cell Biol. 134 (1996), 1031–1049.
5. Begley, M., Hill, C., Gahan, C.G.M., Bile salt hydrolase activity in probiotics. Appl. Environ. Microbiol. 72 (2006), 1729–1738.
6. Berglund, J.J., Riegler, M., Zolotarevsky, Y., Wenzl, E., Turner, J.R., Regulation of human jejunal transmucosal resistance and MLC phosphorylation by Na +-glucose cotransport. Am. J. Physiol. 281 (2001), G1487–G1493.
7. Boccuto, L., Chen, C.-F., Pittman, A.R., Skinner, C.D., McCartney, H.J., Jones, K., Bochner, B.R., Stevenson, R.E., Schwartz, C.E., Decreased tryptophan metabolism in patients with autism spectrum disorders. Mol. Autism, 4, 2013, 16.
8. Buffington, Shelly A., Di, Prisco, Gonzalo, V., Auchtung, Thomas A., Ajami, Nadim J., Petrosino, Joseph F., Costa-Mattioli, M., Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell 165 (2016), 1762–1775.
9. Careaga, M., Schwartzer, J., Ashwood, P., Inflammatory profiles in the BTBR mouse: how relevant are they to autism spectrum disorders?. Brain Behav. Immun. 43 (2015), 11–16.
10. Collins, J., Borojevic, R., Verdu, E., Huizinga, J., Ratcliffe, E., Intestinal microbiota influence the early postnatal development of the enteric nervous system. Neurogastroenterol. Motil. 26 (2014), 98–107.
11. Coretti, L., Cristiano, C., Florio, E., Scala, G., Lama, A., Keller, S., Cuomo, M., Russo, R., Pero, R., Paciello, O., et al. Sex-related alterations of gut microbiota composition in the BTBR mouse model of autism spectrum disorder. Sci Rep, 7, 2017, 45356.
12. de Aguiar Vallim, Thomas Q., Tarling, Elizabeth J., Edwards, Peter A., Pleiotropic roles of bile acids in metabolism. Cell Metab. 17 (2013), 657–669.
13. de Magistris, L., Familiari, V., Pascotto, A., Sapone, A., Frolli, A., Iardino, P., Carteni, M., De Rosa, M., Francavilla, R., Riegler, G., et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J. Pediatr. Gastroenterol. Nutr. 51 (2010), 418–424.
14. Desbonnet, L., Clarke, G., Shanahan, F., Dinan, T.G., Cryan, J.F., Microbiota is essential for social development in the mouse. Mol. Psychiatry 19 (2014), 146–148.
15. Desbonnet, L., Clarke, G., Traplin, A., O'Sullivan, O., Crispie, F., Moloney, R.D., Cotter, P.D., Dinan, T.G., Cryan, J.F., Gut microbiota depletion from early adolescence in mice: implications for brain and behaviour. Brain Behav. Immun. 48 (2015), 165–173.
16. D'Eufemia, P., Celli, M., Finocchiaro, R., Pacifico, L., Viozzi, L., Zaccagnini, M., Cardi, E., Giardini, O., Abnormal intestinal permeability in children with autism. Acta Paediatr. 85 (1996), 1076–1079.
17. Duan, Y., Chen, Y., Hu, W., Li, X., Yang, X., Zhou, X., Yin, Z., Kong, D., Yao, Z., Hajjar, D.P., et al. Peroxisome proliferator-activated receptor γ activation by ligands and dephosphorylation induces proprotein convertase subtilisin kexin type 9 and low density lipoprotein receptor expression. J. Biol. Chem. 287 (2012), 23667–23677.
18. Érces, D., Varga, G., Fazekas, B., Kovács, T., Tőkés, T., Tiszlavicz, L., Fülöp, F., Vécsei, L., Boros, M., Kaszaki, J., N-methyl-D-aspartate receptor antagonist therapy suppresses colon motility and inflammatory activation six days after the onset of experimental colitis in rats. Eur. J. Pharmacol. 691 (2012), 225–234.
19. Fiorentino, M., Sapone, A., Senger, S., Camhi, S.S., Kadzielski, S.M., Buie, T.M., Kelly, D.L., Cascella, N., Fasano, A., Blood–brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders. Mol. Autism, 7, 2016, 49.
20. Furness, J.B., Types of neurons in the enteric nervous system. J. Auton. Nerv. Syst. 81 (2000), 87–96.
21. Gadaleta, R.M., van Erpecum, K.J., Oldenburg, B., Willemsen, E.C.L., Renooij, W., Murzilli, S., Klomp, L.W.J., Siersema, P.D., Schipper, M.E.I., Danese, S., et al. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 60:4 (2011), 463–472.
22. Ghia, J.E., Li, N., Wang, H., Collins, M., Deng, Y., El–Sharkawy, R.T., Côté F., Mallet, J., Khan, W.I., Serotonin has a key role in pathogenesis of experimental colitis. Gastroenterology 137 (2009), 1649–1660.
23. Gilbert, J.A., Krajmalnik-Brown, R., Porazinska, D.L., Weiss, S.J., Knight, R., Toward effective probiotics for autism and other neurodevelopmental disorders. Cell 155 (2013), 1446–1448.
24. Glover, L.E., Bowers, B.E., Saeedi, B., Ehrentraut, S.F., Campbell, E.L., Bayless, A.J., Dobrinskikh, E., Kendrick, A.A., Kelly, C.J., Burgess, A., et al. Control of creatine metabolism by HIF is an endogenous mechanism of barrier regulation in colitis. Proc. Natl. Acad. Sci. 110 (2013), 19820–19825.
25. Green, A.R., Curzon, G., Effects of hydrocortisone and immobilization on tryptophan metabolism in brain and liver of rats of different ages. Biochem. Pharmacol. 24 (1975), 713–716.
26. Heo, Y., Zhang, Y., Gao, D., Miller, V.M., Lawrence, D.A., Aberrant immune responses in a mouse with behavioral disorders. PLoS One, 6, 2011, e20912.
27. Heredia, D.J., Gershon, M.D., Koh, S.D., Corrigan, R.D., Okamoto, T., Smith, T.K., Important role of mucosal serotonin in colonic propulsion and peristaltic reflexes: in vitro analyses in mice lacking tryptophan hydroxylase 1. J. Physiol. 591 (2013), 5939–5957.
28. Hsiao, E.Y., McBride, S.W., Hsien, S., Sharon, G., Hyde, E.R., McCue, T., Codelli, J.A., Chow, J., Reisman, S.E., Petrosino, J.F., Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopment disorders. Cell, 2013, 155.
29. Inagaki, T., Moschetta, A., Lee, Y.-K., Peng, L., Zhao, G., Downes, M., Yu, R.T., Shelton, J.M., Richardson, J.A., Repa, J.J., et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc. Natl. Acad. Sci. U. S. A. 103 (2006), 3920–3925.
30. Johansson, M.E.V., Larsson, J.M.H., Hansson, G.C., The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host–microbial interactions. Proc. Natl. Acad. Sci. 108 (2011), 4659–4665.
31. Joyce, S.A., Gahan, C.G.M., Bile acid modifications at the microbe-host interface: potential for nutraceutical and pharmaceutical interventions in host health. Annu. Rev. Food Sci. Technol. 7 (2016), 313–333.
32. Joyce, S.A., MacSharry, J., Casey, P.G., Kinsella, M., Murphy, E.F., Shanahan, F., Hill, C., Gahan, C.G.M., Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut. Proc. Natl. Acad. Sci. 111 (2014), 7421–7426.
33. Kang, D.W., Park, J.G., Ilhan, Z.E., Wallstrom, G., Labaer, J., Adams, J.B., Krajmalnik-Brown, R., Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PLoS One, 2013, 8.
34. Kang, D.-W., Adams, J.B., Gregory, A.C., Borody, T., Chittick, L., Fasano, A., Khoruts, A., Geis, E., Maldonado, J., McDonough-Means, S., et al. Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome, 5, 2017, 10.
35. Kaszaki, J., Palásthy, Z., érczes, D., Rácz, A., Torday, C., Varga, G., Vécsei, L., Boros, M., Kynurenic acid inhibits intestinal hypermotility and xanthine oxidase activity during experimental colon obstruction in dogs. Neurogastroenterol. Motil. 20 (2008), 53–62.
36. Kelly, J.R., Kennedy, P.J., Cryan, J.F., Dinan, T.G., Clarke, G., Hyland, N.P., Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front. Cell. Neurosci., 9, 2015, 392.
37. Kennedy, P.J., Cryan, J.F., Dinan, T.G., Clarke, G., Kynurenine pathway metabolism and the microbiota-gut-brain axis. Neuropharmacology 112:Part B (2017), 399–412.
38. Keszthelyi, D., Troost, F.J., Masclee, A.A.M., Understanding the role of tryptophan and serotonin metabolism in gastrointestinal function. Neurogastroenterol. Motil. 21 (2009), 1239–1249.
39. Kim, J.-W., Choi, C.S., Kim, K.C., Park, J.H., Seung, H., Joo, S.H., Yang, S.M., Shin, C.Y., Park, S.H., Gastrointestinal tract abnormalities induced by prenatal valproic acid exposure in rat offspring. Toxicol. Res. 29 (2013), 173–179.
40. Klein, M.S., Newell, C., Bomhof, M.R., Reimer, R.A., Hittel, D.S., Rho, J.M., Vogel, H.J., Shearer, J., Metabolomic modeling to monitor host responsiveness to gut microbiota manipulation in the BTBRT + tf/j mouse. J. Proteome Res. 15 (2016), 1143–1150.
41. Kong, B., Wang, L., Chiang, J.Y.L., Zhang, Y., Klaassen, C.D., Guo, G.L., Mechanism of tissue-specific farnesoid X receptor in suppressing the expression of genes in bile-acid synthesis in mice. Hepatology 56 (2012), 1034–1043.
42. Kumar, H., Sharma, B., Minocycline ameliorates prenatal valproic acid induced autistic behaviour, biochemistry and blood brain barrier impairments in rats. Brain Res. 1630 (2016), 83–97.
43. Lim, C.K., Essa, M.M., de Paula Martins, R., Lovejoy, D.B., Bilgin, A.A., Waly, M.I., Al-Farsi, Y.M., Al-Sharbati, M., Al-Shaffae, M.A., Guillemin, G.J., Altered kynurenine pathway metabolism in autism: implication for immune-induced glutamatergic activity. Autism Res., 2015.
44. 4 receptor-mediated neuroprotection and neurogenesis in the enteric nervous system of adult mice. J. Neurosci. 29 (2009), 9683–9699.
45. Lorenzo-Zúñiga, V., Bartolí R., Planas, R., Hofmann, A.F., Viñado, B., Hagey, L.R., Hernández, J.M., Mañé J., Alvarez, M.A., Ausina, V., et al. Oral bile acids reduce bacterial overgrowth, bacterial translocation, and endotoxemia in cirrhotic rats. Hepatology 37 (2003), 551–557.
46. Luna, R.A., Oezguen, N., Balderas, M., Venkatachalam, A., Runge, J.K., Versalovic, J., Veenstra-VanderWeele, J., Anderson, G.M., Savidge, T., Williams, K.C., Distinct microbiome-neuroimmune signatures correlate with functional abdominal pain in children with autism spectrum disorder. Cell. Mol. Gastroenterol. Hepatol. 3:2 (2017), 218–230.
47. Lyall, K., Croen, L., Daniels, J., Fallin, M.D., Ladd-Acosta, C., Lee, B.K., Park, B.Y., Snyder, N.W., Schendel, D., Volk, H., et al. The Changing epidemiology of autism spectrum disorders. Annu. Rev. Public Health, 38, 2017 (null).
48. Mawe, G.M., Hoffman, J.M., Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets. Nat. Rev. Gastroenterol. Hepatol. 10 (2013), 473–486.
49. McElhanon, B.O., McCracken, C., Karpen, S., Sharp, W.G., Gastrointestinal symptoms in autism spectrum disorder: a meta-analysis. Pediatrics 133 (2014), 872–883.
50. Meyza, K.Z., Blanchard, D.C., The BTBR mouse model of idiopathic autism – Current view on mechanisms. Neurosci. Biobehav. Rev. 76 (2017), 99–110.
51. Meyza, K.Z., Defensor, E.B., Jensen, A.L., Corley, M.J., Pearson, B.L., Pobbe, R.L.H., Bolivar, V.J., Blanchard, D.C., Blanchard, R.J., The BTBR T + tf/J mouse model for autism spectrum disorders–in search of biomarkers. Behav. Brain Res. 251 (2013), 25–34.
52. Moy, S.S., Nadler, J.J., Young, N.B., Perez, A., Holloway, L.P., Barbaro, R.P., Barbaro, J.R., Wilson, L.M., Threadgill, D.W., Lauder, J.M., et al. Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred strains. Behav. Brain Res. 176 (2007), 4–20.
53. Mukherji, A., Kobiita, A., Ye, T., Chambon, P., Homeostasis in intestinal epithelium is orchestrated by the circadian clock and microbiota cues transduced by TLRs. Cell 153 (2013), 812–827.
54. Muller, C.L., Anacker, A.M.J., Veenstra-VanderWeele, J., The serotonin system in autism spectrum disorder: from biomarker to animal models. Neuroscience 321 (2016), 24–41.
55. Neufeld, K.M., Kang, N., Bienenstock, J., Foster, J.A., Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol. Motil., 23, 2011, 255 (e119).
56. Newell, C., Bomhof, M.R., Reimer, R.A., Hittel, D.S., Rho, J.M., Shearer, J., Ketogenic diet modifies the gut microbiota in a murine model of autism spectrum disorder. Mol. Autism, 7, 2016, 37.
57. Obata, Y., Pachnis, V., The effect of microbiota and the immune system on the development and organization of the enteric nervous system. Gastroenterology 151 (2016), 836–844.
58. Onore, C.E., Careaga, M., Babineau, B.A., Schwartzer, J.J., Berman, R.F., Ashwood, P., Inflammatory macrophage phenotype in BTBR T + tf/J mice. Front. Neurosci., 7, 2013, 158.
59. Rea, K., Dinan, T.G., Cryan, J.F., The microbiome: A key regulator of stress and neuroinflammation. Neurobiol. Stress 4 (2016), 23–33.
60. Ridlon, J.M., Alves, J.M., Hylemon, P.B., Bajaj, J.S., Cirrhosis, bile acids and gut microbiota. Gut Microbes 4 (2013), 382–387.
61. Ruskin, D.N., Svedova, J., Cote, J.L., Sandau, U., Rho, J.M., Kawamura, M. Jr., Boison, D., Masino, S.A., Ketogenic diet improves core symptoms of autism in BTBR mice. PLoS One, 8, 2013, e65021.
62. Sandhu, K.V., Sherwin, E., Schellekens, H., Stanton, C., Dinan, T.G., Cryan, J.F., Feeding the microbiota-gut-brain axis: diet, microbiome, and neuropsychiatry. Transl. Res. 179 (2017), 223–244.
63. Sayin, Sama I., Wahlström, A., Felin, J., Jäntti, S., Marschall, H.-U., Bamberg, K., Angelin, B., Hyötyläinen, T., Orešič M., Bäckhed, F., Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 17 (2013), 225–235.
64. Shen, L., Black, E.D., Witkowski, E.D., Lencer, W.I., Guerriero, V., Schneeberger, E.E., Turner, J.R., Myosin light chain phosphorylation regulates barrier function by remodeling tight junction structure. J. Cell Sci. 119 (2006), 2095–2106.
65. Sherwin, E., Dinan, T.G., Cryan, J.F., Recent developments in understanding the role of the gut microbiota in brain health and disease. Ann. N. Y. Acad. Sci., 2017, 1–21.
66. Shin, D.-J., Campos, J.A., Gil, G., Osborne, T.F., PGC-1α activates CYP7A1 and bile acid biosynthesis. J. Biol. Chem. 278 (2003), 50047–50052.
67. Slattery, J.A., Page, A.J., Dorian, C.L., Brierley, S.M., Blackshaw, L.A., Potentiation of mouse vagal afferent mechanosensitivity by ionotropic and metabotropic glutamate receptors. J. Physiol. 577 (2006), 295–306.
68. Sommer, F., Backhed, F., The gut microbiota - masters of host development and physiology. Nat. Rev. Microbiol. 11 (2013), 227–238.
69. Thiagarajah, J.R., Verkman, A.S., CFTR inhibitors for treating diarrheal disease. Clin. Pharmacol. Ther. 92 (2012), 287–290.
70. Tomova, A., Husarova, V., Lakatosova, S., Bakos, J., Vlkova, B., Babinska, K., Ostatnikova, D., Gastrointestinal microbiota in children with autism in Slovakia. Physiol. Behav., 138, 2015.
71. Turner, J.R., Rill, B.K., Carlson, S.L., Carnes, D., Kerner, R., Mrsny, R.J., Madara, J.L., Physiological regulation of epithelial tight junctions is associated with myosin light-chain phosphorylation. Am. J. Phys. Cell Physiol. 273 (1997), C1378–C1385.
72. Varian, B.J., Poutahidis, T., DiBenedictis, B.T., Levkovich, T., Ibrahim, Y., Didyk, E., Shikhman, L., Cheung, H.K., Hardas, A., Ricciardi, C.E., et al. Microbial lysate upregulates host oxytocin. Brain Behav. Immun. 61 (2017), 36–49.
73. Vuong, H.E., Hsiao, E.Y., Emerging roles for the gut microbiome in autism spectrum disorder. Biol. Psychiatry 81 (2017), 411–423.
74. Wohleb, E.S., McKim, D.B., Sheridan, J.F., Godbout, J.P., Monocyte trafficking to the brain with stress and inflammation: a novel axis of immune-to-brain communication that influences mood and behavior. Neuroinflam. Behav., 2015, 34.
75. Yano, Jessica M., Yu, K., Donaldson, Gregory P., Shastri, Gauri G., Ann, P., Ma, L., Nagler, Cathryn R., Ismagilov, Rustem F., Mazmanian, Sarkis K., Hsiao, Elaine Y., Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161 (2015), 264–276.
76. Zihni, C., Mills, C., Matter, K., Balda, M.S., Tight junctions: from simple barriers to multifunctional molecular gates. Nat. Rev. Mol. Cell Biol. 17 (2016), 564–580.