Diarrhoeal pathogenesis in Salmonella infection may result from an imbalance in intestinal epithelial differentiation through reduced Notch signalling.
Salmonella
diarrhoea
down-regulated in adenoma
enteroid
foodborne illness
intestinal transport
Journal
The Journal of physiology
ISSN: 1469-7793
Titre abrégé: J Physiol
Pays: England
ID NLM: 0266262
Informations de publication
Date de publication:
04 2022
04 2022
Historique:
received:
04
11
2021
accepted:
20
01
2022
pubmed:
1
2
2022
medline:
16
4
2022
entrez:
31
1
2022
Statut:
ppublish
Résumé
Infections with non-typhoidal Salmonella spp. represent the most burdensome foodborne illnesses worldwide, yet despite their prevalence, the mechanism through which Salmonella elicits diarrhoea is not entirely known. Intestinal ion transporters play important roles in fluid and electrolyte homeostasis in the intestine. We have previously shown that infection with Salmonella caused decreased colonic expression of the chloride/bicarbonate exchanger SLC26A3 (down-regulated in adenoma; DRA) in a mouse model. In this study, we focused on the mechanism of DRA downregulation during Salmonella infection, by using murine epithelial enteroid-derived monolayers (EDMs). The decrease in DRA expression caused by infection was recapitulated in EDMs and accompanied by increased expression of Atonal Homolog 1 (ATOH1), the goblet cell marker Muc2 and the enteroendocrine cell marker ChgA. This suggested biased epithelial differentiation towards the secretory, rather than absorptive phenotype. In addition, the downstream Notch effector, Notch intracellular domain (NICD) and Hes1 were decreased following Salmonella infection. The relevance of Notch signalling was further investigated using a γ-secretase inhibitor, which recapitulated the downregulation in Hes1 and DRA as well as upregulation in ATOH1 and Muc2 seen following infection. Our findings suggest that Salmonella infection may result in a shift from absorptive to secretory cell types through Notch inhibition, which explains why there is a decreased capacity for absorption and ultimately the accumulation of diarrhoeal fluid. Our work also shows the value of EDMs as a model to investigate mechanisms that might be targeted for therapy of diarrhoea caused by Salmonella infection. KEY POINTS: Salmonella is a leading foodborne pathogen known to cause high-chloride-content diarrhoea. Salmonella infection of murine enteroid-derived monolayers decreased DRA expression. Salmonella infection resulted in upregulation of the secretory epithelial marker ATOH1, the goblet cell marker Muc2 and the enteroendocrine cell marker ChgA. Downregulation of DRA may result from infection-induced Notch inhibition, as reflected by decreased expression of Notch intracellular domain and Hes1, as well as from decreased HNF1α signalling. The imbalance in intestinal epithelial differentiation favouring secretory over absorptive cell types is a possible mechanism by which Salmonella elicits diarrhoea and may be relevant therapeutically.
Substances chimiques
Antiporters
0
Chloride-Bicarbonate Antiporters
0
Chlorides
0
Slc26a3 protein, mouse
0
Sulfate Transporters
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1851-1865Subventions
Organisme : NIH HHS
ID : DK099275
Pays : United States
Organisme : NIH HHS
ID : DK107585
Pays : United States
Informations de copyright
© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.
Références
Barrett KE & Keely SJ (2006). Integrative physiology and pathophysiology of intestinal electrolyte transport. In Physiology of the Gastrointestinal Tract, vols 1 and 2, 4th edn, ed. Johnson LR, pp. 1931-1951. Academic Press, San Diego.
Boyle EC, Brown NF & Finlay BB (2006). Salmonella enterica serovar Typhimurium effectors SopB, SopE, SopE2 and SipA disrupt tight junction structure and function. Cell Microbiol 8, 1946-1957.
Cao L, Kuratnik A, Xu W, Gibson JD, Kolling FT, Falcone ER, Ammar M, Van Heyst MD, Wright DL, Nelson CE & Giardina C (2015). Development of intestinal organoids as tissue surrogates: cell composition and the epigenetic control of differentiation. Mol Carcinog 54, 189-202.
Chernova MN, Jiang L, Friedman DJ, Darman RB, Lohi H, Kere J, Vandorpe DH & Alper SL (2005). Functional comparison of mouse slc26a6 anion exchanger with human SLC26A6 polypeptide variants: differences in anion selectivity, regulation, and electrogenicity. J Biol Chem 280, 8564-8580.
D'Angelo A, Bluteau O, Garcia-Gonzalez MA, Gresh L, Doyen A, Garbay S, Robine S & Pontoglio M (2010). Hepatocyte nuclear factor 1α and β control terminal differentiation and cell fate commitment in the gut epithelium. Development 137, 1573-1582.
Das S, Jayaratne R & Barrett KE (2018). The role of ion transporters in the pathophysiology of infectious diarrhea. Cell Mol Gastroenterol Hepatol 6, 33-45.
Das S, Owen KA, Ly KT, Park D, Black SG, Wilson JM, Sifri CD, Ravichandran KS, Ernst PB & Casanova JE (2011). Brain angiogenesis inhibitor 1 (BAI1) is a pattern recognition receptor that mediates macrophage binding and engulfment of Gram-negative bacteria. Proc Nat Acad Sci U S A 108, 2136-2141.
De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A & Kopan R (1999). A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain. Nature 398, 518-522.
Field M (2003). Intestinal ion transport and the pathophysiology of diarrhea. J Clin Invest 111, 931-943.
Foulke-Abel J, In J, Yin J, Zachos NC, Kovbasnjuk O, Estes MK, de Jonge H & Donowitz M (2016). Human enteroids as a model of upper small intestinal ion transport physiology and pathophysiology. Gastroenterology 150, 638-649.
Fre S, Huyghe M, Mourikis P, Robine S, Louvard D & Artavanis-Tsakonas S (2005). Notch signals control the fate of immature progenitor cells in the intestine. Nature 435, 964-968.
Freel RW, Morozumi M & Hatch M (2009). Parsing apical oxalate exchange in Caco-2BBe1 monolayers: siRNA knockdown of SLC26A6 reveals the role and properties of PAT-1. Am J Physiol Gastrointest Liver Physiol 297, G918-G929.
Geibel JP (2005). Secretion and absorption of colonic crypts. Annu Rev Physiol 67, 471-490.
Grubb BR, Lee E, Pace AJ, Koller BH & Boucher RC (2000). Intestinal transport in NKCC1-deficient mice. Am J Physiol Gastrointest Liver Physiol 279, G707-G718.
Gruber AD, Elble RC, Ji HL, Schreur KD, Fuller CM & Pauli BU (1998). Genomic cloning, moelcular characterization, and functional analysis of human CLCA1, the first human member of the family of Ca2+-activated Cl− channel proteins. Genomics 54, 200-214.
Guandalini S (2011). Probiotics for prevention and treatment of diarrhea. J Clin Gastroenterol 45, S149-S153.
Hoglund P, Haila S, Socha J, Tomaszewski L, Saarialho-Kere U, Karjalainen-Lindsberg ML, Airola K, Holmberg C, de la Chapelle A & Kere J (1996). Mutations of the Down-regulated in adenoma (DRA) gene cause congenital chloride diarrhoea. Nat Genet 14, 316-319.
Jensen J, Pedersen EE, Galante P, Hald J, Heller RS, Ishibashi M, Kageyama R, Guillemot F, Serup P & Madsen OD (2000). Control of endodermal endocrine development by Hes-1. Nat Genet 24, 36-44.
Kumar A, Chatterjee I, Gujral T, Alakkam A, Coffing H, Anbazhagan AN, Borthakur A, Saksena S, Gill RK, Alrefai WA & Dudeja PK (2017). Activation of nuclear factor-κB by tumor necrosis factor in intestinal epithelial cells and mouse intestinal epithelia reduces expression of the chloride transporter SLC26A3. Gastroenterology 153, 1338-1350.e1333.
Liu X, Lu R, Wu S & Sun J (2010). Salmonella regulation of intestinal stem cells through the Wnt/β-catenin pathway. FEBS Lett 584, 911-916.
Lu R, Liu X, Wu S, Xia Y, Zhang YG, Petrof EO, Claud EC & Sun J (2012). Consistent activation of the β-catenin pathway by Salmonella type-three secretion effector protein AvrA in chronically infected intestine. Am J Physiol Gastrointest Liver Physiol 303, G1113-1125.
Majowicz SE, Musto J, Scallan E, Angulo FJ, Kirk M, O'Brien SJ, Jones TF, Fazil A & Hoekstra RM; International Collaboration on Enteric Disease “Burden of Illness” Studies (2010). The global burden of nontyphoidal Salmonella gastroenteritis. Clin Infect Dis 50, 882-889.
Marchelletta RR, Gareau MG, McCole DF, Okamoto S, Roel E, Klinkenberg R, Guiney DG, Fierer J & Barrett KE (2013). Altered expression and localization of ion transporters contribute to diarrhea in mice with salmonella-induced enteritis. Gastroenterology 145, 1358-1368.
Marchelletta RR, Gareau MG, Okamoto S, Guiney DG, Barrett KE & Fierer J (2015). Salmonella-induced diarrhea occurs in the absence of IL-8 receptor (CXCR2)-dependent neutrophilic inflammation. J Infect Dis 212, 128-136.
Matthews JB, Hassan I, Meng S, Archer SY, Hrnjez BJ & Hodin RA (1998). Na-K-2Cl cotransporter gene expresion and function during enterocyte differentiation. Modulation of Cl− secretory capacity by butyrate. J Clin Invest 101, 2072-2079.
Miyoshi H & Stappenbeck TS (2013). In vitro expansion and genetic modification of gastrointestinal stem cells in spheroid culture. Nat Protoc 8, 2471-2482.
Pauli BU, Abdel-Ghany M, Cheng HC, Gruber AD, Archibald HA & Elble RC (2000). Molecular characteristics and functional diversity of CLCA family members. Clin Exp Pharmacol Physiol 27, 901-905.
Pin C, Watson AJ & Carding SR (2012). Modelling the spatio-temporal cell dynamics reveals novel insights on cell differentiation and proliferation in the small intestinal crypt. PLoS One 7, e37115.
Raheja G, Singh V, Ma K, Boumendjel R, Borthakur A, Gill RK, Saksena S, Alrefai WA, Ramaswamy K & Dudeja PK (2010). Lactobacillus acidophilus stimulates the expression of SLC26A3 via a transcriptional mechanism. Am J Physiol Gastrointest Liver Physiol 298, G395-401.
Resta-Lenert S & Barrett KE (2002). Enteroinvasive bacteria alter barrier and transport properties of human intestinal epithelium: role of iNOS and COX-2. Gastroenterology 122, 1070-1087.
Richmond CA & Breault DT (2010). Regulation of gene expression in the intestinal epithelium. Prog Mol Biol Transl Sci 96, 207-229.
Rodilla V, Villanueva A, Obrador-Hevia A, Robert-Moreno A, Fernandez-Majada V, Grilli A, Lopez-Bigas N, Bellora N, Alba MM, Torres F, Dunach M, Sanjuan X, Gonzalez S, Gridley T, Capella G, Bigas A & Espinosa L (2009). Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer. Proc Nat Acad Sci U S A 106, 6315-6320.
Sahoo D, Swanson L, Sayed IM, Katkar GD, Ibeawuchi SR, Mittal Y, Pranadinata RF, Tindle C, Fuller M, Stec DL, Chang JT, Sandborn WJ, Das S & Ghosh P (2021). Artificial intelligence guided discovery of a barrier-protective therapy in inflammatory bowel disease. Nat Commun 12, 4246.
Sato T, Stange DE, Ferrante M, Vries RG, Van Es JH, Van den Brink S, Van Houdt WJ, Pronk A, Van Gorp J, Siersema PD & Clevers H (2011). Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. Gastroenterology 141, 1762-1772.
Sayed IM, Suarez K, Lim E, Singh S, Pereira M, Ibeawuchi SR, Katkar G, Dunkel Y, Mittal Y, Chattopadhyay R, Guma M, Boland BS, Dulai PS, Sandborn WJ, Ghosh P & Das S (2020). Host engulfment pathway controls inflammation in inflammatory bowel disease. FEBS J 287, 3967-3988.
Sayed IM, Tindle C, Fonseca AG, Ghosh P & Das S (2021). Functional assays with human patient-derived enteroid monolayers to assess the human gut barrier. STAR Protoc 2, 100680.
Schweinfest CW, Spyropoulos DD, Henderson KW, Kim JH, Chapman JM, Barone S, Worrell RT, Wang Z & Soleimani M (2006). slc26a3 (dra)-deficient mice display chloride-losing diarrhea, enhanced colonic proliferation, and distinct up-regulation of ion transporters in the colon. J Biol Chem 281, 37962-37971.
Singh V, Kumar A, Raheja G, Anbazhagan AN, Priyamvada S, Saksena S, Jhandier MN, Gill RK, Alrefai WA, Borthakur A & Dudeja PK (2014). Lactobacillus acidophilus attenuates downregulation of DRA function and expression in inflammatory models. Am J Physiol Gastrointest Liver Physiol 307, G623-631.
Stanger BZ, Datar R, Murtaugh LC & Melton DA (2005). Direct regulation of intestinal fate by Notch. Proc Nat Acad Sci U S A 102, 12443-12448.
Tafazoli F, Magnusson KE & Zheng L (2003). Disruption of epithelial barrier integrity by Salmonella enterica serovar Typhimurium requires geranylgeranylated proteins. Infect Immun 71, 872-881.
Tian H, Biehs B, Chiu C, Siebel CW, Wu Y, Costa M, de Sauvage FJ & Klein OD (2015). Opposing activities of Notch and Wnt signaling regulate intestinal stem cells and gut homeostasis. Cell Rep 11, 33-42.
van Es JH & Clevers H (2005). Notch and Wnt inhibitors as potential new drugs for intestinal neoplastic disease. Trends Mol Med 11, 496-502.
van Es JH, van Gijn ME, Riccio O, van den Born M, Vooijs M, Begthel H, Cozijnsen M, Robine S, Winton DJ, Radtke F & Clevers H (2005). Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435, 959-963.
Welsh MK, Smith PL, Fromm M & Frizzell RA (1982). Crypts are the site of intestinal fluid and electrolyte secretion. Science 218, 1219-1221.
Zheng X, Tsuchiya K, Okamoto R, Iwasaki M, Kano Y, Sakamoto N, Nakamura T & Watanabe M (2011). Suppression of hath1 gene expression directly regulated by hes1 via notch signaling is associated with goblet cell depletion in ulcverative colitis. Inflamm Bowel Dis 11, 2251-2260.