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Regular article Gastrointestinal, hepatobiliary, and pancreatic pathology| Volume 191, ISSUE 5, P872-884, May 01, 2021

Lactobacillus acidophilus Induces a Strain-specific and Toll-Like Receptor 2–Dependent Enhancement of Intestinal Epithelial Tight Junction Barrier and Protection Against Intestinal Inflammation

Published:February 15, 2021DOI:https://doi.org/10.1016/j.ajpath.2021.02.003
      Defective intestinal tight junction (TJ) barrier is an important pathogenic factor of inflammatory bowel disease. To date, no effective therapies that specifically target the intestinal TJ barrier are available. The purpose of this study was to identify probiotic bacterial species or strains that induce a rapid and sustained enhancement of intestinal TJ barrier and protect against the development of intestinal inflammation by targeting the TJ barrier. After high-throughput screening of >20 Lactobacillus and other probiotic bacterial species or strains, a specific strain of Lactobacillus acidophilus, referred to as LA1, uniquely produced a marked enhancement of the intestinal TJ barrier. LA1 attached to the apical membrane surface of intestinal epithelial cells in a Toll-like receptor (TLR)-2–dependent manner and caused a rapid increase in enterocyte TLR-2 membrane expression and TLR-2/TLR-1 and TLR-2/TLR-6 hetero-complex–dependent enhancement in intestinal TJ barrier function. Oral administration of LA1 caused a rapid enhancement in mouse intestinal TJ barrier, protected against a dextran sodium sulfate (DSS) increase in intestinal permeability, and prevented the DSS-induced colitis in a TLR-2– and intestinal TJ barrier–dependent manner. In conclusion, we report for the first time that a specific strain of LA causes a strain-specific enhancement of intestinal TJ barrier through a novel mechanism that involves the TLR-2 receptor complex and protects against the DSS-induced colitis by targeting the intestinal TJ barrier.
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      References

        • Ma T.Y.
        • Nighot P.
        • Al-Sadi R.
        Tight junctions and the intestinal barrier.
        in: Physiology of the Gastrointestinal Tract. ed 6. Elsevier Academic Press, Burlington, MA2018
        • Hollander D.
        • Vadheim C.M.
        • Brettholz E.
        • Petersen G.M.
        • Delahunty T.J.
        • Rotter J.
        Increased intestinal permeability in patients with Crohn's disease and their relatives. A possible etiologic factor.
        Ann Intern Med. 1986; 105: 883-885
        • Turner J.R.
        Molecular basis of epithelial barrier regulation: from basic mechanisms to clinical application.
        Am J Pathol. 2006; 169: 1901-1909
        • Arnott I.D.
        • Kingstone K.
        • Ghosh S.
        Abnormal intestinal permeability predicts relapse in inactive Crohn disease.
        Scand J Gastroenterol. 2000; 35: 1163-1169
        • Irvine E.J.
        • Marshall J.K.
        Increased intestinal permeability precedes the onset of Crohn's disease in a subject with familial risk.
        Gastroenterology. 2000; 119: 1740-1744
        • Iwata M.
        • Nakano H.
        • Matsuura Y.
        • Nagasaka M.
        • Misawa M.
        • Mizuta S.
        • Ito I.
        • Saito T.
        • Ito T.
        • Hokama M.
        • Kamiya M.
        • Hobara R.
        • Watanabe M.
        • Takahama K.
        [Intestinal permeability in Crohn's disease and effects of elemental dietary therapy].
        Nihon Shokakibyo Gakkai Zasshi. 2001; 98: 636-643
        • Seksik P.
        • Sokol H.
        • Lepage P.
        • Vasquez N.
        • Manichanh C.
        • Mangin I.
        • Pochart P.
        • Dore J.
        • Marteau P.
        Review article: the role of bacteria in onset and perpetuation of inflammatory bowel disease.
        Aliment Pharmacol Ther. 2006; 24: 11-18
        • Ostergaard M.V.
        • Cilieborg M.S.
        • Skovgaard K.
        • Schmidt M.
        • Sangild P.T.
        • Bering S.B.
        Preterm birth reduces nutrient absorption with limited effect on immune gene expression and gut colonization in pigs.
        J Pediatr Gastroenterol Nutr. 2015; 61: 481-490
        • Yu L.C.
        Microbiota dysbiosis and barrier dysfunction in inflammatory bowel disease and colorectal cancers: exploring a common ground hypothesis.
        J Biomed Sci. 2018; 25: 79
        • Hold G.L.
        • Smith M.
        • Grange C.
        • Watt E.R.
        • El-Omar E.M.
        • Mukhopadhya I.
        Role of the gut microbiota in inflammatory bowel disease pathogenesis: what have we learnt in the past 10 years?.
        World J Gastroenterol. 2014; 20: 1192-1210
        • Lan N.
        • Ashburn J.
        • Shen B.
        Fecal microbiota transplantation for Clostridium difficile infection in patients with ileal pouches.
        Gastroenterol Rep (Oxf). 2017; 5: 200-207
        • Lopez J.
        • Grinspan A.
        Fecal microbiota transplantation for inflammatory bowel disease.
        Gastroenterol Hepatol (N Y). 2016; 12: 374-379
        • Kulecka M.
        • Paziewska A.
        • Zeber-Lubecka N.
        • Ambrozkiewicz F.
        • Kopczynski M.
        • Kuklinska U.
        • Pysniak K.
        • Gajewska M.
        • Mikula M.
        • Ostrowski J.
        Prolonged transfer of feces from the lean mice modulates gut microbiota in obese mice.
        Nutr Metab (Lond). 2016; 13: 57
        • Grover S.
        • Rashmi H.M.
        • Srivastava A.K.
        • Batish V.K.
        Probiotics for human health -new innovations and emerging trends.
        Gut Pathog. 2012; 4: 15
        • Blackwood B.P.
        • Yuan C.Y.
        • Wood D.R.
        • Nicolas J.D.
        • Grothaus J.S.
        • Hunter C.J.
        Probiotic Lactobacillus species strengthen intestinal barrier function and tight junction integrity in experimental necrotizing enterocolitis.
        J Probiotics Health. 2017; 5: 159
        • Eun C.S.
        • Kim Y.S.
        • Han D.S.
        • Choi J.H.
        • Lee A.R.
        • Park Y.K.
        Lactobacillus casei prevents impaired barrier function in intestinal epithelial cells.
        APMIS. 2011; 119: 49-56
        • Guo S.
        • Gillingham T.
        • Guo Y.
        • Meng D.
        • Zhu W.
        • Walker W.A.
        • Ganguli K.
        Secretions of Bifidobacterium infantis and Lactobacillus acidophilus protect intestinal epithelial barrier function.
        J Pediatr Gastroenterol Nutr. 2017; 64: 404-412
        • Hummel S.
        • Veltman K.
        • Cichon C.
        • Sonnenborn U.
        • Schmidt M.A.
        Differential targeting of the E-cadherin/beta-catenin complex by gram-positive probiotic lactobacilli improves epithelial barrier function.
        Appl Environ Microbiol. 2012; 78: 1140-1147
        • Lepine A.F.P.
        • de Wit N.
        • Oosterink E.
        • Wichers H.
        • Mes J.
        • de Vos P.
        Lactobacillus acidophilus attenuates Salmonella-induced stress of epithelial cells by modulating tight-junction genes and cytokine responses.
        Front Microbiol. 2018; 9: 1439
        • Montalto M.
        • Maggiano N.
        • Ricci R.
        • Curigliano V.
        • Santoro L.
        • Di Nicuolo F.
        • Vecchio F.M.
        • Gasbarrini A.
        • Gasbarrini G.
        Lactobacillus acidophilus protects tight junctions from aspirin damage in HT-29 cells.
        Digestion. 2004; 69: 225-228
        • Mujagic Z.
        • de Vos P.
        • Boekschoten M.V.
        • Govers C.
        • Pieters H.H.
        • de Wit N.J.
        • Bron P.A.
        • Masclee A.A.
        • Troost F.J.
        The effects of Lactobacillus plantarum on small intestinal barrier function and mucosal gene transcription; a randomized double-blind placebo controlled trial.
        Sci Rep. 2017; 7: 40128
        • Parassol N.
        • Freitas M.
        • Thoreux K.
        • Dalmasso G.
        • Bourdet-Sicard R.
        • Rampal P.
        Lactobacillus casei DN-114 001 inhibits the increase in paracellular permeability of enteropathogenic Escherichia coli-infected T84 cells.
        Res Microbiol. 2005; 156: 256-262
        • Resta-Lenert S.
        • Barrett K.E.
        Live probiotics protect intestinal epithelial cells from the effects of infection with enteroinvasive Escherichia coli (EIEC).
        Gut. 2003; 52: 988-997
        • Wang H.
        • Zhang Q.
        • Niu Y.
        • Zhang X.
        • Lu R.
        Surface-layer protein from Lactobacillus acidophilus NCFM attenuates tumor necrosis factor-alpha-induced intestinal barrier dysfunction and inflammation.
        Int J Biol Macromol. 2019; 136: 27-34
        • Zakostelska Z.
        • Kverka M.
        • Klimesova K.
        • Rossmann P.
        • Mrazek J.
        • Kopecny J.
        • Hornova M.
        • Srutkova D.
        • Hudcovic T.
        • Ridl J.
        • Tlaskalova-Hogenova H.
        Lysate of probiotic Lactobacillus casei DN-114 001 ameliorates colitis by strengthening the gut barrier function and changing the gut microenvironment.
        PLoS One. 2011; 6: e27961
        • Al-Sadi R.
        • Ye D.
        • Dokladny K.
        • Ma T.Y.
        Mechanism of IL-1beta-induced increase in intestinal epithelial tight junction permeability.
        J Immunol. 2008; 180: 5653-5661
        • Al-Sadi R.
        • Khatib K.
        • Guo S.
        • Ye D.
        • Youssef M.
        • Ma T.
        Occludin regulates macromolecule flux across the intestinal epithelial tight junction barrier.
        Am J Physiol Gastrointest Liver Physiol. 2011; 300: G1054-G1064
        • Ye D.
        • Guo S.
        • Al-Sadi R.
        • Ma T.Y.
        MicroRNA regulation of intestinal epithelial tight junction permeability.
        Gastroenterology. 2011; 141: 1323-1333
        • Nighot P.
        • Al-Sadi R.
        • Rawat M.
        • Guo S.
        • Watterson D.M.
        • Ma T.
        Matrix metalloproteinase 9-induced increase in intestinal epithelial tight junction permeability contributes to the severity of experimental DSS colitis.
        Am J Physiol Gastrointest Liver Physiol. 2015; 309: G988-G997
        • Wirtz S.
        • Neufert C.
        • Weigmann B.
        • Neurath M.F.
        Chemically induced mouse models of intestinal inflammation.
        Nat Protoc. 2007; 2: 541-546
        • Johnson-Henry K.C.
        • Donato K.A.
        • Shen-Tu G.
        • Gordanpour M.
        • Sherman P.M.
        Lactobacillus rhamnosus strain GG prevents enterohemorrhagic Escherichia coli O157:H7-induced changes in epithelial barrier function.
        Infect Immun. 2008; 76: 1340-1348
        • Cenci G.
        • Rossi J.
        • Trotta F.
        • Caldini G.
        Lactic acid bacteria isolated from dairy products inhibit genotoxic effect of 4-nitroquinoline-1-oxide in SOS-chromotest.
        Syst Appl Microbiol. 2002; 25: 483-490
        • Laparra J.M.
        • Glahn R.P.
        • Miller D.D.
        Assessing potential effects of inulin and probiotic bacteria on Fe availability from common beans (Phaseolus vulgaris L.) to Caco-2 cells.
        J Food Sci. 2009; 74: H40-H46
        • Makras L.
        • Triantafyllou V.
        • Fayol-Messaoudi D.
        • Adriany T.
        • Zoumpopoulou G.
        • Tsakalidou E.
        • Servin A.
        • De Vuyst L.
        Kinetic analysis of the antibacterial activity of probiotic lactobacilli towards Salmonella enterica serovar Typhimurium reveals a role for lactic acid and other inhibitory compounds.
        Res Microbiol. 2006; 157: 241-247
        • Lundin A.
        • Bok C.M.
        • Aronsson L.
        • Bjorkholm B.
        • Gustafsson J.A.
        • Pott S.
        • Arulampalam V.
        • Hibberd M.
        • Rafter J.
        • Pettersson S.
        Gut flora, Toll-like receptors and nuclear receptors: a tripartite communication that tunes innate immunity in large intestine.
        Cell Microbiol. 2008; 10: 1093-1103
        • Nandakumar N.S.
        • Pugazhendhi S.
        • Ramakrishna B.S.
        Effects of enteropathogenic bacteria & lactobacilli on chemokine secretion & Toll like receptor gene expression in two human colonic epithelial cell lines.
        Indian J Med Res. 2009; 130: 170-178
        • Paolillo R.
        • Romano Carratelli C.
        • Sorrentino S.
        • Mazzola N.
        • Rizzo A.
        Immunomodulatory effects of Lactobacillus plantarum on human colon cancer cells.
        Int Immunopharmacol. 2009; 9: 1265-1271
        • Seya T.
        • Funami K.
        • Taniguchi M.
        • Matsumoto M.
        Antibodies against human Toll-like receptors (TLRs): TLR distribution and localization in human dendritic cells.
        J Endotoxin Res. 2005; 11: 369-374
        • Al-Sadi R.
        • Guo S.
        • Ye D.
        • Dokladny K.
        • Alhmoud T.
        • Ereifej L.
        • Said H.M.
        • Ma T.Y.
        Mechanism of IL-1beta modulation of intestinal epithelial barrier involves p38 kinase and activating transcription factor-2 activation.
        J Immunol. 2013; 190: 6596-6606
        • Al-Sadi R.
        • Guo S.
        • Dokladny K.
        • Smith M.A.
        • Ye D.
        • Kaza A.
        • Watterson D.M.
        • Ma T.Y.
        Mechanism of interleukin-1beta induced-increase in mouse intestinal permeability in vivo.
        J Interferon Cytokine Res. 2012; 32: 474-484
        • Iwaya H.
        • Maeta K.
        • Hara H.
        • Ishizuka S.
        Mucosal permeability is an intrinsic factor in susceptibility to dextran sulfate sodium-induced colitis in rats.
        Exp Biol Med (Maywood). 2012; 237: 451-460
        • Madsen K.L.
        Inflammatory bowel disease: lessons from the IL-10 gene-deficient mouse.
        Clin Invest Med. 2001; 24: 250-257
        • Mankertz J.
        • Schulzke J.D.
        Altered permeability in inflammatory bowel disease: pathophysiology and clinical implications.
        Curr Opin Gastroenterol. 2007; 23: 379-383
        • Jost T.
        • Lacroix C.
        • Braegger C.
        • Chassard C.
        Impact of human milk bacteria and oligosaccharides on neonatal gut microbiota establishment and gut health.
        Nutr Rev. 2015; 73: 426-437
        • Bengmark S.
        Colonic food: pre- and probiotics.
        Am J Gastroenterol. 2000; 95: S5-S7
        • Barbara G.
        • Zecchi L.
        • Barbaro R.
        • Cremon C.
        • Bellacosa L.
        • Marcellini M.
        • De Giorgio R.
        • Corinaldesi R.
        • Stanghellini V.
        Mucosal permeability and immune activation as potential therapeutic targets of probiotics in irritable bowel syndrome.
        J Clin Gastroenterol. 2012; 46: S52-S55
        • Cucchiara S.
        • Falconieri P.
        • Di Nardo G.
        • Parcelii M.A.
        • Dito L.
        • Grandinetti A.
        New therapeutic approach in the management of intestinal disease: probiotics in intestinal disease in paediatric age.
        Dig Liver Dis. 2002; 34: S44-S47
        • Dai C.
        • Zhao D.H.
        • Jiang M.
        VSL#3 probiotics regulate the intestinal epithelial barrier in vivo and in vitro via the p38 and ERK signaling pathways.
        Int J Mol Med. 2012; 29: 202-208
        • Madsen K.
        • Cornish A.
        • Soper P.
        • McKaigney C.
        • Jijon H.
        • Yachimec C.
        • Doyle J.
        • Jewell L.
        • De Simone C.
        Probiotic bacteria enhance murine and human intestinal epithelial barrier function.
        Gastroenterology. 2001; 121: 580-591
        • Mennigen R.
        • Nolte K.
        • Rijcken E.
        • Utech M.
        • Loeffler B.
        • Senninger N.
        • Bruewer M.
        Probiotic mixture VSL#3 protects the epithelial barrier by maintaining tight junction protein expression and preventing apoptosis in a murine model of colitis.
        Am J Physiol Gastrointest Liver Physiol. 2009; 296: G1140-G1149
        • Albertini B.
        • Vitali B.
        • Passerini N.
        • Cruciani F.
        • Di Sabatino M.
        • Rodriguez L.
        • Brigidi P.
        Development of microparticulate systems for intestinal delivery of Lactobacillus acidophilus and Bifidobacterium lactis.
        Eur J Pharm Sci. 2010; 40: 359-366
        • Martin F.P.
        • Sprenger N.
        • Montoliu I.
        • Rezzi S.
        • Kochhar S.
        • Nicholson J.K.
        Dietary modulation of gut functional ecology studied by fecal metabonomics.
        J Proteome Res. 2010; 9: 5284-5295
        • Swerdlow M.P.
        • Kennedy D.R.
        • Kennedy J.S.
        • Washabau R.J.
        • Henthorn P.S.
        • Moore P.F.
        • Carding S.R.
        • Felsburg P.J.
        Expression and function of TLR2, TLR4, and Nod2 in primary canine colonic epithelial cells.
        Vet Immunol Immunopathol. 2006; 114: 313-319
        • Wells J.M.
        • Rossi O.
        • Meijerink M.
        • van Baarlen P.
        Epithelial crosstalk at the microbiota-mucosal interface.
        Proc Natl Acad Sci U S A. 2011; 108: 4607-4614
        • Aoyama T.
        • Paik Y.H.
        • Seki E.
        Toll-like receptor signaling and liver fibrosis.
        Gastroenterol Res Pract. 2010; 2010: 192543
        • Carvalho F.A.
        • Aitken J.D.
        • Gewirtz A.T.
        • Vijay-Kumar M.
        TLR5 activation induces secretory interleukin-1 receptor antagonist (sIL-1Ra) and reduces inflammasome-associated tissue damage.
        Mucosal Immunol. 2011; 4: 102-111
        • Chen L.W.
        • Chang W.J.
        • Chen P.H.
        • Liu W.C.
        • Hsu C.M.
        TLR ligand decreases mesenteric ischemia and reperfusion injury-induced gut damage through TNF-alpha signaling.
        Shock. 2008; 30: 563-570
        • Ferwerda G.
        • Girardin S.E.
        • Kullberg B.J.
        • Le Bourhis L.
        • de Jong D.J.
        • Langenberg D.M.
        • van Crevel R.
        • Adema G.J.
        • Ottenhoff T.H.
        • Van der Meer J.W.
        • Netea M.G.
        NOD2 and toll-like receptors are nonredundant recognition systems of Mycobacterium tuberculosis.
        PLoS Pathog. 2005; 1: 279-285
        • Cario E.
        Barrier-protective function of intestinal epithelial Toll-like receptor 2.
        Mucosal Immunol. 2008; 1: S62-S66
        • Schenk M.
        • Belisle J.T.
        • Modlin R.L.
        TLR2 looks at lipoproteins.
        Immunity. 2009; 31: 847-849
        • Kang J.Y.
        • Lee J.O.
        Structural biology of the Toll-like receptor family.
        Annu Rev Biochem. 2011; 80: 917-941
        • Motoi Y.
        • Shibata T.
        • Takahashi K.
        • Kanno A.
        • Murakami Y.
        • Li X.
        • Kasahara T.
        • Miyake K.
        Lipopeptides are signaled by Toll-like receptor 1, 2 and 6 in endolysosomes.
        Int Immunol. 2014; 26: 563-573
        • Matsumoto C.
        • Oda T.
        • Yokoyama S.
        • Tominari T.
        • Hirata M.
        • Miyaura C.
        • Inada M.
        Toll-like receptor 2 heterodimers, TLR2/6 and TLR2/1 induce prostaglandin E production by osteoblasts, osteoclast formation and inflammatory periodontitis.
        Biochem Biophys Res Commun. 2012; 428: 110-115
        • Chang J.H.
        • Shim Y.Y.
        • Cha S.K.
        • Chee K.M.
        Probiotic characteristics of lactic acid bacteria isolated from kimchi.
        J Appl Microbiol. 2010; 109: 220-230
        • Rao Y.X.
        • Chen J.
        • Chen L.L.
        • Gu W.Z.
        • Shu X.L.
        [Changes in tight junction protein expression and permeability of colon mucosa in rats with dextran sulfate sodium-induced inflammatory bowel disease].
        Zhongguo Dang Dai Er Ke Za Zhi. 2012; 14: 976-981
        • Poritz L.S.
        • Garver K.I.
        • Green C.
        • Fitzpatrick L.
        • Ruggiero F.
        • Koltun W.A.
        Loss of the tight junction protein ZO-1 in dextran sulfate sodium induced colitis.
        J Surg Res. 2007; 140: 12-19