Oral administration of a recombinant cholera toxin B subunit promotes mucosal healing in the colon.
Cholera toxin B subunit (CTB) is a component of a licensed oral cholera vaccine. However, CTB has pleiotropic immunomodulatory effects whose impacts on the gut are not fully understood. Here, we found that oral administration in mice of a plant-made recombinant CTB (CTBp) significantly increased several immune cell populations in the colon lamina propria. Global gene expression analysis revealed that CTBp had more pronounced impacts on the colon than the small intestine, with significant activation of TGFβ-mediated pathways in the colon epithelium. The clinical relevance of CTBp-induced impacts on colonic mucosa was examined. In a human colon epithelial model using Caco2 cells, CTBp, but not the non-GM1-binding mutant G33D-CTBp, induced TGFβ-mediated wound healing. In a dextran sodium sulfate (DSS) acute colitis mouse model, oral administration of CTBp protected against colon mucosal damage as manifested by mitigated body weight loss, decreased histopathological scores, and blunted escalation of inflammatory cytokine levels while inducing wound healing-related genes. Furthermore, biweekly oral administration of CTBp significantly reduced disease severity and tumorigenesis in the azoxymethane/DSS model of ulcerative colitis and colon cancer. Altogether, these results demonstrate CTBp's ability to enhance mucosal healing in the colon, highlighting its potential application in ulcerative colitis therapy besides cholera vaccination.
Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA.
K J
KJ
Baldauf
Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA.|Owensboro Cancer Research Program of James Graham Brown Cancer Center at University of Louisville School of Medicine, Owensboro, Kentucky, USA.
J M
JM
Royal
Owensboro Cancer Research Program of James Graham Brown Cancer Center at University of Louisville School of Medicine, Owensboro, Kentucky, USA.
J C
JC
Kouokam
James Graham Brown Cancer Center, Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, USA.
B
B
Haribabu
James Graham Brown Cancer Center, Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, USA.
V R
VR
Jala
Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky, USA.
K
K
Yaddanapudi
Owensboro Cancer Research Program of James Graham Brown Cancer Center at University of Louisville School of Medicine, Owensboro, Kentucky, USA.|Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky, USA.
K T
KT
Hamorsky
Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky, USA.
G W
GW
Dryden
Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA.|Owensboro Cancer Research Program of James Graham Brown Cancer Center at University of Louisville School of Medicine, Owensboro, Kentucky, USA.
N
N
Matoba
D000284:Administration, Oral; D000818:Animals; D001397:Azoxymethane; D018938:Caco-2 Cells; D002771:Cholera / Q000276:immunology* / Q000517:prevention & control; D002772:Cholera Toxin / Q000276:immunology*; D022121:Cholera Vaccines / Q000276:immunology*; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000150:complications / Q000276:immunology*; D003106:Colon / Q000473:pathology*; D003110:Colonic Neoplasms / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009092:Mucous Membrane / Q000276:immunology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014945:Wound Healing
D022121:Cholera Vaccines; D016212:Transforming Growth Factor beta; D002772:Cholera Toxin; D016264:Dextran Sulfate; D001397:Azoxymethane