Bacterial Translocation Is Linked to Increased Intestinal IFN-&#947;, IL-4, IL-17, and mucin-2 in Cholestatic Rats

Natali Vega-Magaña; Vidal Delgado-Rizo; Leonel García-Benavides; Susana del Toro-Arreola; Jorge Segura-Ortega; Adelaida Sara M Zepeda Morales; José Sergio Zepeda-Nuño; Marta Escarra-Senmarti; Jorge Gutiérrez-Franco; Jesse Haramati; Miriam R Bueno-Topete

2018, Number 2

Ann Hepatol 2018; 17 (2)

Bacterial Translocation Is Linked to Increased Intestinal IFN-γ, IL-4, IL-17, and mucin-2 in Cholestatic Rats

Vega-Magaña N, Delgado-Rizo V, García-Benavides L, del Toro-Arreola S, Segura-Ortega J, Zepeda MASM, Zepeda-Nuño JS, Escarra-Senmarti M, Gutiérrez-Franco J, Haramati J, Bueno-Topete MR

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ABSTRACT

Background and rationale for the study. Bacterial translocation is an important triggering factor of infection and mortality in cirrhosis. In a rat model using bile duct ligation (BDL), bacterial translocation appears within 24 h after ligation. The dynamic between TH1/TH2/TH17 cytokines and the integrity of the colonic mucosa in the context of cirrhosis is little known. This study aims to determine the link between bacterial translocation and intestinal inflammation in a cholestasis model. Additionally, alterations of the colonic mucus layer and the bacterial load were also addressed. Results. Bacterial translocation detected by microbiological cultures and MALDI-TOF showed that Escherichia coli predominates in mesenteric lymph nodes of BDL rats. Intestinal bacterial load analyzed by qPCR indicates a dramatic Escherichia/Shigella overgrowth at 8 and 30 days post-BDL. IFN-γ, IL-4, and IL-17 evaluated by Western blotting were increased at 8 and 30 days in the small intestine. In the colon, in contrast, only IFN-γ was significantly increased. The colonic mucus layer and mucin-2 expression determined by Alcian blue staining and immunohistochemistry surprisingly showed an increase in the mucus layer thickness related to increased mucin-2 expression during the entire process of liver damage. Hepatic enzymes, as well as collagen I, collagen III, TNF-α, and IL-6 liver gene expression were increased. In conclusion, bacterial overgrowth associated with bacterial translocation is linked to the over-expression of IFN-γ, IL-4, IL-17 and mucin-2. These molecules might facilitate the intestinal permeability through exacerbating the inflammatory process and disturbing tight junctions, leading to the perpetuation of the liver damage.

REFERENCES

Taneja SK, Dhiman RK. Prevention and management of bacterial infections in cirrhosis. Int J Hepatol 2011; 2011: 784540.
Elshaer D, Begun J. The role of barrier function, autophagy, and cytokines in maintaining intestinal homeostasis. Semin Cell Dev Biol 2016.
Soufli I, Toumi R, Rafa H, Touil-Boukoffa C. Overview of cytokines and nitric oxide involvement in immuno-pathogenesis of inflammatory bowel diseases. World J Gastrointest Pharmacol Ther 2016; 7(3): 353-60.
Lazarevic V, Glimcher LH. T-bet in disease. Nat Immunol 2011; 12(7): 597-606.
Allen JE, Sutherland TE. Host protective roles of type 2 immunity: parasite killing and tissue repair, flip sides of the same coin. Semin Immunol 2014; 26(4): 329-40.
Iwashita J, Sato Y, Sugaya H, Takahashi N, Sasaki H, Abe T. mRNA of MUC2 is stimulated by IL-4, IL-13 or TNF-alpha through a mitogen-activated protein kinase pathway in human colon cancer cells. Immunol Cell Biol 2003; 81(4): 275-82.
Oshima T, Miwa H, Joh T. Changes in the expression of claudins in active ulcerative colitis. J Gastroenterol Hepatol 2008; 23(Suppl. 2): S146-S150.
Wisner DM, Harris LR, Green CL, Poritz LS. Opposing regulation of the tight junction protein claudin-2 by interferon-gamma and interleukin-4. J Surg Res 2008; 144(1): 1-7.
Akdis M, Palomares O, van de Veen W, van Splunter M, Akdis CA. TH17 and TH22 cells: a confusion of antimicrobial response with tissue inflammation versus protection. J Allergy Clin Immunol 2012; 129(6): 1438-49-51.
Hirota K, Turner J-E, Villa M, Duarte JH, Demengeot J, Steinmetz OM, Stockinger B. Plasticity of Th17 cells in Peyer's patches is responsible for the induction of T cell-dependent IgA responses. Nat Immunol 2013; 14(4): 372-9.
Etzold S, Juge N. Structural insights into bacterial recognition of intestinal mucins. Curr Opin Struct Biol 2014; 28: 23-31.
Fouts DE, Torralba M, Nelson KE, Brenner DA, Schnabl B. Bacterial translocation and changes in the intestinal microbiome in mouse models of liver disease. J Hepatol 2012; 56(6): 1283-92.
Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, Denk H, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995; 22(6): 696-9.
Chinen T, Komai K, Muto G, Morita R, Inoue N, Yoshida H, Sekiya T, et al. Prostaglandin E2 and SOCS1 have a role in intestinal immune tolerance. Nat Commun 2011; 2: 190.
Erben U, Loddenkemper C, Doerfel K, Spieckermann S, Haller D, Heimesaat MM, Zeitz M, et al. A guide to histomorphological evaluation of intestinal inflammation in mouse models. Int J Clin Exp Pathol 2014; 7(8): 4557.
Ogata Y, Nishi M, Nakayama H, Kuwahara T, Ohnishi Y, Tashiro S. Role of bile in intestinal barrier function and its inhibitory effect on bacterial translocation in obstructive jaundice in rats. J Surg Res 2003; 115(1): 18-23.
Eutamene H, Lamine F, Chabo C, Theodorou V, Rochat F, Bergonzelli GE, Corthésy-Theulaz I, et al. Synergy between Lactobacillus paracasei and its bacterial products to counteract stress-induced gut permeability and sensitivity increase in rats. J Nutr 2007; 137(8): 1901-7.
Wiest R, Lawson M, Geuking M. Pathological bacterial translocation in liver cirrhosis. J Hepatol 2014; 60(1): 197-209.
Francés R, Zapater P, González-Navajas JM, Muñoz C, Caño R, Moreu R, Pascual S, et al. Bacterial DNA in patients with cirrhosis and noninfected ascites mimics the soluble immune response established in patients with spontaneous bacterial peritonitis. Hepatology 2008; 47(3): 978-85.
Ridlon JM, Alves JM, Hylemon PB, Bajaj JS. Cirrhosis, bile acids and gut microbiota: unraveling a complex relationship. Gut Microbes 2013; 4(5): 382-7.
Kordzaya DJ, Goderdzishvili VT. Bacterial translocation in obstructive jaundice in rats: role of mucosal lacteals. Eur J Surg 2000; 166(5): 367-74.
Cui X, Shan X, Qian J, Ji Q, Wang L, Wang X, Li M, et al. The suppressor of cytokine signaling SOCS1 promotes apoptosis of intestinal epithelial cells via p53 signaling in Crohn's disease. Exp Mol Pathol 2016; 101(1): 1-11.
Cortez VS, Colonna M. Diversity and function of group 1 innate lymphoid cells. Immunol Lett 2016.
Intlekofer AM, Takemoto N, Wherry EJ, Longworth SA, Northrup JT, Palanivel VR, Mullen A, et al. Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat Immunol 2005; 6(12): 1236-44.
Harmon C, Robinson MW, Fahey R, Whelan S, Houlihan DD, Geoghegan J, O'Farrelly C, et al. Tissue-resident Eomes(hi) T-bet(lo) CD56(bright) NK cells with reduced proinflammatory potential are enriched in the adult human liver. Eur J Immunol 2016; 46(9): 2111-20.
Li Q, Zhang Q, Wang M, Zhao S, Ma J, Luo N, Li N, et al. Interferon- gamma and tumor necrosis factor-alpha disrupt epithelial barrier function by altering lipid composition in membrane microdomains of tight junction. Clin Immunol Orlando Fla 2008; 126(1): 67-80.
Meng J, Banerjee S, Li D, Sindberg GM, Wang F, Ma J, Roy S. Opioid Exacerbation of Gram-positive sepsis, induced by Gut Microbial Modulation, is Rescued by IL-17A Neutralization. Sci Rep 2015; 5: 10918.
Bergstrom KSB, Xia L. Mucin-type O-glycans and their roles in intestinal homeostasis. Glycobiology 2013; 23(9): 1026-37.
Hartmann P, Chen P, Wang HJ, Wang L, McCole DF, Brandl K, Stärkel P, et al. Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice. Hepatology 2013; 58(1): 108-19.
Grewal RK, Mahmood A. Ethanol induced changes in glycosylation of mucins in rat intestine. Ann Gastroenterol 2009; 22(3): 178-83.
Gäbele E, Dostert K, Hofmann C, Wiest R, Schölmerich J, Hellerbrand C, et al. DSS induced colitis increases portal LPS levels and enhances hepatic inflammation and fibrogenesis in experimental NASH. J Hepatol 2011; 55(6): 1391-9.
Zapater P, Gómez-Hurtado I, Peiró G, González-Navajas JM, García I, Giménez P, et al. Beta-Adrenergic Receptor 1 Selective Antagonism Inhibits Norepinephrine-Mediated TNF-Alpha Downregulation in Experimental Liver Cirrhosis. Jacobs R (Ed.). PLoS ONE 2012; 7(8): e43371.
Knittel T, Müller L, Saile B, Ramadori G. Effect of tumour necrosis factor-alpha on proliferation, activation and protein synthesis of rat hepatic stellate cells. J Hepatol 1997; 27(6): 1067-80.
Dranoff JA, Wells RG. Portal fibroblasts: Underappreciated mediators of biliary fibrosis. Hepatol Baltim Md 2010; 51(4): 1438-44.
Nieto N. Oxidative-stress and IL-6 mediate the fibrogenic effects of [corrected] Kupffer cells on stellate cells. Hepatol Baltim Md 2006; 44(6): 1487-501.