Cefdinir Microsphere Modulated Microflora and Liver Immunological Response to Diet Induced Diabetes in Mice

Author(s): Sweta Patel , Dipeeka Mandaliya , Bhumika Prajapati , Sunny Kumar , Sriram Seshadri* .

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets

Volume 19 , Issue 3 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Objective: Gut microbiota is currently targeted for various diseases especially metabolic disorders such as diabetes. Our strategy is to alter gut microflora via specific antibiotic to reduce load of inflammation in the liver that increases as a result of high carbohydrate diet. Th1, Th17 and Treg are important immune cell types which decide the type of inflammatory response. Liver is tolerogenic in nature with low Th17/Treg ratio. In diabetics, this ratio decreases even more, and can cause liver trauma.

Method: The present study tries to find relationship between gut flora and immune cells such as Th1/Th17/Treg and their role in liver metabolism using diet induced diabetic mice model.

Result: Upon alteration of flora using Cefdinir in different forms, one could help lower the level of Treg cells thus increasing the ratio. Gut flora is strongly associated with the immunity in the liver. Targeted alteration of gut flora helps us to restore insulin sensitivity.

Conclusion: Colon targeted Cefdinir gives more promising results, opens colonic bacteria as target for improving gut, liver inflammation and insulin sensitivity.

Keywords: Diabetes, inflammation, Th1/Th17/Treg cells, gut microflora, cefdinir, high carbohydrate diet.

[1]
Herman, M.A.; Kahn, B.B. Glucose transport and sensing in the maintenance of glucose homeostasis and metabolic harmony. J. Clin. Invest., 2006, 116(7), 1767-1775.
[2]
Wu, C.C.; Sytwu, H.K.; Lu, K.C.; Lin, Y.F. Role of T cells in type 2 diabetic nephropathy. Exp. Diabetes Res., 2011, 2011, 514738.
[3]
Shoelson, S.E.; Lee, J.; Goldfine, A.B. Inflammation and insulin resistance. J. Clin. Invest., 2006, 116(7), 1793-1801.
[4]
Kahn, S.E.; Cooper, M.E.; Del, P.S. Pathophysiology and treatment of type 2 diabetes: Perspectives on the past, present and future. Lancet, 2014, 383(9922), 1068-1083.
[5]
Kubaszek, A.; Pihlajamäki, J.; Komarovski, V.; Lindi, V.; Lindström, J.; Eriksson, J.; Timo, T.V.; Helena, H.; Pirjo, I.P.; Sirkka, K.; Jaakko, T.; Matti, U.; Markku, L. Promoter polymorphisms of the TNF-α (G-308A) and IL-6 (C-174G) genes predict the conversion from impaired glucose tolerance to Type 2 diabetes: The finnish diabetes prevention study. Diabetes, 2003, 52(7), 1872-1876.
[6]
Van Beelen, A.J.; Zelinkova, Z.; Taanman-Kueter, E.W.; Muller, F.J.; Hommes, D.W.; Zaat, S.A.; Kapsenberg, M.L.; de Jong, E.C. Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells. Immunity, 2007, 27(4), 660-669.
[7]
Ilan, Y.; Maron, R.; Tukpah, A.M.; Maioli, T.U.; Murugaiyan, G.; Yang, K.; Wu, H.Y.; Weiner, H.L. Induction of regulatory T cells decreases adipose inflammation and alleviates insulin resistance in ob/ob mice. Proc. Natl. Acad. Sci., 2010, 107(21), 9765-9770.
[8]
Knoll, P.; Schlaak, J.; Uhrig, A.; Kempf, P.; zum Büschenfelde, K-H.M.; Gerken, G. Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge. J. Hepatol., 1995, 22, 226-229.
[9]
Horst, A.K.; Neumann, K.; Diehl, L.; Tiegs, G. Modulation of liver tolerance by conventional and nonconventional antigen-presenting cells and regulatory immune cells. Cell. Mol. Immunol., 2016, 13(3), 277-292.
[10]
Robinson, M.W.; Harmon, C.; O’Farrelly, C. Liver immunology and its role in inflammation and homeostasis. Cell. Mol. Immunol., 2016, 13(3), 267-276.
[11]
Jena, P.K.; Singh, S.; Prajapati, B.; Nareshkumar, G.; Mehta, T.; Seshadri, S. Impact of targeted specific antibiotic delivery for gut microbiota modulation on high-fructose-fed rats. Appl. Biochem. Biotechnol., 2014, 72(8), 3810-3826.
[12]
Prajapati, B.; Jena, P.K.; Mehta, T.; Seshadri, S. Preparation and optimization of moxifloxacin microspheres for colon targeted delivery using quality by design approach: In vitro and in vivo study. Curr. Drug Deliv., 2016, 13(7), 1021-1033.
[13]
Patel, H.; Yadav, N.; Parmar, R.; Patel, S.; Singh, A.P.; Shrivastava, N.; Dalai, S.K. Frequent inoculations with radiation attenuated sporozoite is essential for inducing sterile protection that correlates with a threshold level of Plasmodia liver-stage specific CD8 + T cells. Cell. Immunol., 2017, 317, 48-54.
[14]
Cani, P.D.; Bibiloni, R.; Knauf, C.; Waget, A.; Neyrinck, A.M.; Delzenne, N.M.; Burcelin, R. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes, 2008, 57(6), 1470-1481.
[15]
Garidou, L.; Pomié, C.; Klopp, P.; Waget, A.; Charpentier, J.; Aloulou, M.; Giry, A.; Serino, M.; Stenman, L.; Lahtinen, S.; Dray, C. The gut microbiota regulates intestinal CD4 T cells expressing RORγt and controls metabolic disease. Cell Metab., 2015, 22(1), 100-112.
[16]
Zeng, C.; Shi, X.; Zhang, B.; Liu, H.; Zhang, L.; Ding, W.; Zhao, Y. The imbalance of Th17/Th1/Tregs in patients with type 2 diabetes: Relationship with metabolic factors and complications. J. Mol. Med., 2012, 90(2), 175-186.
[17]
Kawabe, T.; Sun, S.L.; Fujita, T.; Yamaki, S.; Asao, A.; Takahashi, T.; So, T.; Ishii, N. Homeostatic proliferation of naive CD4+ T cells in mesenteric lymph nodes generates gut-tropic Th17 cells. J. Immunol., 2013, 190, 5788-5798.
[18]
Cavallari, J.F.; Denou, E.; Foley, K.P.; Khan, W.I.; Schertzer, J.D. Different Th17 immunity in gut, liver, and adipose tissues during obesity: The role of diet, genetics, and microbes. Gut Microbes, 2016, 7, 82-89.
[19]
Min, Y.W.; Rhee, P.L. The role of microbiota on the gut immunology. Clin. Ther., 2015, 37(5), 968-975.
[20]
Ray, S.; De Salvo, C.; Pizarro, T.T. Central role of IL-17/Th17 immune responses and the gut microbiota in the pathogenesis of intestinal fibrosis. Curr. Opin. Gastroenterol., 2014, 30(6), 531-538.
[21]
Son, G.; Kremer, M.; Hines, I.N. Contribution of gut bacteria to liver pathobiology. Gastroenterol. Res. Pract., 2010, 2010, 1-13.
[22]
Dong, P.; Yang, Y.; Wang, W. The role of intestinal bifidobacteria on immune system development in young rats. Early Hum. Dev., 2010, 86(1), 51-58.
[23]
Ivanov, I.I.; de Llanos Frutos, R.; Manel, N.; Yoshinaga, K.; Rifkin, D.B.; Sartor, R.B.; Finlay, B.B.; Littman, D.R. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe, 2008, 4(4), 337-349.
[24]
Kolls, J.K.; Khader, S.A. The role of Th17 cytokines in primary mucosal immunity. Cytokine Growth Factor Rev., 2010, 21(6), 443-448.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 19
ISSUE: 3
Year: 2019
Page: [349 - 357]
Pages: 9
DOI: 10.2174/1871530319666181224122115
Price: $58

Article Metrics

PDF: 22
HTML: 3