Skip to main content
Log in

Three-tissue microphysiological system for studying inflammatory responses in gut-liver Axis

  • Published:
Biomedical Microdevices Aims and scope Submit manuscript

Abstract

The interaction between the gut and the liver, often known as the gut-liver axis, play crucial roles in modulating the body’s responses to the xenobiotics as well as progression of diseases. Dysfunction of the axis can cause metabolic disorders as well as obesity, diabetes, and fatty liver disease. During the progression of such diseases, inflammatory responses involving the immune system also play an important part. In this study, we developed a three-tissue microphysiological system (MPS) that can accommodate three different cell types in separated compartments connected via fluidic channels in a microfluidic device. Using computational fluid dynamics, geometry of fluidic channels and flow conditions were optimized for seeding and culturing different cell types in the three-tissue MPS. Caco-2 (gut), RAW264.7 (immune), and HepG2 (liver) cells were seeded and cultured in the chip. Stimulation of the gut cells in the MPS with lipopolysaccharide (LPS) resulted in induction of inflammatory response and production of nitric oxide (NO) in all connected chambers. The anti-inflammatory effect of luteolin was demonstrated. Our study demonstrates that the three-tissue MPS can recapitulate the inflammatory responses involving the gut, liver and immune cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • D. Adawi, G. Molin, B. Jeppsson, HPB (Oxford) 1(4), 173–186 (1999)

    Google Scholar 

  • A. Ahluwalia, A. Misto, F. Vozzi, C. Magliaro, G. Mattei, M.C. Marescotti, A. Avogaro, E. Iori, PLoS One 13(2), e0192824 (2018)

    Google Scholar 

  • S. Akira, K. Takeda, T. Kaisho, Nat. Immunol. 2(8), 675 (2001)

    Google Scholar 

  • G. Arango Duque, A. Descoteaux, Front. Immunol. 5, 491 (2014)

    Google Scholar 

  • Y. Belkaid, T.W. Hand, Cell 157(1), 121–141 (2014)

    Google Scholar 

  • C. Chelakkot, J. Ghim, S.H. Ryu, Exp. Mol. Med. 50(8), 1–9 (2018)

    Google Scholar 

  • L. Chen, H. Deng, H. Cui, J. Fang, Z. Zuo, J. Deng, Y. Li, X. Wang, L. Zhao, Oncotarget 9(6), 7204 (2018)

    Google Scholar 

  • L. Chen, Y. Zhang, X. Kong, S. Peng, J. Tian, Bioorg. Med. Chem. Lett. 17(11), 2979–2982 (2007)

    Google Scholar 

  • W.L. Chen, C. Edington, E. Suter, J. Yu, J.J. Velazquez, J.G. Velazquez, M. Shockley, E.M. Large, R. Venkataramanan, D.J. Hughes, Biotechnol. Bioeng. 114(11), 2648–2659 (2017)

    Google Scholar 

  • M. Chi, B. Yi, S. Oh, D.-J. Park, J.H. Sung, S. Park, Biomed. Microdevices 17(3), 58 (2015)

    Google Scholar 

  • H. Chiao, S. Foster, R. Thomas, J. Lipton, R.A. Star, J. Clin, Invest. 97(9), 2038–2044 (1996)

    Google Scholar 

  • A. Choe, S.K. Ha, I. Choi, N. Choi, J.H. Sung, Biomed. Microdevices 19(1), 4 (2017)

    Google Scholar 

  • K.W. Chung, E.K. Lee, D.H. Kim, H.J. An, N.D. Kim, D.S. Im, J. Lee, B.P. Yu, H.Y. Chung, Aging Cell 14(4), 524–533 (2015)

    Google Scholar 

  • D. Compare, P. Coccoli, A. Rocco, O. Nardone, S. De Maria, M. Cartenì, G. Nardone, Nutr. Metab. Cardiovasc. Dis. 22(6), 471–476 (2012)

    Google Scholar 

  • M. Conlon, A. Bird, Nutrients 7(1), 17–44 (2015)

    Google Scholar 

  • T. Courau, J. Bonnereau, J. Chicoteau, H. Bottois, R. Remark, L.A. Miranda, A. Toubert, M. Blery, T. Aparicio, M. Allez, J. Immunother. Cancer 7(1), 74 (2019)

    Google Scholar 

  • J.K. Dowman, J. Tomlinson, P. Newsome, QJM 103(2), 71–83 (2009)

    Google Scholar 

  • J. Edmison, A.J. McCullough, Clin. Liver Dis. 11(1), 75–104 (2007)

    Google Scholar 

  • C.J. Edwards, J. Rheumatol. 35(8), 1477–1479 (2008)

    Google Scholar 

  • S.M.A. El-Kader, E.M.S. El-Den Ashmawy, World J. Hepatol. 7(6), 846 (2015)

    Google Scholar 

  • H. Fang, R.A. Pengal, X. Cao, L.P. Ganesan, M.D. Wewers, C.B. Marsh, S. Tridandapani, J. Immunol. 173(1), 360–366 (2004)

    Google Scholar 

  • R.M. Forsythe, D.Z. Xu, Q. Lu, E.A. Deitch, Shock 17(3), 180–184 (2002)

    Google Scholar 

  • H. Fukui, World J. Hepatol. 7(3), 425 (2015)

    Google Scholar 

  • Y. Gao, N.R. Hannan, S. Wanyonyi, N. Konstantopolous, J. Pagnon, H.C. Feng, J.B. Jowett, K.-H. Kim, K. Walder, G.R. Collier, Cytokine 33(5), 246–251 (2006)

    Google Scholar 

  • I. García-Ruiz, P. Solís-Muñoz, D. Fernández-Moreira, T. Muñoz-Yagüe, J.A. Solís-Herruzo, Dis. Model. Mech. 8(2), 183–191 (2015)

    Google Scholar 

  • U.C. Ghoshal, R. Shukla, U. Ghoshal, Gut Liver 11(2), 196 (2017)

    Google Scholar 

  • V. Giannelli, V. Di Gregorio, V. Iebba, M. Giusto, S. Schippa, M. Merli, U. Thalheimer, World J. Gastroenterol. 20(45), 16795 (2014)

    Google Scholar 

  • M.J. Gomez-Lechon, M.T. Donato, A. Martínez-Romero, N. Jiménez, J.V. Castell, J.-E. O’Connor, Chem.-Biol. Interact 165(2), 106–116 (2007)

    Google Scholar 

  • C.M. Guinane, P.D. Cotter, Ther. Adv. Gastroenterol. 6(4), 295–308 (2013)

    Google Scholar 

  • S. Guo, R. Al-Sadi, H.M. Said, T.Y. Ma, Am. J. Pathol. 182(2), 375–387 (2013)

    Google Scholar 

  • C. Hu, D.D. Kitts, Mol. Cell. Biochem. 265(1–2), 107–113 (2004)

    Google Scholar 

  • B. Hyun, S. Shin, A. Lee, S. Lee, Y. Song, N.-J. Ha, K.-H. Cho, K. Kim, Immune Netw. 13(4), 123–132 (2013)

    Google Scholar 

  • K. Kanazawa, M. Uehara, H. Yanagitani, T. Hashimoto, Arch. Biochem. Biophys. 455(2), 197–203 (2006)

    Google Scholar 

  • K. Kazankov, S.M.D. Jørgensen, K.L. Thomsen, H.J. Møller, H. Vilstrup, J. George, D. Schuppan, H. Grønbæk, Nat. Rev. Gastroenterol. Hepatol. 16(3), 145–159 (2018)

    Google Scholar 

  • Z.Y. Kho, S.K. Lal, Front. Microbiol. 9, 1835 (2018)

    Google Scholar 

  • D. Kiefer, L. Ali-Akbarian, Altern. Ther. Health Med 10(3), 22–30 (2004)

    Google Scholar 

  • H.J. Kim, D. Huh, G. Hamilton, D.E. Ingber, Lab Chip 12(12), 2165–2174 (2012)

    Google Scholar 

  • S.H. Kim, J.W. Lee, I. Choi, Y.C. Kim, J.B. Lee, J.H. Sung, J. Nanosci, Nanotechnol. 13(11), 7220–7228 (2013)

    Google Scholar 

  • G. Kolios, Z. Brown, R.L. Robson, D.A. Robertson, J. Westwick, Br. J. Pharmacol. 116(7), 2866–2872 (1995)

    Google Scholar 

  • P. Konturek, I. Harsch, K. Konturek, M. Schink, T. Konturek, M. Neurath, Y. Zopf, Medical Sciences 6(3), 79 (2018)

    Google Scholar 

  • O. Kutlu, H.N. Kaleli, E. Ozer, Can. J. Gastroenterol. Hepatol. 2018, 8543763 (2018)

    Google Scholar 

  • M. Lara, C.Y. Chen, P. Mannor, O. Dur, P.G. Menon, A.P. Yoganathan, K. Pekkan, Ann. Biomed. Eng. 39(9), 2398 (2011)

    Google Scholar 

  • D.W. Lee, S.K. Ha, I. Choi, J.H. Sung, Biomed. Microdevices 19(4), 100 (2017a)

    Google Scholar 

  • H. Lee, D.S. Kim, S.K. Ha, I. Choi, J.M. Lee, J.H. Sung, Biotechnol. Bioeng. 114(2), 432–443 (2017b)

    Google Scholar 

  • J.B. Lee, J.H. Sung, Biotechnol. J. 8(11), 1258–1266 (2013)

    Google Scholar 

  • S.H. Lee, S.K. Ha, I. Choi, N. Choi, T.H. Park, J.H. Sung, Biotechnol. J. 11(6), 746–756 (2016)

    Google Scholar 

  • S.H. Lee, J.H. Sung, Adv. Healthc. Mater. 7(2), 1700419 (2018a)

    Google Scholar 

  • S.Y. Lee, J.H. Sung, Biotechnol. Bioeng. 115(11), 2817–2827 (2018b)

    Google Scholar 

  • R. Lentle, P. Janssen, J. Comp, Physiol. 178(6), 673–690 (2008)

    Google Scholar 

  • N. Levy, Int. J. Stroke 7(5), 440–442 (2012)

    Google Scholar 

  • C. Liu, A. Li, Y.B. Weng, M.L. Duan, B.E. Wang, S.W. Zhang, World J. Gastroenterol. 15(46), 5843–5850 (2009)

    Google Scholar 

  • J.F. Liu, Y. Ma, Y. Wang, Z.Y. Du, J.K. Shen, H.L. Peng, Phytother. Res. 25(4), 588–596 (2011)

    Google Scholar 

  • C.J. Lowenstein, E.W. Alley, P. Raval, A.M. Snowman, S.H. Snyder, S.W. Russell, W.J. Murphy, Proc. Natl. Acad. Sci. U. S. A. 90(20), 9730–9734 (1993)

    Google Scholar 

  • S.M. Lucas, N.J. Rothwell, R.M. Gibson, Br. J. Pharmacol. 147(S1), S232–S240 (2006)

    Google Scholar 

  • J. Luther, J.J. Garber, H. Khalili, M. Dave, S.S. Bale, R. Jindal, D.L. Motola, S. Luther, S. Bohr, S.W. Jeoung, Cell. Mol. Gastroenterol. Hepatol. 1(2), 222–232. e222 (2015)

  • M.N. Martinez, The AAPS Journal 13(4), 632–649 (2011)

  • I. Maschmeyer, A.K. Lorenz, K. Schimek, T. Hasenberg, A.P. Ramme, J. Hübner, M. Lindner, C. Drewell, S. Bauer, A. Thomas, Lab Chip 15(12), 2688–2699 (2015)

    Google Scholar 

  • C. Mengus, M.G. Muraro, V. Mele, F. Amicarella, C. Manfredonia, F. Foglietta, S. Muenst, S.D. Soysal, G. Iezzi, G.C. Spagnoli, ACS Biomater. Sci. Eng. 4(2), 314–323 (2017)

    Google Scholar 

  • A. Michielan, R. D’Incà, Mediat. Inflamm. 2015, 628157 (2015)

    Google Scholar 

  • L. Miele, V. Valenza, G. La Torre, M. Montalto, G. Cammarota, R. Ricci, R. Masciana, A. Forgione, M.L. Gabrieli, G. Perotti, Hepatology 49(6), 1877–1887 (2009)

    Google Scholar 

  • R. Milo, P. Jorgensen, U. Moran, G. Weber, M. Springer, Nucleic Acids Res. 38(suppl_1), D750-D753 (2009)

  • S. Mörkl, S. Lackner, A. Meinitzer, H. Mangge, M. Lehofer, B. Halwachs, G. Gorkiewicz, K. Kashofer, A. Painold, A. Holl, Eur. J. Nutr. 57(8), 2985–2997 (2018)

    Google Scholar 

  • Q. Mu, J. Kirby, C.M. Reilly, X.M. Luo, Front. Immunol. 8, 598 (2017)

    Google Scholar 

  • B.P. Mulhall, J.P. Ong, Z.M. Younossi, J. Gastroenterol, Hepatol. 17(11), 1136–1143 (2002)

    Google Scholar 

  • M. Nikolic, T. Sustersic, N. Filipovic, Front Bioeng. Biotechnol. 6, 120 (2018)

    Google Scholar 

  • Y. Nishitani, K. Yamamoto, M. Yoshida, T. Azuma, K. Kanazawa, T. Hashimoto, M. Mizuno, Biofactors 39(5), 522–533 (2013)

    Google Scholar 

  • S.Y. Park, G.E. Ji, Y.T. Ko, H.K. Jung, Z. Ustunol, J.J. Pestka, Int. J. Food Microbiol. 46(3), 231–241 (1999)

    Google Scholar 

  • M.G. Pike, R.J. Heddle, P. Boulton, M.W. Turner, D.J. Atherton, J. Invest, Dermatol. 86(2), 101–104 (1986)

    Google Scholar 

  • M. Pinto, Biol. Cell. 47, 323–330 (1983)

    Google Scholar 

  • K. Ray, Nat. Rev. Gastroenterol. Hepatol. 12(3), 123 (2015)

    Google Scholar 

  • Y.S. Seo, V.H. Shah, Clin. Mol. Hepatol. 18(4), 337 (2012)

    Google Scholar 

  • J.H. Sung, C. Kam, M.L. Shuler, Lab Chip 10(4), 446–455 (2010)

    Google Scholar 

  • J.H. Sung, J. Koo, M.L. Shuler, Biochip J. 13, 115–126 (2019)

    Google Scholar 

  • J.H. Sung, M.L. Shuler, Ann. Biomed. Eng. 40(6), 1289–1300 (2012)

    Google Scholar 

  • J.H. Sung, Y.I. Wang, N. Narasimhan Sriram, M. Jackson, C. Long, J.J. Hickman, M.L. Shuler, Anal. Chem. 91(1), 330–351 (2018)

    Google Scholar 

  • T. Takiishi, C.I.M. Fenero, N.O.S. Câmara, Tissue Barriers 5(4), e1373208 (2017)

    Google Scholar 

  • T. Tanoue, Y. Nishitani, K. Kanazawa, T. Hashimoto, M. Mizuno, Biochem. Biophys. Res. Commun. 374(3), 565–569 (2008)

    Google Scholar 

  • L. Tao, T.A. Reese, Trends Immunol. 38(3), 181–193 (2017)

    Google Scholar 

  • K. Te Sligte, I. Bourass, J. Sels, A. Driessen, R. Stockbrűgger, G. Koek, Eur. J. Intern. Med. 15(1), 10–21 (2004)

    Google Scholar 

  • X. Wang, P.J. Quinn, Endotoxins: Structure, Function and Recognition, 1st edn. (Springer, Dordrecht, 2010), pp. 3–25

    Google Scholar 

  • T.M. Wassenaar, K. Zimmermann, Eur. J. Microbiol. Immunol. 8(3), 63–69 (2018)

    Google Scholar 

  • A. Wigg, I. Roberts-Thomson, R. Dymock, P. McCarthy, R. Grose, A. Cummins, Gut 48(2), 206–211 (2001)

    Google Scholar 

  • A. Xagorari, C. Roussos, A. Papapetropoulos, Br. J. Pharmacol. 136(7), 1058–1064 (2002)

    Google Scholar 

  • Y. Xia, G.M. Whitesides, Annu. Rev. Mater. Res. 28(1), 153–184 (1998)

    Google Scholar 

  • L.C.H. Yu, A.N. Flynn, J.R. Turner, A.G. Buret, FASEB J. 19(13), 1822–1835 (2005)

    Google Scholar 

  • C. Zhu, P. Xie, F. Zhao, L. Zhang, W. An, Y. Zhan, Int. J. Clin. Exp. Pathol. 7(10), 6807 (2014)

    Google Scholar 

Download references

Acknowledgments

This work was supported by National Research Foundation of Korea (Basic Research Lab, 2019R1A4A1025958), and Hongik University Research Fund. This work was also supported by the Technology Innovation Program funded by the Ministry of Trade, Industry & Energy (MOTIE), Republic of Korea (20008414, Development of intestine-liver-kidney multiorgan tissue chip mimicking absorption distribution metabolism excretion of drug), Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2018R1A6A1A03024231), the Ministry of Science and ICT (MSIT) (2018R1C1B5085757).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Seung Hwan Lee or Jong Hwan Sung.

Ethics declarations

Conflict of interest

The authors declare no financial or commercial conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jeon, Jw., Choi, N., Lee, S.H. et al. Three-tissue microphysiological system for studying inflammatory responses in gut-liver Axis. Biomed Microdevices 22, 65 (2020). https://doi.org/10.1007/s10544-020-00519-y

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s10544-020-00519-y

Keywords

Navigation