Lactobacillus pentosus strain S-PT84 improves steatohepatitis by maintaining gut permeability

in Journal of Endocrinology
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  • 1 Advanced Preventive Medical Sciences Research Center, Kanazawa University, Kanazawa, Japan
  • 2 Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
  • 3 Department of Biofunctional Science and Technology, Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima, Japan

Correspondence should be addressed to M Nagashimada: nakanaga@staff.kanazawa-u.ac.jp

*(Y Sakai and H Arie contributed equally to this work)

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Intestinal mucosal barrier dysfunction is closely related to the pathogenesis of nonalcoholic steatohepatitis (NASH). Gut immunity has been recently demonstrated to regulate gut barrier function. The Lactobacillus pentosus strain S-PT84 activates helper T cells and natural killer/natural killer T cells. In this study, we examined the effect of S-PT84 on NASH progression induced by high-cholesterol/high-fat diet (CL), focusing on the immune responses involved in gut barrier function. C57BL/6 mice were fed a normal chow or CL diet with or without 1 × 1010 S-PT84 for 22 weeks. S-PT84 administration improved hepatic steatosis by decreasing triglyceride and free fatty acid levels by 34% and 37%, respectively. Furthermore, S-PT84 inhibited the development of hepatic inflammation and fibrosis, suppressed F4/80+ macrophage/Kupffer cell infiltration, and reduced liver hydroxyproline content. Administration of S-PT84 alleviated hyperinsulinemia and enhanced hepatic insulin signalling. Compared with mice fed CL diet, mice fed CL+S-PT84 had 71% more CD11c-CD206+ M2 macrophages, resulting in a significantly decreased M1/M2 macrophage ratio in the liver. Moreover, S-PT84 inhibited the CL diet-mediated increase in intestinal permeability. Additionally, S-PT84 reduced the recruitment of interleukin-17-producing T cells and increased the levels of intestinal tight junction proteins, including zonula occludens-1, occludin, claudin-3, and claudin-7. In conclusion, our findings suggest that S-PT84 attenuates diet-induced insulin resistance and subsequent NASH development by maintaining gut permeability. Thus, S-PT84 represents a feasible approach to prevent the development of NASH.

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  • Arslan N 2014 Obesity, fatty liver disease and intestinal microbiota. World Journal of Gastroenterology 20 . (https://doi.org/10.3748/wjg.v20.i44.16452)

    • Search Google Scholar
    • Export Citation
  • Bischoff SC, Barbara G, Buurman W, Ockhuizen T, Schulzke JD, Serino M, Tilg H, Watson A & Wells JM 2014 Intestinal permeability – a new target for disease prevention and therapy. BMC Gastroenterology 14 189. (https://doi.org/10.1186/s12876-014-0189-7)

    • Search Google Scholar
    • Export Citation
  • Blaschitz C & Raffatellu M 2010 Th17 cytokines and the gut mucosal barrier. Journal of Clinical Immunology 30 . (https://doi.org/10.1007/s10875-010-9368-7)

    • Search Google Scholar
    • Export Citation
  • Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM & Chabo C 2007 Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56 . (https://doi.org/10.2337/db06-1491)

    • Search Google Scholar
    • Export Citation
  • Chen L, Zou Y, Peng J, Lu F, Yin Y, Li F & Yang J 2015 Lactobacillus acidophilus suppresses colitis-associated activation of the IL-23/Th17 axis. Journal of Immunology Research 2015 909514. (https://doi.org/10.1155/2015/909514)

    • Search Google Scholar
    • Export Citation
  • Clayburgh DR, Barrett TA, Tang Y, Meddings JB, Van Eldik LJ, Watterson DM, Clarke LL, Mrsny RJ & Turner JR 2005 Epithelial myosin light chain kinase-dependent barrier dysfunction mediates T cell activation-induced diarrhea in vivo. Journal of Clinical Investigation 115 . (https://doi.org/10.1172/JCI24970)

    • Search Google Scholar
    • Export Citation
  • Denning TL, Wang YC, Patel SR, Williams IR & Pulendran B 2007 Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nature Immunology 8 . (https://doi.org/10.1038/ni1511)

    • Search Google Scholar
    • Export Citation
  • Diehl AM & Day C 2017 Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis. New England Journal of Medicine 377 . (https://doi.org/10.1056/NEJMra1503519)

    • Search Google Scholar
    • Export Citation
  • Fotbolcu H & Zorlu E 2016 Nonalcoholic fatty liver disease as a multi-systemic disease. World Journal of Gastroenterology 22 . (https://doi.org/10.3748/wjg.v22.i16.4079)

    • Search Google Scholar
    • Export Citation
  • Friedman SL, Neuschwander-Tetri BA, Rinella M & Sanyal AJ 2018 Mechanisms of NAFLD development and therapeutic strategies. Nature Medicine 24 . (https://doi.org/10.1038/s41591-018-0104-9)

    • Search Google Scholar
    • Export Citation
  • Gonzalez-Mariscal L, Betanzos A, Nava P & Jaramillo BE 2003 Tight junction proteins. Progress in Biophysics and Molecular Biology 81 . (https://doi.org/10.1016/s0079-6107(0200037-8)

    • Search Google Scholar
    • Export Citation
  • Groschwitz KR & Hogan SP 2009 Intestinal barrier function: molecular regulation and disease pathogenesis. Journal of Allergy and Clinical Immunology 124 ; quiz . (https://doi.org/10.1016/j.jaci.2009.05.038)

    • Search Google Scholar
    • Export Citation
  • Izumo T, Izumi F, Nakagawa I, Kitagawa Y, Shibata H & Kiso Y 2011a Influence of Lactobacillus pentosus S-PT84 ingestion on the mucosal immunity of healthy and Salmonella Typhimurium-infected mice. Biosci Microflora 30 . (https://doi.org/10.12938/bifidus.30.27)

    • Search Google Scholar
    • Export Citation
  • Izumo T, Ida M, Maekawa T, Furukawa Y, Kitagawa Y & Kiso Y 2011b Comparison of the immunomodulatory effects of live and heat-killed Lactobacillus pentosus. Journal of Health Science 57 . (https://doi.org/10.1248/jhs.57.304)

    • Search Google Scholar
    • Export Citation
  • Izumo T, Maekawa T, Ida M, Kishi A, Akatani K, Kitagawa Y & Kiso Y 2011c Effect of Lactobacillus pentosus S-PT84 ingestion on IFN-alpha production from plasmacytoid dendritic cells by virus stimulation. Bioscience, Biotechnology, and Biochemistry 75 . (https://doi.org/10.1271/bbb.100696)

    • Search Google Scholar
    • Export Citation
  • Kazankov K, Jorgensen SMD, Thomsen KL, Moller HJ, Vilstrup H, George J, Schuppan D & Gronbaek H 2019 The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nature Reviews: Gastroenterology and Hepatology 16 . (https://doi.org/10.1038/s41575-018-0082-x)

    • Search Google Scholar
    • Export Citation
  • Kitade H, Sawamoto K, Nagashimada M, Inoue H, Yamamoto Y, Sai Y, Takamura T, Yamamoto H, Miyamoto K & Ginsberg HN 2012 CCR5 plays a critical role in obesity-induced adipose tissue inflammation and insulin resistance by regulating both macrophage recruitment and M1/M2 status. Diabetes 61 . (https://doi.org/10.2337/db11-1506)

    • Search Google Scholar
    • Export Citation
  • Koizumi S, Wakita D, Sato T, Mitamura R, Izumo T, Shibata H, Kiso Y, Chamoto K, Togashi Y & Kitamura H 2008 Essential role of toll-like receptors for dendritic cell and NK1.1(+) cell-dependent activation of type 1 immunity by Lactobacillus pentosus strain S-PT84. Immunology Letters 120 . (https://doi.org/10.1016/j.imlet.2008.06.003)

    • Search Google Scholar
    • Export Citation
  • Kremer M, Thomas E, Milton RJ, Perry AW, van Rooijen N, Wheeler MD, Zacks S, Fried M, Rippe RA & Hines IN 2010 Kupffer cell and interleukin-12-dependent loss of natural killer T cells in hepatosteatosis. Hepatology 51 . (https://doi.org/10.1002/hep.23292)

    • Search Google Scholar
    • Export Citation
  • Lee JS, Tato CM, Joyce-Shaikh B, Gulen MF, Cayatte C, Chen Y, Blumenschein WM, Judo M, Ayanoglu G & McClanahan TK 2015 Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability. Immunity 43 . (https://doi.org/10.1016/j.immuni.2015.09.003)

    • Search Google Scholar
    • Export Citation
  • Li Z, Soloski MJ & Diehl AM 2005 Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease. Hepatology 42 . (https://doi.org/10.1002/hep.20826)

    • Search Google Scholar
    • Export Citation
  • Luck H, Tsai S, Chung J, Clemente-Casares X, Ghazarian M, Revelo XS, Lei H, Luk CT, Shi SY & Surendra A 2015 Regulation of obesity-related insulin resistance with gut anti-inflammatory agents. Cell Metabolism 21 . (https://doi.org/10.1016/j.cmet.2015.03.001)

    • Search Google Scholar
    • Export Citation
  • Ma X, Hua J & Li Z 2008 Probiotics improve high fat diet-induced hepatic steatosis and insulin resistance by increasing hepatic NKT cells. Journal of Hepatology 49 . (https://doi.org/10.1016/j.jhep.2008.05.025)

    • Search Google Scholar
    • Export Citation
  • Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A & Locati M 2004 The chemokine system in diverse forms of macrophage activation and polarization. Trends in Immunology 25 . (https://doi.org/10.1016/j.it.2004.09.015)

    • Search Google Scholar
    • Export Citation
  • Matsuzawa N, Takamura T, Kurita S, Misu H, Ota T, Ando H, Yokoyama M, Honda M, Zen Y & Nakanuma Y 2007 Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet. Hepatology 46 . (https://doi.org/10.1002/hep.21874)

    • Search Google Scholar
    • Export Citation
  • Meng J, Banerjee S, Li D, Sindberg GM, Wang F, Ma J & Roy S 2015 Opioid exacerbation of gram-positive sepsis, induced by gut microbial modulation, is rescued by IL-17A neutralization. Scientific Reports 5 10918. (https://doi.org/10.1038/srep10918)

    • Search Google Scholar
    • Export Citation
  • Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, Masciana R, Forgione A, Gabrieli ML & Perotti G 2009 Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 49 . (https://doi.org/10.1002/hep.22848)

    • Search Google Scholar
    • Export Citation
  • Musch MW, Clarke LL, Mamah D, Gawenis LR, Zhang Z, Ellsworth W, Shalowitz D, Mittal N, Efthimiou P & Alnadjim Z 2002 T cell activation causes diarrhea by increasing intestinal permeability and inhibiting epithelial Na+/K+-ATPase. Journal of Clinical Investigation 110 . (https://doi.org/10.1172/JCI0215695)

    • Search Google Scholar
    • Export Citation
  • Ni Y, Nagashimada M, Zhan L, Nagata N, Kobori M, Sugiura M, Ogawa K, Kaneko S & Ota T 2015 Prevention and reversal of lipotoxicity-induced hepatic insulin resistance and steatohepatitis in mice by an antioxidant carotenoid, beta-cryptoxanthin. Endocrinology 156 . (https://doi.org/10.1210/en.2014-1776)

    • Search Google Scholar
    • Export Citation
  • Ni Y, Zhuge F, Nagashimada M, Nagata N, Xu L, Yamamoto S, Fuke N, Ushida Y, Suganuma H & Kaneko S 2020 Lycopene prevents the progression of lipotoxicity-induced nonalcoholic steatohepatitis by decreasing oxidative stress in mice. Free Radical Biology and Medicine 152 . (https://doi.org/10.1016/j.freeradbiomed.2019.11.036)

    • Search Google Scholar
    • Export Citation
  • Nonaka Y, Izumo T, Izumi F, Maekawa T, Shibata H, Nakano A, Kishi A, Akatani K & Kiso Y 2008 Antiallergic effects of Lactobacillus pentosus strain S-PT84 mediated by modulation of Th1/Th2 immunobalance and induction of IL-10 production. International Archives of Allergy and Immunology 145 . (https://doi.org/10.1159/000109294)

    • Search Google Scholar
    • Export Citation
  • Ota T, Takamura T, Kurita S, Matsuzawa N, Kita Y, Uno M, Akahori H, Misu H, Sakurai M & Zen Y 2007 Insulin resistance accelerates a dietary rat model of nonalcoholic steatohepatitis. Gastroenterology 132 . (https://doi.org/10.1053/j.gastro.2006.10.014)

    • Search Google Scholar
    • Export Citation
  • Paolella G, Mandato C, Pierri L, Poeta M, Di Stasi M & Vajro P 2014 Gut-liver axis and probiotics: their role in non-alcoholic fatty liver disease. World Journal of Gastroenterology 20 . (https://doi.org/10.3748/wjg.v20.i42.15518)

    • Search Google Scholar
    • Export Citation
  • Rau M, Schilling AK, Meertens J, Hering I, Weiss J, Jurowich C, Kudlich T, Hermanns HM, Bantel H & Beyersdorf N 2016 Progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis is marked by a higher frequency of Th17 cells in the liver and an increased Th17/resting regulatory T cell ratio in peripheral blood and in the liver. Journal of Immunology 196 . (https://doi.org/10.4049/jimmunol.1501175)

    • Search Google Scholar
    • Export Citation
  • Suzuki T 2013 Regulation of intestinal epithelial permeability by tight junctions. Cellular and Molecular Life Sciences 70 . (https://doi.org/10.1007/s00018-012-1070-x)

    • Search Google Scholar
    • Export Citation
  • Suzuki T & Hara H 2010 Dietary fat and bile juice, but not obesity, are responsible for the increase in small intestinal permeability induced through the suppression of tight junction protein expression in LETO and OLETF rats. Nutrition and Metabolism 7 19. (https://doi.org/10.1186/1743-7075-7-19)

    • Search Google Scholar
    • Export Citation
  • Tanoue T, Atarashi K & Honda K 2016 Development and maintenance of intestinal regulatory T cells. Nature Reviews: Immunology 16 . (https://doi.org/10.1038/nri.2016.36)

    • Search Google Scholar
    • Export Citation
  • Tilg H & Moschen AR 2010 Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 52 . (https://doi.org/10.1002/hep.24001)

    • Search Google Scholar
    • Export Citation
  • Tilg H, Cani PD & Mayer EA 2016 Gut microbiome and liver diseases. Gut 65 . (https://doi.org/10.1136/gutjnl-2016-312729)

  • Zeng Y, Zhang H, Zong L, Tsao R, Arie H, Izumo T, Shibata H & Mine Y 2019 Lactobacillus pentosus S-PT84 prevents LPS-induced low-grade chronic inflammation in a C57BL/6J mouse model. Journal of Functional Foods 62 103526. (https://doi.org/10.1016/j.jff.2019.103526)

    • Search Google Scholar
    • Export Citation
  • Zhou Y, Inoue N, Ozawa R, Maekawa T, Izumo T, Kitagawa Y, Kiso Y, Shibata H & Ikeda I 2013 Effects of heat-killed Lactobacillus pentosus S-PT84 on postprandial hypertriacylglycerolemia in rats. Bioscience, Biotechnology, and Biochemistry 77 . (https://doi.org/10.1271/bbb.120830)

    • Search Google Scholar
    • Export Citation
  • Zhou D, Pan Q, Liu XL, Yang RX, Chen YW, Liu C & Fan JG 2017 Clostridium butyricum B1 alleviates high-fat diet-induced steatohepatitis in mice via enterohepatic immunoregulation. Journal of Gastroenterology and Hepatology 32 . (https://doi.org/10.1111/jgh.13742)

    • Search Google Scholar
    • Export Citation
  • Zhuge F, Ni Y, Nagashimada M, Nagata N, Xu L, Mukaida N, Kaneko S & Ota T 2016 DPP-4 inhibition by linagliptin attenuates obesity-related inflammation and insulin resistance by regulating M1/M2 macrophage polarization. Diabetes 65 . (https://doi.org/10.2337/db16-0317)

    • Search Google Scholar
    • Export Citation