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Probiotic Lactobacillus casei Zhang reduces pro-inflammatory cytokine production and hepatic inflammation in a rat model of acute liver failure

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Abstract

Purpose

In this study, we sought to find the effects and mechanisms of probiotic Lactobacillus casei Zhang (L. casei Zhang) on the pro-inflammatory cytokine production and hepatic inflammatory response in a rat model of acute liver failure induced by lipopolysaccharide (LPS) and d-galactosamine (GalN).

Methods

Male Wistar rats were orally administrated with or without L. casei Zhang for 30 days prior to challenge with LPS and GalN. Dexamethasone administrated group serving as a positive anti-inflammation control. Serum, intestinal and liver samples were collected 8 h after LPS/GalN challenge for histological, molecular and biochemical analysis.

Results

LPS/GalN challenge alone resulted in significantly increased production of endotoxin, tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1β) and nitric oxide as compared to the normal control rats. Pretreatment with L. casei Zhang not only reduced these changes, but also attenuated hepatic inflammation as shown by improved histological assessment, decreased myeloperoxidase activity and reduced expression of IL-1β and inducible nitric oxide synthase in the liver. L. casei Zhang supplementation significantly inhibited LPS/GalN-triggered phosphorylation of ERK, JNK and p-38 MAPK, but increased the expression of TLR2, TLR9 and PPAR-γ. Moreover, L. casei Zhang treatment prevented intestinal injury and modulated the intestinal ecology by increasing the fecal Lactobacillus and Bifidobacterium levels.

Conclusions

Probiotic L. casei Zhang reduces LPS/GalN-induced pro-inflammatory cytokine and hepatic inflammation through modulating the TLR-MAPK-PPAR-γ signaling pathways and intestinal microbiota.

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Abbreviations

ALF:

Acute liver failure

GalN:

Galactosamine

LPS:

Lipopolysaccharide

MAPK:

Mitogen-activated protein kinase

MPO:

Myeloperoxidase

NF-κB:

Nuclear factor κB

PPAR-γ:

Peroxisome proliferator-activated receptor gamma

TLRs:

Toll-like receptors

TNF-α :

Tumor necrosis factor-α

References

  1. Bernal W, Wendon J (2013) Acute liver failure. N Engl J Med 369:2525–2534

    Article  CAS  Google Scholar 

  2. Schiødt FV, Lee WM (2003) Fulminant liver disease. Clin Liver Dis 7:331–349

    Article  Google Scholar 

  3. Mukherjee S, Mahmoudi TM, Mukherjee U (2009) Liver transplant for viral hepatitis and fulminant hepatic failure. Minerva Gastroenterol Dietol 55:83–100

    CAS  Google Scholar 

  4. Xu Y, Wang H, Bao S, Tabassam F, Cai W, Xiang X, Zhao G, Wu H, Gao T, Li H, Xie Q (2013) Amelioration of liver injury by continuously targeted intervention against TNFRp55 in rats with acute-on-chronic liver failure. PLoS ONE 8:e68757

    Article  CAS  Google Scholar 

  5. Ben Ari Z, Avlas O, Pappo O, Zilbermints V, Cheporko Y, Bachmetov L, Zemel R, Shainberg A, Sharon E, Grief F, Hochhauser E (2012) Reduced hepatic injury in Toll-like receptor 4-deficient mice following D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure. Cell Physiol Biochem 29:41–50

    Article  CAS  Google Scholar 

  6. Kawasaki T, Kawai T (2014) Toll-like receptor signaling pathways. Front Immunol 5:461

    Article  Google Scholar 

  7. Genolet R, Wahli W, Michalik L (2004) PPARs as drug targets to modulate inflammatory responses? Curr Drug Targets Inflamm Allergy 3:361–375

    Article  CAS  Google Scholar 

  8. Loguercio C, Federico A, Tuccillo C, Terracciano F, D’Auria MV, De Simone C et al (2005) Beneficial effects of a probiotic VSL#3 on parameters of liver dysfunction in chronic liver diseases. J Clin Gastroenterol 39:540–543

    Article  Google Scholar 

  9. Cesaro C, Tiso A, Del Prete A, Cariello R, Tuccillo C, Cotticelli G, Del Vecchio Blanco C, Loguercio C (2011) Gut microbiota and probiotics in chronic liver diseases. Dig Liver Dis 43:431–438

    Article  Google Scholar 

  10. Wang Y, Kirpich I, Liu Y, Ma Z, Barve S, McClain CJ, Feng W (2011) Lactobacillus rhamnosus GG treatment potentiates intestinal hypoxia-inducible factor, promotes intestinal integrity and ameliorates alcohol-induced liver injury. Am J Pathol 179:2866–2875

    Article  CAS  Google Scholar 

  11. Osman N, Adawi D, Ahrné S, Jeppsson B, Molin G (2007) Endotoxin- and D-galactosamine induced liver injury improved by the administration of Lactobacillus, Bifidobacterium and blueberry. Dig Liver Dis 39:849–856

    Article  CAS  Google Scholar 

  12. Rishi P, Bharrhan S, Singh G, Kaur IP (2011) Effect of Lactobacillus plantarum and l-arginine against endotoxin-induced liver injury in a rat model. Life Sci 89:847–853

    Article  CAS  Google Scholar 

  13. Zhang Y, Du RT, Wang LF, Zhang HP (2010) The antioxidative effects of probiotic Lactobacillus casei Zhang on the hyperlipidemic rats. Eur Food Res Technol 231:151–158

    Article  CAS  Google Scholar 

  14. Wang Y, Li Y, Xie J, Zhang Y, Wang J, Sun X, Zhang H (2013) Protective effects of probiotic Lactobacillus casei Zhang against endotoxin- and d-galactosamine-induced liver injury in rats via anti-oxidative and anti-inflammatory capacities. Int Immunopharmacol 15:30–37

    Article  CAS  Google Scholar 

  15. Ya T, Zhang Q, Chu F, Merritt J, Bilige M, Sun T, Du R, Zhang H (2008) Immunological evaluation of Lactobacillus casei Zhang: a newly isolated strain from koumiss in Inner Mongolia, China. BMC Immunol 9:68–76

    Article  Google Scholar 

  16. Xu H, An H, Yu Y, Zhang M, Qi R, Cao X (2003) Ras participates in CpG oligodeoxynucleotide signaling through association with toll-like receptor 9 and promotion of interleukin-1 receptor-associated kinase/tumor necrosis factor receptor-associated factor 6 complex formation in macrophages. J Biol Chem 278:334–340

    Google Scholar 

  17. Chiu CJ, McArdle AH, Brown R, Scott HJ, Gurd FN (1970) Intestinal mucosal lesion in low-flow states. I. A morphological, hemodynamic, and metabolic reappraisal. Arch Surg 101:478–483

    Article  CAS  Google Scholar 

  18. Wang Y, Chen T, Han C, He D, Liu H, An H, Cai Z, Cao X (2007) Lysosome-associated small Rab GTPase Rab7b negatively regulates TLR4 signaling in macrophages by promoting lysosomal degradation of TLR4. Blood 110:962–971

    Article  CAS  Google Scholar 

  19. Zhang Y, Wang L, Zhang J, Li Y, He Q, Li H, Guo X, Guo J, Zhang H (2014) Probiotic Lactobacillus casei Zhang ameliorates high-fructose-induced impaired glucose tolerance in hyperinsulinemia rats. Eur J Nutr 53:221–232

    Article  CAS  Google Scholar 

  20. Wang Y, Xie J, Wang N, Li Y, Sun X, Zhang Y, Zhang H (2013) Lactobacillus casei Zhang modulate cytokine and toll-like receptor expression and beneficially regulate poly I:C-induced immune responses in RAW264.7 macrophages. Microbiol Immunol 57:54–62

    Article  CAS  Google Scholar 

  21. Wang Y, Liu Y, Kirpich I, Ma Z, Wang C, Zhang M, Suttles J, McClain C, Feng W (2013) Lactobacillus rhamnosus GG reduces hepatic TNFα production and inflammation in chronic alcohol-induced liver injury. J Nutr Biochem 24:1609–1615

    Article  CAS  Google Scholar 

  22. Klinke A, Nussbaum C, Kubala L, Friedrichs K, Rudolph TK, Rudolph V et al (2011) Myeloperoxidase attracts neutrophils by physical forces. Blood 117:1350–1358

    Article  CAS  Google Scholar 

  23. Wang H, Li Y (2006) Protective effect of bicyclol on acute hepatic failure induced by lipopolysaccharide and galactosamine in mice. Eur J Pharmacol 534:194–201

    Article  CAS  Google Scholar 

  24. Soares JB, Pimentel-Nunes P, Afonso L, Rolanda C, Lopes P, Roncon-Albuquerque R Jr et al (2012) Increased hepatic expression of TLR2 and TLR4 in the hepatic inflammation-fibrosis-carcinoma sequence. Innate Immun 18:700–708

    Article  Google Scholar 

  25. Agrawal V, Smart K, Jilling T, Hirsch E (2013) Surfactant protein (SP)-A suppresses preterm delivery and inflammation via TLR2. PLoS ONE 8:e63990

    Article  CAS  Google Scholar 

  26. McKimmie CS, Moore M, Fraser AR, Jamieson T, Xu D, Burt C, Pitman NI, Nibbs RJ, McInnes IB, Liew FY, Graham GJ (2009) A TLR2 ligand suppresses inflammation by modulation of chemokine receptors and redirection of leukocyte migration. Blood 113:4224–4231

    Article  CAS  Google Scholar 

  27. Good M, Sodhi CP, Ozolek JA, Buck RH, Goehring KC, Thomas DL, Vikram A, Bibby K, Morowitz MJ, Firek B, Lu P, Hackam DJ (2014) Lactobacillus rhamnosus HN001 decreases the severity of necrotizing enterocolitis in neonatal mice and preterm piglets: evidence in mice for a role of TLR9. Am J Physiol Gastrointest Liver Physiol 306:G1021–G1032

    Article  CAS  Google Scholar 

  28. Peti W, Page R (2013) Molecular basis of MAP kinase regulation. Protein Sci 22:1698–1710

    Article  CAS  Google Scholar 

  29. Wu YL, Lian LH, Wan Y, Nan JX (2010) Baicalein inhibits nuclear factor-κB and apoptosis via c-FLIP and MAPK in D-GalN/LPS induced acute liver failure in murine models. Chem Biol Interact 188:526–534

    Article  CAS  Google Scholar 

  30. Lian LH, Wu YL, Wan Y, Li X, Xie WX, Nan JX (2010) Anti-apoptotic activity of gentiopicroside in D-galactosamine/lipopolysaccharide-induced murine fulminant hepatic failure. Chem Biol Interact 188:127–133

    Article  CAS  Google Scholar 

  31. Jin Q, Jiang S, Wu YL, Bai T, Yang Y, Jin X, Lian LH, Nan JX (2014) Hepatoprotective effect of cryptotanshinone from Salvia miltiorrhiza in D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure. Phytomedicine 21:141–147

    Article  CAS  Google Scholar 

  32. Mencarelli A, Distrutti E, Renga B, D’Amore C, Cipriani S, Palladino G, Donini A, Ricci P, Fiorucci S (2011) Probiotics modulate intestinal expression of nuclear receptor and provide counter-regulatory signals to inflammation-driven adipose tissue activation. PLoS ONE 6:e22978

    Article  CAS  Google Scholar 

  33. Ewaschuk J, Endersby R, Thiel D, Diaz H, Backer J, Ma M, Churchill T, Madsen K (2007) Probiotic bacteria prevent hepatic damage and maintain colonic barrier function in a mouse model of sepsis. Hepatology 46:841–850

    Article  CAS  Google Scholar 

  34. Zhang LL, Gao CY, Fang CQ, Wang YJ, Gao D, Yao GE, Xiang J, Wang JZ, Li JC (2011) PPARγ attenuates intimal hyperplasia by inhibiting TLR4-mediated inflammation in vascular smooth muscle cells. Cardiovasc Res 92:484–493

    Article  CAS  Google Scholar 

  35. Yao J, Pan D, Zhao Y, Zhao L, Sun J, Wang Y, You QD, Xi T, Guo QL, Lu N (2014) Wogonin prevents lipopolysaccharide-induced acute lung injury and inflammation in mice via peroxisome proliferator-activated receptor gamma-mediated attenuation of the nuclear factor-kappaB pathway. Immunology 143:241–257

    Article  CAS  Google Scholar 

  36. Imani Fooladi AA, Mahmoodzadeh Hosseini H, Nourani MR, Khani S, Alavian SM (2013) Probiotic as a novel treatment strategy against liver disease. Hepat Mon 13(2):e7521

    Article  Google Scholar 

  37. Kasravi FB, Adawi D, Molin G, Bengmark S, Jeppsson B (1997) Effect of oral supplementation of lactobacilli on bacterial translocation in acute liver injury induced by d-galactosamine. J Hepatol 26:417–424

    Article  CAS  Google Scholar 

  38. Liu L, Yuan S, Long Y, Guo Z, Sun Y, Li Y, Niu Y, Li C, Mei Q (2009) Immunomodulation of Rheum tanguticum polysaccharide (RTP) on the immunosuppressive effects of dexamethasone (DEX) on the treatment of colitis in rats induced by 2,4,6-trinitrobenzene sulfonic acid. Int Immunopharmacol 9:1568–1577

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. Kerong Zhang and Dr. Charles Hocart from Australian National University for revising the manuscript. This work was supported by grants from the National Natural Science Foundation of China (Grant No. 31270922, 81260662, 81360394), Inner Mongolia Natural Science Foundation (Grant No. 2012MS1156) and the Excellent Young Scientist Foundation of Inner Mongolia Agricultural University (Grant No. 2014XYQ-19).

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    Authors and Affiliations

    1. Department of Pharmaceutical Engineering, College of Life Science, Inner Mongolia Agricultural University, No. 306 Zhaowuda Road, Saihan district, Hohhot, 010018, People’s Republic of China

      Yuzhen Wang, Yunxu Li, Shichao Dong, Huan Liu, Junna Chen, Yan Wang & Shimin Zhao

    2. Clinical Laboratory, Inner Mongolia People’s Hospital, Hohhot, People’s Republic of China

      Jiming Xie

    3. Key Laboratory of Dairy Biotechnology and Bioengineering, Educational Ministry of China, College of Food Science and Engineering, Inner Mongolia Agricultural University, Hohhot, People’s Republic of China

      Yong Zhang & Heping Zhang

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    1. Yuzhen Wang
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    Correspondence to Yuzhen Wang.

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    Yuzhen Wang, Jiming Xie and Yunxu Li have contributed equally to this article.

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    Wang, Y., Xie, J., Li, Y. et al. Probiotic Lactobacillus casei Zhang reduces pro-inflammatory cytokine production and hepatic inflammation in a rat model of acute liver failure. Eur J Nutr 55, 821–831 (2016). https://doi.org/10.1007/s00394-015-0904-3

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