Skip to main content
Log in

Preventing non-alcoholic fatty liver disease through Lactobacillus johnsonii BS15 by attenuating inflammation and mitochondrial injury and improving gut environment in obese mice

  • Applied microbial and cell physiology
  • Published:
Applied Microbiology and Biotechnology Aims and scope Submit manuscript

Abstract

The increasing prevalence of obesity worldwide is associated with a parallel increase in non-alcoholic fatty liver disease (NAFLD). To investigate the effect of Lactobacillus johnsonii BS15 on NAFLD, 120 male ICR mice were randomly divided into four groups and administrated with BS15 (2 × 107 cfu/0.2 mL or 2 × 108 cfu/0.2 mL) or phosphate buffered saline (PBS) throughout a 17-week experimental period. The mice were fed with normal chow diet (NCD) 5 weeks before the experimental period. Afterward, with the exception of the PBS group, NCD was changed into high-fat diet (HFD) for the remaining experimental period. Results showed that BS15-treated HFD mice were protected from hepatic steatosis and hepatocyte apoptosis. BS15 exhibited a positive effect on liver lipid peroxidation through an anti-oxidative stress activity by enhancing the liver antioxidant defense system. In addition, BS15 inhibited the insulin resistance; decreased the mRNA levels of acetyl–CoA carboxylase 1, fatty acid synthase, and peroxisome proliferator-activated receptor γ; and increased the expression of the fasting-induced adipose factor in livers. Meanwhile, BS15 attenuated mitochondria abnormalities when the content of uncoupling protein-2 decreased and cytochrome c increased in NAFLD mice. BS15 also reduced the level of serum lipopolysaccharide in NAFLD mice by lowering the intestinal permeability and adjusting gut flora, followed by the downregulation of the TNFα mRNA level in liver and the serum level of C-reactive protein. These findings suggest that BS15 may be effective in preventing NAFLD induced by HFD.

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
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Alisi A, Pastore A, Ceccarelli S, Panera N, Gnani D, Bruscalupi G, Massimi M, Tozzi G, Piemonte F, Nobili V (2012) Emodin prevents intrahepatic fat accumulation, inflammation and redox status imbalance during diet-induced hepatosteatosis in rats. Int J Mol Sci 13:2276–2289. doi:10.3390/ijms13022276

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Almanza-Perez J, Alarcon-Aguilar F, Blancas-Flores G, Campos-Sepulveda A, Roman-Ramos R, Garcia-Macedo R, Cruz M (2010) Glycine regulates inflammatory markers modifying the energetic balance through PPAR and UCP-2. Biomed Pharmacother 64:534–540

    Article  CAS  PubMed  Google Scholar 

  • Assimakopoulos SF (2013) On the role of intestinal hyperpermeability in complications of cirrhosis. Liver Int 33:495. doi:10.1111/liv.12094

    Article  CAS  PubMed  Google Scholar 

  • Brun P, Castagliuolo I, Leo VD, Buda A, Pinzani M, Palù G, Martines D (2007) Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. Am J Physiol-Gastr L 292:G518–G525. doi:10.1152/ajpgi.00024.2006

    CAS  Google Scholar 

  • Brunt EM, Kleiner DE, Wilson LA, Unalp A, Behling CE, Lavine JE, Neuschwander-Tetri BA (2009) Portal chronic inflammation in nonalcoholic fatty liver disease (NAFLD): a histologic marker of advanced NAFLD-clinicopathologic correlations from the nonalcoholic steatohepatitis clinical research network. Hepatology 49:809–820. doi:10.1002/hep.22724

    Article  PubMed Central  PubMed  Google Scholar 

  • Bugianesi E, Gastaldelli A, Vanni E, Gambino R, Cassader M, Baldi S, Ponti V, Pagano G, Ferrannini E, Rizzetto M (2005) Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia 48:634–642. doi:10.1007/s00125-005-1682-x

    Article  CAS  PubMed  Google Scholar 

  • Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, Burcelin R (2008) Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57:1470–1481

    Article  CAS  PubMed  Google Scholar 

  • Cani PD, Possemiers S, Van de Wiele T, Guiot Y, Everard A, Rottier O, Geurts L, Naslain D, Neyrinck A, Lambert DM (2009) Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 58:1091–1103. doi:10.1136/gut.2008.165886

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chen T, Cui Y, Bai C, Gong T, Peng X, Cui H (2009) Increased apoptotic lymphocyte population in the spleen of young chickens fed diets high in fluorine. Fluoride 42:94

    CAS  Google Scholar 

  • Chen K, Shu G, Peng X, Fang J, Cui H, Chen J, Wang F, Chen Z, Zuo Z, Deng J (2013) Protective role of sodium selenite on histopathological lesions, decreased T-cell subsets and increased apoptosis of thymus in broilers intoxicated with aflatoxin B1. Food Chem Toxicol 59:446–454. doi:10.1016/j.fct.2013.06.032

    Article  CAS  PubMed  Google Scholar 

  • Dostal A, Fehlbaum S, Chassard C, Zimmermann MB, Lacroix C (2013) Low iron availability in continuous in vitro colonic fermentations induces strong dysbiosis of the child gut microbial consortium and a decrease in main metabolites. FEMS Microbiol Ecol 83:161–175. doi:10.1111/j.1574-6941.2012.01461.x

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Dowman JK, Tomlinson J, Newsome P (2010) Pathogenesis of non-alcoholic fatty liver disease. QJM 103:71–83. doi:10.1093/qjmed/hcp158

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Epstein FH, Tilg H, Diehl AM (2000) Cytokines in alcoholic and nonalcoholic steatohepatitis. New Engl J Med 343:1467–1476. doi:10.1056/NEJM200011163432007

    Article  Google Scholar 

  • Farré R, De Vos R, Geboes K, Verbecke K, Berghe PV, Depoortere I, Blondeau K, Tack J, Sifrim D (2007) Critical role of stress in increased oesophageal mucosa permeability and dilated intercellular spaces. Gut 56:1191–1197. doi:10.1136/gut.2006.113688

    Article  PubMed Central  PubMed  Google Scholar 

  • Fei N, Zhao L (2012) An opportunistic pathogen isolated from the gut of an obese human causes obesity in germfree mice. ISME J 7:880–884. doi:10.1038/ismej.2012.153

    Article  PubMed Central  PubMed  Google Scholar 

  • Feldstein AE (2010) Novel insights into the pathophysiology of nonalcoholic fatty liver disease. Semin Liver Dis 30:391–401. doi:10.1055/s-0030-1267539

    Article  CAS  PubMed  Google Scholar 

  • Guo X, Xia X, Tang R, Zhou J, Zhao H, Wang K (2008) Development of a real–time PCR method for Firmicutes and Bacteroidetes in faeces and its application to quantify intestinal population of obese and lean pigs. Lett Appl Microbiol 47:367–373. doi:10.1111/j.1472-765X.2008.02408.x

    Article  CAS  PubMed  Google Scholar 

  • Heilig HG, Zoetendal EG, Vaughan EE, Marteau P, Akkermans AD, de Vos WM (2002) Molecular diversity of Lactobacillus spp. and other lactic acid bacteria in the human intestine as determined by specific amplification of 16S ribosomal DNA. Appl Environ Microbiol 68:114–123. doi:10.1128/AEM.68.1.114-123.2002

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Henao-Mejia J, Elinav E, Thaiss CA, Licona-Limon P, Flavell RA (2013) Role of the intestinal microbiome in liver disease. J Autoimmun 46:66–73

    Article  CAS  PubMed  Google Scholar 

  • Iacono A, Raso GM, Canani RB, Calignano A, Meli R (2011) Probiotics as an emerging therapeutic strategy to treat NAFLD: focus on molecular and biochemical mechanisms. J Nutr Biochem 22:699–711

    Article  CAS  PubMed  Google Scholar 

  • Koek G, Liedorp P, Bast A (2011) The role of oxidative stress in non-alcoholic steatohepatitis. Clin Chim Acta 412:1297–1305

    Article  CAS  PubMed  Google Scholar 

  • Lazo M, Hernaez R, Eberhardt MS, Bonekamp S, Kamel I, Guallar E, Koitesh A, Brancati FL, Clark JM (2013) Prevalence of nonalcoholic fatty liver disease in the United States: The Third National Health and Nutrition Examination Survey, 1988–1994. Am J Epidemiol. doi:10.1093/aje/kws448

    PubMed Central  PubMed  Google Scholar 

  • Lee HY, Park JH, Seok SH, Baek MW, Kim DJ, Lee KE, Paek KS, Lee Y, Park JH (2006) Human originated bacteria, Lactobacillus rhamnosus PL60, produce conjugated linoleic acid and show anti-obesity effects in diet-induced obese mice. BBA-Mol Cell Biol L 1761:736–744. doi:10.1016/j.bbalip.2006.05.007

    CAS  Google Scholar 

  • Ley RE, Bäckhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI (2005) Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A 102:11070–11075. doi:10.1073/pnas.0504978102

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ley RE, Turnbaugh PJ, Klein S, Gordon JI (2006) Microbial ecology: human gut microbes associated with obesity. Nature 444:1022–1023. doi:10.1038/nature05414

    Article  CAS  PubMed  Google Scholar 

  • Malhi H, Gores GJ (2008) Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin Liver Dis 28:360–369. doi:10.1055/s-0028-1091980

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Malhi H, Barreyro FJ, Isomoto H, Bronk SF, Gores GJ (2007) Free fatty acids sensitise hepatocytes to TRAIL mediated cytotoxicity. Gut 56:1124–1131. doi:10.1136/gut.2006.118059

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Miyoshi M, Ogawa A, Higurashi S, Kadooka Y (2013) Anti-obesity effect of Lactobacillus gasseri SBT2055 accompanied by inhibition of pro-inflammatory gene expression in the visceral adipose tissue in diet-induced obese mice. Eur J Nutr. doi:10.1007/s00394-013-0568-9

    Google Scholar 

  • Moore JB (2010) Symposium 1: overnutrition: consequences and solutions. Non-alcoholic fatty liver disease: the hepatic consequences of obesity and the metabolic syndrome. P Nutr Soc 69:211–220. doi:10.1017/S0029665110000030

    Article  CAS  Google Scholar 

  • Oliveira C, Gayotto L, Tatai C, Della Nina BI, Lima ES, Abdalla D, Lopasso FP, Laurindo F, Carrilho FJ (2003) Vitamin C and vitamin E in prevention of nonalcoholic fatty liver disease (NAFLD) in choline deficient diet fed rats. Nutr J 2:1–5

    Article  Google Scholar 

  • Petricevic L, Domig KJ, Nierscher FJ, Krondorfer I, Janitschek C, Kneifel W, Kiss H (2012) Characterisation of the oral, vaginal and rectal Lactobacillus flora in healthy pregnant and postmenopausal women. Eur J Obstet Gynecol Reprod Biol 160:93–99. doi:10.1016/j.ejogrb.2011.10.002

    Article  PubMed  Google Scholar 

  • Rector RS, Thyfault JP, Uptergrove GM, Morris EM, Naples SP, Borengasser SJ, Mikus CR, Laye MJ, Laughlin MH, Booth FW (2010) Mitochondrial dysfunction precedes insulin resistance and hepatic steatosis and contributes to the natural history of non-alcoholic fatty liver disease in an obese rodent model. J Hepatol 5:727–736. doi:10.1016/j.jhep.2009.11.030

    Article  Google Scholar 

  • Ricchi M, Odoardi MR, Carulli L, Anzivino C, Ballestri S, Pinetti A, Fantoni LI, Marra F, Bertolotti M, Banni S (2009) Differential effect of oleic and palmitic acid on lipid accumulation and apoptosis in cultured hepatocytes. J Gastroen Hepatol 24:830–840. doi:10.1111/j.1440-1746.2008.05733.x

  • Ruan H, Lodish HF (2003) Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-α. Cytokine Growth Factor Rev 14:447–455. doi:10.1016/S1359-6101(03)00052-2

    Article  CAS  PubMed  Google Scholar 

  • Sakaguchi S, Furusawa S (2006) Oxidative stress and septic shock: metabolic aspects of oxygen–derived free radicals generated in the liver during endotoxemia. FEMS Immunol Med Microbiol 47:167–177. doi:10.1111/j.1574-695X.2006.00072.x

    Article  CAS  PubMed  Google Scholar 

  • Serviddio G, Bellanti F, Sastre J, Vendemiale G, Altomare E (2010) Targeting mitochondria: a new promising approach for the treatment of liver diseases. Curr Med Chem 17:2325–2337. doi:10.2174/092986710791698530

    Article  CAS  PubMed  Google Scholar 

  • Walter J, Hertel C, Tannock GW, Lis CM, Munro K, Hammes WP (2001) Detection of Lactobacillus, Pediococcus, Leuconostoc, and Weissella species in human feces by using group-specific PCR primers and denaturing gradient gel electrophoresis. Appl Environ Microbiol 67:2578–2585. doi:10.1128/AEM.67.6.2578-2585.2001

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wang Y, Ausman LM, Russell RM, Greenberg AS, Wang XD (2008) Increased apoptosis in high-fat diet-induced nonalcoholic steatohepatitis in rats is associated with c-Jun NH2-terminal kinase activation and elevated proapoptotic Bax. J Nutr 138:1866–1871

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yang S, Zhu H, Li Y, Lin H, Gabrielson K, Trush MA, Diehl AM (2000) Mitochondrial adaptations to obesity-related oxidant stress. Arch Biochem Biophys 378:259–268. doi:10.1006/abbi.2000.1829

    Article  CAS  PubMed  Google Scholar 

  • Yuzefovych LV, Musiyenko SI, Wilson GL, Rachek LI (2013) Mitochondrial DNA damage and dysfunction, and oxidative stress are associated with endoplasmic reticulum stress, protein degradation and apoptosis in high fat diet-induced insulin resistance mice. PLoS ONE 8:e54059

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the Scientific Research Foundation for Returned Overseas Chinese Scholars, State Education Ministry, Science and Technology Support Project of Science and Technology Bureau of Sichuan Province (2013NZ0042), Academic Leader Training fund in Sichuan Province, Program for Changjiang Scholars and Innovative Research Team of the University of China (ITT0848), and International Cooperative Project of Science and Technology Bureau of Sichuan Province (2013HH0055).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Xueqin Ni.

Additional information

Jinge Xin and Dong Zeng are joint first authors.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

PDF 258 kb

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xin, J., Zeng, D., Wang, H. et al. Preventing non-alcoholic fatty liver disease through Lactobacillus johnsonii BS15 by attenuating inflammation and mitochondrial injury and improving gut environment in obese mice. Appl Microbiol Biotechnol 98, 6817–6829 (2014). https://doi.org/10.1007/s00253-014-5752-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00253-014-5752-1

Keywords

Navigation