Abstract
The aim of this study was to investigate how the effects of compound probiotics modulate the gut microbiota, short-chain fatty acid (SCFA), body composition, serum and liver lipids, and inflammatory markers in non-alcoholic fatty liver disease (NAFLD) rats. Twenty-four male SD rats were randomly divided into 3 groups: normal control group (standard feed), high-fat diet (HFD) feeding group (83% standard feed + 10% lard oil + 1.5% cholesterol + 0.5% cholate + 5% sucrose), and compound probiotics intervention group (HFD + 0.6 g × kg−1 × d−1 compound probiotics). The microbial population was assessed by 16S rDNA amplification and sequence analysis. Body composition, serum and liver lipids, serum inflammatory markers, colonic SCFAs, and relative proteins were assessed. The results showed that compound probiotics significantly reduced body weight, visceral and total fat mass, and the levels of hepatic TC and TG and serum TG, FFA, ALT, LPS, IL-1β, and IL-18 (P < 0.05). The proportions of TM7 phylum (0.06 vs 1.57%, P < 0.05) clearly increased, while that of Verrucomicrobia phylum (5.69 vs 2.61%, P < 0.05) clearly decreased. Compound probiotics also increased the representation of Ruminococcus genus (0.95 vs 1.83%, P < 0.05), while the proportion of Veillonella genus decreased (0.10 vs 0.03%, P < 0.05). The levels of colonic SCFAs and GPR43, NLRP3, ASC, and CASPASE-1 proteins also changed significantly (P < 0.05). Compound probiotics modulated gut microbiota, SCFAs, and their receptor GPR43 in NAFLD rats. These changes might inhibit lipid deposition and chronic metabolic inflammation in response to the insult of HFD.
Similar content being viewed by others
References
Wree A, Broderick L, Canbay A, Hoffman HM, Feldstein AE (2013) From NAFLD to NASH to cirrhosis-new insights into disease mechanisms. Nat Rev Gastroenterol Hepatol 10(11):627–636. https://doi.org/10.1038/nrgastro.2013.149
Rinella M, Charlton M (2016) The globalization of non-alcoholic fatty liver disease-prevalence and impact on world health. Hepatology 64(1):4–22. https://doi.org/10.1002/hep.28524
Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M (2016) Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64(1):73–84. https://doi.org/10.1002/hep.28431
Loomba R, Sanyal AJ (2013) The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 10(11):686–690. https://doi.org/10.1038/nrgastro.2013.171
Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM, Hobbs HH (2004) Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40(6):1387–1395. https://doi.org/10.1002/hep.20466
Farrell GC, Wong VW, Chitturi S (2013) NAFLD in Asia—as common and important as in the west. Nat Rev Gastroenterol Hepatol 10(5):307–318. https://doi.org/10.1038/nrgastro.2013.34
Byrne CD, Targher G (2015) NAFLD: a multisystem disease. J Hepatol 62:S47–S64. https://doi.org/10.1016/j.jhep.2014.12.012
Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, Landt CL, Harrison SA (2011) Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 140(1):124–131. https://doi.org/10.1053/j.gastro.2010.09.038
Loomba R, Abraham M, Unalp A, Wilson L, Lavine J, Doo E, Bass NM (2012) Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology 56(3):943–951. https://doi.org/10.1002/hep.25772
Musso G, Gambino R, Cassader M, Pagano G (2011) Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 43(8):617–649. https://doi.org/10.3109/07853890.2010.518623
Musso G, Gambino R, Tabibian JH, Ekstedt M, Kechagias S, Hamaguchi M, Hultcrantz R, Hagstrom H, Yoon SK, Charatcharoenwitthaya P, George J, Barrera F, Hafliethadottir S, Bjornsson ES, Armstrong MJ, Hopkins LJ, Gao X, Francque S, Verrijken A, Yilmaz Y, Lindor KD, Charlton M, Haring R, Lerch MM, Rettig R, Volzke H, Ryu S, Li G, Wong LL, Machado M, Cortez-Pinto H, Yasui K, Cassader M (2014) Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis. PLoS Med 11(7):e1001680. https://doi.org/10.1371/journal.pmed.1001680
Tilg H, Moschen AR (2010) Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 52(5):1836–1846. https://doi.org/10.1002/hep.24001
Bechmann LP, Hannivoort RA, Gerken G, Hotamisligil GS, Trauner M, Canbay A (2012) The interaction of hepatic lipid and glucose metabolism in liver diseases. J Hepatol 56(4):952–964. https://doi.org/10.1016/j.jhep.2011.08.025
Wree A, Kahraman A, Gerken G, Canbay A (2011) Obesity affects the liver—the link between adipocytes and hepatocytes. Digestion 83(1-2):124–133. https://doi.org/10.1159/000318741
Rawls JF, Mahowald MA, Ley RE, Gordon JI (2006) Reciprocal gut microbiota transplants from zebrafish and mice to germ-free recipients reveal host habitat selection. Cell 127(2):423–433. https://doi.org/10.1016/j.cell.2006.08.043
Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP, Egholm M, Henrissat B, Heath AC, Knight R, Gordon JI (2009) A core gut microbiome in obese and lean twins. Nature 457(7228):480–484. https://doi.org/10.1038/nature07540
Yang LH, Cai J, Chen DF (2012) Alteration and significance of intestinal flora in patients with NASH. J Clin Hepatol 28:124–126
Spencer MD, Hamp TJ, Reid RW, Fischer LM, Zeisel SH, Fodor AA (2011) Association between composition of the human gastrointestinal microbiome and development of fatty liver with choline deficiency. Gastroenterology 140(3):976–986. https://doi.org/10.1053/j.gastro.2010.11.049
Liang Y, Lin C, Wang S, Z Yupei, H Li, Wang G, Li Y, Deng Y, He Y, He Q, C Xiaoshuang, Y Qinhe, New targets for prevention and treatment of obesity related NAFLD: short-chain fatty acids and short-chain fatty acid receptors signaling pathways, Journal of Chongqing Medical University, (2016) 628–631
Thorburn AN, Macia L, Mackay CR (2014) Diet, metabolites, and “western-lifestyle” inflammatory diseases. Immunity 40(6):833–842. https://doi.org/10.1016/j.immuni.2014.05.014
Tan J, McKenzie C, Potamitis M, Thorburn AN, Mackay CR, Macia L (2014) The role of short-chain fatty acids in health and disease. Adv Immunol 121:91–119. https://doi.org/10.1016/B978-0-12-800100-4.00003-9
Koh A, De Vadder F, Kovatcheva-Datchary P, Backhed F (2016) From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell 165(6):1332–1345. https://doi.org/10.1016/j.cell.2016.05.041
Wang Y, Xie J, Li Y, Dong S, Liu H, Chen J, Wang Y, Zhao S, Zhang Y, Zhang H (2016) Probiotic lactobacillus casei Zhang reduces pro-inflammatory cytokine production and hepatic inflammation in a rat model of acute liver failure. Eur J Nutr 55(2):821–831. https://doi.org/10.1007/s00394-015-0904-3
Siddiqui H, Nederbragt AJ, Lagesen K, Jeansson SL, Jakobsen KS (2011) Assessing diversity of the female urine microbiota by high throughput sequencing of 16S rDNA amplicons. BMC Microbiol 11(1):244. https://doi.org/10.1186/1471-2180-11-244
Zhao G, Nyman M, Jonsson JA (2006) Rapid determination of short-chain fatty acids in colonic contents and faeces of humans and rats by acidified water-extraction and direct-injection gas chromatography. Biomed Chromatogr 20(8):674–682. https://doi.org/10.1002/bmc.580
Ogasawara M, Hirose A, Ono M, Aritake K, Nozaki Y, Takahashi M, Okamoto N, Sakamoto S, Iwasaki S, Asanuma T, Taniguchi T, Urade Y, Onishi S, Saibara T, Oben JA (2011) A novel and comprehensive mouse model of human non-alcoholic steatohepatitis with the full range of dysmetabolic and histological abnormalities induced by gold thioglucose and a high-fat diet. Liver Int 31(4):542–551. https://doi.org/10.1111/j.1478-3231.2010.02443.x
Perla FM, Prelati M, Lavorato M, Visicchio D, Anania C (2017) The role of lipid and lipoprotein metabolism in non-alcoholic fatty liver disease. Children (Basel) 4(6):1–14. https://doi.org/10.3390/children4060046
Shapiro H, Suez J, Elinav E (2017) Personalized microbiome-based approaches to metabolic syndrome management and prevention. J Diabetes 9(3):226–236. https://doi.org/10.1111/1753-0407.12501
Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ (2005) Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 115(5):1343–1351. https://doi.org/10.1172/jci23621
Harrison SA, Oliver D, Arnold HL, Gogia S, Neuschwander-Tetri BA (2008) Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease. Gut 57(10):1441–1447. https://doi.org/10.1136/gut.2007.146019
Poeta M, Pierri L, Vajro P (2017) Gut-liver axis derangement in non-alcoholic fatty liver disease. Children (Basel) 4(8):1–19. https://doi.org/10.3390/children4080066
He X, McLean JS, Edlund A, Yooseph S, Hall AP, Liu SY, Dorrestein PC, Esquenazi E, Hunter RC, Cheng G, Nelson KE, Lux R, Shi W (2015) Cultivation of a human-associated TM7 phylotype reveals a reduced genome and epibiotic parasitic lifestyle. Proc Natl Acad Sci U S A 112(1):244–249. https://doi.org/10.1073/pnas.1419038112
Rooks MG, Garrett WS (2016) Gut microbiota, metabolites and host immunity. Nat Rev Immunol 16(6):341–352. https://doi.org/10.1038/nri.2016.42
Porras D, Nistal E, Martinez-Florez S, Pisonero-Vaquero S, Olcoz JL, Jover R, Gonzalez-Gallego J, Garcia-Mediavilla MV, Sanchez-Campos S (2017) Protective effect of quercetin on high-fat diet-induced non-alcoholic fatty liver disease in mice is mediated by modulating intestinal microbiota imbalance and related gut-liver axis activation. Free Radic Biol Med 102:188–202. https://doi.org/10.1016/j.freeradbiomed.2016.11.037
Graham C, Mullen A, Whelan K (2015) Obesity and the gastrointestinal microbiota: a review of associations and mechanisms. Nutr Rev 73(6):376–385. https://doi.org/10.1093/nutrit/nuv004
De Vadder F, Kovatcheva-Datchary P, Goncalves D, Vinera J, Zitoun C, Duchampt A, Backhed F, Mithieux G (2014) Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 156(1-2):84–96. https://doi.org/10.1016/j.cell.2013.12.016
Puertollano E, Kolida S, Yaqoob P (2014) Biological significance of short-chain fatty acid metabolism by the intestinal microbiome. Curr Opin Clin Nutr Metab Care 17(2):139–144. https://doi.org/10.1097/mco.0000000000000025
Fabbrini E, Sullivan S, Klein S (2010) Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology 51(2):679–689. https://doi.org/10.1002/hep.23280
Zhu L, Baker RD, Baker SS (2014) Gut microbiome and nonalcoholic fatty liver diseases. Pediatr Res 77(1-2):245–251. https://doi.org/10.1038/pr.2014.157
Endo H, Niioka M, Kobayashi N, Tanaka M, Watanabe T (2013) Butyrate-producing probiotics reduce nonalcoholic fatty liver disease progression in rats: new insight into the probiotics for the gut-liver axis. PLoS One 8(5):e63388. https://doi.org/10.1371/journal.pone.0063388
Ley RE, Turnbaugh PJ, Klein S, Gordon JI (2006) Microbial ecology: human gut microbes associated with obesity. Nature 444(7122):1022–1023. https://doi.org/10.1038/4441022a
Lu Y, Fan C, Li P, Lu Y, Chang X, Qi K (2016) Short chain fatty acids prevent high-fat-diet-induced obesity in mice by regulating G protein-coupled receptors and gut microbiota. Sci Rep 6(1):37589. https://doi.org/10.1038/srep37589
Louis P, Hold GL, Flint HJ (2014) The gut microbiota, bacterial metabolites and colorectal cancer. Nat Rev Microbiol 12(10):661–672. https://doi.org/10.1038/nrmicro3344
Zhu L, Baker SS, Gill C, Liu W, Alkhouri R, Baker RD, Gill SR (2013) Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 57(2):601–609. https://doi.org/10.1002/hep.26093
Tanaka N, Matsubara T, Krausz KW, Patterson AD, Gonzalez FJ (2012) Disruption of phospholipid and bile acid homeostasis in mice with nonalcoholic steatohepatitis. Hepatology 56(1):118–129. https://doi.org/10.1002/hep.25630
Yamashita H, Fujisawa K, Ito E, Idei S, Kawaguchi N, Kimoto M, Hiemori M, Tsuji H (2007) Improvement of obesity and glucose tolerance by acetate in Type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Biosci Biotechnol Biochem 71:1236–1243
Perry RJ, Peng L, Barry NA, Cline GW, Zhang D, Cardone RL, Petersen KF, Kibbey RG, Goodman AL, Shulman GI (2016) Acetate mediates a microbiome-brain-beta-cell axis to promote metabolic syndrome. Nature 534(7606):213–217. https://doi.org/10.1038/nature18309
Wright RS, Anderson JW, Bridges SR (1990) Propionate inhibits hepatocyte lipid synthesis. Proc Soc Exp Biol Med 195:26–29
Cornall LM, Mathai ML, Hryciw DH, McAinch AJ (2011) Diet-induced obesity up-regulates the abundance of GPR43 and GPR120 in a tissue specific manner. Cell Physiol Biochem 28(5):949–958. https://doi.org/10.1159/000335820
Macia L, Tan J, Vieira AT, Leach K, Stanley D, Luong S, Maruya M, Ian McKenzie C, Hijikata A, Wong C, Binge L, Thorburn AN, Chevalier N, Ang C, Marino E, Robert R, Offermanns S, Teixeira MM, Moore RJ, Flavell RA, Fagarasan S, Mackay CR (2015) Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat Commun 6:6734. https://doi.org/10.1038/ncomms7734
Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, Thaiss CA, Kau AL, Eisenbarth SC, Jurczak MJ, Camporez JP, Shulman GI, Gordon JI, Hoffman HM, Flavell RA (2012) Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482:179–185. https://doi.org/10.1038/nature10809
He M, Shi B (2017) Gut microbiota as a potential target of metabolic syndrome: the role of probiotics and prebiotics. Cell Biosci 7(1):54. https://doi.org/10.1186/s13578-017-0183-1
Acknowledgments
We thank Pinghe Yin, Yang Hu, and Huanyong Li from Jinan University Analytical and Testing Center for technical assistance and Guangzhou Genedenovo Biotechnology Co. Ltd. for providing the methods for partial bioinformatics analysis.
Funding
This work was supported in part by the National Natural Science Foundation of China (no. 81774165, 81573844), the Natural Science Foundation of Guangdong in China (no. 2016A030313824), Traditional Chinese Medicine Bureau of Guangdong in China (no. 20161065), and the National Health and Family Planning Commission of Guangdong in China (no. A2016583 and A2017228).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Animal experiments were approved by the animal care and use committee of Jinan University and were in compliance with the guidelines for the “Care and Use of Animals.”
Conflict of Interests
The authors declare that they have no conflict of interest.
Electronic supplementary material
Supplementary Table 1
(PDF 50.6 kb)
Supplementary Table 2
(PDF 47 kb)
Supplementary Table 3
(PDF 68.5 kb)
Supplementary Table 4
(PDF 130 kb)
Supplementary Table 5
(PDF 69.6 kb)
Supplementary Table 6
(PDF 69.8 kb)
Supplementary Table 7
(PDF 68.1 kb)
Supplementary Table 8
(PDF 66.6 kb)
ESM 9
(PDF 542 kb)
ESM 10
(PDF 425 kb)
Rights and permissions
About this article
Cite this article
Liang, Y., Liang, S., Zhang, Y. et al. Oral Administration of Compound Probiotics Ameliorates HFD-Induced Gut Microbe Dysbiosis and Chronic Metabolic Inflammation via the G Protein-Coupled Receptor 43 in Non-alcoholic Fatty Liver Disease Rats. Probiotics & Antimicro. Prot. 11, 175–185 (2019). https://doi.org/10.1007/s12602-017-9378-3
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12602-017-9378-3