Bifidobacterium adolescentis CGMCC 15058 alleviates liver injury, enhances the intestinal barrier and modifies the gut microbiota in d-galactosamine-treated rats
Acute liver failure is a drastic, unpredictable clinical syndrome with high mortality. Various preventive and adjuvant therapies based on modulating the gut flora have been proposed for hepatic injury. We aimed to explore the preventive and therapeutic effects of Bifidobacterium adolescentis CGMCC15058 on rat liver failure, as well as the potential microecological and immunological mechanisms of those effects. B. adolescentis CGMCC15058 (3 × 109 CFU), isolated from healthy human stool, was gavaged to Sprague–Dawley rats for 14 days. Acute liver injury was induced on the 15th day by intraperitoneal injection of d-galactosamine. After 24 h, liver and terminal ileum histology, liver function, plasma cytokines, bacterial translocation and gut microbiota composition were assessed. We found that pretreatment with B. adolescentis significantly relieved elevated serum levels of alanine aminotransferase (ALT), total bile acid and lipopolysaccharide-binding protein and enhanced the expression of mucin 4 and the tight junction protein zonula occludens-1. B. adolescentis exhibited anti-inflammatory properties as indicated by decreased levels of mTOR and the inflammatory cytokines TNF-α and IL-6, as well as elevated levels of the anti-inflammatory cytokine interleukins-10 in the liver. Similar anti-inflammatory signs were also found in plasma. B. adolescentis significantly altered the microbial community, depleting the common pathogenic taxon Proteus and markedly enriching the taxa Coriobacteriaceae, Bacteroidales and Allobaculum, which are involved in regulating the metabolism of lipids and aromatic amino acids. Our findings not only suggest B. adolescentis acts as a prospective probiotic against liver failure but also provide new insights into the prevention and treatment of liver disease.
KeywordsAcute liver failure Bifidobacterium adolescentis d-galactosamine Gut microbiota
Y.L. and L. Lv designed and conceived the experiments. Y.L., J. Ye., D.F. and D.S. performed the experiments and collected samples. L.Y. and X.B. performed DNA extractions. X.J. oversaw the RT-PCR and immunohistochemical staining. Y.L., L. Lv and J. Ye performed library construction and sequencing and designed the analysis. Q.W., P. CG and J. Wu analysed the data. D.S. drafted the manuscript. All authors contributed to and approved the final article.
This study was supported by the National Science Foundation of China (NSFC) (81330011, 81790631 and 81570512) and the National Basic Research Program of China (973 program) (2013CB531401).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
All procedures were performed according to the 2011 National Institutes of Health Guide for the care and use of laboratory animals and were approved by the Animal Care and Use Committee of the First Affiliated Hospital, School of Medicine, Zhejiang University.
All participants in this study provided a written informed consent before sample collection. The research is in accordance with the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Institutional Review Board of the First Affiliated Hospital of Zhejiang University.
- Arrazuria R, Elguezabal N, Juste RA, Derakhshani H, Khafipour E (2016) Mycobacterium avium subspecies paratuberculosis infection modifies gut microbiota under different dietary conditions in a rabbit model. Front Microbiol 7:446. https://doi.org/10.3389/fmicb.2016.00446 CrossRefPubMedPubMedCentralGoogle Scholar
- Aspinall RJ, Weis SM, Barnes L, Lutu-Fuga K, Bylund DJ, Pockros PJ, Cheresh DA (2011) A Src family kinase inhibitor improves survival in experimental acute liver failure associated with elevated cerebral and circulating vascular endothelial growth factor levels. Liver Int 31:1222–1230. https://doi.org/10.1111/j.1478-3231.2011.02554.x CrossRefPubMedPubMedCentralGoogle Scholar
- Bajaj JS, Hylemon PB, Ridlon JM, Heuman DM, Daita K, White MB, Monteith P, Noble NA, Sikaroodi M, Gillevet PM (2012) Colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic encephalopathy and is linked to cognition and inflammation. Am J Physiol Gastrointest Liver Physiol 303:G675–G685. https://doi.org/10.1152/ajpgi.00152.2012 CrossRefPubMedPubMedCentralGoogle Scholar
- Bajaj JS, Heuman DM, Hylemon PB, Sanyal AJ, Puri P, Sterling RK, Luketic V, Stravitz RT, Siddiqui MS, Fuchs M, Thacker LR, Wade JB, Daita K, Sistrun S, White MB, Noble NA, Thorpe C, Kakiyama G, Pandak WM, Sikaroodi M, Gillevet PM (2014) Randomised clinical trial: Lactobacillus GG modulates gut microbiome, metabolome and endotoxemia in patients with cirrhosis. Aliment Pharmacol Ther 39:1113–1125. https://doi.org/10.1111/apt.12695 CrossRefPubMedPubMedCentralGoogle Scholar
- Belenguer A, Duncan SH, Calder AG, Holtrop G, Louis P, Lobley GE, Flint HJ (2006) Two routes of metabolic cross-feeding between Bifidobacterium adolescentis and butyrate-producing anaerobes from the human gut. Appl Environ Microbiol 72:3593–3599. https://doi.org/10.1128/AEM.72.5.3593-3599.2006 CrossRefPubMedPubMedCentralGoogle Scholar
- Bubnov RV, Babenko LP, Lazarenko LM, Mokrozub VV, Demchenko OA, Nechypurenko OV, Spivak MY (2017) Comparative study of probiotic effects of Lactobacillus and Bifidobacteria strains on cholesterol levels, liver morphology and the gut microbiota in obese mice. EPMA J 8:357–376. https://doi.org/10.1007/s13167-017-0117-3 CrossRefPubMedPubMedCentralGoogle 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. https://doi.org/10.2337/db07-1403 CrossRefPubMedGoogle Scholar
- Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD, Costello EK, Fierer N, Pena AG, Goodrich JK, Gordon JI, Huttley GA, Kelley ST, Knights D, Koenig JE, Ley RE, Lozupone CA, McDonald D, Muegge BD, Pirrung M, Reeder J, Sevinsky JR, Turnbaugh PJ, Walters WA, Widmann J, Yatsunenko T, Zaneveld J, Knight R (2010) QIIME allows analysis of high-throughput community sequencing data. Nat Methods 7:335–336. https://doi.org/10.1038/nmeth.f.303 CrossRefPubMedPubMedCentralGoogle Scholar
- Del Chierico F, Nobili V, Vernocchi P, Russo A, Stefanis C, Gnani D, Furlanello C, Zandona A, Paci P, Capuani G, Dallapiccola B, Miccheli A, Alisi A, Putignani L (2017) Gut microbiota profiling of pediatric nonalcoholic fatty liver disease and obese patients unveiled by an integrated meta-omics-based approach. Hepatology 65:451–464. https://doi.org/10.1002/hep.28572 CrossRefPubMedGoogle Scholar
- Dong F, Du YR, Xie W, Strong JA, He XJ, Zhang JM (2012) Increased function of the TRPV1 channel in small sensory neurons after local inflammation or in vitro exposure to the pro-inflammatory cytokine GRO/KC. Neurosci Bull 28:155–164. https://doi.org/10.1007/s12264-012-1208-8 CrossRefPubMedPubMedCentralGoogle Scholar
- Fang D, Shi D, Lv L, Gu S, Wu W, Chen Y, Guo J, Li A, Hu X, Guo F, Ye J, Li Y, Li L (2017) Bifidobacterium pseudocatenulatum LI09 and Bifidobacterium catenulatum LI10 attenuate D-galactosamine-induced liver injury by modifying the gut microbiota. Sci Rep 7:8770. https://doi.org/10.1038/s41598-017-09395-8 CrossRefPubMedPubMedCentralGoogle Scholar
- Frick JS, Fink K, Kahl F, Niemiec MJ, Quitadamo M, Schenk K, Autenrieth IB (2007) Identification of commensal bacterial strains that modulate Yersinia enterocolitica and dextran sodium sulfate-induced inflammatory responses: implications for the development of probiotics. Infect Immun 75:3490–3497. https://doi.org/10.1128/IAI.00119-07 CrossRefPubMedPubMedCentralGoogle Scholar
- Hackstein CP, Assmus LM, Welz M, Klein S, Schwandt T, Schultze J, Förster I, Gondorf F, Beyer M, Kroy D, Kurts C, Trebicka J, Kastenmüller W, Knolle PA, Abdullah Z (2017) Gut microbial translocation corrupts myeloid cell function to control bacterial infection during liver cirrhosis. Gut 66:507–518. https://doi.org/10.1136/gutjnl-2015-311224 CrossRefPubMedGoogle Scholar
- Jaeschke H, Fisher MA, Lawson JA, Simmons CA, Farhood A, Jones DA (1998) Activation of caspase 3 (CPP32)-like proteases is essential for TNF-alpha-induced hepatic parenchymal cell apoptosis and neutrophil-mediated necrosis in a murine endotoxin shock model. J Immunol 160:3480–3486PubMedGoogle Scholar
- Kovatcheva-Datchary P, Nilsson A, Akrami R, Lee YS, De Vadder F, Arora T, Hallen A, Martens E, Bjorck I, Backhed F (2015) Dietary fiber-induced improvement in glucose metabolism is associated with increased abundance of Prevotella. Cell Metab 22:971–982. https://doi.org/10.1016/j.cmet.2015.10.001 CrossRefPubMedGoogle Scholar
- Lang AL, Beier JI (2018) Interaction of volatile organic compounds and underlying liver disease: a new paradigm for risk. Biol Chem. https://doi.org/10.1515/hsz-2017-0324
- Langille MG, Zaneveld J, Caporaso JG, McDonald D, Knights D, Reyes JA, Clemente JC, Burkepile DE, Vega Thurber RL, Knight R, Beiko RG, Huttenhower C (2013) Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nat Biotechnol 31:814–821. https://doi.org/10.1038/nbt.2676 CrossRefPubMedPubMedCentralGoogle Scholar
- Lebrun LJ, Lenaerts K, Kiers D, Pais de Barros JP, Le Guern N, Plesnik J, Thomas C, Bourgeois T, Dejong CHC, Kox M, Hundscheid IHR, Khan NA, Mandard S, Deckert V, Pickkers P, Drucker DJ, Lagrost L, Grober J (2017) Enteroendocrine L cells sense LPS after gut barrier injury to enhance GLP-1 secretion. Cell Rep 21:1160–1168. https://doi.org/10.1016/j.celrep.2017.10.008 CrossRefPubMedGoogle Scholar
- Luo M, Yang XX, Tan B, Zhou XP, Xia HM, Xue J, Xu X, Qing Y, Li CR, Qiu JF, Li YL (2016) Distribution of common pathogens in patients with pyogenic liver abscess in China: a meta-analysis. Eur J Clin Microbiol Infect Dis 35:1557–1565. https://doi.org/10.1007/s10096-016-2712-y CrossRefPubMedPubMedCentralGoogle Scholar
- Lv LX, Hu XJ, Qian GR, Zhang H, Lu HF, Zheng BW, Jiang L, Li LJ (2014) Administration of Lactobacillus salivarius LI01 or Pediococcus pentosaceus LI05 improves acute liver injury induced by D-galactosamine in rats. Appl Microbiol Biotechnol 98:5619–5632. https://doi.org/10.1007/s00253-014-5638-2 CrossRefPubMedGoogle Scholar
- Moratalla A, Caparros E, Juanola O, Portune K, Puig-Kroger A, Estrada-Capetillo L, Bellot P, Gomez-Hurtado I, Pinero P, Zapater P, Gonzalez-Navajas JM, Such J, Sanz Y, Frances R (2016a) Bifidobacterium pseudocatenulatum CECT7765 induces an M2 anti-inflammatory transition in macrophages from patients with cirrhosis. J Hepatol 64:135–145. https://doi.org/10.1016/j.jhep.2015.08.020 CrossRefPubMedGoogle Scholar
- Moratalla A, Gomez-Hurtado I, Moya-Perez A, Zapater P, Peiro G, Gonzalez-Navajas JM, Gomez Del Pulgar EM, Such J, Sanz Y, Frances R (2016b) Bifidobacterium pseudocatenulatum CECT7765 promotes a TLR2-dependent anti-inflammatory response in intestinal lymphocytes from mice with cirrhosis. Eur J Nutr 55:197–206. https://doi.org/10.1007/s00394-015-0837-x CrossRefPubMedGoogle Scholar
- Okada T, Kawakami S, Nakamura Y, Han KH, Ohba K, Aritsuka T, Uchino H, Shimada K, Sekikawa M, Ishii H, Fukushima M (2011) Amelioration of D-galactosamine-induced acute liver injury in rats by dietary supplementation with betaine derived from sugar beet molasses. Biosci Biotechnol Biochem 75:1335–1341. https://doi.org/10.1271/bbb.110105 CrossRefPubMedGoogle Scholar
- Raza GS, Putaala H, Hibberd AA, Alhoniemi E, Tiihonen K, Makela KA, Herzig KH (2017) Polydextrose changes the gut microbiome and attenuates fasting triglyceride and cholesterol levels in Western diet fed mice. Sci Rep 7:5294. https://doi.org/10.1038/s41598-017-05259-3 CrossRefPubMedPubMedCentralGoogle Scholar
- Reddivari L, Veeramachaneni DNR, Walters WA, Lozupone C, Palmer J, Hewage MKK, Bhatnagar R, Amir A, Kennett MJ, Knight R, Vanamala JKP (2017) Perinatal bisphenol a exposure induces chronic inflammation in rabbit offspring via modulation of gut bacteria and their metabolites. mSystems 2. https://doi.org/10.1128/mSystems.00093-17
- Shah NJ, John S (2018) Liver failure, acute on chronic. StatPearls Publishing, Treasure IslandGoogle Scholar
- Singh R, Bullard J, Kalra M, Assefa S, Kaul AK, Vonfeldt K, Strom SC, Conrad RS, Sharp HL, Kaul R (2011) Status of bacterial colonization, Toll-like receptor expression and nuclear factor-kappa B activation in normal and diseased human livers. Clin Immunol 138:41–49. https://doi.org/10.1016/j.clim.2010.09.006 CrossRefPubMedGoogle Scholar
- Spruss A, Henkel J, Kanuri G, Blank D, Puschel GP, Bischoff SC, Bergheim I (2012) Female mice are more susceptible to nonalcoholic fatty liver disease: sex-specific regulation of the hepatic AMP-activated protein kinase-plasminogen activator inhibitor 1 cascade, but not the hepatic endotoxin response. Mol Med 18:1346–1355. https://doi.org/10.2119/molmed.2012.00223 CrossRefPubMedPubMedCentralGoogle Scholar
- Yamada T, Kunimatsu T, Miyata K, Yabushita S, Sukata T, Kawamura S, Seki T, Okuno Y, Mikami N (2004) Enhanced rat Hershberger assay appears reliable for detection of not only (anti-)androgenic chemicals but also thyroid hormone modulators. Toxicol Sci 79:64–74. https://doi.org/10.1093/toxsci/kfh093 CrossRefPubMedGoogle Scholar
- Yu L, Zhao XK, Cheng ML, Yang GZ, Wang B, Liu HJ, Hu YX, Zhu LL, Zhang S, Xiao ZW, Liu YM, Zhang BF, Mu M (2017) Saccharomyces boulardii administration changes gut microbiota and attenuates D-Galactosamine-induced liver injury. Sci Rep 7:1359. https://doi.org/10.1038/s41598-017-01271-9 CrossRefPubMedPubMedCentralGoogle Scholar
- Zinkernagel MS, Zysset-Burri DC, Keller I, Berger LE, Leichtle AB, Largiader CR, Fiedler GM, Wolf S (2017) Association of the intestinal microbiome with the development of neovascular age-related macular degeneration. Sci Rep 7:40826. https://doi.org/10.1038/srep40826 CrossRefPubMedPubMedCentralGoogle Scholar