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Improved hemodynamic and liver function in portal hypertensive cirrhotic rats after administration of B. pseudocatenulatum CECT 7765

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Abstract

Purpose

Evaluating whether changes in gut microbiota induced by a bifidobacterial strain may have an effect on the hepatic vascular function in portal hypertensive cirrhotic rats.

Methods

Bile duct ligation (BDL) was performed in rats. A subgroup of animals received B. pseudocatenulatum CECT7765 (109 cfu/daily ig.) for 1 week prior to laparotomy. Hemodynamic, biochemical and inflammatory markers were evaluated. Ileal microbiota composition was identified. Statistical analysis was performed.

Results

Sham-operated (n = 6), BDL (n = 6) and BDL treated with bifidobacteria (n = 8) rats were included. B. pseudocatenulatum CECT7765 significantly decreased proteobacteria (p = 0.001) and increased Bacteroidetes (p = 0.001) relative abundance. The bifidobacteria decreased the Firmicutes/Bacteroidetes ratio in the BDL model (p = 0.03). BDL with bifidobacteria vs BDL rats showed: significantly reduced portal vein area, portal flow, congestion index, alkaline phosphatase and total bilirubin, significantly increased serum cytokines and nitric oxide levels, gene expression levels of bile acids receptor FXR and endothelial nitric oxide synthase. Quantitative changes in the Clostridiales and Bacteroidales orders were independently associated with variations in portal vein area and portal flow, while changes in the Proteobacteria phylum were independently associated with congestion. Variations in all liver function markers significantly correlated with total OTUs mainly in the Firmicutes, but only changes in the Clostridiales were independently associated with alkaline phosphatase in the ANCOVA analysis.

Conclusion

Hemodynamic alterations and liver dysfunction induced by BDL in rats are partially restored after oral administration of B. pseudocatenulatum CECT7765. Results provide a proof-of-concept for the beneficial effect of this bifidobacterial strain in reducing complications derived from portal hypertension in cirrhosis.

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References

  1. Bosch J, Pizcueta P, Feu F, Fernandez M, Garcia-Pagan JC (1992) Pathophysiology of portal hypertension. Gastroenterol Clin N Am 21:1–14

    CAS  Google Scholar 

  2. Bataller R, Brenner DA (2005) Liver fibrosis. J Clin Invest 115:209–218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Colombato LA, Albillos A, Groszmann RJ (1992) Temporal relationship of peripheral vasodilatation, plasma volume expansion and the hyperdynamic circulatory state in portal-hypertensive rats. Hepatology 15:323–328

    Article  CAS  PubMed  Google Scholar 

  4. Fernandez J, Ruiz del Arbol L, Gomez C, Durandez R, Serradilla R, Guarner C et al (2006) Norfloxacin vs ceftriaxone in the prophylaxis of infections in patients with advanced cirrhosis and hemorrhage. Gastroenterology 131:1049–1056 (quiz 1285)

    Article  CAS  PubMed  Google Scholar 

  5. Rimola A, Garcia-Tsao G, Navasa M, Piddock LJ, Planas R, Bernard B et al (2000) Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. Int Ascites Club J Hepatol 32:142–153

    CAS  Google Scholar 

  6. Bajaj JS, Ridlon JM, Hylemon PB, Thacker LR, Heuman DM, Smith S et al (2012) Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol 302:G168-175

    Article  CAS  Google Scholar 

  7. Bajaj JS, Hylemon PB, Ridlon JM, Heuman DM, Daita K, White MB et al (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:G675-685

    Article  CAS  Google Scholar 

  8. Chen Y, Yang F, Lu H, Wang B, Chen Y, Lei D et al (2011) Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 54:562–572

    Article  PubMed  Google Scholar 

  9. Morencos FC, de las Heras Castano G, Martin Ramos L, Lopez Arias MJ, Ledesma F, Pons Romero F (1995) Small bowel bacterial overgrowth in patients with alcoholic cirrhosis. Digest Dis Sci 40:1252–1256

    Article  CAS  PubMed  Google Scholar 

  10. Pande C, Kumar A, Sarin SK (2009) Small-intestinal bacterial overgrowth in cirrhosis is related to the severity of liver disease. Aliment Pharmacol Ther 29:1273–1281

    Article  CAS  PubMed  Google Scholar 

  11. Bauer TM, Steinbruckner B, Brinkmann FE, Ditzen AK, Schwacha H, Aponte JJ et al (2001) Small intestinal bacterial overgrowth in patients with cirrhosis: prevalence and relation with spontaneous bacterial peritonitis. Am J Gastroenterol 96:2962–2967

    Article  CAS  PubMed  Google Scholar 

  12. Chang CS, Chen GH, Lien HC, Yeh HZ (1998) Small intestine dysmotility and bacterial overgrowth in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology 28:1187–1190

    Article  CAS  PubMed  Google Scholar 

  13. Gupta N, Kumar A, Sharma P, Garg V, Sharma BC, Sarin SK (2013) Effects of the adjunctive probiotic VSL#3 on portal haemodynamics in patients with cirrhosis and large varices: a randomized trial. Liver Int 33:1148–1157

    Article  CAS  PubMed  Google Scholar 

  14. Rahimi RS, Rockey DC (2012) Complications of cirrhosis. Curr Opin Gastroenterol 28:223–229

    Article  PubMed  Google Scholar 

  15. Wiest R, Chen F, Cadelina G, Groszmann RJ, Garcia-Tsao G (2003) Effect of Lactobacillus-fermented diets on bacterial translocation and intestinal flora in experimental prehepatic portal hypertension. Dig Dis Sci 48:1136–1141

    Article  CAS  PubMed  Google Scholar 

  16. Moratalla A, Gomez-Hurtado I, Santacruz A, Moya A, Peiro G, Zapater P et al (2014) Protective effect of Bifidobacterium pseudocatenulatum CECT7765 against induced bacterial antigen translocation in experimental cirrhosis. Liver Int 34:850–858

    Article  CAS  PubMed  Google Scholar 

  17. Moratalla A, Caparros E, Juanola O, Portune K, Puig-Kroger A, Estrada-Capetillo L et al (2016) Bifidobacterium pseudocatenulatum CECT7765 induces an M2 anti-inflammatory transition in macrophages from patients with cirrhosis. J Hepatol 64:135–145

    Article  CAS  PubMed  Google Scholar 

  18. Kountouras J, Billing BH, Scheuer PJ (1984) Prolonged bile duct obstruction: a new experimental model for cirrhosis in the rat. Br J Exp Pathol 65:305–311

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Wu MJ, Chen M, Sang S, Hou LL, Tian ML, Li K et al (2017) Protective effects of hydrogen rich water on the intestinal ischemia/reperfusion injury due to intestinal intussusception in a rat model. Med Gas Res 7:101–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Claesson MJ, Wang Q, O’Sullivan O, Greene-Diniz R, Cole JR, Ross RP et al (2010) Comparison of two next-generation sequencing technologies for resolving highly complex microbiota composition using tandem variable 16S rRNA gene regions. Nucleic Acids Res 38:e200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Schloss PD, Westcott SL, Ryabin T, Hall JR, Hartmann M, Hollister EB et al (2009) Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities. Appl Environ Microbiol 75:7537–7541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kozich JJ, Westcott SL, Baxter NT, Highlander SK, Schloss PD (2013) Development of a dual-index sequencing strategy and curation pipeline for analyzing amplicon sequence data on the MiSeq Illumina sequencing platform. Appl Environ Microbiol 79:5112–5120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Pruesse E, Quast C, Knittel K, Fuchs BM, Ludwig W, Peplies J et al (2007) SILVA: a comprehensive online resource for quality checked and aligned ribosomal RNA sequence data compatible with ARB. Nucleic Acids Res 35:7188–7196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Edgar RC, Haas BJ, Clemente JC, Quince C, Knight R (2011) UCHIME improves sensitivity and speed of chimera detection. Bioinformatics 27:2194–2200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cole JR, Wang Q, Fish JA, Chai B, McGarrell DM, Sun Y et al (2014) Ribosomal database project: data and tools for high throughput rRNA analysis. Nucleic Acids Res 42:D633–642

    Article  CAS  PubMed  Google Scholar 

  26. Evans J, Sheneman L, Foster J (2006) Relaxed neighbor joining: a fast distance-based phylogenetic tree construction method. J Mol Evol 62:785–792

    Article  CAS  PubMed  Google Scholar 

  27. Matsuki T, Watanabe K, Fujimoto J, Miyamoto Y, Takada T, Matsumoto K et al (2002) Development of 16S rRNA-gene-targeted group-specific primers for the detection and identification of predominant bacteria in human feces. Appl Environ Microbiol 68:5445–5451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Matsuki T, Watanabe K, Fujimoto J, Takada T, Tanaka R (2004) Use of 16S rRNA gene-targeted group-specific primers for real-time PCR analysis of predominant bacteria in human feces. Appl Environ Microbiol 70:7220–7228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Santacruz A, Collado MC, Garcia-Valdes L, Segura MT, Martin-Lagos JA, Anjos T et al (2010) Gut microbiota composition is associated with body weight, weight gain and biochemical parameters in pregnant women. Br J Nutr 104:83–92

    Article  CAS  PubMed  Google Scholar 

  30. Seitz BM, Krieger-Burke T, Fink GD, Watts SW (2016) Serial measurements of splanchnic vein diameters in rats using high-frequency ultrasound. Front Pharmacol 7:116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Guarner C, Runyon BA, Young S, Heck M, Sheikh MY (1997) Intestinal bacterial overgrowth and bacterial translocation in cirrhotic rats with ascites. J Hepatol 26:1372–1378

    Article  CAS  PubMed  Google Scholar 

  32. Guarner C, Soriano G (2005) Bacterial translocation and its consequences in patients with cirrhosis. Eur J Gastroenterol Hepatol 17:27–31

    Article  CAS  PubMed  Google Scholar 

  33. Berg RD (1992) Bacterial translocation from the gastrointestinal tract. J Med 23:217–244

    CAS  PubMed  Google Scholar 

  34. Wiest R, Garcia-Tsao G (2005) Bacterial translocation (BT) in cirrhosis. Hepatology 41:422–433

    Article  CAS  PubMed  Google Scholar 

  35. Wiest R, Groszmann RJ (2002) The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough. Hepatology 35:478–491

    Article  CAS  PubMed  Google Scholar 

  36. Theodorakis NG, Wang YN, Skill NJ, Metz MA, Cahill PA, Redmond EM et al (2003) The role of nitric oxide synthase isoforms in extrahepatic portal hypertension: studies in gene-knockout mice. Gastroenterology 124:1500–1508

    Article  CAS  PubMed  Google Scholar 

  37. Quigley EM (1996) Gastrointestinal dysfunction in liver disease and portal hypertension. Gut-liver interactions revisited. Dig Dis Sci 41:557–561

    Article  CAS  PubMed  Google Scholar 

  38. Lopez-Talavera JC, Merrill WW, Groszmann RJ (1995) Tumor necrosis factor alpha: a major contributor to the hyperdynamic circulation in prehepatic portal-hypertensive rats. Gastroenterology 108:761–767

    Article  CAS  PubMed  Google Scholar 

  39. Thalheimer U, Triantos CK, Samonakis DN, Patch D, Burroughs AK (2005) Infection, coagulation, and variceal bleeding in cirrhosis. Gut 54:556–563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rincon D, Vaquero J, Hernando A, Galindo E, Ripoll C, Puerto M et al (2014) Oral probiotic VSL#3 attenuates the circulatory disturbances of patients with cirrhosis and ascites. Liver Int 34:1504–1512

    Article  CAS  PubMed  Google Scholar 

  41. Everard A, Cani PD (2013) Diabetes, obesity and gut microbiota. Best Pract Res Clin Gastroenterol 27:73–83

    Article  CAS  PubMed  Google Scholar 

  42. Yang T, Santisteban MM, Rodriguez V, Li E, Ahmari N, Carvajal JM et al (2015) Gut dysbiosis is linked to hypertension. Hypertension 65:1331–1340

    Article  CAS  PubMed  Google Scholar 

  43. Marques FZ, Nelson E, Chu PY, Horlock D, Fiedler A, Ziemann M et al (2017) High-fiber diet and acetate supplementation change the gut microbiota and prevent the development of hypertension and heart failure in hypertensive mice. Circulation 135:964–977

    Article  CAS  PubMed  Google Scholar 

  44. Zhang X, Zhao Y, Xu J, Xue Z, Zhang M, Pang X et al (2015) Modulation of gut microbiota by berberine and metformin during the treatment of high-fat diet-induced obesity in rats. Sci Rep 5:14405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sina C, Gavrilova O, Forster M, Till A, Derer S, Hildebrand F et al (2009) G protein-coupled receptor 43 is essential for neutrophil recruitment during intestinal inflammation. J Immunol 183:7514–7522

    Article  CAS  PubMed  Google Scholar 

  46. Kumar A, Wu H, Collier-Hyams LS, Kwon YM, Hanson JM, Neish AS (2009) The bacterial fermentation product butyrate influences epithelial signaling via reactive oxygen species-mediated changes in cullin-1 neddylation. J Immunol 182:538–546

    Article  CAS  PubMed  Google Scholar 

  47. Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D et al (2009) Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461:1282–1286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. De Filippo C, Cavalieri D, Di Paola M, Ramazzotti M, Poullet JB, Massart S et al (2010) Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci USA 107:14691–14696

    Article  PubMed  PubMed Central  Google Scholar 

  49. Li Z, Yang S, Lin H, Huang J, Watkins PA, Moser AB et al (2003) Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 37:343–350

    Article  CAS  PubMed  Google Scholar 

  50. 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  PubMed  Google Scholar 

  51. Giannini EG, Testa R, Savarino V (2005) Liver enzyme alteration: a guide for clinicians. CMAJ 172:367–379

    Article  PubMed  PubMed Central  Google Scholar 

  52. Inagaki T, Moschetta A, Lee YK, Peng L, Zhao G, Downes M et al (2006) Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci USA 103:3920–3925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Verbeke L, Farre R, Verbinnen B, Covens K, Vanuytsel T, Verhaegen J et al (2015) The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats. Am J Pathol 185:409–419

    Article  CAS  PubMed  Google Scholar 

  54. Lorenzo-Zuniga V, Bartoli R, Planas R, Hofmann AF, Vinado B, Hagey LR et al (2003) Oral bile acids reduce bacterial overgrowth, bacterial translocation, and endotoxemia in cirrhotic rats. Hepatology 37:551–557

    Article  CAS  PubMed  Google Scholar 

  55. Park YJ, Qatanani M, Chua SS, LaRey JL, Johnson SA, Watanabe M et al (2008) Loss of orphan receptor small heterodimer partner sensitizes mice to liver injury from obstructive cholestasis. Hepatology 47:1578–1586

    Article  CAS  PubMed  Google Scholar 

  56. Marschall HU, Wagner M, Bodin K, Zollner G, Fickert P, Gumhold J et al (2006) Fxr(−/−) mice adapt to biliary obstruction by enhanced phase I detoxification and renal elimination of bile acids. J Lipid Res 47:582–592

    Article  CAS  PubMed  Google Scholar 

  57. Thabut D, Massard J, Gangloff A, Carbonell N, Francoz C, Nguyen-Khac E et al (2007) Model for end-stage liver disease score and systemic inflammatory response are major prognostic factors in patients with cirrhosis and acute functional renal failure. Hepatology 46:1872–1882

    Article  PubMed  Google Scholar 

  58. Vairappan B (2015) Endothelial dysfunction in cirrhosis: Role of inflammation and oxidative stress. World J Hepatol 7:443–459

    Article  PubMed  PubMed Central  Google Scholar 

  59. Moratalla A, Gomez-Hurtado I, Moya-Perez A, Zapater P, Peiro G, Gonzalez-Navajas JM et al (2016) Bifidobacterium pseudocatenulatum CECT7765 promotes a TLR2-dependent anti-inflammatory response in intestinal lymphocytes from mice with cirrhosis. Eur J Nutr 55:197–206

    Article  CAS  PubMed  Google Scholar 

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Funding

This work has been partially funded by Grants PI16/0967 from Instituto de Salud Carlos III, Madrid, Spain, PROMETEO/2016/001 from Generalitat Valenciana, Valencia, Spain, by FEDER funds and by the European Union’s Seventh Framework Program under the grant agreement no 613979 (MyNewGut).

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Authors and Affiliations

  1. CIBERehd, Instituto de Salud Carlos III, Madrid, Spain

    Isabel Gómez-Hurtado, Pedro Zapater, Oriol Juanola, Anabel Fernández-Iglesias, José M. González-Navajas, Jordi Gracia-Sancho & Rubén Francés

  2. Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL-Fundación FISABIO), Alicante, Spain

    Pedro Zapater, José M. González-Navajas & Rubén Francés

  3. Dpto. Medicina Clínica, Universidad Miguel Hernández, San Juan, Spain

    Pedro Zapater, Oriol Juanola & Rubén Francés

  4. Grupo de Ecofisiología Bacteriana, IATA-CSIC, Valencia, Spain

    Kevin Portune & Yolanda Sanz

  5. Liver Vascular Biology Research Group, IDIBAPS, Barcelona, Spain

    Anabel Fernández-Iglesias & Jordi Gracia-Sancho

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  1. Isabel Gómez-Hurtado
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  2. Pedro Zapater
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  3. Kevin Portune
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Correspondence to Rubén Francés.

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Gómez-Hurtado, I., Zapater, P., Portune, K. et al. Improved hemodynamic and liver function in portal hypertensive cirrhotic rats after administration of B. pseudocatenulatum CECT 7765. Eur J Nutr 58, 1647–1658 (2019). https://doi.org/10.1007/s00394-018-1709-y

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  • DOI: https://doi.org/10.1007/s00394-018-1709-y

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