The role of the gut microbiota in nonalcoholic fatty liver disease - Nature Reviews Gastroenterology & Hepatology
- ️Quigley, Eamonn M. M.
- ️Tue Nov 02 2010
Hoefert, B. Über die bakterienbefunde im duodenalsaft von gesunden und kranken. Zschr. Klin. Med. 92, 221–235 (1921).
Quigley, E. M. Gastrointestinal dysfunction in liver disease and portal hypertension. Gut–liver interactions revisited. Dig. Dis. Sci. 41, 557–561 (1996).
Yang, C. Y., Chang, C. S. & Chen, G. H. Small-intestinal bacterial overgrowth in patients with liver cirrhosis, diagnosed with glucose H2 or CH4 breath tests. Scand. J. Gastroenterol. 33, 867–871 (1998).
Chesta, J., Silva, M., Thompson, L., del Canto, E. & Defilippi, C. Bacterial overgrowth in small intestine in patients with liver cirrhosis [Spanish]. Rev. Med. Chil. 119, 626–632 (1991).
Casafont, F., Almohalla, C., Garcia Pajares, F. & Pons Romero, F. Intestinal bacteria overgrowth in chronic hepatopathies [Spanish]. Rev. Med. Univ. Navarra 42, 183–187 (1998).
Madrid, A. M., Hurtado, C., Venegas, M., Cumsille, F. & Defilippi, C. Long-term treatment with cisapride and antibiotics in liver cirrhosis: effect on small intestinal motility, bacterial overgrowth, and liver function. Am. J. Gastroenterol. 96, 1251–1255 (2001).
Madrid, A. M., Cumsille, F. & Defilippi, C. Altered small bowel motility in patients with liver cirrhosis depends on severity of liver disease. Dig. Dis. Sci. 42, 738–742 (1997).
Chesta, J. et al. Patients with liver cirrhosis: mouth–cecum transit time and gastric emptying of solid foods [Spanish]. Rev. Med. Chil. 119, 1248–1253 (1991).
Park, C. H. et al. Neostigmine for the treatment of acute hepatic encephalopathy with acute intestinal pseudo-obstruction in a cirrhotic patient. J. Korean Med. Sci. 20, 150–152 (2005).
Aldersley, M. A. & Howdle, P. D. Intestinal permeability and liver disease. Eur. J. Gastroenterol. Hepatol. 11, 401–403 (1999).
Bouin, M. et al. Increased oro-cecal transit time in grade I or II hepatic encephalopathy. Gastroenterol. Clin. Biol. 28, 1240–1244 (2004).
Maheshwari, A., Thomas, A. & Thuluvath, P. J. Patients with autonomic neuropathy are more likely to develop hepatic encephalopathy. Dig. Dis. Sci. 49, 1584–1588 (2004).
Toh, Y. et al. Assessing the permeability of the gastrointestinal mucosa after oral administration of phenolsulfonphthalein. Hepatogastroenterology 44, 1147–1151 (1997).
Keshavarzian, A. et al. Leaky gut in alcoholic cirrhosis: a possible mechanism for alcohol-induced liver damage. Am. J. Gastroenterol. 94, 200–207 (1999).
Thalheimer, U. et al. Altered intestinal function precedes the appearance of bacterial DNA in serum and ascites in patients with cirrhosis: a pilot study. Eur. J. Gastroenterol. Hepatol. 22, 1228–1234 (2010).
González Alonso, R., González García, M. & Albillos Martínez, A. Physiopathology of bacterial translocation and spontaneous bacterial peritonitis in cirrhosis [Spanish]. Gastroenterol. Hepatol. 30, 78–84 (2007).
Nolan, J. P. Intestinal endotoxins as mediators of hepatic injury—an idea whose time has come again. Hepatology 10, 887–891 (1989).
Kirsch, R. et al. Rodent nutritional model of steatohepatitis: effects of endotoxin (lipopolysaccharide) and tumor necrosis factor α deficiency. J. Gastroenterol. Hepatol. 21, 174–182 (2006).
Fabbrini, E., Sullivan, S. & Klein, S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology 51, 679–689 (2010).
Bäckhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718–15723 (2004).
Eckburg, P. B. et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005).
Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).
Bajzer, M. & Seeley, R. J. Physiology: obesity and gut flora. Nature 444, 1009–1010 (2006).
Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006).
Zhang, H. et al. Human gut microbiota in obesity and after gastric bypass. Proc. Natl Acad. Sci. USA 106, 2365–2370 (2009).
Kalliomäki, M., Collado, M. C., Salminen, S. & Isolauri, E. Early differences in fecal microbiota composition in children may predict overweight. Am. J. Clin. Nutr. 87, 534–538 (2008).
Webb, P. & Annis, J. F. Adaptation to overeating in lean and overweight men and women. Hum. Nutr. Clin. Nutr. 37, 117–131 (1983).
Comstock, L. E. & Coyne, M. J. Bacteroides thetaiotaomicron: a dynamic, niche-adapted human symbiont. Bioessays 25, 926–929 (2003).
Samuel, B. S. & Gordon, J. I. A humanized gnotobiotic mouse model of host-archaeal-bacterial mutualism. Proc. Natl Acad. Sci. USA 103, 10011–10016 (2006).
Bäckhed, F., Manchester, J. K., Semenkovich, C. F. & Gordon, J. I. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc. Natl Acad. Sci. USA 104, 979–984 (2007).
Jones, B. V., Begley, M., Hill, C., Gahan, C. G. & Marchesi, J. R. Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome. Proc. Natl Acad. Sci. USA 105, 13580–13585 (2008).
Lorenzo-Zúñiga, V. et al. Oral bile acids reduce bacterial overgrowth, bacterial translocation, and endotoxemia in cirrhotic rats. Hepatology 37, 551–557 (2003).
Ogata, Y. et al. Role of bile in intestinal barrier function and its inhibitory effect on bacterial translocation in obstructive jaundice in rats. J. Surg. Res. 115, 18–23 (2003).
Houten, S. M., Watanabe, M. & Auwerx, J. Endocrine functions of bile acids. EMBO J. 25, 1419–1425 (2006).
Martin, F. P. et al. A top-down systems biology view of microbiome-mammalian metabolic interactions in a mouse model. Mol. Syst. Biol. 3, 112 (2007).
Pagano, G. et al. Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome: further evidence for an etiologic association. Hepatology 35, 367–372 (2002).
Farrell, G. C. Signalling links in the liver: knitting SOCS with fat and inflammation. J. Hepatol. 43, 193–196 (2005).
Li, Z. et al. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 37, 343–350 (2003).
Brun, P. et al. Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G518–G525 (2007).
Kim, J. J. & Sears, D. D. TLR4 and insulin resistance. Gastroenterol. Res. Pract. doi:10.1155/2010/212563.
Cani, P. D. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772 (2007).
Creely, S. J. et al. Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 292, E740–E747 (2007).
Peraldi, P. & Spiegelman, B. TNF-α and insulin resistance: summary and future prospects. Mol. Cell Biochem. 182, 169–175 (1998).
Chou, C. J., Membrez, M. & Blancher, F. Gut decontamination with norfloxacin and ampicillin enhances insulin sensitivity in mice. Nestle Nutr. Workshop Ser. Pediatr. Program. 62, 127–140 (2008).
Cani, P. D. et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57, 1470–1481 (2008).
Schwartz, R. F., Neu, J., Schatz, D., Atkinson, M. A. & Wasserfall, C. Comment on: Brugman, S. et al. (2006) Antibiotic treatment partially protects against type 1 diabetes in the Bio-Breeding diabetes-prone rat. Is the gut flora involved in the development of type 1 diabetes? Diabetologia 49, 2105–2108. Diabetologia 50, 220–221 (2007).
Wen, L. et al. Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 455, 1109–1113 (2008).
Brugman, S. et al. Antibiotic treatment partially protects against type 1 diabetes in the Bio-Breeding diabetes-prone rat. Is the gut flora involved in the development of type 1 diabetes? Diabetologia 49, 2105–2108 (2006).
Calcinaro, F. et al. Oral probiotic administration induces interleukin-10 production and prevents spontaneous autoimmune diabetes in the non-obese diabetic mouse. Diabetologia 48, 1565–1575 (2005).
Buchman, A. L. et al. Choline deficiency: a cause of hepatic steatosis during parenteral nutrition that can be reversed with intravenous choline supplementation. Hepatology 22, 1399–1403 (1995).
Teramoto, K., Bowers, J. L., Khettry, U., Palombo, J. D. & Clouse, M. E. A rat fatty liver transplant model. Transplantation 55, 737–741 (1993).
Weltman, M. D., Farrell, G. C. & Liddle, C. Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation. Gastroenterology 111, 1645–1653 (1996).
Zeisel, S. H., Wishnok, J. S. & Blusztajn, J. K. Formation of methylamines from ingested choline and lecithin. J. Pharmacol. Exp. Ther. 225, 320–324 (1983).
Nicholson, J. K. & Wilson, I. D. Opinion: understanding 'global' systems biology: metabonomics and the continuum of metabolism. Nat. Rev. Drug Discov. 2, 668–676 (2003).
Lang, D. H. et al. Isoform specificity of trimethylamine N-oxygenation by human flavin-containing monooxygenase (FMO) and P450 enzymes: selective catalysis by FMO3. Biochem. Pharmacol. 56, 1005–1012 (1998).
al-Waiz, M., Mikov, M., Mitchell, S. C. & Smith, R. L. The exogenous origin of trimethylamine in the mouse. Metabolism 41, 135–136 (1992).
Dumas, M. E. et al. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc. Natl Acad. Sci. USA 103, 12511–12516 (2006).
Fassio, E., Alvarez, E., Domínguez, N., Landeira, G. & Longo, C. Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies. Hepatology 40, 820–826 (2004).
Harrison, S. A., Torgerson, S. & Hayashi, P. H. The natural history of nonalcoholic fatty liver disease: a clinical histopathological study. Am. J. Gastroenterol. 98, 2042–2047 (2003).
Bugianesi, E. et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 123, 134–140 (2002).
Quigley, E. M., Marsh, M. N., Shaffer, J. L. & Markin, R. S. Hepatobiliary complications of total parenteral nutrition. Gastroenterology 104, 286–301 (1993).
Carter, B. A. & Karpen, S. J. Intestinal failure-associated liver disease: management and treatment strategies past, present, and future. Semin. Liver Dis. 27, 251–258 (2007).
Pappo, I. et al. Polymyxin B reduces total parenteral nutrition-associated hepatic steatosis by its antibacterial activity and by blocking deleterious effects of lipopolysaccharide. JPEN J. Parenter. Enteral Nutr. 16, 529–532 (1992).
Soza, A. et al. Increased orocecal transit time in patients with nonalcoholic fatty liver disease. Dig. Dis. Sci. 50, 1136–1140 (2005).
Cope, K., Risby, T. & Diehl, A. M. Increased gastrointestinal ethanol production in obese mice: implications for fatty liver disease pathogenesis. Gastroenterology 119, 1340–1347 (2000).
Fan, J. G., Xu, Z. J. & Wang, G. L. Effect of lactulose on establishment of a rat non-alcoholic steatohepatitis model. World J. Gastroenterol. 11, 5053–5056 (2005).
Corrodi, P. Jejunoileal bypass: change in the flora of the small intestine and its clinical impact. Rev. Infect. Dis. 6 (Suppl. 1), S80–S84 (1984).
Vanderhoof, J. A., Tuma, D. J., Antonson, D. L. & Sorrell, M. F. Effect of antibiotics in the prevention of jejunoileal bypass-induced liver dysfunction. Digestion 23, 9–15 (1982).
Drenick, E. J., Fisler, J. & Johnson, D. Hepatic steatosis after intestinal bypass—prevention and reversal by metronidazole, irrespective of protein-calorie malnutrition. Gastroenterology 82, 535–548 (1982).
Kim, W. R. et al. Recurrence of nonalcoholic steatohepatitis following liver transplantation. Transplantation 62, 1802–1805 (1996).
Lichtman, S. N., Keku, J., Schwab, J. H. & Sartor, R. B. Hepatic injury associated with small bowel bacterial overgrowth in rats is prevented by metronidazole and tetracycline. Gastroenterology 100, 513–519 (1991).
Nazim, M., Stamp, G. & Hodgson, H. J. Non-alcoholic steatohepatitis associated with small intestinal diverticulosis and bacterial overgrowth. Hepatogastroenterology 36, 349–351 (1989).
Crowell, M. D., Cheskin, L. J. & Musial, F. Prevalence of gastrointestinal symptoms in obese and normal weight binge eaters. Am. J. Gastroenterol. 89, 387–391 (1994).
Verne, G. N. & Sninsky, C. A. Diabetes and the gastrointestinal tract. Gastroenterol. Clin. North Am. 27, 861–874, vi–vii (1998).
Cuoco, L. et al. Eradication of small intestinal bacterial overgrowth and oro-cecal transit in diabetics. Hepatogastroenterology 49, 1582–1586 (2002).
Basilisco, G. et al. Orocecal transit delay in obese patients. Dig. Dis. Sci. 34, 509–512 (1989).
Castañeda, T. R., Tong, J., Datta, R., Culler, M. & Tschöp, M. H. Ghrelin in the regulation of body weight and metabolism. Front. Neuroendocrinol. 31, 44–60 (2010).
Camilleri, M., Papathanasopoulos, A. & Odunsi, S. T. Actions and therapeutic pathways of ghrelin for gastrointestinal disorders. Nat. Rev. Gastroenterol. Hepatol. 6, 343–352 (2009).
Sajjad, A. et al. Ciprofloxacin suppresses bacterial overgrowth, increases fasting insulin but does not correct low acylated ghrelin concentration in non-alcoholic steatohepatitis. Aliment Pharmacol. Ther. 22, 291–299 (2005).
Yalniz, M. et al. Serum adipokine and ghrelin levels in nonalcoholic steatohepatitis. Mediators Inflamm. 2006, 34295 (2006).
Wigg, A. J. et al. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut 48, 206–211 (2001).
Abu-Shanab, A. et al. Small intestinal bacterial overgrowth in non-alcoholic steato-hepatitis; association with Toll-like receptor 4 expression and plasma levels of interleukin 8. Dig Dis. Sci. (2010) (in press).
Fu, X. S. & Jiang, F. Cisapride decreasing orocecal transit time in patients with nonalcoholic steatohepatitis. Hepatobiliary Pancreat. Dis. Int. 5, 534–537 (2006).
Riordan, S. M. et al. Small intestinal bacterial overgrowth, intestinal permeability, and non-alcoholic steatohepatitis. Gut 50, 136–138 (2002).
Miele, L. et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 49, 1877–1887 (2009).
Solga, S. F. & Diehl, A. M. Non-alcoholic fatty liver disease: lumen-liver interactions and possible role for probiotics. J. Hepatol. 38, 681–687 (2003).
Neal, M. D. et al. Enterocyte TLR4 mediates phagocytosis and translocation of bacteria across the intestinal barrier. J. Immunol. 176, 3070–3079 (2006).
Amar, J. et al. Energy intake is associated with endotoxemia in apparently healthy men. Am. J. Clin. Nutr. 87, 1219–1223 (2008).
Vreugdenhil, A. C. et al. Lipopolysaccharide (LPS)-binding protein mediates LPS detoxification by chylomicrons. J. Immunol. 170, 1399–1405 (2003).
Wright, S. D., Ramos, R. A., Tobias, P. S., Ulevitch, R. J. & Mathison, J. C. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 249, 1431–1433 (1990).
Beutler, B., Hoebe, K., Du, X. & Ulevitch, R. J. How we detect microbes and respond to them: the Toll-like receptors and their transducers. J. Leukoc. Biol. 74, 479–485 (2003).
Yudkin, J. S., Stehouwer, C. D., Emeis, J. J. & Coppack, S. W. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler. Thromb. Vasc. Biol. 19, 972–978 (1999).
Dandona, P. et al. Tumor necrosis factor-α in sera of obese patients: fall with weight loss. J. Clin. Endocrinol. Metab. 83, 2907–2910 (1998).
Zahorska-Markiewicz, B., Janowska, J., Olszanecka-Glinianowicz, M. & Zurakowski, A. Serum concentrations of TNF-α and soluble TNF-α receptors in obesity. Int. J. Obes. Relat. Metab. Disord. 24, 1392–1395 (2000).
Hotamisligil, G. S., Murray, D. L., Choy, L. N. & Spiegelman, B. M. Tumor necrosis factor α inhibits signaling from the insulin receptor. Proc. Natl Acad. Sci. USA 91, 4854–4858 (1994).
Feinstein, R., Kanety, H., Papa, M. Z., Lunenfeld, B. & Karasik, A. Tumor necrosis factor-α suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates. J. Biol. Chem. 268, 26055–26058 (1993).
del Aguila, L. F., Claffey, K. P. & Kirwan, J. P. TNF-α impairs insulin signaling and insulin stimulation of glucose uptake in C2C12 muscle cells. Am. J. Physiol. 276, E849–E855 (1999).
Uysal, K. T., Wiesbrock, S. M., Marino, M. W. & Hotamisligil, G. S. Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature 389, 610–614 (1997).
Diehl, A. M. Cytokine regulation of liver injury and repair. Immunol. Rev. 174, 160–171 (2000).
Yang, S. Q., Lin, H. Z., Lane, M. D., Clemens, M. & Diehl, A. M. Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis. Proc. Natl Acad. Sci. USA 94, 2557–2562 (1997).
Tobias, P. S., Soldau, K., Gegner, J. A., Mintz, D. & Ulevitch, R. J. Lipopolysaccharide binding protein-mediated complexation of lipopolysaccharide with soluble CD14. J. Biol. Chem. 270, 10482–10488 (1995).
Su, G. L. Lipopolysaccharides in liver injury: molecular mechanisms of Kupffer cell activation. Am. J. Physiol. Gastrointest. Liver Physiol. 283, G256–G265 (2002).
Baldwin, A. S. Jr. The NF-κB and IκB proteins: new discoveries and insights. Annu. Rev. Immunol. 14, 649–683 (1996).
Ruiz, A. G. et al. Lipopolysaccharide-binding protein plasma levels and liver TNF-α gene expression in obese patients: evidence for the potential role of endotoxin in the pathogenesis of non-alcoholic steatohepatitis. Obes. Surg. 17, 1374–1380 (2007).
Szabo, G., Velayudham, A., Romics, L. Jr & Mandrekar, P. Modulation of non-alcoholic steatohepatitis by pattern recognition receptors in mice: the role of Toll-like receptors 2 and 4. Alcohol Clin. Exp. Res. 29 (11 Suppl.), 140S–145S (2005).
Rivera, C. A. et al. Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J. Hepatol. 47, 571–579 (2007).
Iimuro, Y., Gallucci, R. M., Luster, M. I., Kono, H. & Thurman, R. G. Antibodies to tumor necrosis factor α attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat. Hepatology 26, 1530–1537 (1997).
Brun, P., Castagliuolo, I., Pinzani, M., Palù, G. & Martines, D. Exposure to bacterial cell wall products triggers an inflammatory phenotype in hepatic stellate cells. Am. J. Physiol. Gastrointest. Liver Physiol. 289, G571–G578 (2005).
Paik, Y. H. et al. Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatology 37, 1043–1055 (2003).
Bataller, R. & Brenner, D. A. Liver fibrosis. J. Clin. Invest. 115, 209–218 (2005).
Mezey, E. in Schiff's Diseases of the Liver (eds Schiff, E. R., Sorrell, M. F. & Maddrey, W. C.) 1185–1197 (Lippincott-Raven, Philadelphia, 1999).
Faggioni, R. et al. Leptin deficiency enhances sensitivity to endotoxin-induced lethality. Am. J. Physiol. 276, R136–R142 (1999).
Gustot, T. et al. Differential liver sensitization to Toll-like receptor pathways in mice with alcoholic fatty liver. Hepatology 43, 989–1000 (2006).
Baraona, E., Julkunen, R., Tannenbaum, L. & Lieber, C. S. Role of intestinal bacterial overgrowth in ethanol production and metabolism in rats. Gastroenterology 90, 103–110 (1986).
Adachi, Y., Moore, L. E., Bradford, B. U., Gao, W. & Thurman, R. G. Antibiotics prevent liver injury in rats following long-term exposure to ethanol. Gastroenterology 108, 218–224 (1995).
Nair, S., Cope, K., Risby, T. H. & Diehl, A. M. Obesity and female gender increase breath ethanol concentration: potential implications for the pathogenesis of nonalcoholic steatohepatitis. Am. J. Gastroenterol. 96, 1200–1204 (2001).
Cani, P. D. & Delzenne, N. M. The role of the gut microbiota in energy metabolism and metabolic disease. Curr. Pharm. Des. 15, 1546–1558 (2009).
Cani, P. D., Dewever, C. & Delzenne, N. M. Inulin-type fructans modulate gastrointestinal peptides involved in appetite regulation (glucagon-like peptide-1 and ghrelin) in rats. Br. J. Nutr. 92, 521–526 (2004).
Cani, P. D., Neyrinck, A. M., Maton, N. & Delzenne, N. M. Oligofructose promotes satiety in rats fed a high-fat diet: involvement of glucagon-like peptide-1. Obes. Res. 13, 1000–1007 (2005).
Delzenne, N. M., Cani, P. D., Daubioul, C. & Neyrinck, A. M. Impact of inulin and oligofructose on gastrointestinal peptides. Br. J. Nutr. 93 (Suppl. 1), S157–S161 (2005).
Archer, B. J., Johnson, S. K., Devereux, H. M. & Baxter, A. L. Effect of fat replacement by inulin or lupin-kernel fibre on sausage patty acceptability, post-meal perceptions of satiety and food intake in men. Br. J. Nutr. 91, 591–599 (2004).
Cani, P. D., Joly, E., Horsmans, Y. & Delzenne, N. M. Oligofructose promotes satiety in healthy human: a pilot study. Eur. J. Clin. Nutr. 60, 567–572 (2006).
Hildebrandt, M. A. et al. High-fat diet determines the composition of the murine gut microbiome independently of obesity. Gastroenterology 137, 1716–1724 (2009).
Martin, F. P. et al. Probiotic modulation of symbiotic gut microbial–host metabolic interactions in a humanized microbiome mouse model. Mol. Syst. Biol. 4, 157 (2008).
Qing, L. & Wang, T. Lactic acid bacteria prevent alcohol-induced steatohepatitis in rats by acting on the pathways of alcohol metabolism. Clin. Exp. Med. 8, 187–191 (2008).
Marotta, F. et al. Experimental acute alcohol pancreatitis-related liver damage and endotoxemia: synbiotics but not metronidazole have a protective effect. Chin. J. Dig. Dis. 6, 193–197 (2005).
Forsyth, C. B. et al. Lactobacillus GG treatment ameliorates alcohol-induced intestinal oxidative stress, gut leakiness, and liver injury in a rat model of alcoholic steatohepatitis. Alcohol 43, 163–172 (2009).
Cani, P. D. et al. Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia 50, 2374–2383 (2007).
Stadlbauer, V. et al. Effect of probiotic treatment on deranged neutrophil function and cytokine responses in patients with compensated alcoholic cirrhosis. J. Hepatol. 48, 945–951 (2008).
Salminen, S. & Salminen, E. Lactulose, lactic acid bacteria, intestinal microecology and mucosal protection. Scand. J. Gastroenterol. Suppl. 222, 45–48 (1997).
Loguercio, C. et al. Gut–liver axis: a new point of attack to treat chronic liver damage? Am. J. Gastroenterol. 97, 2144–2146 (2002).
Al-Salami, H. et al. Probiotic treatment reduces blood glucose levels and increases systemic absorption of gliclazide in diabetic rats. Eur. J. Drug Metab. Pharmacokinet. 33, 101–106 (2008).
De Smet, I., De Boever, P. & Verstraete, W. Cholesterol lowering in pigs through enhanced bacterial bile salt hydrolase activity. Br. J. Nutr. 79, 185–194 (1998).
Armstrong, M. J. & Carey, M. C. The hydrophobic-hydrophilic balance of bile salts. Inverse correlation between reverse-phase high performance liquid chromatographic mobilities and micellar cholesterol-solubilizing capacities. J. Lipid Res. 23, 70–80 (1982).
Heuman, D. M. Quantitative estimation of the hydrophilic–hydrophobic balance of mixed bile salt solutions. J. Lipid Res. 30, 719–730 (1989).
Heuman, D. M., Hylemon, P. B. & Vlahcevic, Z. R. Regulation of bile acid synthesis. III. Correlation between biliary bile salt hydrophobicity index and the activities of enzymes regulating cholesterol and bile acid synthesis in the rat. J. Lipid Res. 30, 1161–1171 (1989).
Narushima, S., Ito, K., Kuruma, K. & Uchida, K. Composition of cecal bile acids in ex-germfree mice inoculated with human intestinal bacteria. Lipids 35, 639–644 (2000).
Tannock, G. W. A special fondness for lactobacilli. Appl. Environ. Microbiol. 70, 3189–3194 (2004).
Terahara, M., Nishide, S. & Kaneko, T. Preventive effect of Lactobacillus delbrueckii subsp. bulgaricus on the oxidation of LDL. Biosci. Biotechnol. Biochem. 64, 1868–1873 (2000).
Xiao, J. Z. et al. Effects of milk products fermented by Bifidobacterium longum on blood lipids in rats and healthy adult male volunteers. J. Dairy Sci. 86, 2452–2461 (2003).
Pereira, D. I. & Gibson, G. R. Effects of consumption of probiotics and prebiotics on serum lipid levels in humans. Crit. Rev. Biochem. Mol. Biol. 37, 259–281 (2002).
Larkin, T. A., Astheimer, L. B. & Price, W. E. Dietary combination of soy with a probiotic or prebiotic food significantly reduces total and LDL cholesterol in mildly hypercholesterolaemic subjects. Eur. J. Clin. Nutr. 63, 238–245 (2009).
Yadav, H., Jain, S. & Sinha, P. R. Oral administration of dahi containing probiotic Lactobacillus acidophilus and Lactobacillus casei delayed the progression of streptozotocin-induced diabetes in rats. J. Dairy Res. 75, 189–195 (2008).
Lee, H. Y. et al. Human originated bacteria, Lactobacillus rhamnosus PL60, produce conjugated linoleic acid and show anti-obesity effects in diet-induced obese mice. Biochim. Biophys. Acta 1761, 736–744 (2006).
Wall, R. et al. Metabolic activity of the enteric microbiota influences the fatty acid composition of murine and porcine liver and adipose tissues. Am. J. Clin. Nutr. 89, 1393–1401 (2009).
Lee, Y. K. et al. Quantitative approach in the study of adhesion of lactic acid bacteria to intestinal cells and their competition with enterobacteria. Appl. Environ. Microbiol. 66, 3692–3697 (2000).
Madsen, K. et al. Probiotic bacteria enhance murine and human intestinal epithelial barrier function. Gastroenterology 121, 580–591 (2001).
Resta-Lenert, S. & Barrett, K. E. Live probiotics protect intestinal epithelial cells from the effects of infection with enteroinvasive Escherichia coli (EIEC). Gut 52, 988–997 (2003).
Ghosh, S., van Heel, D. & Playford, R. J. Probiotics in inflammatory bowel disease: is it all gut flora modulation? Gut 53, 620–622 (2004).
Kanauchi, O. et al. Increased growth of Bifidobacterium and Eubacterium by germinated barley foodstuff, accompanied by enhanced butyrate production in healthy volunteers. Int. J. Mol. Med. 3, 175–179 (1999).
Haller, D. et al. Non-pathogenic bacteria elicit a differential cytokine response by intestinal epithelial cell/leucocyte co-cultures. Gut 47, 79–87 (2000).
Grönlund, M. M., Arvilommi, H., Kero, P., Lehtonen, O. P. & Isolauri, E. Importance of intestinal colonisation in the maturation of humoral immunity in early infancy: a prospective follow up study of healthy infants aged 0–6 months. Arch. Dis. Child Fetal Neonatal Ed. 83, F186–F192 (2000).
Eizaguirre, I. et al. Probiotic supplementation reduces the risk of bacterial translocation in experimental short bowel syndrome. J. Pediatr. Surg. 37, 699–702 (2002).
Chiva, M. et al. Effect of Lactobacillus johnsonii La1 and antioxidants on intestinal flora and bacterial translocation in rats with experimental cirrhosis. J. Hepatol. 37, 456–462 (2002).
Adawi, D., Kasravi, F. B., Molin, G. & Jeppsson, B. Effect of Lactobacillus supplementation with and without arginine on liver damage and bacterial translocation in an acute liver injury model in the rat. Hepatology 25, 642–647 (1997).
Adawi, D., Ahrné, S. & Molin, G. Effects of different probiotic strains of Lactobacillus and Bifidobacterium on bacterial translocation and liver injury in an acute liver injury model. Int. J. Food Microbiol. 70, 213–220 (2001).
Lirussi, F., Mastropasqua, E., Orando, S. & Orlando, R. Probiotics for non-alcoholic fatty liver disease and/or steatohepatitis. Cochrane Database Syst. Rev. Issue 1, Art. No.: CD005165. doi:10.1002/14651858.CD005165.pub2 (2007).