- Fouhy, F., Ross, R. P., Fitzgerald, G. F., Stanton, C. & Cotter, P. D. Composition of the early intestinal microbiota: knowledge, knowledge gaps and the use of high-throughput sequencing to address these gaps. Gut Microbes 3, 203–220 (2012).
Article PubMed PubMed Central Google Scholar
- Prakash, S., Tomaro-Duchesneau, C., Saha, S. & Cantor, A. The gut microbiota and human health with an emphasis on the use of microencapsulated bacterial cells. J. Biomed. Biotechnol. 2011, 981214 (2011).
Article PubMed PubMed Central Google Scholar
- Fraher, M. H., O’Toole, P. W. & Quigley, E. M. M. Techniques used to characterize the gut microbiota: a guide for the clinician. Nat. Rev. Gastroenterol. Hepatol. 9, 312–322 (2012).
Article CAS PubMed Google Scholar
- Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010).
CAS PubMed PubMed Central Google Scholar
- Li, J. et al. An integrated catalog of reference genes in the human gut microbiome. Nat. Biotechnol. 32, 834–841 (2014).
Article CAS PubMed Google Scholar
- Karlsson, F., Tremaroli, V., Nielsen, J. & Bäckhed, F. Assessing the human gut microbiota in metabolic diseases. Diabetes 62, 3341–3349 (2013).
Article CAS PubMed PubMed Central Google Scholar
- Lynch, S. V. & Pedersen, O. The human intestinal microbiome in health and disease. N. Engl. J. Med. 375, 2369–2379 (2016).
Article CAS PubMed Google Scholar
- Bäckhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718–15723 (2004).
Article PubMed CAS PubMed Central Google Scholar
- Ridaura, V. K. et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341, 1241214 (2013).
Article PubMed CAS Google Scholar
- 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).
Article CAS PubMed Google Scholar
- Le Chatelier, E. et al. Richness of human gut microbiome correlates with metabolic markers. Nature 500, 541 (2013).
Article PubMed CAS Google Scholar
- Cotillard, A. et al. Dietary intervention impact on gut microbial gene richness. Nature 500, 585–588 (2013).
Article CAS PubMed Google Scholar
- Moreno-Indias, I., Cardona, F., Tinahones, F. J. & Queipo-Ortuño, M. I. Impact of the gut microbiota on the development of obesity and type 2 diabetes mellitus. Front. Microbiol. 5, 190 (2014).
Article PubMed PubMed Central Google Scholar
- Qin, J. et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60 (2012).
Article CAS PubMed Google Scholar
- Karlsson, F. H. et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498, 99–103 (2013).
Article CAS PubMed Google Scholar
- Tilg, H., Zmora, N., Adolph, T. E. & Elinav, E. The intestinal microbiota fuelling metabolic inflammation. Nat. Rev. Immunol. 20, 40–54 (2020).
Article CAS PubMed Google Scholar
- Aron-Wisnewsky, J. & Clément, K. The gut microbiome, diet, and links to cardiometabolic and chronic disorders. Nat. Rev. Nephrol. 12, 169–181 (2016).
Article CAS PubMed Google Scholar
- Plovier, H. et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat. Med. 23, 107–113 (2017).
Article CAS PubMed Google Scholar
- Dewulf, E. M. et al. Insight into the prebiotic concept: lessons from an exploratory, double blind intervention study with inulin-type fructans in obese women. Gut 62, 1112–1121 (2013).
Article CAS PubMed Google Scholar
- Davis, C. D. The gut microbiome and its role in obesity. Nutr. Today 51, 167–174 (2016).
Article PubMed PubMed Central Google Scholar
- Vrieze, A. et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 143, 913–916.e7 (2012).
Article CAS PubMed Google Scholar
- Kootte, R. S. et al. Improvement of insulin sensitivity after lean donor feces in metabolic syndrome is driven by baseline intestinal microbiota composition. Cell Metab. 26, 611–619 (2017).
Article CAS PubMed Google Scholar
- European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD) & European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. Diabetologia 59, 1121–1140 (2016).
Article Google Scholar
- Estes, C., Razavi, H., Loomba, R., Younossi, Z. & Sanyal, A. J. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology 67, 123–133 (2018).
Article CAS PubMed Google Scholar
- Noureddin, M. et al. NASH leading cause of liver transplant in women: updated analysis of indications for liver transplant and ethnic and gender variances. Am. J. Gastroenterol. 113, 1649–1659 (2018).
Article PubMed PubMed Central Google Scholar
- Castera, L. Diagnosis of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: non-invasive tests are enough. Liver Int. 38 (Suppl. 1), 67–70 (2018).
Article PubMed Google Scholar
- Van Herck, M. A., Vonghia, L. & Francque, S. M. Animal models of nonalcoholic fatty liver disease-a starter’s guide. Nutrients 9, 1072 (2017).
Article PubMed Central CAS Google Scholar
- Aron-Wisnewsky, J., Gaborit, B., Dutour, A. & Clement, K. Gut microbiota and non-alcoholic fatty liver disease: new insights. Clin. Microbiol. Infect. 19, 338–348 (2013).
Article CAS PubMed Google Scholar
- Wieland, A., Frank, D. N., Harnke, B. & Bambha, K. Systematic review: microbial dysbiosis and nonalcoholic fatty liver disease. Aliment. Pharmacol. Ther. 42, 1051–1063 (2015).
Article CAS PubMed Google Scholar
- Roychowdhury, S., Selvakumar, P. C. & Cresci, G. A. The role of the gut microbiome in nonalcoholic fatty liver disease. Med. Sci. 6, 47 (2018).
Google Scholar
- Bedossa, P. et al. Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Hepatology 56, 1751–1759 (2012). This work proposes a novel algorithm to classify patients as without NAFLD, with NAFLD or with overt NASH that is more robust than previous algorithms; since its development, it has been used in many studies.
Article PubMed Google Scholar
- Brunt, E. M. et al. Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology 53, 810–820 (2011).
Article CAS PubMed Google Scholar
- Hagström, H. et al. SAF score and mortality in NAFLD after up to 41 years of follow-up. Scand. J. Gastroenterol. 52, 87–91 (2017).
Article PubMed Google Scholar
- Pais, R. et al. A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. J. Hepatol. 59, 550–556 (2013).
Article CAS PubMed Google Scholar
- Schuppan, D. & Afdhal, N. H. Liver cirrhosis. Lancet 371, 838–851 (2008).
Article CAS PubMed PubMed Central Google Scholar
- Fingas, C. D., Best, J., Sowa, J.-P. & Canbay, A. Epidemiology of nonalcoholic steatohepatitis and hepatocellular carcinoma. Clin. Liver Dis. 8, 119–122 (2016).
Article Google Scholar
- Ratziu, V., Bellentani, S., Cortez-Pinto, H., Day, C. & Marchesini, G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J. Hepatol. 53, 372–384 (2010).
Article PubMed Google Scholar
- Karlas, T., Wiegand, J. & Berg, T. Gastrointestinal complications of obesity: non-alcoholic fatty liver disease (NAFLD) and its sequelae. Best. Pract. Res. Clin. Endocrinol. Metab. 27, 195–208 (2013).
Article CAS PubMed Google Scholar
- Nusrat, S., Khan, M. S., Fazili, J. & Madhoun, M. F. Cirrhosis and its complications: evidence based treatment. World J. Gastroenterol. 20, 5442–5460 (2014).
Article CAS PubMed PubMed Central Google Scholar
- Lu, Z.-Y., Shao, Z., Li, Y.-L., Wulasihan, M. & Chen, X.-H. Prevalence of and risk factors for non-alcoholic fatty liver disease in a Chinese population: an 8-year follow-up study. World J. Gastroenterol. 22, 3663–3669 (2016).
Article CAS PubMed PubMed Central Google Scholar
- Fazel, Y., Koenig, A. B., Sayiner, M., Goodman, Z. D. & Younossi, Z. M. Epidemiology and natural history of non-alcoholic fatty liver disease. Metabolism 65, 1017–1025 (2016).
Article CAS PubMed Google Scholar
- Wong, V. W.-S. et al. Beneficial effects of lifestyle intervention in non-obese patients with non-alcoholic fatty liver disease. J. Hepatol. 69, 1349–1356 (2018).
Article PubMed Google Scholar
- Ching-Yeung, Yu, B., Kwok, D. & Wong, V. W. Magnitude of nonalcoholic fatty liver disease: eastern perspective. J. Clin. Exp. Hepatol. 9, 491–496 (2019).
Article Google Scholar
- Yki-Järvinen, H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol. 2, 901–910 (2014).
Article PubMed CAS Google Scholar
- European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD) & European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J. Hepatol. 64, 1388–1402 (2016).
Google Scholar
- Vanni, E. et al. From the metabolic syndrome to NAFLD or vice versa? Digestive Liver Dis. 42, 320–330 (2010).
Article CAS Google Scholar
- Yki-Järvinen, H. & Luukkonen, P. K. Diabetes, liver cancer and cirrhosis: what next? Hepatology 68, 1220–1222 (2018).
Article PubMed Google Scholar
- Younossi, Z. M. et al. Pathologic criteria for nonalcoholic steatohepatitis: Interprotocol agreement and ability to predict liver-related mortality. Hepatology 53, 1874–1882 (2011).
Article PubMed Google Scholar
- Sumida, Y., Nakajima, A. & Itoh, Y. Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J. Gastroenterol. 20, 475–485 (2014).
Article PubMed PubMed Central Google Scholar
- Shen, J. et al. Non-invasive diagnosis of non-alcoholic steatohepatitis by combined serum biomarkers. J. Hepatol. 56, 1363–1370 (2012).
Article CAS PubMed Google Scholar
- Dasarathy, S. et al. Validity of real time ultrasound in the diagnosis of hepatic steatosis: a prospective study. J. Hepatol. 51, 1061–1067 (2009).
Article PubMed PubMed Central Google Scholar
- Wildman-Tobriner, B. et al. Association between magnetic resonance imaging-proton density fat fraction and liver histology features in patients with nonalcoholic fatty liver disease or nonalcoholic steatohepatitis. Gastroenterology 155, 1428–1435.e2 (2018).
Article PubMed Google Scholar
- Friedrich-Rust, M., Poynard, T. & Castera, L. Critical comparison of elastography methods to assess chronic liver disease. Nat. Rev. Gastroenterol. Hepatol. 13, 402–411 (2016).
Article PubMed Google Scholar
- Xiao, G. et al. Comparison of laboratory tests, ultrasound, or magnetic resonance elastography to detect fibrosis in patients with nonalcoholic fatty liver disease: a meta-analysis. Hepatology 66, 1486–1501 (2017).
Article CAS PubMed Google Scholar
- Wong, V. W.-S. et al. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology 51, 454–462 (2010).
Article CAS PubMed Google Scholar
- Papagianni, M., Sofogianni, A. & Tziomalos, K. Non-invasive methods for the diagnosis of nonalcoholic fatty liver disease. World J. Hepatol. 7, 638–648 (2015).
Article PubMed PubMed Central Google Scholar
- Dyson, J. K., Anstee, Q. M. & McPherson, S. Non-alcoholic fatty liver disease: a practical approach to diagnosis and staging. Frontline Gastroenterol. 5, 211 (2014).
Article CAS PubMed Google Scholar
- Morra, R. et al. FibroMAXTM: towards a new universal biomarker of liver disease? Expert. Rev. Mol. Diagnostics 7, 481–490 (2007).
Article Google Scholar
- Alkhouri, N. et al. Evaluation of circulating markers of hepatic apoptosis and inflammation in obese children with and without obstructive sleep apnea. Sleep. Med. 16, 1031–1035 (2015).
Article PubMed Google Scholar
- Gunn, N. T. & Shiffman, M. L. The use of liver biopsy in nonalcoholic fatty liver disease: when to biopsy and in whom. Clin. Liver Dis. 22, 109–119 (2018).
Article PubMed Google Scholar
- Vilar-Gomez, E. & Chalasani, N. Non-invasive assessment of non-alcoholic fatty liver disease: clinical prediction rules and blood-based biomarkers. J. Hepatol. 68, 305–315 (2018).
Article CAS PubMed Google Scholar
- Eddowes, P. J. et al. Accuracy of fibroscan controlled attenuation parameter and liver stiffness measurement in assessing steatosis and fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology 156, 1717–1730 (2019).
Article PubMed Google Scholar
- Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012).
Article CAS PubMed PubMed Central Google Scholar
- Le Roy, T. et al. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut 62, 1787–1794 (2013).
Article PubMed CAS Google Scholar
- Farrell, G. et al. Mouse models of nonalcoholic steatohepatitis Towards optimization of their relevance to human NASH. Hepatology 69, 2241–2257 (2019).
Article PubMed Google Scholar
- Nguyen, T. L. A., Vieira-Silva, S., Liston, A. & Raes, J. How informative is the mouse for human gut microbiota research? Dis. Model. Mech. 8, 1–16 (2015).
Article CAS PubMed PubMed Central Google Scholar
- Chiu, C.-C. et al. Nonalcoholic fatty liver disease is exacerbated in high-fat diet-fed gnotobiotic mice by colonization with the gut microbiota from patients with nonalcoholic steatohepatitis. Nutrients 9, 1220 (2017).
Article PubMed Central CAS Google Scholar
- Le Roy, T. et al. Comparative evaluation of microbiota engraftment following fecal microbiota transfer in mice models: age, kinetic and microbial status matter. Front. Microbiol. 9, 3289 (2018).
Article PubMed Google Scholar
- Hoyles, L. et al. Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women. Nat. Med. 24, 1070–1080 (2018). This work reveals molecular networks linking the gut microbiome (using metagenomic analysis) and the host phenome (hepatic transcriptome as well as urine and plasma metabolome) to hepatic steatosis.
Article CAS PubMed PubMed Central Google Scholar
- Brandl, K. & Schnabl, B. Intestinal microbiota and nonalcoholic steatohepatitis. Curr. Opin. Gastroenterol. 33, 128–133 (2017).
Article CAS PubMed PubMed Central Google Scholar
- Leung, C., Rivera, L., Furness, J. B. & Angus, P. W. The role of the gut microbiota in NAFLD. Nat. Rev. Gastroenterol. Hepatol. 13, 412–425 (2016).
Article CAS PubMed Google Scholar
- Loomba, R. Role of imaging-based biomarkers in NAFLD: recent advances in clinical application and future research directions. J. Hepatol. 68, 296–304 (2018).
Article PubMed Google Scholar
- Wang, B. et al. Altered fecal microbiota correlates with liver biochemistry in nonobese patients with non-alcoholic fatty liver disease. Sci. Rep. 6, 32002 (2016).
Article CAS PubMed PubMed Central Google Scholar
- Shen, F. et al. Gut microbiota dysbiosis in patients with non-alcoholic fatty liver disease. Hepatobiliary Pancreat. Dis. Int. 16, 375–381 (2017). This work was one of the first to use the HiSeq 2000 platform to sequence the microbiome and discover a microbial related signature of NAFLD (biopsy proven) as compared with healthy individuals as controls in a Chinese cohort.
Article PubMed Google Scholar
- Raman, M. et al. Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 11, 868–875.e1-3 (2013).
Article CAS PubMed Google Scholar
- Loomba, R. et al. Gut microbiome based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease. Cell Metab. 25, 1054–1062.e5 (2017). This work offers a first microbiota signature of NAFLD-related fibrosis severity using whole-genome shotgun sequencing to sequence the microbiome in patients with biopsy-proven NASH and fibrosis.
Article CAS PubMed PubMed Central Google Scholar
- Zhu, L. et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 57, 601–609 (2013).
Article CAS PubMed Google Scholar
- Del Chierico, F. et al. Gut microbiota profiling of pediatric nonalcoholic fatty liver disease and obese patients unveiled by an integrated meta-omics-based approach. Hepatology 65, 451–464 (2017). This work provides a microbial signature of NAFLD–NASH in children and uses several control groups (one of individuals with obesity without NAFLD and one of healthy individuals).
Article PubMed CAS Google Scholar
- Boursier, J. et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 63, 764–775 (2016).
Article CAS PubMed Google Scholar
- Mouzaki, M. et al. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology 58, 120–127 (2013).
Article CAS PubMed Google Scholar
- Michail, S. et al. Altered gut microbial energy and metabolism in children with non-alcoholic fatty liver disease. FEMS Microbiol. Ecol. 91, 1–9 (2015).
Article PubMed CAS Google Scholar
- Da Silva, H. E. et al. Nonalcoholic fatty liver disease is associated with dysbiosis independent of body mass index and insulin resistance. Sci. Rep. 8, 1466 (2018).
Article PubMed PubMed Central CAS Google Scholar
- Wong, V. W. et al. Molecular characterization of the fecal microbiota in patients with nonalcoholic steatohepatitis–a longitudinal study. PLOS ONE 8, e62885 (2013).
Article CAS PubMed PubMed Central Google Scholar
- Aron-Wisnewsky, J. et al. Major microbiota dysbiosis in severe obesity: fate after bariatric surgery. Gut https://doi.org/10.1136/gutjnl-2018-316103 (2018).
Article PubMed Google Scholar
- Pedersen, H. K. et al. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature 535, 376–381 (2016).
Article CAS PubMed Google Scholar
- Forslund, K. et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528, 262–266 (2015).
Article CAS PubMed PubMed Central Google Scholar
- Chen, Y. et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 54, 562–572 (2011).
Article PubMed Google Scholar
- Chen, Y. et al. Dysbiosis of small intestinal microbiota in liver cirrhosis and its association with etiology. Sci. Rep. 6, 34055 (2016).
Article CAS PubMed PubMed Central Google Scholar
- Bajaj, J. S. et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J. Hepatol. 60, 940–947 (2014). This paper discusses the gut microbial signature of patients with cirrhosis compared with that of healthy individuals, then addresses whether this signature is stable over time in compensated cirrhosis as well as further assessing the changes in patients undergoing decompensated cirrhosis.
Article CAS PubMed Google Scholar
- Qin, N. et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 513, 59–64 (2014). The first study to offer a microbial signature of liver cirrhosis in adults, comparing 98 patients with 83 healthy individuals using quantitative metagenomics.
Article CAS PubMed Google Scholar
- Caussy, C. et al. A gut microbiome signature for cirrhosis due to nonalcoholic fatty liver disease. Nat. Commun. 10, 1406 (2019).
Article PubMed PubMed Central CAS Google Scholar
- Iebba, V. et al. Combining amplicon sequencing and metabolomics in cirrhotic patients highlights distinctive microbiota features involved in bacterial translocation, systemic inflammation and hepatic encephalopathy. Sci. Rep. 8, 8210 (2018).
Article PubMed PubMed Central CAS Google Scholar
- Cani, P. D. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772 (2007).
Article CAS PubMed Google Scholar
- Mao, J.-W. et al. Intestinal mucosal barrier dysfunction participates in the progress of nonalcoholic fatty liver disease. Int. J. Clin. Exp. Pathol. 8, 3648–3658 (2015).
CAS PubMed PubMed Central Google Scholar
- Quévrain, E. et al. Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn’s disease. Gut 65, 415–425 (2016).
Article PubMed CAS Google Scholar
- Sokol, H. et al. Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflamm. Bowel Dis. 15, 1183–1189 (2009).
Article CAS PubMed Google Scholar
- Rajilic´-Stojanovic´, M. et al. Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome. Gastroenterology 141, 1792–1801 (2011).
Article PubMed CAS Google Scholar
- Furet, J.-P. et al. Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes 59, 3049–3057 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Sharpton, S. R., Ajmera, V. & Loomba, R. Emerging role of the gut microbiome in nonalcoholic fatty liver disease: from composition to function. Clin. Gastroenterol. Hepatol. 17, 296–306 (2019).
Article CAS PubMed Google Scholar
- Harte, A. L. et al. Elevated endotoxin levels in non-alcoholic fatty liver disease. J. Inflamm. 7, 15 (2010).
Article CAS Google Scholar
- Arab, J. P., Karpen, S. J., Dawson, P. A., Arrese, M. & Trauner, M. Bile acids and nonalcoholic fatty liver disease: molecular insights and therapeutic perspectives. Hepatology 65, 350–362 (2017).
Article PubMed Google Scholar
- Cruz-Ramón, V., Chinchilla-López, P., Ramírez-Pérez, O. & Méndez-Sánchez, N. Bile acids in nonalcoholic fatty liver disease: new concepts and therapeutic advances. Ann. Hepatol. 16, S58–S67 (2017).
Article PubMed CAS Google Scholar
- Chiang, J. Y. L. Bile acid metabolism and signaling in liver disease and therapy. Liver Res. 1, 3–9 (2017).
Article PubMed PubMed Central Google Scholar
- Canfora, E. E., Jocken, J. W. & Blaak, E. E. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat. Rev. Endocrinol. 11, 577–591 (2015).
Article CAS PubMed Google Scholar
- Schwiertz, A. et al. Microbiota and SCFA in lean and overweight healthy subjects. Obesity 18, 190–195 (2010).
Article PubMed Google Scholar
- Raubenheimer, P. J., Nyirenda, M. J. & Walker, B. R. A choline-deficient diet exacerbates fatty liver but attenuates insulin resistance and glucose intolerance in mice fed a high-fat diet. Diabetes 55, 2015 (2006).
Article CAS PubMed Google Scholar
- Yu, D. et al. Higher dietary choline intake is associated with lower risk of nonalcoholic fatty liver in normal-weight Chinese women. J. Nutr. 144, 2034–2040 (2014).
Article CAS PubMed PubMed Central Google Scholar
- Spencer, M. D. et al. Association between composition of the human gastrointestinal microbiome and development of fatty liver with choline deficiency. Gastroenterology 140, 976–986 (2011).
Article CAS PubMed Google Scholar
- 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).
Article CAS PubMed PubMed Central Google Scholar
- Chen, Y. et al. Associations of gut-flora-dependent metabolite trimethylamine-N-oxide, betaine and choline with non-alcoholic fatty liver disease in adults. Sci. Rep. 6, 19076 (2016).
Article CAS PubMed PubMed Central Google Scholar
- Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011).
Article CAS PubMed PubMed Central Google Scholar
- Tang, W. H. W. et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl. J. Med. 368, 1575–1584 (2013).
Article CAS PubMed PubMed Central Google Scholar
- Koeth, R. A. et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19, 576–585 (2013).
Article CAS PubMed PubMed Central Google Scholar
- Dumas, M.-E., Kinross, J. & Nicholson, J. K. Metabolic phenotyping and systems biology approaches to understanding metabolic syndrome and fatty liver disease. Gastroenterology 146, 46–62 (2014).
Article PubMed Google Scholar
- Di Ciaula, A. et al. Bile acid physiology. Ann. Hepatol. 16 (Suppl. 1), S4–S14 (2017).
Article PubMed CAS Google Scholar
- Wahlström, A., Sayin, S. I., Marschall, H.-U. & Bäckhed, F. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 24, 41–50 (2016).
Article PubMed CAS Google Scholar
- Sayin, S. I. et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 17, 225–235 (2013).
Article CAS PubMed Google Scholar
- Staley, C., Weingarden, A. R., Khoruts, A. & Sadowsky, M. J. Interaction of gut microbiota with bile acid metabolism and its influence on disease states. Appl. Microbiol. Biotechnol. 101, 47–64 (2017).
Article CAS PubMed Google Scholar
- Ridlon, J. M., Kang, D. J., Hylemon, P. B. & Bajaj, J. S. Bile acids and the gut microbiome. Curr. Opin. Gastroenterol. 30, 332–338 (2014).
Article PubMed PubMed Central Google Scholar
- Liu, H., Hu, C., Zhang, X. & Jia, W. Role of gut microbiota, bile acids and their cross-talk in the effects of bariatric surgery on obesity and type 2 diabetes. J. Diabetes Investig. 9, 13–20 (2018).
Article PubMed Google Scholar
- Kakiyama, G. et al. Modulation of the fecal bile acid profile by gut microbiota in cirrhosis. J. Hepatol. 58, 949–955 (2013).
Article CAS PubMed PubMed Central Google Scholar
- Chávez-Talavera, O., Tailleux, A., Lefebvre, P. & Staels, B. Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease. Gastroenterology 152, 1679–1694.e3 (2017).
Article PubMed CAS Google Scholar
- Caussy, C. et al. Link between gut-microbiome derived metabolite and shared gene-effects with hepatic steatosis and fibrosis in NAFLD. Hepatology https://doi.org/10.1002/hep.29892 (2018).
Article PubMed Google Scholar
- Volynets, V. et al. Nutrition, intestinal permeability, and blood ethanol levels are altered in patients with nonalcoholic fatty liver disease (NAFLD). Digestive Dis. Sci. 57, 1932–1941 (2012).
Article CAS Google Scholar
- Bashiardes, S., Shapiro, H., Rozin, S., Shibolet, O. & Elinav, E. Non-alcoholic fatty liver and the gut microbiota. Mol. Metab. 5, 782–794 (2016).
Article CAS PubMed PubMed Central Google Scholar
- Yuan, J. et al. Fatty liver disease caused by high-alcohol-producing Klebsiella pneumoniae. Cell Metab. 30, 675–688.e7 (2019).
Article CAS PubMed Google Scholar
- Kolodziejczyk, A. A., Zheng, D., Shibolet, O. & Elinav, E. The role of the microbiome in NAFLD and NASH. EMBO Mol. Med. 11, e9302 (2019).
Article PubMed CAS Google Scholar
- Chu, H., Duan, Y., Yang, L. & Schnabl, B. Small metabolites, possible big changes: a microbiota-centered view of non-alcoholic fatty liver disease. Gut 68, 359–370 (2019).
Article CAS PubMed Google Scholar
- Brown, A. J. et al. The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J. Biol. Chem. 278, 11312–11319 (2003).
Article CAS PubMed Google Scholar
- Samuel, B. S. et al. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc. Natl Acad. Sci. USA 105, 16767–16772 (2008).
Article CAS PubMed PubMed Central Google Scholar
- den Besten, G. et al. Gut-derived short-chain fatty acids are vividly assimilated into host carbohydrates and lipids. Am. J. Physiol. Gastrointest. Liver Physiol. 305, G900–G910 (2013).
Article CAS Google Scholar
- Rau, M. et al. Fecal SCFAs and SCFA-producing bacteria in gut microbiome of human NAFLD as a putative link to systemic T-cell activation and advanced disease. United European Gastroenterol. J. 6, 1496–1507 (2018).
Article CAS PubMed PubMed Central Google Scholar
- Rau, M. et al. Progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis is marked by a higher frequency of Th17 cells in the liver and an increased Th17/resting regulatory T cell ratio in peripheral blood and in the Liver. J. Immunol. 196, 97–105 (2016).
Article CAS PubMed Google Scholar
- Sun, M., Wu, W., Liu, Z. & Cong, Y. Microbiota metabolite short chain fatty acids, GPCR, and inflammatory bowel diseases. J. Gastroenterol. 52, 1–8 (2017).
Article CAS PubMed Google Scholar
- Maslowski, K. M. et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 1282–1286 (2009).
Article CAS PubMed PubMed Central Google Scholar
- Wen, W. & Schwabe, R. F. Soluble fibers improve metabolic syndrome but may cause liver disease and hepatocellular carcinoma. Hepatology 70, 739–741 (2019).
PubMed Google Scholar
- Singh, V. et al. Dysregulated microbial fermentation of soluble fiber induces cholestatic liver cancer. Cell 175, 679–694 (2018).
Article CAS PubMed PubMed Central Google Scholar
- Aron-Wisnewsky, J., Warmbrunn, M., Nieuwdorp, M. & Clément, K. Nonalcoholic fatty liver disease: modulating gut microbiota to improve severity? Gastroenterology https://doi.org/10.1053/j.gastro.2020.01.049 (2020).
Article PubMed Google Scholar
- Kim, M. et al. Histone deacetylase inhibition attenuates hepatic steatosis in rats with experimental Cushing’s syndrome. Korean J. Physiol. Pharmacol. 22, 23–33 (2018).
Article CAS PubMed Google Scholar
- Loomba, R., Sirlin, C. B., Schwimmer, J. B. & Lavine, J. E. Advances in pediatric nonalcoholic fatty liver disease. Hepatology 50, 1282–1293 (2009).
Article CAS PubMed Google Scholar
- Nobili, V. et al. NAFLD in children: new genes, new diagnostic modalities and new drugs. Nat. Rev. Gastroenterol. Hepatol. 16, 517–530 (2019).
Article PubMed Google Scholar
- Vos, M. B. et al. NASPGHAN clinical practice guideline for the diagnosis and treatment of nonalcoholic fatty liver disease in children: recommendations from the expert committee on NAFLD (ECON) and the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN). J. Pediatr. Gastroenterol. Nutr. 64, 319–334 (2017).
Article PubMed PubMed Central Google Scholar
- Deschasaux, M. et al. Depicting the composition of gut microbiota in a population with varied ethnic origins but shared geography. Nat. Med. 24, 1526–1531 (2018).
Article CAS PubMed Google Scholar
- Bambha, K. et al. Ethnicity and nonalcoholic fatty liver disease. Hepatology 55, 769–780 (2012).
Article CAS PubMed Google Scholar
- Gangarapu, V., Yildiz, K., Ince, A. T. & Baysal, B. Role of gut microbiota: obesity and NAFLD. Turk. J. Gastroenterol. 25, 133–140 (2014).
Article PubMed Google Scholar
- Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006).
Article CAS PubMed Google Scholar
- Jie, Z. et al. The gut microbiome in atherosclerotic cardiovascular disease. Nat. Commun. 8, 845 (2017).
Article PubMed PubMed Central CAS Google Scholar
- Karlsson, C. L. J. et al. The microbiota of the gut in preschool children with normal and excessive body weight. Obesity 20, 2257–2261 (2012).
Article PubMed Google Scholar
- Tilg, H., Moschen, A. R. & Roden, M. NAFLD and diabetes mellitus. Nat. Rev. Gastroenterol. Hepatol. 14, 32–42 (2017).
Article CAS PubMed Google Scholar
- Loomba, R. et al. Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology 56, 943–951 (2012).
Article PubMed Google Scholar
- Larsen, N. et al. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS One 5, e9085 (2010).
Article PubMed PubMed Central CAS Google Scholar
- Falony, G. et al. Population-level analysis of gut microbiome variation. Science 352, 560–564 (2016).
Article CAS PubMed Google Scholar
- Maier, L. et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 555, 623–628 (2018).
Article CAS PubMed PubMed Central Google Scholar
- Rhee, E. J. Nonalcoholic fatty liver disease and diabetes: an epidemiological perspective. Endocrinol. Metab. 34, 226–233 (2019).
Article Google Scholar
- Lonardo, A., Ballestri, S., Marchesini, G., Angulo, P. & Loria, P. Nonalcoholic fatty liver disease: a precursor of the metabolic syndrome. Dig. Liver Dis. 47, 181–190 (2015).
Article PubMed Google Scholar
- Wu, H. et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat. Med. 23, 850–858 (2017). The first study to decipher the effect of metformin on the gut microbiota signature in a randomized control trial, including individuals with drug-naive T2DM, using metagenomic analysis and gut stimulator experiments with faecal transfer in germ-free mice.
Article CAS PubMed Google Scholar
- Shin, N.-R. et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 63, 727–735 (2014).
Article CAS PubMed Google Scholar
- Depommier, C. et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat. Med. 25, 1096–1103 (2019).
Article CAS PubMed PubMed Central Google Scholar
- Dao, M. C. et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut 65, 426–436 (2016).
Article CAS PubMed Google Scholar
- Pastori, D. et al. The efficacy and safety of statins for the treatment of non-alcoholic fatty liver disease. Dig. Liver Dis. 47, 4–11 (2015).
Article CAS PubMed Google Scholar
- Caparrós-Martín, J. A. et al. Statin therapy causes gut dysbiosis in mice through a PXR-dependent mechanism. Microbiome 5, 95 (2017).
Article PubMed PubMed Central Google Scholar
- Imhann, F. et al. Proton pump inhibitors affect the gut microbiome. Gut 65, 740–748 (2016).
Article CAS PubMed Google Scholar
- Yeh, M. M. & Brunt, E. M. Pathology of nonalcoholic fatty liver disease. Am. J. Clin. Pathol. 128, 837–847 (2007).
Article PubMed Google Scholar
- Koch, L. K. & Yeh, M. M. Nonalcoholic fatty liver disease (NAFLD): diagnosis, pitfalls, and staging. Ann. Diagn. Pathol. 37, 83–90 (2018).
Article PubMed Google Scholar
- Reinke, H. & Asher, G. Circadian clock control of liver metabolic functions. Gastroenterology 150, 574–580 (2016).
Article PubMed Google Scholar
- Parsons, M. J. et al. Social jetlag, obesity and metabolic disorder: investigation in a cohort study. Int. J. Obes. 39, 842–848 (2015).
Article CAS Google Scholar
- Asher, G. & Sassone-Corsi, P. Time for food: the intimate interplay between nutrition, metabolism, and the circadian clock. Cell 161, 84–92 (2015).
Article CAS PubMed Google Scholar
- Archer, S. N. et al. Mistimed sleep disrupts circadian regulation of the human transcriptome. Proc. Natl Acad. Sci. USA 111, E682–E691 (2014).
Article CAS PubMed PubMed Central Google Scholar
- Thaiss, C. A. et al. Microbiota diurnal rhythmicity programs host transcriptome oscillations. Cell 167, 1495–1510 (2016).
Article CAS PubMed Google Scholar
- Thaiss, C. A. et al. Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell 159, 514–529 (2014).
Article CAS PubMed Google Scholar
- Leone, V. et al. Effects of diurnal variation of gut microbes and high-fat feeding on host circadian clock function and metabolism. Cell Host Microbe 17, 681–689 (2015).
Article CAS PubMed PubMed Central Google Scholar
- Thomas, V., Clark, J. & Doré, J. Fecal microbiota analysis: an overview of sample collection methods and sequencing strategies. Future Microbiol. https://doi.org/10.2217/fmb.15.87 (2015).
Article PubMed Google Scholar
- Poretsky, R., Rodriguez-R, L. M., Luo, C., Tsementzi, D. & Konstantinidis, K. T. Strengths and limitations of 16S rRNA gene amplicon sequencing in revealing temporal microbial community dynamics. PLOS ONE 9, e93827 (2014).
Article PubMed PubMed Central CAS Google Scholar
- Ranjan, R., Rani, A., Metwally, A., McGee, H. S. & Perkins, D. L. Analysis of the microbiome: advantages of whole genome shotgun versus 16S amplicon sequencing. Biochem. Biophys. Res. Commun. 469, 967–977 (2016).
Article CAS PubMed Google Scholar
- Youssef, N. et al. Comparison of species richness estimates obtained using nearly complete fragments and simulated pyrosequencing-generated fragments in 16S rRNA gene-based environmental surveys. Appl. Environ. Microbiol. 75, 5227–5236 (2009).
Article CAS PubMed PubMed Central Google Scholar
- Caporaso, J. G. et al. QIIME allows analysis of high-throughput community sequencing data. Nat. Methods 7, 335–336 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Schloss, P. D. et al. Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities. Appl. Environ. Microbiol. 75, 7537 (2009).
Article CAS PubMed PubMed Central Google Scholar
- Langille, M. G. I. et al. Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nat. Biotechnol. 31, 814 (2013).
Article CAS PubMed PubMed Central Google Scholar
- Ten Hoopen, P. et al. The metagenomic data life-cycle: standards and best practices. Gigascience 6, 1–11 (2017).
PubMed PubMed Central Google Scholar
- Olson, E. M., Lin, N. U., Krop, I. E. & Winer, E. P. The ethical use of mandatory research biopsies. Nat. Rev. Clin. Oncol. 8, 620–625 (2011).
Article PubMed PubMed Central Google Scholar
- Peppercorn, J. et al. Ethics of mandatory research biopsy for correlative end points within clinical trials in oncology. J. Clin. Oncol. 28, 2635–2640 (2010).
Article PubMed PubMed Central Google Scholar
- López-Contreras, B. E. et al. Composition of gut microbiota in obese and normal-weight Mexican school-age children and its association with metabolic traits. Pediatr. Obes. 13, 381–388 (2018).
Article PubMed Google Scholar
- Dao, M. C. et al. A data integration multi-omics approach to study calorie restriction-induced changes in insulin sensitivity. Front. Physiol. 9, 1958 (2018).
Article PubMed Google Scholar
- Kayser, B. D. et al. Serum lipidomics reveals early differential effects of gastric bypass compared to banding on phospholipids and sphingolipids independent of differences in weight loss. Int. J. Obes. 41, 917–925 (2017).
Article CAS Google Scholar
- Kayser, B. D. et al. Phosphatidylglycerols are induced by gut dysbiosis and inflammation, and favorably modulate adipose tissue remodeling in obesity. FASEB J. 33, 4741–4754 (2019).
Article CAS PubMed PubMed Central Google Scholar
- Dao, M. C. et al. A data integration multi-omics approach to study calorie restriction-induced changes in insulin sensitivity. Front. Physiol. 9, 1958 (2019).
Article PubMed PubMed Central Google Scholar
- Wright, E. K. et al. Microbial factors associated with postoperative Crohn’s disease recurrence. J. Crohns Colitis 11, 191–203 (2017).
Article PubMed Google Scholar
- Alberti, K. G. et al. Harmonizing the metabolic syndrome: a joint interim statement of the international diabetes federation task force on epidemiology and prevention; national heart, lung, and blood institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120, 1640–1645 (2009).
Article CAS PubMed Google Scholar
- Grattagliano, I. et al. Utility of noninvasive methods for the characterization of nonalcoholic liver steatosis in the family practice. The “VARES” Italian multicenter study. Ann. Hepatol. 12, 70–77 (2013).
Article PubMed Google Scholar