|Year : 2018 | Volume
| Issue : 6 | Page : 163-166
Novel insights into the role of bacterial gut microbiota in hepatocellular carcinoma
Lei Zhang1, Guoyu Qiu2, Xiaohui Xu2, Yufeng Zhou3, Ruiming Chang4
1 Department of Biliary- Surgery, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
2 Department of Traditional Chinese Medicine and Chemical Drug, Lanzhou Institutes for Food and Drug Control, Lanzhou, Gansu, China
3 Laboratory Animal Center, Sun Yat-Sen University, Guangzhou, Guangdong, China
4 Boji Medical Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
|Date of Web Publication||28-Dec-2018|
Dr. Ruiming Chang
Boji Medical Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang West Road, Guangzhou 510120, Guangdong
Source of Support: None, Conflict of Interest: None
Hepatocellular carcinoma (HCC) mostly develops in patients with chronic liver disease, driven by a vicious cycle of liver injury, inflammation, and regeneration. Increasing evidence points to the influence of bacterial gut microbiota influence on chronic liver disease and the development of HCC. We will review how bacterial gut microbiota contributes to HCC and relevant therapeutic strategies, focusing on alterations of the bacterial gut microbiota at different disease stages and mechanisms by which it contributes to disease progression and HCC development in different types of liver diseases.
Keywords: Bacteria gut microbiota, liver diseases, mechanisms
|How to cite this article:|
Zhang L, Qiu G, Xu X, Zhou Y, Chang R. Novel insights into the role of bacterial gut microbiota in hepatocellular carcinoma. Cancer Transl Med 2018;4:163-6
|How to cite this URL:|
Zhang L, Qiu G, Xu X, Zhou Y, Chang R. Novel insights into the role of bacterial gut microbiota in hepatocellular carcinoma. Cancer Transl Med [serial online] 2018 [cited 2019 Aug 19];4:163-6. Available from: http://www.cancertm.com/text.asp?2018/4/6/163/248974
| Introduction|| |
Hepatocellular carcinoma (HCC) is the most common primary carcinoma of the liver. Most cases arise in chronically inflamed and subsequently cirrhotic livers. Drug abuse, alcohol abuse, autoimmunity, or infections are major risk factors., Large bodies of evidence have shown the influence of the gut microbiota on human health. Although it benefits the host in metabolism and immunity,, it is also increasingly recognized in disease processes. As bacteria are most dominant in the gut, we will focus on the bacterial gut microbiota. It takes part in disease development not only via local effects but also at distant sites, such as the liver, along the gut-microbiota-liver axis.,,, Owing to its anatomical connection, not only does the liver absorb nutrient substance, but it is also the first target of the bacterial gut microbiota. The intestinal mucosal barrier ensures that exposure is minimal; however, failing barrier contributes to the progression of liver diseases and thereby increases the risk of the development of HCC as the end stage of the chronic liver disease process., Here, we will concentrate on how bacterial gut microbiota contributes to liver disease progression at various stages and promote HCC in all processes and therapeutic strategies to interrupt this disease-promoting pathway.
| Mechanisms Underlying the Intestinal Mucosal Barrier|| |
The intestinal mucosal barrier prevents microbes and metabolites crossing across the mucosa.,, Its function relies on intact epithelial lining, mucosa-associated lymphoid tissue, mucus layer, and secretory IgA. Intestinal mucosal barrier dysfunction can result in activation of the immune system and secretion of inflammatory mediators, which promote the development of disease processes. Owing to its close anatomical connection to the liver, not only does the liver absorb nutrition but is also the first target of the bacterial gut microbiota. Mechanisms underlying the failure of the intestinal mucosal barrier are most likely multifactorial, including bacterial dysbiosis, increased permeability, and inflammatory cytokines. Liver diseases exert major effects on the bacterial gut microbiota, resulting in dysbacteriosis and increased intestinal permeability. It has been demonstrated that patients with cirrhosis show increased pathogenic bacteria, along with decreased beneficial properties. However, the current understanding of bacterial gut microbiota remains incomplete. Thus, well-designed studies are still needed.
Liver fibrosis and cirrhosis
Although inflammation is a common feature of chronic hepatic diseases and correlates with the development and progression to HCC, the molecular mechanism among these processes of chronic liver injury is unclear.
Liver fibrosis is the hepatic response to long-term damage and commonly progresses to advanced chronic liver disease. The inflammatory responses are mediated by interaction between microbiota-associated molecular patterns and pattern recognition receptors, particularly the Toll-like receptors (TLRs). Stimulation of TLRs in the liver, activates hepatic stellate cells (HSCs), which further increase liver fibrosis. The majority of studies on the gut-microbiota-liver axis have focused on lipopolysaccharide (LPS) activity via binding to the receptor TLR4. Strong evidence points out important contribution of the LPS/TLR4 pathway to liver fibrosis. TLR4 is expressed in multiple hepatic cell types, including hepatocytes, HSCs, and Kupffer cells. LPS seems to promote liver diseases via multiple pathways. A study of Seki et al. has shown intestinal microflora as the main source of portal LPS, representing an important prerequisite for the development of liver fibrosis during chronic liver injury, and antibiotics suppress hepatic fibrosis in part, which highlights a key role of TLR4. Disruption of the intestinal mucosal barrier results in increased LPS levels and fibrosis. Conversely, the inhibition of TLR4 signal suppresses this process. Mean LPS levels increase in patients with cirrhosis. However, Tabibian et al. have shown an increased liver fibrosis in germ-free mice. Further studies are needed to investigate how the bacterial gut microbiota affects liver fibrosis.
Alcoholic liver disease
Alcoholic liver disease (ALD) encompasses the manifestations of alcohol overconsumption, including fatty liver, alcoholic hepatitis, and hepatitis with liver fibrosis or cirrhosis. ALD contributes to about half of all cirrhosis cases.,, The ability of ethanol and its metabolite acetaldehyde to disrupt tight junctions contributes to the high levels of bacterial translocation in ALD. Even single dose of alcohol has been shown to increase bacterial translocation and LPS level (14). A number of functional studies have shown a key contribution of the gut/microbiota/TLR4 axis to ALD, which fits well with the well-established clinical observation that alcohol abuse is an important cofactor in promoting liver disease development and HCC. Although ALD might have a lower relative risk of causing HCC, the number of patients with alcoholic cirrhosis represents the high number of HCCs caused by ALD.
Fatty liver disease
Being recognized as a disease in recent years, fatty liver disease is becoming the leading cause of CLD.,,, There is a strong association between fatty liver disease, such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and bacterial gut microbiota. Studies have shown a close connection of the bacterial gut microbiota to metabolism, and the bacterial gut microbiota from obese individuals is more efficient at energy extraction., Henao-Mejia et al. found that increased intestinal permeability and metabolic endotoxemia contribute to the progression of NASH in mice. Likewise, intestinal permeability is shown to be increased in patients with NAFLD. Data from human studies also support the concept that the alternations of the bacterial gut microbiota contribute to the development of fatty liver diseases.
Alterations in the bacterial gut microbiota not only occur in advanced CLD but also are characteristic in several types of early CLD. Hence, gut microbiota might contribute to disease progression at various stages and promote HCC in all processes. High LPS levels in rodents and patients with HCC demonstrate the presence of leaky gut. Studies in animal model have provided evidence that the intestinal permeability contributes to HCC progression. TLR4 is present in multiple hepatic cell types, including Kupffer cells, HSCs, endothelial cells, and hepatocytes. TLR4 activation enhances invasive ability of HCC cells and induces the epithelial-mesenchymal transition. Some experiments have provided evidence that the leaky gut, via LPS and its receptor TLR4, makes essential contributions to HCC. Disruption of the gut barrier not only results in increased systemic LPS levels and increased liver fibrosis but also promotes HCC formation., Conversely, the inhibition of TLR4 suppresses liver inflammation, fibrosis, and HCC formation.,
Increasing evidence supports a key role of dysbiosis in the development of CLD and HCC. Evidence suggests that such effect is mediated by bacterial metabolites, possibly in a disease-specific manner. The finding that the bacterial gut microbiota of patients with compensated cirrhosis differs from that of patients with decompensated cirrhosis suggests that cirrhosis stage drives gut microbiota changes. In addition to alterations in bacterial composition, evidence demonstrates bacterial overgrowth, which in turn is associated with increased circulating LPS levels. In the past few years, studies have demonstrated differences in the duodenal and salivary microbiota between healthy individuals and patients with cirrhosis., This suggests that there are also qualitative and quantitative changes that might be linked to changes in the more distal microbiota, which might contribute to the pathophysiology of CLD as well as the development of HCC.
| Targeting Microbiota to Prevent Liver Diseases|| |
On the basis of its contribution to liver diseases, the gut-microbiota-liver pathway is a promising target for prevention. With increased understanding of its underlying mechanisms, approaches to target the axis are increasing.
Probiotics and prokinetics
Probiotics have been used as a way of providing health benefits by restoring beneficial bacteria., Although studies have shown its effectiveness, controversy remains debating on the inability to permanently colonize the intestinal tract, unknown mechanisms, and lack of large-scale studies. To date, probiotics have only been investigated in animal models. Further studies are required in human.
Gut dysmotility is another factor that contributes to bacterial overgrowth in liver cirrhosis. The prokinetic drug cisapride not only decreases intestinal transit time but also inhibits intestinal bacterial overgrowth and bacterial translocation. One of the purported mechanisms is increased adrenergic activity. Nonselective β-adrenergic blockers decrease intestinal transit time and reduce intestinal bacterial overgrowth, intestinal permeability, and bacterial translocation.,,
The composition of the intestinal microbiota can be altered with diet and probiotics, which produce mild temporary changes, or with antibiotics, which produce large changes in the bacterial composition of the intestines. Antibiotics are one of the most efficient approaches to interrupt bacterial gut microbiota. Decreasing the number of bacterial gut microbiota will reduce translocation and inhibit inflammation. Administration of antibiotics at late stage was proven to be more efficient than administering at earlier stage of liver diseases, which supports that the prevention of liver diseases by antibiotics could be applied in advanced patients. However, results from animal model cannot be converted to patients directly, as long-term treatment with antibiotics would be harmful, due to dysbacteriosis. Thus, the use of single antibiotics with high safety might be the only feasible approach.
Fecal microbiota transplantation
The first description of fecal microbiota transplantation (FMT) as a therapeutic agent came from China. The first use of FMT was described in 1958, for the treatment of pseudomembranous colitis. To date, most clinical experience with the use of FMT has focused on relapsing Clostridium difficile infection. However, patients receiving FMT are usually present with reduced microbial diversity. Thus, these patients not only represent an ideal candidate for transplantation but also have a disease with reduced bacterial diversity. Moreover, it is of concern that infections might happen. In the future, FMT should be defined as clear mixtures of bacteria and with the same beneficial effects. Then, it will not only alleviate concerns about pathogens but also make it more acceptable.
| Conclusion|| |
It has been shown that bacterial gut microbiota makes a key influence to liver disease. Detailed knowledge about this disease-promoting axis could enable the development of therapeutic strategies. However, current understanding is largely from animal models, demanding more human studies in the future.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Sherman M. Hepatocellular carcinoma: epidemiology, risk factors, and screening. Semin Liver Dis
2005; 25 (2): 143–54.
Yuen MF, Tanaka Y, Fong DY, Fung J, Wong DK, Yuen JC, But DY, Chan AO, Wong BC, Mizokami M, Lai CL. Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B. J Hepatol
2009; 50 (1): 80–8.
Rooks MG, Garrett WS. Gut microbiota, metabolites and host immunity. Nat Rev Immunol
2016; 16 (6): 341–52.
Tremaroli V, Backhed F. Functional interactions between the gut microbiota and host metabolism. Nature
2012; 489 (7415): 242–9.
Schroeder BO, Backhed F. Signals from the gut microbiota to distant organs in physiology and disease. Nat Med
2016; 22 (10): 1079–89.
Dethlefsen L, McFall-Ngai M, Relman DA. An ecological and evolutionary perspective on human-microbe mutualism and disease. Nature
2007; 449 (7164): 811–8.
Schnabl B, Brenner DA. Interactions between the intestinal microbiome and liver diseases. Gastroenterology
2014; 146 (6): 1513–24.
Chu H, Khosravi A, Kusumawardhani IP, Kwon AH, Vasconcelos AC, Cunha LD, Mayer AE, Shen Y, Wu WL, Kambal A, Targan SR, Xavier RJ, Ernst PB, Green DR, McGovern DP, Virgin HW, Mazmanian SK. Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease. Science
2016; 352 (6289): 1116–20.
Lamas B, Richard ML, Leducq V, Pham HP. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med
2016; 22 (6): 598–605.
Schwabe RF, Jobin C. The microbiome and cancer. Nat Rev Cancer
2013; 13 (11): 800–12.
Dapito DH, Mencin A, Gwak GY, Pradere JP, Jang MK, Mederacke I, Caviglia JM, Khiabanian H, Adeyemi A, Bataller R, Lefkowitch JH, Bower M, Friedman R, Sartor RB, Rabadan R, Schwabe RF. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell
2012; 21 (4): 504–16.
Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, Iwakura Y, Oshima K, Morita H, Hattori M, Honda K, Ishikawa Y, Hara E, Ohtani N. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature
2013; 499 (7456): 97–101.
Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol
2009; 9 (11): 799–809.
Pradere JP, Troeger JS, Dapito DH, Mencin AA, Schwabe RF. Toll-like receptor 4 and hepatic fibrogenesis. Semin Liver Dis
2010; 30 (3): 232–44.
Peterson LW, Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol
2014; 14 (3): 141–53.
Yu LX, Schwabe RF. The gut microbiome and liver cancer: mechanisms and clinical translation. Nat Rev Gastroenterol Hepatol
2017; 14 (9): 527–39.
Spadoni I, Zagato E, Bertocchi A, Paolinelli R, Hot E, Di Sabatino A, Caprioli F, Bottiglieri L, Oldani A, Viale G, Penna G, Dejana E, Rescigno M. A gut-vascular barrier controls the systemic dissemination of bacteria. Science
2015; 350 (6262): 830–4.
Qin N, Yang F, Li A, Prifti E, Chen Y, Shao L, Guo J, Le Chatelier E, Yao J, Wu L, Zhou J, Ni S, Liu L, Pons N, Batto JM, Kennedy SP, Leonard P, Yuan C, Ding W, Chen Y, Hu X, Zheng B, Qian G, Xu W, Ehrlich SD, Zheng S, Li L. Alterations of the human gut microbiome in liver cirrhosis. Nature
2014; 513 (7516): 59–64.
Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell
2010; 140 (6): 805–20.
Chassaing B, Etienne-Mesmin L, Gewirtz AT. Microbiota-liver axis in hepatic disease. Hepatology
2014; 59 (1): 328–39.
Seki E, De Minicis S, Osterreicher CH, Kluwe J, Osawa Y, Brenner DA, Schwabe RF. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med
2007; 13 (11): 1324–32.
Gabele E, Dostert K, Hofmann C, Wiest R, Scholmerich J, Hellerbrand C, Obermeier F. DSS induced colitis increases portal LPS levels and enhances hepatic inflammation and fibrogenesis in experimental NASH. J Hepatol
2011; 55 (6): 1391–9.
Lin RS, Lee FY, Lee SD, Tsai YT, Lin HC, Lu RH, Hsu WC, Huang CC, Wang SS, Lo KJ. Endotoxemia in patients with chronic liver diseases: relationship to severity of liver diseases, presence of esophageal varices, and hyperdynamic circulation. J Hepatol
1995; 22 (2): 165–72.
Tabibian JH, O'Hara SP, Trussoni CE, Tietz PS, Splinter PL, Mounajjed T, Hagey LR, LaRusso NF. Absence of the intestinal microbiota exacerbates hepatobiliary disease in a murine model of primary sclerosing cholangitis. Hepatology
2016; 63 (1): 185–96.
Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology
2011; 141 (5): 1572–85.
Stickel F, Datz C, Hampe J, Bataller R. Pathophysiology and management of alcoholic liver disease: update 2016. Gut Liver
2017; 11 (2): 173–88.
Tome S, Lucey MR. Review article: current management of alcoholic liver disease. Aliment Pharmacol Ther
2004; 19 (7): 707–14.
Rao RK, Seth A, Sheth P. Recent advances in alcoholic liver disease I. Role of intestinal permeability and endotoxemia in alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol
2004; 286 (6): G881–4.
Szabo G. Gut-liver axis in alcoholic liver disease. Gastroenterology
2015; 148 (1): 30–6.
Siu L, Foont J, Wands JR. Hepatitis C virus and alcohol. Semin Liver Dis
2009; 29 (2): 188–99.
Sanyal AJ, Yoon SK, Lencioni R. The etiology of hepatocellular carcinoma and consequences for treatment. Oncologist
2010; 15(Suppl 4): 14–22.
Michelotti GA, Machado MV, Diehl AM. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol
2013; 10 (11): 656–65.
Clark JM. The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol
2006; 40(Suppl 1): S5–10.
Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology
2010; 51 (5): 1820–32.
Yki-Jarvinen H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol
2014; 2 (11): 901–10.
Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP, Egholm M, Henrissat B, Heath AC, Knight R, Gordon JI. A core gut microbiome in obese and lean twins. Nature
2009; 457 (7228): 480–4.
Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature
2006; 444 (7122): 1027–31.
Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, Thaiss CA, Kau AL, Eisenbarth SC, Jurczak MJ, Camporez JP, Shulman GI, Gordon JI, Hoffman HM, Flavell RA. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature
2012; 482 (7384): 179–85.
Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, Mascianà R, Forgione A, Gabrieli ML, Perotti G, Vecchio FM, Rapaccini G, Gasbarrini G, Day CP, Grieco A. Author information increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology
2009; 49 (6): 1877–87.
Zhang HL, Yu LX, Yang W, Tang L, Lin Y, Wu H, Zhai B, Tan YX, Shan L, Liu Q, Chen HY, Dai RY, Qiu BJ, He YQ, Wang C, Zheng LY, Li YQ, Wu FQ, Li Z, Yan HX, Wang HY. Profound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats. J Hepatol
2012; 57 (4): 803–12.
Jing YY, Han ZP, Sun K, Zhang SS, Hou J, Liu Y, Li R, Gao L, Zhao X, Zhao QD, Wu MC, Wei LX. Toll-like receptor 4 signaling promotes epithelial-mesenchymal transition in human hepatocellular carcinoma induced by lipopolysaccharide. BMC Med
2012; 10: 98.
Achiwa K, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Hayashi K, Hirooka Y, Katano Y, Goto H. DSS colitis promotes tumorigenesis and fibrogenesis in a choline-deficient high-fat diet-induced NASH mouse model. Biochem Biophys Res Commun
2016; 470 (1): 15–21.
Bajaj JS, Betrapally NS, Gillevet PM. Decompensated cirrhosis and microbiome interpretation. Nature
2015; 525 (7569): E1–2.
Bauer TM, Schwacha H, Steinbruckner B, Brinkmann FE, Ditzen AK, Aponte JJ, Pelz K, Berger D, Kist M, Blum HE. Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxemia. Am J Gastroenterol
2002; 97 (9): 2364–70.
Chen Y, Ji F, Guo J, Shi D, Fang D, Li L. Dysbiosis of small intestinal microbiota in liver cirrhosis and its association with etiology. Sci Rep
2016; 6: 34055.
Bajaj JS, Betrapally NS, Hylemon PB, Heuman DM, Daita K, White MB, Unser A, Thacker LR, Sanyal AJ, Kang DJ, Sikaroodi M, Gillevet PM. Salivary microbiota reflects changes in gut microbiota in cirrhosis with hepatic encephalopathy. Hepatology
2015; 62 (4): 1260–71.
Vrieze A, de Groot PF, Kootte RS, Knaapen M, van Nood E, Nieuwdorp M. Fecal transplant: a safe and sustainable clinical therapy for restoring intestinal microbial balance in human disease? Best Pract Res Clin Gastroenterol
2013; 27 (1): 127–37.
Patel R, DuPont HL. New approaches for bacteriotherapy: prebiotics, new-generation probiotics, and synbiotics. Clin Infect Dis
2015; 60(Suppl 2): S108–21.
Natividad JM, Verdu EF. Modulation of intestinal barrier by intestinal microbiota: pathological and therapeutic implications. Pharmacol Res
2013; 69 (1): 42–51.
Yan AW, Fouts DE, Brandl J, Starkel P, Torralba M, Schott E, Tsukamoto H, Nelson KE, Brenner DA, Schnabl B. Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology
2011; 53 (1): 96–105.
Zapater P, Cano R, Llanos L, Ruiz-Alcaraz AJ, Pascual S, Barquero C, Moreu R, Bellot P, Horga JF, Muñoz C, Pérez J, García-Peñarrubia P, Pérez-Mateo M, Such J, Francés R. Norfloxacin modulates the inflammatory response and directly affects neutrophils in patients with decompensated cirrhosis. Gastroenterology
2009; 137 (5): 1669–79.
Zhang SC, Wang W, Ren WY, He BM, Zhou K, Zhu WN. Effect of cisapride on intestinal bacterial and endotoxin translocation in cirrhosis. World J Gastroenterol
2003; 9 (3): 534–8.
Kootte RS, Vrieze A, Holleman F, Dallinga-Thie GM, Zoetendal EG, de Vos WM, Groen AK, Hoekstra JB, Stroes ES, Nieuwdorp M. The therapeutic potential of manipulating gut microbiota in obesity and type 2 diabetes mellitus. Diabetes Obes Metab
2012; 14 (2): 112–20.
Zhang F, Luo W, Shi Y, Fan Z, Ji G. Should we standardize the 1,700-year-old fecal microbiota transplantation? Am J Gastroenterol
2012; 107 (11): 1755.
Eiseman B, Silen W, Bascom GS, Kauvar AJ. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery
1958; 44 (5): 854–9.
Van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG, Speelman P, Dijkgraaf MG, Keller JJ. Duodenal infusion of donor feces for recurrent clostridium difficile. N Engl J Med
2013; 368 (5): 407–15.
Kelly CP. Fecal microbiota transplantation – An old therapy comes of age. N Engl J Med
2013; 368 (5): 474–5.