Adipositas, Typ-2-Diabetes und das Mikrobiom, unser zweites Genom

R. Chakaroun; H. Heyne; M. Blüher; M. Stumvoll

doi:10.1055/s-0042-101020

Diabetologie und Stoffwechsel, Inhaltsverzeichnis

Diabetologie und Stoffwechsel 2016; 11(01): 102-112
DOI: 10.1055/s-0042-101020

Übersicht

Adipositas, Typ-2-Diabetes und das Mikrobiom, unser zweites Genom

Obesity, Type 2 Diabetes and the Microbiome, Our Second Genome

R. Chakaroun

¹Department of Endocrinology, University Medical Center Leipzig, Germany

,

H. Heyne

²Institute of Human Genetics, University Medical Center Leipzig, Germany

,

M. Blüher

¹Department of Endocrinology, University Medical Center Leipzig, Germany

,

M. Stumvoll

¹Department of Endocrinology, University Medical Center Leipzig, Germany

› Institutsangaben

Abstract

Zusammenfassung

Die Darmbakterien wurden lange Zeit als Kommensale oder Nebenschauspieler bei Darmerkrankungen und weiterer Infektionen aufgefasst. Dank moderner Sequenzierungsmethoden ist es in den letzten 10 Jahren gelungen diese auf kompositioneller und funktioneller Ebene zu charakterisieren. Es bestehen vielfältige Hinweise für eine Schlüsselrolle der Darmmikrobiota in der Entstehung von Adipositas und Diabetes mellitus Typ 2, aber auch chronisch entzündlichen Darmerkrankungen, neurologischen und psychiatrischen Erkrankungen sowie bestimmten Krebsarten.

Das Darmmikrobiom ist teilweise vererbbar, jedoch primär durch multiple Umwelteinflüsse modulierbar. Bis zur Ausreifung des Mikrobioms mit dem 3. Lebensjahr können vielfältige Störfaktoren wie Antibiotikaexposition, die Umwelt, aber auch die Ernährung dessen Komposition verändern und dadurch vermutlich lebenslange tiefgreifende Verschiebungen im Stoffwechsel und Phänotyp des Wirts hervorrufen.

Vor allem Studien im Mausmodell zeigen eine überzeugende Kausalität zwischen Veränderungen im Darmmikrobiom und dem Auftreten kardiometabolischer Erkrankungen.

Genaue pathophysiologische Mechanismen, die zur Entwicklung und Progression des metabolischen Syndroms führen, werden in der Wechselwirkung von bakteriellen Produkten mit dem Immunsystem des Wirts vermutet. Diese können beispielsweise Lipopolysacchariden aus der Hülle gramnegativer Bakterien, kurzkettige Fettsäuren aus der Fermentation von unlöslichen Ballaststoffen oder weitere Metabolite sein. Daraus resultieren eine gestörte Darmpermeabilität sowie eine systemische subklinische Inflammation. Zudem können sie in Glukose- und Fettstoffwechselkaskaden eingreifen und Veränderungen in der Funktion des Fettgewebes hervorrufen.

Die Darmbakterien fungieren somit als Bindeglied zwischen äusserer und innerer Umwelt. Besonders attraktiv erscheint deshalb die Möglichkeit die bakterielle Dysfunktion gezielt mittels Modulierung der Darmmikrobiota zu behandeln. Dies kann über entsprechende Umwelteinflüsse, Ernährung, Medikamente oder individuelle Bakteriotherapien wie Präbiotika-, Probiotika-, Antibiotika- oder Synbiotikaeinsatz erfolgen.

Ziel dieses Artikels ist es, die aktuelle Datenlage zur Rolle des Darmmikrobioms in der Pathophysiologie von Adipositas und Diabetes mellitus Typ 2 darzustellen und auf offene Fragestellungen einzugehen.

Abstract

For a long time overlooked as a mere bystander, a commensal organism or partially a nuisance, the gut microbiota has emerged as a key player in the modulation of the immune system and metabolism. Changes in the composition or function of the microbiota have been reported to be associated with metabolic diseases such as obesity, type 2 diabetes and insulin resistance but also with the development and progression of cardiovascular disease, inflammatory bowel disease, certain types of cancer and psychiatric diseases.

Partially heritable, the gut microbiome is already fully developed within the first 3 years of life of the human host. During this critical phase, the child but also his or her microbiome is susceptible to perturbations via changes in environment, antibiotic exposure and diet leading to possible lifelong impact on the metabolism and the phenotype. Studies in mice have supported a strong causality between shifts in the microbiome and development of the metabolic syndrome.

Mechanisms linking alterations in the microbiome with subsequent diseases include signaling through lipopolysaccharides from gram negative bacteria walls and interactions with the host immune system, fermentation of indigestible fibres to short chain fatty acids, modulation of bile acids and bile acid signaling. Interactions between the microbiome, its products and the immune system may lead to an increased gut permeability resulting in a systemic subclinical inflammation (leaky gut hypothesis), but can also alter signaling pathways influencing glucose and lipid metabolism, fat storage and adipose tissue function. Moreover, host specific factors such as age, diet, antibiotics and environmental exposition, have also been linked to shifts in the microbiota. Based upon available evidence, it can be hypothesized that the microbiota may mediate the influence of environmental and individual factors leading to the development of obesity and type 2 diabetes. Emerging applications such as fecal transplants are showing promising results in the resolution of infectious disease and might pose novel alternatives in the treatment of metabolic diseases, paving the way to an individualized “Bacteriotherapy”.

Thus, the aim of this review is to discuss the potential role of the gut microbiome in the pathophysiology of obesity and type 2 diabetes and shed light on emerging research and clinical applications.

Schlüsselwörter

Endotoxinämie - Enterotypen - Dysbiosis - Mikrobiom - Mikrobiota - Diabetes mellitus Typ 2 - Adipositas

Key words

Microbiome - Microbiota - Obesity - Diabetes mellitus Type 2 - Dysbiosis - Endotoxenemia

Volltext

Referenzen

Literatur
1 Tremaroli V, Bäckhed F. Functional interactions between the gut microbiota and host metabolism. Nature 2012; 489: 242-249
2 Qin J et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010; 464: 59-65
3 Lepage P et al. A metagenomic insight into our gut’s microbiome. Gut 2013; 62: 146-158
4 Flint HJ, Scott KP, Louis P et al. The role of the gut microbiota in nutrition and health. Nat. Rev. Gastroenterol. Hepatol 2012; 9: 577-589
5 Klöting N et al. Insulin-sensitive obesity. Am J Physiol Endocrinol Metab 2010; 299: E506-E515
6 Johnson AMF, Olefsky JM. The origins and drivers of insulin resistance. Cell 2013; 152: 673-684
7 Gerner RR, Wieser V, Moschen AR et al. Metabolic inflammation: role of cytokines in the crosstalk between adipose tissue and liver. Can J Physiol Pharmacol 2013; 91: 867-872
8 Chakaroun R et al. Effects of weight loss and exercise on chemerin serum concentrations and adipose tissue expression in human obesity. Metabolism 2012; 61: 706-714
9 Kau AL, Ahern PP, Griffin NW et al. Human nutrition, the gut microbiome and the immune system. Nature 2011; 474: 327-336
10 Griffin JL, Wang X, Stanley E. Does Our Gut Microbiome Predict Cardiovascular Risk?: A Review of the Evidence From Metabolomics. Circ Cardiovasc Genet 2015; 8: 187-191
11 Sommer F, Bäckhed F. The gut microbiota--masters of host development and physiology. Nat Rev Microbiol 2013; 11: 227-238
12 Bringiotti R et al. Intestinal microbiota: The explosive mixture at the origin of inflammatory bowel disease?. World J Gastrointest Pathophysiol 2014; 5: 550-559
13 Luna RA, Foster JA. Gut brain axis: diet microbiota interactions and implications for modulation of anxiety and depression. Curr Opin Biotechnol 2014; 32C: 35-41
14 Koren O et al. Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell 2012; 150: 470-480
15 Mueller NT et al. Prenatal exposure to antibiotics, cesarean section and risk of childhood obesity. Int J Obes 2005 2015; 39: 665-670
16 Ajslev TA, Andersen CS, Gamborg M et al. Childhood overweight after establishment of the gut microbiota: the role of delivery mode, pre-pregnancy weight and early administration of antibiotics. Int J Obes 2005 2011; 35: 522-529
17 Koenig JE et al. Succession of microbial consortia in the developing infant gut microbiome. Proc Natl Acad Sci USA 2011; 108 (Suppl. 01) 4578-4585
18 Salazar N et al. The human intestinal microbiome at extreme ages of life. Dietary intervention as a way to counteract alterations. Front Genet 2014; 5: 406
19 Yatsunenko T et al. Human gut microbiome viewed across age and geography. Nature 2012; 486: 222-227
20 Francino MP. Early development of the gut microbiota and immune health. Pathog Basel Switz 2014; 3: 769-790
21 Martin R et al. Early life: gut microbiota and immune development in infancy. Benef Microbes 2010; 1: 367-382
22 Kim MS, Hwang SS, Park EJ et al. Strict vegetarian diet improves the risk factors associated with metabolic diseases by modulating gut microbiota and reducing intestinal inflammation. Environ Microbiol Rep 2013; 5: 765-775
23 Turnbaugh PJ et al. A core gut microbiome in obese and lean twins. Nature 2009; 457: 480-484
24 Goodrich JK et al. Human genetics shape the gut microbiome. Cell 2014; 159: 789-799
25 Trasande L et al. Infant antibiotic exposures and early-life body mass. Int J Obes 2005 2013; 37: 16-23
26 Cox LM, Blaser MJ. Antibiotics in early life and obesity. Nat Rev Endocrinol 2015; 11: 182-190
27 Gaskins HR, Collier CT, Anderson DB. Antibiotics as growth promotants: mode of action. Anim Biotechnol 2002; 13: 29-42
28 Wong JM. Gut microbiota and cardiometabolic outcomes: influence of dietary patterns and their associated components. Am J Clin Nutr 2014; 100 (Suppl. 01) 369S-377S
29 Devkota S et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice. Nature 2012; 487: 104-108
30 David LA et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 2014; 505: 559-563
31 Barnard ND, Katcher HI, Jenkins DJA et al. Vegetarian and vegan diets in type 2 diabetes management. Nutr Rev 2009; 67: 255-263
32 Ogawa A, Kadooka Y, Kato K et al. Lactobacillus gasseri SBT2055 reduces postprandial and fasting serum non-esterified fatty acid levels in Japanese hypertriacylglycerolemic subjects. Lipids Health Dis 2014; 13: 36
33 Kadooka Y et al. Effect of Lactobacillus gasseri SBT2055 in fermented milk on abdominal adiposity in adults in a randomised controlled trial. Br. J. Nutr 2013; 110: 1696-1703
34 Cani PD, Joly E, Horsmans Y et al. Oligofructose promotes satiety in healthy human: a pilot study. Eur. J. Clin. Nutr 2006; 60: 567-572
35 Parnell JA, Reimer RA. Weight loss during oligofructose supplementation is associated with decreased ghrelin and increased peptide YY in overweight and obese adults. Am. J. Clin. Nutr 2009; 89: 1751-1759
36 Davis LMG, Martínez I, Walter J et al. Barcoded pyrosequencing reveals that consumption of galactooligosaccharides results in a highly specific bifidogenic response in humans. PloS One 2011; 6: e25200
37 Sarbini SR, Kolida S, Gibson GR et al. In vitro fermentation of commercial α-gluco-oligosaccharide by faecal microbiota from lean and obese human subjects. Br. J. Nutr 2013; 109: 1980-1989
38 Dehghan P, Pourghassem Gargari B, Asghari Jafar-abadi M. Oligofructose-enriched inulin improves some inflammatory markers and metabolic endotoxemia in women with type 2 diabetes mellitus: A randomized controlled clinical trial. Nutrition 2014; 30: 418-423
39 Suez J et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature 2014; 514: 181-186
40 Swithers SE. Artificial sweeteners are not the answer to childhood obesity. Appetite 2015;
41 Biedermann L et al. Smoking cessation induces profound changes in the composition of the intestinal microbiota in humans. PloS One 2013; 8: e59260
42 Qiao Y et al. Effects of resveratrol on gut microbiota and fat storage in a mouse model with high-fat-induced obesity. Food Funct 2014; 5: 1241-1249
43 Bäckhed F et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl. Acad. Sci. U.S. A 2004; 101: 15718-15723
44 Bäckhed F, Manchester JK, Semenkovich CF et al. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc. Natl. Acad. Sci. U.S.A 2007; 104: 979-984
45 Schwiertz A et al. Microbiota and SCFA in lean and overweight healthy subjects. Obes. Silver Spring Md 2010; 18: 190-195
46 Le Chatelier E et al. Richness of human gut microbiome correlates with metabolic markers. Nature 2013; 500: 541-546
47 Everard A et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc. Natl. Acad. Sci. U.S.A 2013; 110: 9066-9071
48 Shin NR et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 2014; 63: 727-735
49 Amar J et al. Blood microbiota dysbiosis is associated with the onset of cardiovascular events in a large general population: the D.E.S.I.R. study. PloS One 2013; 8: e54461
50 Arumugam M et al. Enterotypes of the human gut microbiome. Nature 2011; 473: 174-180
51 Wu GD et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 2011; 334: 105-108
52 Knights D et al. Rethinking ‘enterotypes’. Cell Host Microbe 2014; 16: 433-437
53 Ridaura VK et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 2013; 341: 1241214
54 Cani PD et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008; 57: 1470-1481
55 Ghoshal S, Witta J, Zhong J et al. Chylomicrons promote intestinal absorption of lipopolysaccharides. J. Lipid Res 2009; 50: 90-97
56 Ravussin Y et al. Responses of gut microbiota to diet composition and weight loss in lean and obese mice. Obes. Silver Spring Md 2012; 20: 738-747
57 Murphy EF et al. Composition and energy harvesting capacity of the gut microbiota: relationship to diet, obesity and time in mouse models. Gut 2010; 59: 1635-1642
58 Hildebrandt MA et al. High-fat diet determines the composition of the murine gut microbiome independently of obesity. Gastroenterology 2009; 137: 1716-1724.e1-e2
59 Cotillard A et al. Dietary intervention impact on gut microbial gene richness. Nature 2013; 500: 585-588
60 Smith MI et al. Gut microbiomes of Malawian twin pairs discordant for kwashiorkor. Science 2013; 339: 548-554
61 Subramanian S et al. Persistent gut microbiota immaturity in malnourished Bangladeshi children. Nature 2014; 510: 417-421
62 Engeli S et al. Activation of the peripheral endocannabinoid system in human obesity. Diabetes 2005; 54: 2838-2843
63 Blüher M et al. Dysregulation of the Peripheral and Adipose Tissue Endocannabinoid System in Human Abdominal Obesity. Diabetes 2006; 55: 3053-3060
64 Di Marzo V et al. Changes in plasma endocannabinoid levels in viscerally obese men following a 1 year lifestyle modification programme and waist circumference reduction: associations with changes in metabolic risk factors. Diabetologia 2009; 52: 213-217
65 Lambert DM, Muccioli GG. Endocannabinoids and related N-acylethanolamines in the control of appetite and energy metabolism: emergence of new molecular players. Curr. Opin. Clin. Nutr. Metab. Care 2007; 10: 735-744
66 Kirkham TC, Williams CM, Fezza F et al. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br. J. Pharmacol 2002; 136: 550-557
67 Ravinet Trillou C et al. Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. Am. J. Physiol. Regul. Integr. Comp. Physiol 2003; 284: R345-R353
68 Gary-Bobo M et al. The cannabinoid CB1 receptor antagonist rimonabant (SR141716) inhibits cell proliferation and increases markers of adipocyte maturation in cultured mouse 3T3 F442A preadipocytes. Mol. Pharmacol 2006; 69: 471-478
69 Hoareau L et al. Anti-inflammatory effect of palmitoylethanolamide on human adipocytes. Obes. Silver Spring Md 2009; 17: 431-438
70 Di Marzo V et al. Biosynthesis and inactivation of the endocannabinoid 2-arachidonoylglycerol in circulating and tumoral macrophages. Eur. J. Biochem. FEBS 1999; 264: 258-267
71 Muccioli GG et al. The endocannabinoid system links gut microbiota to adipogenesis. Mol. Syst. Biol 2010; 6: 392
72 Geurts L, Neyrinck AM, Delzenne NM et al. Gut microbiota controls adipose tissue expansion, gut barrier and glucose metabolism: novel insights into molecular targets and interventions using prebiotics. Benef. Microbes 2014; 5: 3-17
73 Cani PD, Geurts L, Matamoros S et al. Glucose metabolism: focus on gut microbiota, the endocannabinoid system and beyond. Diabetes Metab 2014; 40: 246-257
74 Cani PD. Crosstalk between the gut microbiota and the endocannabinoid system: impact on the gut barrier function and the adipose tissue. Clin. Microbiol. Infect. Off. Publ. Eur. Soc. Clin. Microbiol. Infect. Dis 2012; 4 (Suppl. 18) 50-53
75 Qin J et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 2012; 490: 55-60
76 Karlsson FH et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 2013; 498: 99-103
77 Amar J et al. Involvement of tissue bacteria in the onset of diabetes in humans: evidence for a concept. Diabetologia 2011; 54: 3055-3061
78 Napolitano A et al. Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PloS One 2014; 9: e100778
79 Burcelin R et al. Metagenome and metabolism: the tissue microbiota hypothesis. Diabetes Obes. Metab 2013; 3 (Suppl. 15) 61-70
80 Amar J, Balkau B, Burcelin R. Use of blood or tissue bacteriome for prediction, diagnosis and prevention of metabolic diseases and their cardiovascular complications. 2012; http://www.google.com/patents/WO2012131099A1
81 Cani PD et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007; 56: 1761-1772
82 Pussinen PJ, Havulinna AS, Lehto M et al. Endotoxemia is associated with an increased risk of incident diabetes. Diabetes Care 2011; 34: 392-397
83 Jayashree B et al. Increased circulatory levels of lipopolysaccharide (LPS) and zonulin signify novel biomarkers of proinflammation in patients with type 2 diabetes. Mol. Cell. Biochem 2014; 388: 203-210
84 Creely SJ et al. Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am. J. Physiol. Endocrinol. Metab 2007; 292: E740-E747
85 McCowen KC et al. Sustained endotoxemia leads to marked down-regulation of early steps in the insulin-signaling cascade. Crit. Care Med 2001; 29: 839-846
86 Liang H, Hussey SE, Sanchez-Avila A et al. Effect of lipopolysaccharide on inflammation and insulin action in human muscle. PloS One 2013; 8: e63983
87 Mehta NN et al. Experimental endotoxemia induces adipose inflammation and insulin resistance in humans. Diabetes 2010; 59: 172-181
88 Vijay-Kumar M et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 2010; 328: 228-231
89 Caricilli AM et al. Gut microbiota is a key modulator of insulin resistance in TLR 2 knockout mice. PLoS Biol 2011; 9: e1001212
90 Stienstra R et al. Inflammasome is a central player in the induction of obesity and insulin resistance. Proc. Natl. Acad. Sci. U.S.A 2011; 108: 15324-15329
91 Information NC. for B., Pike US. N.L. of M. 8600 R., MD, B., Usa, 20894. Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. – PubMed – NCBI. https://webvpn.uni-leipzig.de/+CSCO+1h756767633A2F2F6A6A6A2E61706F762E61797A2E6176752E746269++/pubmed/12711604
92 Layden BT, Angueira AR, Brodsky M et al. Short chain fatty acids and their receptors: new metabolic targets. Transl. Res 2013; 161: 131-140
93 Gao Z et al. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes 2009; 58: 1509-1517
94 Lin HV et al. Butyrate and Propionate Protect against Diet-Induced Obesity and Regulate Gut Hormones via Free Fatty Acid Receptor 3-Independent Mechanisms. PLoS ONE 2012; 7: e35240
95 Karlsson F, Tremaroli V, Nielsen J et al. Assessing the human gut microbiota in metabolic diseases. Diabetes 2013; 62: 3341-3349
96 Larsen N et al. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PloS One 2010; 5: e9085
97 Brahe LK, Astrup A, Larsen LH. Is butyrate the link between diet, intestinal microbiota and obesity-related metabolic diseases?. Obes. Rev. Off. J. Int. Assoc. Study Obes 2013; 14: 950-959
98 Zhang X et al. Human gut microbiota changes reveal the progression of glucose intolerance. PloS One 2013; 8: e71108
99 Machiels K et al. A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut 2014; 63: 1275-1283
100 Wang W et al. Increased proportions of Bifidobacterium and the Lactobacillus group and loss of butyrate-producing bacteria in inflammatory bowel disease. J. Clin. Microbiol 2014; 52: 398-406
101 Wu N et al. Dysbiosis signature of fecal microbiota in colorectal cancer patients. Microb. Ecol 2013; 66: 462-470
102 Alokail MS et al. Effects of probiotics in patients with diabetes mellitus type 2: study protocol for a randomized, double-blind, placebo-controlled trial. Trials 2013; 14: 195
103 Asemi Z, Khorrami-Rad A, Alizadeh SA et al. Effects of synbiotic food consumption on metabolic status of diabetic patients: a double-blind randomized cross-over controlled clinical trial. Clin. Nutr. Edinb. Scotl 2014; 33: 198-203
104 Kellow NJ, Coughlan MT, Savige GS et al. Effect of dietary prebiotic supplementation on advanced glycation, insulin resistance and inflammatory biomarkers in adults with pre-diabetes: a study protocol for a double-blind placebo-controlled randomised crossover clinical trial. BMC Endocr. Disord 2014; 14: 55
105 Ladirat SE et al. Exploring the effects of galacto-oligosaccharides on the gut microbiota of healthy adults receiving amoxicillin treatment. Br. J. Nutr 2014; 112: 536-546
106 Tolhurst G et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 2012; 61: 364-371
107 Kim CH, Park J, Kim M. Gut microbiota-derived short-chain Fatty acids, T cells, and inflammation. Immune Netw 2014; 14: 277-288
108 Ridlon JM, Kang DJ, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. J. Lipid Res 2006; 47: 241-259
109 Swann JR et al. Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proc. Natl. Acad. Sci. U.S.A 2011; 108 (Suppl. 01) 4523-4530
110 Miyata M et al. Enterobacteria modulate intestinal bile acid transport and homeostasis through apical sodium-dependent bile acid transporter (SLC10A2) expression. J. Pharmacol. Exp. Ther 2011; 336: 188-196
111 Kurdi P, Kawanishi K, Mizutani K et al. Mechanism of growth inhibition by free bile acids in lactobacilli and bifidobacteria. J. Bacteriol 2006; 188: 1979-1986
112 Inagaki T et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc. Natl. Acad. Sci. U.S.A 2006; 103: 3920-3925
113 Lorenzo-Zúñiga V et al. Oral bile acids reduce bacterial overgrowth, bacterial translocation, and endotoxemia in cirrhotic rats. Hepatol. Baltim. Md 2003; 37: 551-557
114 Islam KBMS et al. Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology 2011; 141: 1773-1781
115 Li F et al. Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat. Commun 2013; 4: 2384
116 Lax S et al. Longitudinal analysis of microbial interaction between humans and the indoor environment. Science 2014; 345: 1048-1052
117 Social behavior and the microbiome | eLife. http://elifesciences.org/content/4/e07322
118 Stool substitute transplant therapy for the eradication of Clostridium difficile infection: ‘RePOOPulating’ the gut | Microbiome. | Full Text. at http://microbiomejournal.biomedcentral.com/articles/10.1186/2049-2618-1-3
119 Alang N, Kelly CR. Weight Gain After Fecal Microbiota Transplantation. Open Forum Infect. Dis 2015; 2: ofv004
120 Vrieze A et al. Transfer of Intestinal Microbiota From Lean Donors Increases Insulin Sensitivity in Individuals With Metabolic Syndrome. Gastroenterology 2012; 143: 913-916.e7