The gastrointestinal microbiota plays a central role in the host metabolism of bile acids through deconjugation and dehydroxylation reactions, which generate unconjugated free bile acids and secondary bile acids respectively. These microbially generated bile acids are particularly potent signalling molecules that interact with host bile acid receptors (including the farnesoid X receptor, vitamin D receptor and TGR5 receptor) to trigger cellular responses that play essential roles in host lipid metabolism, electrolyte transport and immune regulation. Perturbations of microbial populations in the gut can therefore profoundly alter bile acid profiles in the host to impact upon the digestive and signalling properties of bile acids in the human superorganism. A number of recent studies have clearly demonstrated the occurrence of microbial disturbances allied to alterations in host bile acid profiles that occur across a range of disease states. Intestinal diseases including irritable bowel syndrome, inflammatory bowel disease (IBD), short bowel syndrome and Clostridium difficile infection all exhibit concurrent alterations in the composition of the gut microbiota and changes to host bile acid profiles. Similarly, extraintestinal diseases and syndromes such as asthma and obesity may be linked to aberrant bile acid profiles in the host. Here, we focus upon recent studies that highlight the links between alterations to gut microbial communities and altered bile acid profiles across a range of diseases from asthma to IBD.

1.
Vinolo MA, Rodrigues HG, Nachbar RT, Curi R: Regulation of inflammation by short chain fatty acids. Nutrients 2011;3:858-876.
2.
Tremaroli V, Backhed F: Functional interactions between the gut microbiota and host metabolism. Nature 2012;489:242-249.
3.
Keitel V, Kubitz R, Haussinger D: Endocrine and paracrine role of bile acids. World J Gastroenterol 2008;14:5620-5629.
4.
Ridlon JM, Kang DJ, Hylemon PB, Bajaj JS: Gut microbiota, cirrhosis, and alcohol regulate bile acid metabolism in the gut. Dig Dis 2015;33:338-345.
5.
Tang WH, Hazen SL: The contributory role of gut microbiota in cardiovascular disease. J Clin Invest 2014;124:4204-4211.
6.
Duboc H, Rajca S, Rainteau D, Benarous D, Maubert MA, Quervain E, Thomas G, Barbu V, Humbert L, Despras G, Bridonneau C, Dumetz F, Grill JP, Masliah J, Beaugerie L, Cosnes J, Chazouilleres O, Poupon R, Wolf C, Mallet JM, Langella P, Trugnan G, Sokol H, Seksik P: Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases. Gut 2013;62:531-539.
7.
Ogilvie LA, Jones BV: Dysbiosis modulates capacity for bile acid modification in the gut microbiomes of patients with inflammatory bowel disease: a mechanism and marker of disease? Gut 2012;61:1642-1643.
8.
Labbe A, Ganopolsky JG, Martoni CJ, Prakash S, Jones ML: Bacterial bile metabolising gene abundance in Crohn's, ulcerative colitis and type 2 diabetes metagenomes. PLoS One 2014;9:e115175.
9.
Buffie CG, Bucci V, Stein RR, McKenney PT, Ling L, Gobourne A, No D, Liu H, Kinnebrew M, Viale A, Littmann E, van den Brink MR, Jenq RR, Taur Y, Sander C, Cross JR, Toussaint NC, Xavier JB, Pamer EG: Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nature 2015;517:205-208.
10.
Weingarden AR, Chen C, Bobr A, Yao D, Lu Y, Nelson VM, Sadowsky MJ, Khoruts A: Microbiota transplantation restores normal fecal bile acid composition in recurrent Clostridium difficile infection. Am J Physiol Gastrointest Liver Physiol 2014;306:G310-G319.
11.
Dior M, Delagreverie H, Duboc H, Jouet P, Coffin B, Brot L, Humbert L, Trugnan G, Seksik P, Sokol H, Rainteau D, Sabate JM: Interplay between bile acid metabolism and microbiota in irritable bowel syndrome. Neurogastroenterol Motil 2016;28:1330-1340
12.
Pereira-Fantini PM, Lapthorne S, Joyce SA, Dellios NL, Wilson G, Fouhy F, Thomas SL, Scurr M, Hill C, Gahan CG, Cotter PD, Fuller PJ, Hardikar W, Bines JE: Altered FXR signalling is associated with bile acid dysmetabolism in short bowel syndrome-associated liver disease. J Hepatol 2014;61:1115-1125.
13.
Pereira-Fantini PM, Bines JE, Lapthorne S, Fouhy F, Scurr M, Cotter PD, Gahan CG, Joyce SA: Short bowel syndrome (SBS)-associated alterations within the gut-liver axis evolve early and persist long-term in the piglet model of short bowel syndrome. J Gastroenterol Hepatol 2016, Epub ahead of print.
14.
Arrieta MC, Stiemsma LT, Dimitriu PA, Thorson L, Russell S, Yurist-Doutsch S, Kuzeljevic B, Gold MJ, Britton HM, Lefebvre DL, Subbarao P, Mandhane P, Becker A, McNagny KM, Sears MR, Kollmann T; CHILD Study Investigators, Mohn WW, Turvey SE, Finlay BB: Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci Transl Med 2015;7:307ra152.
15.
Ridaura VK, Faith JJ, Rey FE, Cheng J, Duncan AE, Kau AL, Griffin NW, Lombard V, Henrissat B, Bain JR, Muehlbauer MJ, Ilkayeva O, Semenkovich CF, Funai K, Hayashi DK, Lyle BJ, Martini MC, Ursell LK, Clemente JC, Van Treuren W, Walters WA, Knight R, Newgard CB, Heath AC, Gordon JI: Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 2013;341:1241214.
16.
Korpela K, Salonen A, Virta LJ, Kekkonen RA, Forslund K, Bork P, de Vos WM: Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children. Nat Commun 2016;7:10410.
17.
Li T, Chiang JY: Bile acid signaling in metabolic disease and drug therapy. Pharmacol Rev 2014;66:948-983.
18.
Joyce SA, Gahan CG: Bile acid modifications at the microbe-host interface: potential for nutraceutical and pharmaceutical interventions in host health. Annu Rev Food Sci Technol 2016;7:313-333.
19.
Begley M, Sleator RD, Gahan CG, Hill C: Contribution of three bile-associated loci, bsh, pva, and btlB, to gastrointestinal persistence and bile tolerance of listeria monocytogenes. Infect Immun 2005;73:894-904.
20.
Ridlon JM, Kang DJ, Hylemon PB: Bile salt biotransformations by human intestinal bacteria. J Lipid Res 2006;47:241-259.
21.
Jones BV, Begley M, Hill C, Gahan CG, Marchesi JR: Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome. Proc Natl Acad Sci U S A 2008;105:13580-13585.
22.
Begley M, Gahan CG, Hill C: The interaction between bacteria and bile. FEMS Microbiol Rev 2005;29:625-651.
23.
Fang F, Li Y, Bumann M, Raftis EJ, Casey PG, Cooney JC, Walsh MA, O'Toole PW: Allelic variation of bile salt hydrolase genes in Lactobacillus salivarius does not determine bile resistance levels. J Bacteriol 2009;191:5743-5757.
24.
Joyce SA, MacSharry J, Casey PG, Kinsella M, Murphy EF, Shanahan F, Hill C, Gahan CG: Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut. Proc Natl Acad Sci U S A 2014;111:7421-7426.
25.
Joyce SA, Shanahan F, Hill C, Gahan CG: Bacterial bile salt hydrolase in host metabolism: potential for influencing gastrointestinal microbe-host crosstalk. Gut Microbes 2014;5:669-674.
26.
Ridlon JM, Hylemon PB: Identification and characterization of two bile acid coenzyme A transferases from Clostridium scindens, a bile acid 7α-dehydroxylating intestinal bacterium. J Lipid Res 2012;53:66-76.
27.
Islam KB, Fukiya S, Hagio M, Fujii N, Ishizuka S, Ooka T, Ogura Y, Hayashi T, Yokota A: Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology 2011;141:1773-1781.
28.
Devkota S, Wang Y, Musch MW, Leone V, Fehlner-Peach H, Nadimpalli A, Antonopoulos DA, Jabri B, Chang EB: Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in il10-/- mice. Nature 2012;487:104-108.
29.
Matsuoka K, Kanai T: The gut microbiota and inflammatory bowel disease. Semin Immunopathol 2015;37:47-55.
30.
Cao Y, Shen J, Ran ZH: Association between faecalibacterium prausnitzii reduction and inflammatory bowel disease: a meta-analysis and systematic review of the literature. Gastroenterol Res Pract 2014;2014:872725.
31.
Martin R, Miquel S, Chain F, Natividad JM, Jury J, Lu J, Sokol H, Theodorou V, Bercik P, Verdu EF, Langella P, Bermudez-Humaran LG: Faecalibacterium prausnitzii prevents physiological damages in a chronic low-grade inflammation murine model. BMC Microbiol 2015;15:67.
32.
Gadaleta RM, van Erpecum KJ, Oldenburg B, Willemsen EC, Renooij W, Murzilli S, Klomp LW, Siersema PD, Schipper ME, Danese S, Penna G, Laverny G, Adorini L, Moschetta A, van Mil SW: Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 2011;60:463-472.
33.
Keitel V, Donner M, Winandy S, Kubitz R, Haussinger D: Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem Biophys Res Commun 2008;372:78-84.
34.
Sun J, Mustafi R, Cerda S, Chumsangsri A, Xia YR, Li YC, Bissonnette M: Lithocholic acid down-regulation of NF-kappaB activity through vitamin D receptor in colonic cancer cells. J Steroid Biochem Mol Biol 2008;111:37-40.
35.
Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T, Mende DR, Li J, Xu J, Li S, Li D, Cao J, Wang B, Liang H, Zheng H, Xie Y, Tap J, Lepage P, Bertalan M, Batto JM, Hansen T, Le Paslier D, Linneberg A, Nielsen HB, Pelletier E, Renault P, Sicheritz-Ponten T, Turner K, Zhu H, Yu C, Li S, Jian M, Zhou Y, Li Y, Zhang X, Li S, Qin N, Yang H, Wang J, Brunak S, Dore J, Guarner F, Kristiansen K, Pedersen O, Parkhill J, Weissenbach J; MetaHIT Consortium, Bork P, Ehrlich SD: A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010;464:59-65.
36.
Gu S, Chen Y, Zhang X, Lu H, Lv T, Shen P, Lv L, Zheng B, Jiang X, Li L: Identification of key taxa that favor intestinal colonization of Clostridium difficile in an adult Chinese population. Microbes Infect 2016;18:30-38.
37.
Sorg JA, Sonenshein AL: Bile salts and glycine as cogerminants for Clostridium difficile spores. J Bacteriol 2008;190:2505-2512.
38.
Bhattacharjee D, Francis MB, Ding X, McAllister KN, Shrestha R, Sorg JA: Reexamining the germination phenotypes of several Clostridium difficile strains suggests another role for the CspC germinant receptor. J Bacteriol 2015;198:777-786.
39.
Spiller R: Irritable bowel syndrome: new insights into symptom mechanisms and advances in treatment. F1000Res 2016;5:pii:F1000 Faculty Rev-780.
40.
Chang C, Lin H: Dysbiosis in gastrointestinal disorders. Best Pract Res Clin Gastroenterol 2016;30:3-15.
41.
Camilleri M, Lasch K, Zhou W: Irritable bowel syndrome: methods, mechanisms, and pathophysiology. The confluence of increased permeability, inflammation, and pain in irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 2012;303:G775-G785.
42.
Cryan JF, Dinan TG: Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci 2012;13:701-712.
43.
Pyleris E, Giamarellos-Bourboulis EJ, Tzivras D, Koussoulas V, Barbatzas C, Pimentel M: The prevalence of overgrowth by aerobic bacteria in the small intestine by small bowel culture: relationship with irritable bowel syndrome. Dig Dis Sci 2012;57:1321-1329.
44.
Giamarellos-Bourboulis E, Tang J, Pyleris E, Pistiki A, Barbatzas C, Brown J, Lee CC, Harkins TT, Kim G, Weitsman S, Barlow GM, Funari VA, Pimentel M: Molecular assessment of differences in the duodenal microbiome in subjects with irritable bowel syndrome. Scand J Gastroenterol 2015;50:1076-1087.
45.
Wedlake L, A'Hern R, Russell D, Thomas K, Walters JR, Andreyev HJ: Systematic review: the prevalence of idiopathic bile acid malabsorption as diagnosed by seHCAT scanning in patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther 2009;30:707-717.
46.
Duboc H, Rainteau D, Rajca S, Humbert L, Farabos D, Maubert M, Grondin V, Jouet P, Bouhassira D, Seksik P, Sokol H, Coffin B, Sabate JM: Increase in fecal primary bile acids and dysbiosis in patients with diarrhea-predominant irritable bowel syndrome. Neurogastroenterol Motil 2012;24:513-520, e246-e517.
47.
Mroz MS, Keating N, Ward JB, Sarker R, Amu S, Aviello G, Donowitz M, Fallon PG, Keely SJ: Farnesoid X receptor agonists attenuate colonic epithelial secretory function and prevent experimental diarrhoea in vivo. Gut 2014;63:808-817.
48.
Dey N, Wagner VE, Blanton LV, Cheng J, Fontana L, Haque R, Ahmed T, Gordon JI: Regulators of gut motility revealed by a gnotobiotic model of diet-microbiome interactions related to travel. Cell 2015;163:95-107.
49.
Duro D, Mitchell PD, Kalish LA, Martin C, McCarthy M, Jaksic T, Dunn J, Brandt ML, Nobuhara KK, Sylvester KG, Moss RL, Duggan C: Risk factors for parenteral nutrition-associated liver disease following surgical therapy for necrotizing enterocolitis: a Glaser Pediatric Research Network Study [corrected]. J Pediatr Gastroenterol Nutr 2011;52:595-600.
50.
Freudenberg F, Gothe F, Beigel F, Rust C, Koletzko S: Serum 7-alpha-hydroxy-4-cholesten-3-one as a marker for bile acid loss in children. J Pediatr 2013;163:1367-1371.e1.
51.
Galman C, Arvidsson I, Angelin B, Rudling M: Monitoring hepatic cholesterol 7alpha-hydroxylase activity by assay of the stable bile acid intermediate 7alpha-hydroxy-4-cholesten-3-one in peripheral blood. J Lipid Res 2003;44:859-866.
52.
Joly F, Mayeur C, Bruneau A, Noordine ML, Meylheuc T, Langella P, Messing B, Duee PH, Cherbuy C, Thomas M: Drastic changes in fecal and mucosa-associated microbiota in adult patients with short bowel syndrome. Biochimie 2010;92:753-761.
53.
Gomez-Ospina N, Potter CJ, Xiao R, Manickam K, Kim MS, Kim KH, Shneider BL, Picarsic JL, Jacobson TA, Zhang J, He W, Liu P, Knisely AS, Finegold MJ, Muzny DM, Boerwinkle E, Lupski JR, Plon SE, Gibbs RA, Eng CM, Yang Y, Washington GC, Porteus MH, Berquist WE, Kambham N, Singh RJ, Xia F, Enns GM, Moore DD: Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis. Nat Commun 2016;7:10713.
54.
Arrieta MC, Finlay B: The intestinal microbiota and allergic asthma. J Infect 2014;69(suppl 1):S53-S55.
55.
Herbst T, Sichelstiel A, Schar C, Yadava K, Burki K, Cahenzli J, McCoy K, Marsland BJ, Harris NL: Dysregulation of allergic airway inflammation in the absence of microbial colonization. Am J Respir Crit Care Med 2011;184:198-205.
56.
Russell SL, Gold MJ, Willing BP, Thorson L, McNagny KM, Finlay BB: Perinatal antibiotic treatment affects murine microbiota, immune responses and allergic asthma. Gut Microbes 2013;4:158-164.
57.
Thavagnanam S, Fleming J, Bromley A, Shields MD, Cardwell CR: A meta-analysis of the association between caesarean section and childhood asthma. Clin Exp Allergy 2008;38:629-633.
58.
Leung JY, Li AM, Leung GM, Schooling CM: Mode of delivery and childhood hospitalizations for asthma and other wheezing disorders. Clin Exp Allergy 2015;45:1109-1117.
59.
Park YH, Kim KW, Choi BS, Jee HM, Sohn MH, Kim KE: Relationship between mode of delivery in childbirth and prevalence of allergic diseases in Korean children. Allergy Asthma Immunol Res 2010;2:28-33.
60.
Stokholm J, Thorsen J, Chawes BL, Schjorring S, Krogfelt KA, Bonnelykke K, Bisgaard H: Cesarean section changes neonatal gut colonization. J Allergy Clin Immunol 2016;138:881-889.e2.
61.
Arrieta MC, Stiemsma LT, Amenyogbe N, Brown EM, Finlay B: The intestinal microbiome in early life: health and disease. Front Immunol 2014;5:427.
62.
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;444:1027-1031.
63.
Zhang Y, Ge X, Heemstra LA, Chen WD, Xu J, Smith JL, Ma H, Kasim N, Edwards PA, Novak CM: Loss of FXR protects against diet-induced obesity and accelerates liver carcinogenesis in ob/ob mice. Mol Endocrinol 2012;26:272-280.
64.
Ley RE, Turnbaugh PJ, Klein S, Gordon JI: Microbial ecology: human gut microbes associated with obesity. Nature 2006;444:1022-1023.
65.
Le Chatelier E, Nielsen T, Qin J, Prifti E, Hildebrand F, Falony G, Almeida M, Arumugam M, Batto JM, Kennedy S, Leonard P, Li J, Burgdorf K, Grarup N, Jorgensen T, Brandslund I, Nielsen HB, Juncker AS, Bertalan M, Levenez F, Pons N, Rasmussen S, Sunagawa S, Tap J, Tims S, Zoetendal EG, Brunak S, Clement K, Dore J, Kleerebezem M, Kristiansen K, Renault P, Sicheritz-Ponten T, de Vos WM, Zucker JD, Raes J, Hansen T; MetaHIT consortium, Bork P, Wang J, Ehrlich SD, Pedersen O: Richness of human gut microbiome correlates with metabolic markers. Nature 2013;500:541-546.
66.
Dethlefsen L, Relman DA: Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci U S A 2011;108(suppl 1):4554-4561.
67.
Trasande L, Blustein J, Liu M, Corwin E, Cox LM, Blaser MJ: Infant antibiotic exposures and early-life body mass. Int J Obes (Lond) 2013;37:16-23.
68.
Bailey LC, Forrest CB, Zhang P, Richards TM, Livshits A, DeRusso PA: Association of antibiotics in infancy with early childhood obesity. JAMA Pediatr 2014;168:1063-1069.
69.
Cho I, Yamanishi S, Cox L, Methe BA, Zavadil J, Li K, Gao Z, Mahana D, Raju K, Teitler I, Li H, Alekseyenko AV, Blaser MJ: Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature 2012;488:621-626.
70.
Guban J, Korver DR, Allison GE, Tannock GW: Relationship of dietary antimicrobial drug administration with broiler performance, decreased population levels of Lactobacillus salivarius, and reduced bile salt deconjugation in the ileum of broiler chickens. Poult Sci 2006;85:2186-2194.
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