The Gut Microbiota as a Therapeutic Target in IBD and Metabolic Disease: A Role for the Bile Acid Receptors FXR and TGR5.
The gut microbiota plays a crucial role in regulating many physiological systems of the host, including the metabolic and immune system. Disturbances in microbiota composition are increasingly correlated with disease; however, the underlying mechanisms are not well understood. Recent evidence suggests that changes in microbiota composition directly affect the metabolism of bile salts. Next to their role in digestion of dietary fats, bile salts function as signaling molecules for bile salt receptors such as Farnesoid X receptor (FXR) and G protein-coupled bile acid receptor (TGR5). Complementary to their role in metabolism, FXR and TGR5 are shown to play a role in intestinal homeostasis and immune regulation. This review presents an overview of evidence showing that changes in bile salt pool and composition due to changes in gut microbial composition contribute to the pathogenesis of inflammatory bowel disease and metabolic disease, possibly through altered activation of TGR5 and FXR. We further discuss how dietary interventions, such as pro- and synbiotics, may be used to treat metabolic disease and inflammatory bowel disease (IBD) through normalization of bile acid dysregulation directly or indirectly through normalization of the intestinal microbiota.
Nutricia Research, 3584 CT, Utrecht, The Netherlands. Annemarie.baars@danone.com.
Annemarie
A
Baars
Nutricia Research, 3584 CT, Utrecht, The Netherlands. Annemarie.oosting@danone.com.
Annemarie
A
Oosting
Nutricia Research, 3584 CT, Utrecht, The Netherlands. jan.knol@danone.com.|Laboratory of Microbiology, Wageningen University, 6703 HB, Wageningen, The Netherlands. jan.knol@danone.com.
Jan
J
Knol
Nutricia Research, 3584 CT, Utrecht, The Netherlands. johan.garssen@danone.com.|Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG, Utrecht, The Netherlands. johan.garssen@danone.com.
Johan
J
Garssen
Nutricia Research, 3584 CT, Utrecht, The Netherlands. jeroen.vanbergen@danone.com.|Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG, Utrecht, The Netherlands. jeroen.vanbergen@danone.com.
Jeroen
J
van Bergenhenegouwen
FXR; TGR5; bile acid dysregulation; dysbiosis; gut microbiota; inflammatory bowel disease; metabolic disease; probiotics
Sci Signal. 2009 Jun 16;2(75):ra28
19531803
PLoS One. 2012;7(4):e34939
22529960
FEMS Microbiol Rev. 2005 Sep;29(4):625-51
16102595
Cell Metab. 2013 May 7;17(5):657-69
23602448
Proc Natl Acad Sci U S A. 2014 Apr 22;111(16):E1610-9
24706920
Proc Natl Acad Sci U S A. 2008 Mar 11;105(10 ):3891-6
18292224
Expert Opin Biol Ther. 2013 May;13(5):631-42
23350815
Lancet. 1993 Apr 10;341(8850):938-41
8096277
Proc Natl Acad Sci U S A. 2007 May 29;104(22):9529-33
17483483
Genome Biol. 2012 Apr 16;13(9):R79
23013615
Biochim Biophys Acta. 2011 Aug;1812(8):851-8
21540105
Hepatology. 2008 Nov;48(5):1632-43
18972444
FEBS Lett. 2014 Nov 17;588(22):4223-33
25307765
Cell. 1995 Jun 2;81(5):687-93
7774010
Nat Immunol. 2014 Apr;15(4):307-10
24646587
Food Dig. 2012 Dec;3(1-3):63-77
23293684
Nat Commun. 2015 Jul 21;6:7715
26197299
PLoS One. 2011;6(8):e23745
21887309
Cell Metab. 2009 Sep;10(3):167-77
19723493
Neurogastroenterol Motil. 2012 Jun;24(6):513-20, e246-7
22356587
Nature. 2013 Aug 29;500(7464):541-6
23985870
Eur J Clin Nutr. 2012 Nov;66(11):1234-41
22990854
Eur J Obstet Gynecol Reprod Biol. 1998 Jun;78(2):141-50
9622311
Gut. 2013 Apr;62(4):654-5
23148122
Hepatology. 2011 Oct;54(4):1421-32
21735468
Mol Cell. 1999 May;3(5):543-53
10360171
N Engl J Med. 2013 Apr 25;368(17):1575-84
23614584
Sci Rep. 2015 May 27;5:10512
26015368
Science. 2013 Sep 6;341(6150):1241214
24009397
Cell Metab. 2013 Feb 5;17 (2):225-35
23395169
Nature. 2006 Dec 21;444(7122):1027-31
17183312
Pharmacology. 1997 Mar;54(3):144-52
9127437
Nat Rev Gastroenterol Hepatol. 2014 Jan;11(1):55-67
23982684
Am J Physiol Endocrinol Metab. 2000 Jul;279(1):E83-7
10893326
Proc Natl Acad Sci U S A. 2014 May 20;111(20):7421-6
24799697
Nature. 2006 Jan 26;439(7075):484-9
16400329
Immunology. 2013 May;139(1):19-29
23566200
J Lipid Res. 2006 Feb;47(2):241-59
16299351
Diabetes. 2011 Jul;60(7):1861-71
21593203
Nat Rev Endocrinol. 2014 Aug;10(8):488-98
24821328
Physiol Rev. 2007 Apr;87(2):507-20
17429039
Biomed Res Int. 2015;2015:806248
25710027
Am J Physiol Gastrointest Liver Physiol. 2014 Jan 1;306(1):G48-58
24177031
J Pharmacol Exp Ther. 2009 Feb;328(2):469-77
18981289
PLoS One. 2012;7(11):e49706
23189156
FEBS Lett. 2008 Jan 9;582(1):2-9
18023286
Cell Host Microbe. 2012 Nov 15;12(5):611-22
23159051
Cell Rep. 2014 Apr 10;7(1):12-8
24656817
Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13580-5
18757757
Science. 2012 Jun 8;336(6086):1268-73
22674334
J Dairy Sci. 1999 Dec;82(12):2530-5
10629797
Biochem J. 1963 Oct;89:57-68
14097367
Mol Cell Endocrinol. 2013 Apr 10;368(1-2):17-29
22609541
ISME J. 2011 Jan;5(1):82-91
20613793
Obesity (Silver Spring). 2010 Jan;18(1):190-5
19498350
J Lipid Res. 2007 Dec;48(12 ):2664-72
17720959
Cell Res. 2008 Nov;18(11):1087-95
18825165
Nat Rev Immunol. 2009 May;9(5):313-23
19343057
Gut. 2011 Apr;60(4):463-72
21242261
Appl Environ Microbiol. 2006 Mar;72(3):1729-38
16517616
Nat Rev Immunol. 2006 Jan;6(1):44-55
16493426
Lancet Infect Dis. 2013 Oct;13(10):889-99
24070562
Pharmacol Res. 2011 Apr;63(4):259-65
21211565
J Lipid Res. 2009 Oct;50(10 ):1955-66
19346330
Arterioscler Thromb Vasc Biol. 2013 Jul;33(7):1663-9
23619297
Appl Biochem Biotechnol. 2012 Dec;168(7):1880-95
23054820
PLoS One. 2014 Sep 19;9(9):e108270
25237811
Int J Obes (Lond). 2008 Nov;32(11):1720-4
18779823
Proc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1:4578-85
20668239
Gut. 2013 Apr;62(4):531-9
22993202
Gastroenterology. 2010 Dec;139(6):1816-9
21029802
J Nutr. 2010 Mar;140(3):648-52
20107145
Gut Pathog. 2014 Jun 14;6:22
25018784
Nature. 2005 Sep 29;437(7059):759-63
16127449
Mayo Clin Proc. 2008 Apr;83(4):460-9
18380992
Physiol Rev. 2009 Jan;89(1):147-91
19126757
Pharmacology. 2002 Aug;65(4):215-21
12119452
Int Arch Allergy Immunol. 2014;165(1):1-8
25277277
Nature. 2013 Aug 29;500(7464):585-8
23985875
Front Biosci (Landmark Ed). 2009 Jan 01;14:2584-98
19273221
Clin Exp Gastroenterol. 2014 Dec 09;7:473-87
25525379
Eur Surg Res. 1993 Jan-Feb;25(1):11-9
8482301
PLoS One. 2014 Apr 22;9(4):e93567
24755711
Gut. 2013 Jan;62(1):146-58
22525886
J Biol Chem. 2014 Oct 10;289(41):28421-32
25138215
Biochem Biophys Res Commun. 2012 Oct 26;427(3):600-5
23022524
Nature. 2012 Sep 13;489(7415):242-9
22972297
Biomed Res Int. 2015;2015:505878
25793197
Trends Microbiol. 1995 Apr;3(4):149-54
7613757
J Biol Chem. 2013 May 10;288(19):13850-62
23546875
Therap Adv Gastroenterol. 2011 Mar;4(2):95-101
21694811
PLoS Comput Biol. 2013;9(1):e1002863
23326225
Hepatology. 2013 Oct;58(4):1451-60
23686672
PLoS One. 2013;8(1):e54472
23372731
Pharm Res. 2013 May;30(5):1447-57
23371517
Dig Liver Dis. 2014 Apr;46(4):302-12
24411485
Nature. 2006 Dec 21;444(7122):1022-3
17183309
BMJ Open. 2014 Aug 25;4(8):e005047
25157183
Nature. 2014 May 8;509(7499):183-8
24670636
Nature. 2010 Mar 4;464(7285):59-65
20203603
Mol Endocrinol. 2011 Jun;25(6):1066-71
21454404
Annu Rev Immunol. 2010;28:623-67
20192812
Mol Endocrinol. 2012 Feb;26(2):272-80
22261820
PLoS One. 2011;6(10):e25637
22046243
J Allergy Clin Immunol. 2013 Sep;132(3):601-607.e8
23900058
Gut. 2008 Nov;57(11):1605-15
18941009
Gut. 2006 Jan;55(1):16-25
16118348
Steroids. 1997 Aug-Sep;62(8-9):564-77
9292932
Biochem Biophys Res Commun. 2002 Nov 15;298(5):714-9
12419312
Hepatology. 2003 Mar;37(3):551-7
12601352
J Biol Chem. 2003 Mar 14;278(11):9435-40
12524422
Gut Pathog. 2013 Apr 30;5(1):10
23631345
Lab Invest. 2010 Oct;90(10 ):1457-67
20531290
Immunol Rev. 2012 Jan;245(1):45-55
22168413
ISME J. 2013 Apr;7(4):707-17
23190729
J Endocrinol. 2006 Oct;191(1):197-205
17065403
Science. 2001 Feb 2;291(5505):881-4
11157169
Nat Commun. 2012;3:1245
23212374
Cell Metab. 2011 Dec 7;14(6):747-57
22152303
J Lipid Res. 1964 Jul;5(3):409-17
5873380
Nat Immunol. 2013 Jul;14(7):676-84
23778795
Annu Rev Food Sci Technol. 2012;3:425-47
22224552
J Lipids. 2012;2012:754067
21991404
Inflamm Bowel Dis. 2006 Feb;12(2):106-11
16432374
J Biol Chem. 2011 Jul 29;286(30):26913-20
21632533
J Lipid Res. 1966 Jan;7(1):77-82
5900224
J Biol Chem. 2006 Apr 21;281(16):11039-49
16446356
J Immunol. 2009 Nov 15;183(10):6251-61
19864602
J Autoimmun. 2013 Oct;46:66-73
24075647
Front Cell Infect Microbiol. 2012 Aug 09;2:104
22919693
Proc Natl Acad Sci U S A. 2006 Jan 24;103(4):1006-11
16410358
PLoS One. 2014 Dec 17;9(12):e115175
25517115
J Hepatol. 2014 Apr;60(4):824-31
24316517
Best Pract Res Clin Gastroenterol. 2014 Aug;28(4):573-83
25194176
Early Hum Dev. 2010 Jul;86 Suppl 1:67-71
20116944
Am Surg. 1992 May;58(5):305-10
1622012
Inflamm Res. 2000 Dec;49(12):744-55
11211928
Inflamm Bowel Dis. 2009 Aug;15(8):1183-9
19235886
Can J Gastroenterol. 2012 Sep;26(9):631-7
22993736
Proc Natl Acad Sci U S A. 2006 Mar 7;103(10 ):3920-5
16473946
BMC Res Notes. 2012 Aug 28;5:461
22929053
J Clin Invest. 2014 Dec;124(12):5424-36
25365223
Nature. 2013 Jun 6;498(7452):99-103
23719380
Proc Natl Acad Sci U S A. 2006 Mar 21;103(12):4333-4
16537368
Nature. 2009 Jan 22;457(7228):480-4
19043404