Funding
This study was supported by The National Natural Science Foundation of
China (81972663, 82173055), Natural Science Foundation of Henan
Province(202300410446, 212300410074), Key Scientific Research Project of
Henan Higher Education Institutions (20A310024), Youth Talent Innovation
Team Support Program of Zhengzhou University (32320290), Provincial and
Ministry co-constructed key projects of Henan Medical Science and
Technology (SBGJ202102134), Key scientific and technological research
projects of Henan Provincial Department of Science and Technology
(212102310117), Health Science and Technology Innovation Project of
Henan Province (YXKC2022016), Henan Provincial Health Commission and
Ministry of Health Co-construction Project, and Henan Provincial Health
and Health Commission Joint Construction Project (LHGJ20200158).
1. Li, Q., Hu, W., Liu, W.X., Zhao, L.Y., Huang, D., Liu, X.D., Chan,
H., Zhang, Y., Zeng, J.D., Coker, O.O., et al. (2021). Streptococcus
thermophilus Inhibits Colorectal Tumorigenesis Through Secreting
β-galactosidase. Gastroenterology 160 , 1179-1193. e1114.
10.1053/j.gastro.2020.09.003.
2. Franzosa, E.A., Sirota-Madi, A., Avila-Pacheco, J., Fornelos, N.,
Haiser, H.J., Reinker, S., Vatanen, T., Hall, A.B., Mallick, H., McIver,
L.J. et al. (2019). Gut microbiome structure and metabolic activity in
patients with IBD Nat Microbiol 4 , 293-305.
10.1038/s41564-018-0306-4.
3. Tilg, H., Zmora, N., Adolph, T.E., Elinav, E. (2020). Intestinal
microbiota fueled metabolic inflammation. Nat Rev Immunol 20 ,
40-54. 10.1038/s41577-019-0198-4.
4. X. Wang, G. Sun, T. Feng, J. Zhang, X. Huang, T. Wang, Z. Xie, X.
Chu, J. Yang, H. Wang et al. (2019). Sodium oligomannate therapeutically
remodels the gut microbiota and suppresses gut bacterial amino
acid-shaped neuroinflammation to inhibit Alzheimer’s disease
progression. Cell Res 29 , 787-803. 10.1038/s41422-019-0216-x.
5. Barcik, W., Boutin, R.C.T., Sokolowska, M., Finlay, B.B. (2020). Role
of Lung and Gut Microbiota in the Pathology of Asthma. Immunity52 , 241-255. 10.1016/j.immuni.2020.01.007.
6. Luck, H., Khan, S., Kim, J. H., Copeland, J. K., Revelo, X. S., Tsai,
S., Chakraborty, M., Cheng, K., Tao Chan, Y., Nøhr, M. K., et al.
(2019). Gut-associated IgA(+) immune cells regulate obesity-related
insulin resistance. Nat Commun 10 , 3650.
10.1038/s41467-019-11370-y.
7. Sorbara, M.T. and Pamer, E.G. (2022). Microbiome-based therapeutics.
Nat Rev Microbiol 20 , 365-380. 10.1038/s41579-021-00667-9.
8. S. Hang, D. Paik, L. Yao, E. Kim, J. Trinath, J. Lu, S. Ha, B. N.
Nelson, S. P. Kelly, L. Wu et al. (2019). Bile acid metabolites control
T(H)17 and T(reg) cell differentiation. Nature 576 , 143-148.
10.1038/s41586-019-1785-z.
9. Zhuang, L., Ding, W., Zhang, Q., Ding, W., Xu, X., Yu, X., Xi, D.
(2021). TGR5 attenuates liver ischemia-reperfusion injury by activating
the Keap1-Nrf2 Signaling pathway in mice Inflammation 44 ,
859-872. 10.1007/s10753-020-01382-y.
10. T. Fu, S. Coulter, E. Yoshihara, T. G. Oh, S. Fang, F. Cayabyab, Q.
Zhu, T. Zhang, M. Leblanc, S. Liu et al. (2019). FXR regulates
intestinal Cancer Stem Cell proliferation. Cell 176 ,
1098-1112.e1018. 10.1016/j.cell.2019.01.036.
11. Mörbe, U. M.; Jørgensen, P. B.; Fenton, T. M.; von Burg, N.; Riis,
L. B.; Spencer, J.; Agace, W. (2021). Human gut-associated lymphoid
tissue (GALT): diversity, structure, and function. Mucosal Immunol14 , 793-802. 10.1038/s41385-021-00389-4.
12. Martens, E.C., Neumann, M., and Desai, M.S. (2018). Interactions
between commensal and pathogenic microorganisms and the intestinal
mucosal barrier. Nat Rev Microbiol 16 , 457-470.
10.1038/s41579-018-0036-x.
13. Mishima, Y., Oka, A., Liu, B., Herzog, J. W., Eun, C. S., Fan, T.
J., Bulik-Sullivan, E., Carroll, I. M., Hansen, J. J., Chen, L., et al.
(2019). The microbiota maintains colonic homeostasis by activating
TLR2/MyD88/PI3K signaling in IL-10-producing regulatory B cells. J Clin
Invest 129 , 3702-3716. 10.1172/jci93820.
14. Schreurs, R., Baumdick, M.E., Sagebiel, A.F., Kaufmann, M., Mokry,
M., Klarenbeek, P.L., Schaltenberg, N., Steinert, F.L., van Rijn, J.M.,
Drewniak, A., et al. (2019). Human Fetal TNF-α-Cytokine-Producing CD4(+)
Effector Memory T Cells Promote Intestinal Development and Mediate
Inflammation Early in Life. Immunity 50 , 462-476.e468.
10.1016/j.immuni.2018.12.010.
15. F. Guendel, M. Kofoed-Branzk, K. Gronke, C. Tizian, M. Witkowski, H.
W. Cheng, G. A. Heinz, F. Heinrich, P. Durek, P. S. Norris, et al.
(2020). Group 3 Innate Lymphoid Cells Program a Distinct Subset of
IL-22BP-Producing Dendritic Cells Demarcating Solitary Intestinal
Lymphoid Tissues. Immunity 53 , 1015-1032.e1018.
10.1016/j.immuni.2020.10.012.
16. Gabanyi, I., Muller, P.A., Feighery, L., Oliveira, T.Y.,
Costa-Pinto, F.A., Mucida, D. (2016). Neuroimmune Interactions Drive
Tissue Programming in Intestinal Macrophages. Cell 164 , 378-391.
10.1016/j.cell.2015.12.023.
17. Mowat, A.M. and Agace, W.W. (2014). Regional specialization within
the intestinal immune system. Nat Rev Immunol 14 , 667-685.
10.1038/nri3738.
18. X. Yang, Y. Guo, C. Chen, B. Shao, L. Zhao, Q. Zhou, J. Liu, G.
Wang, W. Yuan, Z. Sun, Z. (2021). Interaction between intestinal
microbiota and tumor immunity in the tumor microenvironment. Immunology164 , 476-493. 10.1111/imm.13397.
19. Koh, A., De Vadder, F., Kovatcheva-Datchary, P., Bäckhed, F. (2016).
From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key
Bacterial Metabolites. Cell 165 , 1332-1345.
10.1016/j.cell.2016.05.041.
20. Yang, W. & Cong, Y. (2021). Gut microbiota-derived metabolites
regulate host immune responses and immune-related inflammatory diseases.
Cell Mol Immunol 18 , 866-877. 10.1038/s41423-021-00661-4.
21. Lührs, H., Gerke, T., Müller, J.G., Melcher, R., Schauber, J.,
Boxberge, F., Scheppach, W., and Menzel, T. (2002). Butyrate inhibits
NF-κB activation in lamina propria macrophages of patients with
ulcerative colitis. Scand J Gastroenterol 37 , 458-466.
10.1080/003655202317316105.
22. Martin-Gallausiaux, C., Béguet-Crespel, F., Marinelli, L., Jamet,
A., Ledue, F., Blottière, H.M., and Lapaque, N. (2018). Butyrate
produced by gut commensal bacteria activates TGF-beta1 expression
through transcription factor SP1 in human intestinal epithelial cells.
Sci Rep 8 , 9742. 10.1038/s41598-018-28048-y.
23. Trompette, A.; Gollwitzer, E.S.; Yadava, K.; Sichelstiel, A.K.;
Sprenger, N.; Ngom-Bru, C.; Blanchard, C.; Junt, T.; Nicod, L.P.;
Harris, N.L.; Marsland, B.J. (2014). Gut microbiota metabolism in
dietary fiber influences allergic airway disease and hematopoiesis. Nat
Med 20 , 159-166. 10.1038/nm.3444.
24. Zelante, T., Iannitti, R.G., Cunha, C., De Luca, A., Giovannini, G.,
Pieraccini, G., Zecchi, R., D’Angelo, C., Massi-Benedetti, C.,
Fallarino, F., et al. (2013). Tryptophan catabolites from the microbiota
engage aryl hydrocarbon receptors and balance mucosal reactivity via
interleukin-22. Immunity 39 , 372-385.
10.1016/j.immuni.2013.08.003.
25. Partearroyo, T., Úbeda, N., Montero, A., Achón, M., Varela-Moreiras,
G. (2013). Vitamin B(12) and folic acid imbalance modifies NK
cytotoxicity, lymphocyte B, and lymphoproliferation in aged rats.
Nutrients 5 , 4836-4848. 10.3390/nu5124836.
26. Li, Y., Luo, Z.Y., Hu, Y.Y., Bi, Y.W., Yang, J.M., Zou, W.J., Song,
Y.L., Li, S., Shen, T., Li, S.J., et al. (2020). Gut microbiota
regulates autism-like behavior by mediating vitamin B(6) homeostasis in
EphB6-deficient mice. Microbiome 8 , 120.
10.1186/s40168-020-00884-z.
27. Campbell C., McKenney P.T., Konstantinovsky D. Isaeva O.I. Schizas
M. Verter J. Mai C. Jin W.B. Guo C.J. Violante S. et al. (2020).
Bacterial metabolism of bile acids promotes generation of peripheral
regulatory T cells. Nature 581 , 475-479.
10.1038/s41586-020-2193-0.
28. Kuipers, F., de Boer, J.F., Staels, B. (2020). Microbiome modulation
of host adaptive immunity via bile acid modification. Cell Metab31 , 445-447. 10.1016/j.cmet.2020.02.006.
29. X. Song, X. Sun, S. F. Oh, M. Wu, Y. Zhang, W. Zheng, N.
Geva-Zatorsky, R. Jupp, D. Mathis, C. Benoist, and D. L. Kasper, D.L.
(2020). Microbial bile acid metabolites modulate gut RORγ(+) regulatory
T cell homeostasis. Nature 577 , 410-415.
10.1038/s41586-019-1865-0.
30. Jia, W., Xie, G., and Jia, W. (2018). Bile acid-microbiota crosstalk
in gastrointestinal inflammation and carcinogenesis. Nat Rev
Gastroenterol Hepatol 15 , 111-128. 10.1038/nrgastro.2017.119.
31. Vital, M., Rud, T., Rath, S., Pieper, D. H., Schlüter, D. (2019).
Diversity of bacteria expressing bile acid-inducible 7α-dehydroxylation
Genes in the Human Gut. Comput Struct Biotechnol J 17 , 1016-1019.
10.1016/j.csbj.2019.07.012.
32. Tonin, F., Otten, L.G., & Arends, I. (2019). NAD(+) -Dependent
Enzymatic Route for the Epimerization of Hydroxysteroids. ChemSusChem12 , 3192-3203. 10.1002/cssc.201801862.
33. Lozupone, C. A., Stombaugh, J. I., Gordon, J. I., Jansson, J. K.,
Knight, R. (2012). Diversity, stability, and resilience of human gut
microbiota. Nature 489 , 220-230. 10.1038/nature11550.
34. Aguilera-Lizarraga J., Florens M.V., Viola M.F. Jain P. Decraecker
L. Appeltans I. Cuende-Estevez M. Fabre N. Beek K. Perna E. et al.
(2021). Local immune responses to food antigens drive meal-induced
abdominal pain. Nature 590 , 151-156. 10.1038/s41586-020-03118-2.
35. Whibley, N., Tucci, A., Powrie, F. (2019). Regulatory T cell
adaptation in the intestine and skin. Nat Immunol 20 , 386-396.
10.1038/s41590-019-0351-z.
36. Hoffmann, T. W., Pham, H. P., Bridonneau, C., Aubry, C., Lamas, B.,
Martin-Gallausiaux, C., Moroldo, M., Rainteau, D., Lapaque, N., Six, A.
et al. (2016). Microorganisms linked to inflammatory bowel
disease-associated dysbiosis differentially affect host physiology in
gnotobiotic mice. Isme j 10 , 460-477. 10.1038/ismej.2015.127.
37. Henrick B.M., Rodriguez L., Lakshmikanth T. Pou C. Henckel E.
Arzoomand A. Olin A. Wang J. Mikes J. Tan Z. et al. (2021).
Bifidobacteria-mediated immune system imprinting early in life. Cell184 , 3884-3898.e3811. 10.1016/j.cell.2021.05.030.
38. Britton, G.J., Contijoch, E.J., Spindler, M.P., Aggarwala, V.,
Dogan, B., Bongers, G., San Mateo, L., Baltus, A., Das, A., Gevers, D.,
et al. (2020). Defined microbiota transplant restores the Th17/RORγt(+)
regulatory T cell balance in mice colonized with inflammatory bowel
disease microbiota. Proc Natl Acad Sci U S A 117 , 21536-21545.
10.1073/pnas.1922189117.
39. Mazmanian, S.K., Round, J.L., Kasper, D.L. (2008). A microbial
symbiotic factor prevents intestinal inflammatory diseases. Nature453 , 620-625. 10.1038/nature07008.
40. Mager, L.F., Burkhard, R., Pett, N., Cooke, N.C.A., Brown, K.,
Ramay, H., Paik, S., Stagg, J., Groves, R.A., Gallo, M., et al. (2020).
Microbiome-derived inosine modulates response to checkpoint inhibitor
immunotherapy. Science 369 , 1481-1489. 10.1126/science.abc3421.
41. Pandiyan, P., Bhaskaran, N., Zou, M., Schneider, E., Jayaraman, S.,
Huehn, J. (2019). Microbiome-dependent regulation of T(regs) and Th17
Cells in Mucosa. Front Immunol 10 , 426. 10.3389/fimmu.2019.00426.
42. Li W., Hang S., Fang Y., Bae S., et al. (2021). Bacterial bile acid
metabolites modulate T(reg) activity through the nuclear hormone
receptor NR4A1. Cell Host Microbe 29 , 1366-1377. e1369.
10.1016/j.chom.2021.07.013.
43. Bernstein, H., Bernstein, C., Payne, C. M., and Dvorak, K. (2009).
Bile acids are endogenous etiological agents of gastrointestinal cancer.
World J Gastroenterol 15 , 3329-3340. 10.3748/wjg.15.3329.
44. Buffie C.G., Bucci V., et al. (2015). Precision microbiome
reconstitution restores bile acid-mediated resistance to Clostridium
difficile. Nature 517 , 205-208. 10.1038/nature13828.
45. Fiorucci, S., Biagioli, M., Zampella, A., Distrutti, E. (2018). Bile
Acid-activated Receptors Regulate Innate Immunity. Front Immunol9 , 1853. 10.3389/fimmu.2018.01853.
46. Josefowicz, S. Z., Niec, R. E., Kim, H. Y., Treuting, P., Chinen,
T., Zheng, Y., Umetsu, D. T., Rudensky, A. Y. (2012). Extrathymically
generated regulatory T cells control mucosal TH2 inflammation. Nature482 , 395-399. 10.1038/nature10772.
47. Sakaguchi, S., Yamaguchi, T., Nomura, T., Ono, M. (2008). Regulatory
T cells and immune tolerance. Cell 133 , 775-787.
10.1016/j.cell.2008.05.009.
48. Chang, D.; Xing, Q.; Su, Y.; Zhao, X.; Xu, W.; Wang, X.; Dong, C.
(2020). The Conserved Non-coding Sequences CNS6 and CNS9 Control
Cytokine-Induced Rorc Transcription during T Helper 17 Cell
Differentiation. Immunity 53 , 614-626.e614.
10.1016/j.immuni.2020.07.012.
49. Savage, P. A., Klawon, D. E. J., Miller, C. (2020). Regulatory T
Cell development. Annu Rev Immunol 38 , 421-453.
10.1146/annurev-immunol-100219-020937.
50. Tanoue, T., Atarashi, K., Honda, K. (2016). Development and
maintenance of intestinal regulatory T cells. Nat Rev Immunol 16 ,
295-309. 10.1038/nri.2016.36.
51. Gerriets, V. A., & Rathmell, J. C. (2012). Metabolic pathways in T
cell fate and function. Trends Immunol 33 , 168-173.
10.1016/j.it.2012.01.010.
52. X. Liu, Y. Wang, H. Lu, J. Li, X. Yan, M. Xiao, J. Hao, A. Alekseev,
H. Khong, T. Chen et al. (2019). Genome-wide analysis identified NR4A1
as a key mediator of T-cell dysfunction. Nature 567 , 525-529.
10.1038/s41586-019-0979-8.
53. Ma, S.; Patel, S.A.; Abe, Y.; Chen, N.; Patel, P. R.; Cho, B. S.;
Abbasi, N.; Zeng, S.; Schnabl, B.; Chang, J.T.; Huang, W.J.M. (2022).
RORγt phosphorylation protects against T cell-mediated inflammation.
Cell Rep 38 , 110520. 10.1016/j.celrep.2022.110520.
54. Sefik E., Geva-Zatorsky N., Oh S., et al. (2015). MUCOSAL
IMMUNOLOGY. Individual intestinal symbionts induce a distinct population
of RORγ⁺ regulatory T cells. Science 349 , 993-997.
10.1126/science.aaa9420.
55. Mijnheer, G., Lutter, L., Mokry, M., van der Wal, M., Scholman, R.,
Fleskens, V., Pandit, A., Tao, W., Wekking, M., Vervoort, S., et al.
(2021). Conserved transcriptomic and epigenetic signatures of human
effector Treg cells in arthritic joint inflammation. Nat Commun12 , 2710. 10.1038/s41467-021-22975-7.
56. Wan, H. and Dupasquier, M. (2005). Dendritic cells in vivo and in
vitro. Cell Mol Immunol 2 , 28-35.
57. Todorova, D., Zhang, Y., Chen, Q., Liu, J., He, J., Fu, X., Xu, Y.
(2020). hESC-derived immunosuppressive dendritic cells induce immune
tolerance in parental hESC-derived allografts. EBioMedicine 62 :
103120. 10.1016/j.ebiom.2020.103120.
58. Saravia, J., Chapman, N. M., Chi, H. (2019). Helper T cell
differentiation. Cell Mol Immunol 16 , 634-643.
10.1038/s41423-019-0220-6.
59. Patel, D. D., and Kuchroo, V. K. (2015). Th17 Cell Pathway in Human
Immunity: Lessons from Genetics and Therapeutic Interventions. Immunity43 , 1040-1051. 10.1016/j.immuni.2015.12.003.
60. Lee, J. Y., Hall, J. A., Kroehling, L., Wu, L., Najar, T., Nguyen,
H. H., Lin, W. Y., Yeung, S. T., Silva, H. M., Li, D. et al. (2020).
Serum amyloid A proteins induce pathogenic Th17 cells and promote
inflammatory diseases. Cell 180 , 79-91.e16.
10.1016/j.cell.2019.11.026.
61. Paik, D., Yao, L., Zhang, Y., Bae, S., D’Agostino, G.D., Zhang, M.,
Kim, E., Franzosa, E.A., Avila-Pacheco, J., Bisanz, J.E., et al. (2022).
Human gut bacteria produce Τ(Η)17-modulating bile acid metabolites.
Nature 603 , 907-912. 10.1038/s41586-022-04480-z.
62. Lee, E.J., Kwon, J.E., Park, M.J., Jung, K.A., Kim, D.S., Kim, E.K.,
Lee, S.H., Choi, J.Y., Park, S.H., Cho, M.L. (2017). Ursodeoxycholic
acid attenuates experimental autoimmune arthritis by targeting Th17 and
inducing pAMPK and the transcriptional co-repressor SMILE. Immunol Lett188 , 1-8. 10.1016/j.imlet.2017.05.011.
63. Liu, Y., Chen, K., Li, F., Gu, Z., Liu, Q., He, L., Shao, T., Song,
Q., Zhu, F., Zhang, L., et al. (2020). The probiotic Lactobacillus
rhamnosus GG Prevents Liver Fibrosis Through Inhibiting Hepatic Bile
Acid Synthesis and Enhancing Bile Acid Excretion in Mice. Hepatology71 , 2050-2066. 10.1002/hep.30975.
64. Cao W., Kayama H., Chen M.L. Delmas A. Sun A. Kim S.Y. Rangarajan
E.S. McKevitt K. Beck A.P. Jackson C.B. et al. (2017). The xenobiotic
transporter Mdr1 Enforces T Cell homeostasis in the presence of
intestinal bile acids. Immunity 47 , 1182-1196.e1110.
10.1016/j.immuni.2017.11.012.
65. Ridlon, J. M., Harris, S. C., Bhowmik, S., Kang, D. J., and Hylemon,
P. (2016). Consequences of bile salt biotransformation by intestinal
bacteria. Gut Microbes 7 , 22-39. 10.1080/19490976.2015.1127483.
66. Ridlon, J. M., Kang, D. J., and Hylemon, P. (2006).
Biotransformation of bile salts by human intestinal bacteria. J Lipid
Res 47 , 241-259. 10.1194/jlr.R500013-JLR200.
67. van der Lelie, D., Oka, A., Taghavi, S., Umeno, J., Fan, T.J.,
Merrell, K.E., Watson, S.D., Ouellette, L., Liu, B., Awoniyi, M., et al.
(2021). Rationally designed bacterial consortia to treat chronic
immune-mediated colitis and restore intestinal homeostasis. Nat Commun12 , 3105. 10.1038/s41467-021-23460-x.
68. Biagioli, M., Carino, A., Cipriani, S., Francisci, D., Marchianò,
S., Scarpelli, P., Sorcini, D., Zampella, A., and Fiorucci, S. (2017).
The bile acid receptor GPBAR1 regulates the M1/M2 phenotype of
intestinal macrophages and activates GPBAR1 to rescue mice from murine
colitis. J Immunol 199 , 718-733. 10.4049/jimmunol.1700183.
69. Zhou, H., Zhou, S., Shi, Y., Wang, Q., Wei, S., Wang, P., Cheng, F.,
Auwerx, J., Schoonjans, K., and Lu, L. (2021). TGR5/Cathepsin E
signaling regulates macrophage innate immune activation in liver
ischemia and reperfusion injury. Am J Transplant 21 , 1453-1464.
10.1111/ajt.16327.
70. Perino, A., Pols, T.W., Nomura, M., Stein, S., Pellicciari, R.,
Schoonjans, K. (2014). TGR5 reduces macrophage migration through the
mTOR-induced differential translation of C/EBPβ J Clin Invest124 , 5424-5436. 10.1172/jci76289.
71. Zhao, L., Zhang, H., Liu, X., Xue, S., Chen, D., Zou, J., and Jiang,
H. (2022). TGR5 deficiency activates antitumor immunity in non-small
cell lung cancer by suppressing M2 macrophage polarization. Acta Pharm
Sin B 12 , 787-800. 10.1016/j.apsb.2021.07.011.
72. Haselow, K., Bode, J.G., Wammers, M., Ehlting, C., Keitel, V.,
Kleinebrecht, L., Schupp, A.K., Häussinger, D., Graf, D. (2013).
PKA-dependent bile acids induce a switch in the IL-10/IL-12 ratio and
reduce the proinflammatory capability of human macrophages. J Leukoc
Biol 94 , 1253-1264. 10.1189/jlb.0812396.
73. Fueyo-González F., McGinty M., Ningoo M., Anderson L., et al.
(2022). IFN-β acts directly on T cells to prolong allograft survival by
enhancing regulatory T cell induction through Foxp3 acetylation.
Immunity 55 , 459-474.e457. 10.1016/j.immuni.2022.01.011.
74. Romero-Ramírez, L., García-Rama, C., Wu, S., and Mey, J. (2022).
Bile acids attenuate PKM2 pathway activation in proinflammatory
microglia. Sci Rep 12 , 1459. 10.1038/s41598-022-05408-3.
75. Qi, Y. C., Duan, G. Z., Mao, W., Liu, Q., Zhang, Y.L., Li, P.F.
(2020). Taurochenodeoxycholic acid mediates the cAMP-PKA-CREB signaling
pathway. Chin J Nat Med 18 , 898-906.
10.1016/s1875-5364(20)60033-4.
76. K. Yoneno, T. Hisamatsu, K. Shimamura, N. Kamada, R. Ichikawa, M.
Kitazume, M. T. Mori, M. Uo, Y. Namikawa, K. Matsuoka et al. (2013).
TGR5 signalling inhibits the production of pro-inflammatory cytokines by
in vitro differentiated inflammatory and intestinal macrophages in
Crohn’s. Immunology 139 , 19-29. 10.1111/imm.12045.
77. Yang H., Zhou H., Zhuang L., Auwerx J., Schoonjans K., Wang X., Feng
C., Lu L. (2017). Plasma membrane-bound G protein-coupled bile acid
receptor attenuates liver ischemia/reperfusion injury by inhibiting
Toll-like receptor 4 signaling in mice. Liver Transpl 23 , 63-74.
10.1002/lt.24628.
78. Shi, Y., Su, W., Zhang, L., Shi, C., Zhou, J., Wang, P., Wang, H.,
Shi, X., Wei, S., Wang, Q., et al. (2020). TGR5 regulates macrophage
inflammation in Nonalcoholic Steatohepatitis by modulating NLRP3
inflammasome activation. Front Immunol 11 : 609060.
10.3389/fimmu.2020.609060.
79. Liao, C.; Wang, D.; Qin, S.; Zhang, Y.; Chen, J.; Xu, R.; Xu, F.;
Zhang, P. (2022). Inflammatory-Dependent Bidirectional Effect of Bile
Acids on NLRP3 Inflammasome and Its Role in Ameliorating CPT-11-Induced
Colitis. Front Pharmacol 13 , 677738. 10.3389/fphar.2022.677738.
80. Francis, M., Guo, G., Kong, B., Abramova, E.V., Cervelli, J.A., Gow,
A.J., Laskin, J.D., Laskin, D.L. (2020). Regulation of Lung Macrophage
Activation and Oxidative Stress Following Ozone Exposure by Farnesoid X
Receptor. Toxicol Sci 177 , 441-453. 10.1093/toxsci/kfaa111.
81. Parséus, A., Sommer, N., Sommer, F., Caesar, R., Molinaro, A.,
Ståhlman, M., Greiner, T.U., Perkins, R., and Bäckhed, F. (2017).
Microbiota-induced obesity requires the farnesoid X receptor. Gut66 , 429-437. 10.1136/gutjnl-2015-310283.
82. Hao, H., Cao, L., Jiang, C., Che, Y., Zhang, S., Takahashi, S.,
Wang, G., Gonzalez, F.J. (2017). Farnesoid X Receptor Regulation of the
NLRP3 Inflammasome Underlies Cholestasis-Associated Sepsis. Cell Metab25 , 856-867.e855. 10.1016/j.cmet.2017.03.007.
83. Hu, W., Cai, C., Li, Y., Kang, F., Chu, T., and Dong, S. (2022).
Farnesoid X receptor agonists attenuate subchondral bone osteoclast
fusion and osteochondral pathologies of osteoarthritis by suppressing
the JNK1/2/NFATc1 pathway. Faseb j 36 , e22243.
10.1096/fj.202101717R.
84. Jin, D., Lu, T., Ni, M., Wang, H., Zhang, J., Zhong, C., Shen, C.,
Hao, J., Busuttil, R.W., Kupiec-Weglinski, J.W. et al. (2020). Farnesoid
X receptor activation protects the liver from ischemia/reperfusion
injury by upregulating small heterodimer partners in Kupffer cells.
Hepatol Microbiol 4 , 540-554. 10.1002/hep4.1478.
85. Yao, J., Zhou, C.S., Ma, X., Fu, B.Q., Tao, L.S., Chen, M., and Xu,
Y.P. (2014). GW4064 alleviates endotoxin-induced hepatic inflammation by
repressing macrophage activation. World J Gastroenterol 20 ,
14430-14441. 10.3748/wjg.v20.i39.14430.
86. El Kasmi, K. C., Ghosh, S., Anderson, A. L., Devereaux, M. W.,
Balasubramaniyan, N., D’Alessandro, A., Orlicky, D. J., Suchy, F. J.,
Shearn, C. T. and Sokol, R. J. (2022). Pharmacological activation of the
hepatic farnesoid X receptor prevents parenteral nutrition-associated
cholestasis in mice. Hepatology 75 , 252-265. 10.1002/hep.32101.
87. Anakk, S., Bhosale, M., Schmidt, V.A., Johnson, R.L., Finegold,
M.J., Moore, D.D. (2013). Bile acids activate YAP to promote liver
carcinogenesis. Cell Rep 5 , 1060-1069.
10.1016/j.celrep.2013.10.030.
88. Ichikawa, R., T. Takayama, K. Yoneno, N. Kamada, M. T. Kitazume, H.
Higuchi, K. Matsuoka, M. Watanabe, H. Itoh, T. Kanai et al. (2012). Bile
acids induce monocyte differentiation toward interleukin-12
hypo-producing dendritic cells via a TGR5-dependent pathway. Immunology136 , 153-162. 10.1111/j.1365-2567.2012.03554.x.
89. Hu, J., Wang, C., Huang, X., Yi, S., Pan, S., Zhang, Y., Yuan, G.,
Cao, Q., Ye, X., and Li, H. (2021). Gut microbiota-mediated secondary
bile acids regulate dendritic cells to attenuate autoimmune uveitis
through TGR5 signaling. Cell Rep 36 , 109726.
10.1016/j.celrep.2021.109726.
90. Brettschneider, E.E.S., and Terabe, M. (2021). The Role of NKT Cells
in Glioblastoma. Cells 10 . 10.3390/cells10071641.
91. Biagioli, M., Carino, A., Fiorucci, C., Marchianò, S., Di Giorgio,
C., Roselli, R., Magro, M., Distrutti, E., Bereshchenko, O., Scarpelli,
P., et al. (2019). GPBAR1 Functions as Gatekeeper for Liver NKT Cells
and provides Counterregulatory Signals in Mouse Models of
Immune-Mediated Hepatitis. Cell Mol Gastroenterol Hepatol 8 ,
447-473. 10.1016/j.jcmgh.2019.06.003.
92. Shao, J., Ge, T., Tang, C., Wang, G., Pang, L., Chen, Z. (2022).
Synergistic anti-inflammatory effects of the gut microbiota and
lithocholic acid on liver fibrosis. Inflamm Res 71 , 1389-1401.
10.1007/s00011-022-01629-4.
93. Chang, S., Kim, Y.H., Kim, Y.J., Kim, Y.W., Moon, S., Lee, Y.Y.,
Jung, J.S., Kim, Y., Jung, H.E., Kim, T.J., et al. (2018).
Taurodeoxycholate Increases the Number of Myeloid-Derived Suppressor
Cells That Ameliorate Sepsis in Mice. Front Immunol 9 , 1984.
10.3389/fimmu.2018.01984.
94. Zhang H., Liu Y., Bian Z., et al. (2014). Critical roles of
myeloid-derived suppressor cells and FXR activation in immune-mediated
liver injury. J Autoimmun 53 , 55-66. 10.1016/j.jaut.2014.02.010.
95. Nagaishi, T.; Watabe, T.; Kotake, K.; Kumazawa, T.; Aida, T.;
Tanaka, K.; Ono, R.; Ishino, F.; Usami, T.; Miura, T., et al. (2022).
Immunoglobulin A-specific deficiency induces spontaneous inflammation,
specifically in the ileum. Gut 71 , 487-496.
10.1136/gutjnl-2020-322873.
96. Yoshitsugu, R., Liu, H., Kamo, Y., Takeuchi, A., Joe, G.H., Tada,
K., Kikuchi, K., Fujii, N., Kitta, S., Hori, S., et al. (2021).
12α-Hydroxylated bile acid enhances the accumulation of adiponectin and
immunoglobulin A in the rat ileum. Sci Rep 11 , 12939.
10.1038/s41598-021-92302-z.
97. Y. Yoshikawa, T. Tsujii, K. Matsumura, J. Yamao, Y. Matsumura, R.
Kubo, H. Fukui, S. Ishizaka, S. (1992). Immunomodulatory effects of
ursodeoxycholic acid on immune response. Hepatology 16 , 358-364.
10.1002/hep.1840160213.
98. Zhai, Z., Niu, K.M., Liu, Y., Lin, C., and Wu, X. (2021). The Gut
Microbiota-Bile Acids-TGR5 Axis Mediates Eucommia ulmoides leaf extract
alleviation of injury to colonic epithelial integrity. Front Microbiol.12 , 727681. 10.3389/fmicb.2021.727681.
99. Sorrentino, G., Perino, A., Yildiz, E., El Alam, G., Bou Sleiman,
M., Gioiello, A., Pellicciari, R., and Schoonjans, K. (2020). Bile Acids
Signal via TGR5 to activate intestinal stem cells and promote epithelial
regeneration. Gastroenterology 159 , 956-968. e958.
10.1053/j.gastro.2020.05.067.
100. Azuma Y., Uchiyama K., Sugaya T. Yasuda T. Hashimoto H.
Kajiwara-Kubota M. Sugino S. Kitae H. Torii T. Mizushima K. et al.
(2022). Deoxycholic acid delays wound healing in colonic epithelial
cells via the transmembrane G-protein-coupled receptor 5. J
Gastroenterol Hepatol 37 , 134-143. 10.1111/jgh.15676.
101. Chang, C., Jiang, J., Sun, R., Wang, S., Chen, H. (2022).
Downregulation of Serum and Distal Ileum Fibroblast Growth Factor19 in
Bile acid diarrhea Dig Dis Sci 67 , 872-879.
10.1007/s10620-021-07042-x.
102. Vavassori, P., Mencarelli, A., Renga, B., Distrutti, E., Fiorucci,
S. (2009). The bile acid receptor FXR modulates intestinal innate
immunity. J Immunol 183 , 6251-6261. 10.4049/jimmunol.0803978.
103. Modica, S., Murzilli, S., Salvatore, L., Schmidt, D.R., and
Moschetta, A. (2008). Nuclear bile acid receptor FXR protects against
intestinal tumorigenesis. Cancer Res 68 , 9589-9594.
10.1158/0008-5472.Can-08-1791.
104. Zhao, L., Xuan, Z., Song, W., Zhang, S., Li, Z., Song, G., Zhu, X.,
Xie, H., Zheng, S., and Song, P. (2020). A novel role for farnesoid X
receptors in bile acid-mediated intestinal glucose homeostasis. J Cell
Mol Med 24 , 12848-12861. 10.1111/jcmm.15881.
105. Jin, D., Huang, K., Xu, M., Hua, H., Ye, F., Yan, J., Zhang, G.,
and Wang, Y. (2022). Deoxycholic acid induces gastric intestinal
metaplasia by activating STAT3 signaling and disturbing gastric bile
acid metabolism and the microbiota. Gut Microbes 14 , 2120744.
10.1080/19490976.2022.2120744.
106. Yao, Y., Li, X., Xu, B., Luo, L., Guo, Q., Wang, X., Sun, L.,
Zhang, Z., and Li, P. (2022). Cholecystectomy promotes colon
carcinogenesis by activating the Wnt signaling pathway by increasing
deoxycholic acid levels. Cell Commun Signals 20 , 71.
10.1186/s12964-022-00890-8.
107. Kuss, S.K., Best, G.T., Etheredge, C.A., Pruijssers, A.J.,
Frierson, J.M., Hooper, L.V., Dermody, T.S., Pfeiffer, J.K. (2011). The
intestinal microbiota promotes enteric virus replication and systemic
pathogenesis. Science 334 , 249-252. 10.1126/science.1211057.
108. Karst, S. M. (2016). Influence of commensal bacteria on enteric
virus infection Nat Rev Microbiol 14 , 197-204.
10.1038/nrmicro.2015.25.
109. de Graaf, M., van Beek, J., Koopmans, M. (, 2016). Human norovirus
transmission and evolution in a changing world. Nat Rev Microbiol14 , 421-433. 10.1038/nrmicro.2016.48.
110. Grau, K. R.; Zhu, S.; Peterson, S. T.; Helm, E. W.; Philip, D.;
Phillips, M.; Hernandez, A.; Turula, H.; Frasse, P.; Graziano, V. R.; et
al. (2020). The intestinal regionalization of acute norovirus infection
is regulated by the microbiota via bile acid-mediated priming with type
III interferon. Nat Microbiol 5 , 84-92.
10.1038/s41564-019-0602-7.
111. Song, B., Li, P., Yan, S., Liu, Y., Gao, M., Lv, H., Lv, Z., and
Guo, Y. (2022). Effects of dietary Astragalus Polysaccharide
supplementation on the Th17/Treg balance and gut microbiota of broiler
chickens challenged with necrotic enteritis. Front Immunol 13 ,
781934. 10.3389/fimmu.2022.781934.
112. Quraishi, M.N., Acharjee, A., Beggs, A.D., Horniblow, R., Tselepis,
C., Gkoutos, G., Ghosh, S., Rossiter, A.E., Loman, N., van Schaik, W.,
et al. (2020). A Pilot Integrative Analysis of Colonic Gene Expression,
Gut Microbiota, and Immune Infiltration in Primary Sclerosing
Cholangitis-Inflammatory Bowel Disease: Association of Disease With Bile
Acid Pathways. J Crohns Colitis 14 , 935-947.
10.1093/ecco-jcc/jjaa021.
113. Chen, L., Jiao, T., Liu, W., Luo, Y., Wang, J., Guo, X., Tong, X.,
Lin, Z., Sun, C., Wang, K., et al. (2022). Hepatic cytochrome P450 8B1
and cholic acid potentiate intestinal epithelial injury in colitis by
suppressing intestinal stem cell renewal. Cell Stem Cell 29 ,
1366-1381.e1369. 10.1016/j.stem.2022.08.008.
114. Qi, X., Yun, C., Sun, L., Xia, J., Wu, Q., Wang, Y., Wang, L.,
Zhang, Y., Liang, X., Wang, L., et al. (2019). Gut microbiota-bile
acid-interleukin-22 axis orchestrates polycystic ovary syndrome. Nat Med25 , 1225-1233. 10.1038/s41591-019-0509-0.
115. Zheng X., Chen T., Jiang R., et al. (2021). Hyocholic acid species
improve glucose homeostasis through distinct TGR5 and FXR signaling
mechanisms. Cell Metab 33 , 791-803.e797.
10.1016/j.cmet.2020.11.017.
116. Liu, H., Tian, R., Wang, H., Feng, S., Li, H., Xiao, Y., Luan, X.,
Zhang, Z., Shi, N., Niu, H., and Zhang, S. (2020). Gut microbiota from
patients with coronary artery disease contributes to vascular
dysfunction in mice by regulating bile acid metabolism and immune
activation. J Transl Med 18 , 382. 10.1186/s12967-020-02539-x.
117. Fuchs, C.D. and Trauner, M. (2022). Role of bile acids and their
receptors in gastrointestinal and hepatic pathophysiologies. Nat Rev
Gastroenterol Hepatol 19 , 432-450. 10.1038/s41575-021-00566-7.
118. Liu, H.M., Liao, J.F., and Lee, T.Y. (2017). Farnesoid X receptor
agonist GW4064 ameliorates lipopolysaccharide-induced ileocolitis
through TLR4/MyD88 pathway-related mitochondrial dysfunction in mice.
Biochem Biophys Res Commun 490 , 841-848.
10.1016/j.bbrc.2017.06.129.
119. Du, J., Zhang, J., Xiang, X., Xu, D., Cui, K., Mai, K., and Ai, Q.
(2022). Activation of the farnesoid X receptor suppresses ER stress and
inflammation via the YY1/NCK1/PERK pathway in large yellow croaker
(Larimichthys crocea). Front Nutr 9 , 1024631.
10.3389/fnut.2022.1024631.
120. Gong, Y., Li, K., Qin, Y., Zeng, K., Liu, J., Huang, S., Chen, Y.,
Yu, H., Liu, W., Ye, L., and Yang, Y. (2021). Norcholic Acid Promotes
Tumor Progression and Immune Escape by Regulating Farnesoid X Receptor
in Hepatocellular Carcinoma. Front Oncol 11 : 711448.
10.3389/fonc.2021.711448.
121. Ji, G., Ma, L., Yao, H., Ma, S., Si, X., Wang, Y., Bao, X., Ma, L.,
Chen, F., Ma, C., et al. (2020). Precise delivery of obeticholic acid
via a nanoapproach for triggering natural killer T cell-mediated liver
cancer immunotherapy. Acta Pharm Sin B 10 , 2171-2182.
10.1016/j.apsb.2020.09.004.
122. Huang, S., Wu, Y., Zhao, Z., Wu, B., Sun, K., Wang, H., Qin, L.,
Bai, F., Leng, Y., and Tang, W. (2021). A new mechanism of obeticholic
acid in NASH treatment via inhibition of NLRP3 inflammasome activation
in macrophages. Metabolism 120 , 154797.
10.1016/j.metabol.2021.154797.
123. Weber, A.A., Mennillo, E., Yang, X., van der Schoor, L.W.E.,
Jonker, J.W., Chen, S., and Tukey, R.H. (2021). Regulation of Intestinal
UDP-Glucuronosyltransferase 1A1 by the Farnesoid X Receptor Agonist
Obeticholic Acid Is Controlled by Constitutive Androstane Receptor
through Intestinal Maturation. Drug Metab Dispos 49 , 12-19.
10.1124/dmd.120.000240.
124. Li, C., Zhou, W., Li, M., Shu, X., Zhang, L., and Ji, G. (2021).
Salvia-Nelumbinis naturalis extract protects mice against MCD
diet-induced steatohepatitis via activation of colonic FXR-FGF15
pathway. Biomed Pharmacother 139 , 111587.
10.1016/j.biopha.2021.111587.
125. Khoruts, A., Staley, C., and Sadowsky, M.J. (2021). Faecal
microbiota transplantation for Clostridioides difficile: mechanisms and
pharmacology. Nat Rev Gastroenterol Hepatol 18 , 67-80.
10.1038/s41575-020-0350-4.
126. Littmann, E.R., Lee, J.J., Denny, J.E., Alam, Z., Maslanka, J.R.,
Zarin, I., Matsuda, R., Carter, R.A., Susac, B., Saffern, M.S., et al.
(2021). Host immunity modulates the efficacy of microbiota
transplantation for treatment of Clostridioides difficile infection. Nat
Commun 12 , 755. 10.1038/s41467-020-20793-x.
127. Xiao, R., Lei, K., Kuok, H., Deng, W., Zhuang, Y., Tang, Y., Guo,
Z., Qin, H., Bai, L.P., and Li, T. (2022). Synthesis and identification
of lithocholic acid 3-sulfate as RORγt ligand to inhibit Th17 cell
differentiation. J Leukoc Biol 112 , 835-843.
10.1002/jlb.1ma0122-513r.
128. Labiano, I., Agirre-Lizaso, A., Olaizola, P., Echebarria, A.,
Huici-Izagirre, M., Olaizola, I., Esparza-Baquer, A., Sharif, O.,
Hijona, E., Milkiewicz, P., et al. (2022). TREM-2 plays a protective
role in cholestasis by acting as a negative regulator of inflammation. J
Hepatol 77 , 991-1004. 10.1016/j.jhep.2022.05.044.
129. Shen, Y., Lu, C., Song, Z., Qiao, C., Wang, J., Chen, J., Zhang,
C., Zeng, X., Ma, Z., Chen, T., et al. (2022). Ursodeoxycholic acid
reduces antitumor immunosuppression by inducing CHIP-mediated TGF-β
degradation. Nat Commun 13 , 3419. 10.1038/s41467-022-31141-6.
130. Funabashi, M., Grove, T.L., Wang, M., Varma, Y., McFadden, M.E.,
Brown, L.C., Guo, C., Higginbottom, S., Almo, S.C., and Fischbach, M.A.
(2020). A metabolic pathway for bile acid dehydroxylation by the gut
microbiome. Nature 582 , 566-570. 10.1038/s41586-020-2396-4.