Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease
Abstract
BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is characterised by chronic intestinal inflammation, resulting from dysregulation of the mucosal immune system and compromised intestinal epithelial barrier function. The bile salt, nuclear farnesoid X receptor (FXR), was recently implicated in intestinal antibacterial defence and barrier function. The aim of this study was to investigate the therapeutic potential of FXR agonists in the treatment of intestinal inflammation in complementary in vivo and in vitro models. METHODS: Colitis was induced in wild-type (WT) and Fxr-null mice using dextran sodium sulfate, and in WT mice using trinitrobenzenesulfonic acid. Mice were treated with vehicle or the FXR agonist INT-747, and colitis symptoms were assessed daily. Epithelial permeability assays and cytokine expression analysis were conducted in mouse colon and enterocyte-like cells (Caco-2/HT29) treated with medium or INT-747. Inflammatory cytokine secretion was determined by ELISA in various human immune cell types. RESULTS: INT-747-treated WT mice are protected from DSS- and TNBS-induced colitis, as shown by significant reduction of body weight loss, epithelial permeability, rectal bleeding, colonic shortening, ulceration, inflammatory cell infiltration and goblet cell loss. Furthermore, Fxr activation in intestines of WT mice and differentiated enterocyte-like cells downregulates expression of key proinflammatory cytokines and preserves epithelial barrier function. INT-747 significantly decreases tumour necrosis factor α secretion in activated human peripheral blood mononuclear cells, purified CD14 monocytes and dendritic cells, as well as in lamina propria mononuclear cells from patients with IBD. CONCLUSIONS: FXR activation prevents chemically induced intestinal inflammation, with improvement of colitis symptoms, inhibition of epithelial permeability, and reduced goblet cell loss. Furthermore, FXR activation inhibits proinflammatory cytokine production in vivo in the mouse colonic mucosa, and ex vivo in different immune cell populations. The findings provide a rationale to explore FXR agonists as a novel therapeutic strategy for IBD.
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FXR agonists are known to alleviate endoplasmic reticulum stress and suppress oxidative damage by upregulating antioxidant and anti-apoptotic pathways.
“FXR agonists are known to alleviate endoplasmic reticulum stress and suppress oxidative damage by upregulating antioxidant and anti-apoptotic pathways [42, 43].”
From High-throughput human microfluidic organoid-on-a-chip platform for modeling liver diseases and screening nanotherapeutics. (2026) · cites this paper as [42]
A very fine balance between host- and microbiota-produced bile acids is required to support epithelial barrier function and control the inflammatory response in the intestine.
“Multiple reports regarding TGR5 function (Gadaleta et al., 2011;Hartmann et al., 2018;Inagaki et al., 2006;Vavassori et al., 2009) have indicated that a very fine balance between host-and microbiota-produced bile acids is required to support epithelial barrier function and control the inflammatory response in the intestine.”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Gadaleta et al., 2011
Activation of FXR inhibits intestinal inflammation and protects the intestinal barrier in IBD.
“Activation of FXR inhibits intestinal inflammation and protects the intestinal barrier in IBD (Gadaleta et al., 2011).”
From Bacteroides dorei BDX-01 alleviates DSS-induced experimental colitis in mice by regulating intestinal bile salt hydrolase activity and the FXR-NLRP3 signaling pathway (2023) · cites this paper as Gadaleta et al., 2011
FXR activation by GW4064 or obeticholic acid attenuates mucosal injury, ileal barrier permeability, bacterial overgrowth and bacterial translocation in mice and rats.
“Accordingly, FXR activation by agonists GW4064 or obeticholic acid (OCA) attenuates mucosal injury, ileal barrier permeability, bacterial overgrowth and bacterial translocation in mice and rats 20,21,141,142.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [21]
Treatment with a synthetic BAR agonist has protective effects in mouse colitis models, whereas BAR-deficient mice exhibit exacerbated pathology.
“treatment with a synthetic agonist of BAR has protective effects in mouse models of colitis, whereas BAR-deficient (Nr1h4−/−) mice exhibit exacerbated pathology (Gadaleta et al., 2011; Vavassori et al., 2009).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Gadaleta et al., 2011
In the small intestine, bile acids are also very important for the maintenance of epithelial barrier function.
“In the small intestine, they are also very important for the maintenance of epithelial barrier function (Gadaleta et al., 2011; Inagaki et al., 2006).”
From Microbiota-related Changes in Bile Acid & Tryptophan Metabolism are Associated with Gastrointestinal Dysfunction in a Mouse Model of Autism (2017) · cites this paper as Gadaleta et al., 2011
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Bile acids as modulators of gut microbiota composition and function
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“In chemically induced colitis mouse models, FXRdeficiency worsens, while treatment with the FXR agonist obeticholic acid protects from mucosal inflammation and promotes the expression of antibacterial genes.(73) Obeticholic acid-mediated activation of FXR decreases TNF-α production in several immune cell populations e…”
BackgroundInfluentialBile acid transporters and regulatory nuclear receptors in the liver and beyond
Halilbasic, E., Claudel, T., & Trauner, M. A. (2012) · Journal of Hepatology · doi:10.1016/j.jhep.2012.08.002 · Cited by 397 · see citing works
“Under normal conditions, BA-activated FXR controls bacterial overgrowth and maintains the epithelial barrier integrity by induction of multiple anti-inflammatory genes [103] and pharmacological activation of FXR has beneficial effects in the mouse model of colitis [104].”
BackgroundFXR signaling in the enterohepatic system
Matsubara, T., Li, F., & Gonzalez, F. J. (2012) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2012.05.004 · Cited by 383 · see citing works
“6-ECDCA, also known as INT-747, is another efficacious FXR agonist under testing for various diseases associated with bile acid dysfunction, such as liver fibrosis (Fiorucci et al., 2004) and inflammatory bowel disease (Gadaleta et al., 2011).”
BackgroundInfluentialDiet in the Pathogenesis and Treatment of Inflammatory Bowel Diseases
Lee, D. Y., Albenberg, L. G., Compher, C. W., Baldassano, R. N., Piccoli, D. A., Lewis, J. D., & Wu, G. D. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.01.007 · Cited by 377 · see citing works
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“In N U In the small intestine, they are also very important for the maintenance of epithelial barrier function (Gadaleta et al., 2010; Inagaki et al., 2006).”
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The Role of Enterobacteriaceae in Gut Microbiota Dysbiosis in Inflammatory Bowel Diseases
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“, Farnesoid X receptor (FXR)), inferring that the dysbiosis of the gut microbiota’s characteristic of IBDs may alter the capacity for BA modification in this community [103].”
BackgroundThe Function and Role of the Th17/Treg Cell Balance in Inflammatory Bowel Disease
Yan, J., Luo, M., Chen, Z., & He, B. (2020) · Journal of Immunology Research · doi:10.1155/2020/8813558 · Cited by 344 · see citing works
“Clinical observation of using FXR agonist to stimulate IBD patients showed that the secretion of proinflammatory cytokines IL-17, IFN-γ, and TNF in lamina propria mononuclear cells was significantly decreased [65].”
Bile Acid Metabolism and Signaling in Cholestasis, Inflammation, and Cancer
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“For example, FXR modulates intestine immunity and FXR activation was shown to reduce inflammation in inflammatory bowel disease (Gadaleta et al., 2011; Vavassori,Mencarelli, Renga,Distrutti, & Fiorucci, 2009).”
BackgroundConnecting the immune system, systemic chronic inflammation and the gut microbiome: the role of sex
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Emerging roles of bile acids in mucosal immunity and inflammation
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FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2
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Discovery of farnesoid X receptor and its role in bile acid metabolism
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Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon
Ward, J. B. J., Lajczak, N. K., Kelly, O. B., O’Dwyer, A. M., Giddam, A. K., Ní Gabhann, J., Franco, P., Tambuwala, M. M., Jefferies, C. A., Keely, S., et al. (2017) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00256.2016 · Cited by 286 · see citing works
“In this regard, several bile acid receptors are expressed in the colonic epithelium, including TGR5 and the nuclear receptors farnesoid X receptor, pregnane X receptor, and vitamin D receptor, each of which has been shown to protect against colonic inflammation in animal models (12, 29, 35, 40).”
BackgroundBile Acid Metabolism and Signaling
Chiang, J. Y. L. (2013) · Comprehensive physiology · doi:10.1002/j.2040-4603.2013.tb00517.x · Cited by 286 · see citing works
“OCA antagonizes NF-κB-stimulated inflammation in liver (203), modulates innate immunity in animal models of colitis (197), inhibits and preserves the intestinal barrier in inflammatory bowel disease (69), and inhibits vascular smooth muscle cell inflammation and migration (119).”
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Guts and Gall: Bile Acids in Regulation of Intestinal Epithelial Function in Health and Disease
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“ily, has been found to be crucial in numerous hepatobiliary(23-25) and gastrointestinal diseases.(26) FXR is highly expressed in the normal liver, kidney, and intestine.”
BackgroundSorribas, M., Jakob, M. O., Yılmaz, B., Li, H., Stutz, D., Noser, Y., Gottardi, A. D., Moghadamrad, S., Hassan, M., Albillos, A., et al. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.06.017 · Cited by 256 · see citing works
Leaky Gut: Effect of Dietary Fiber and Fats on Microbiome and Intestinal Barrier
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Microbiota Metabolites in Health and Disease
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Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis
Adorini, L., Pruzanski, M., & Shapiro, D. (2012) · Drug Discovery Today · doi:10.1016/j.drudis.2012.05.012 · Cited by 259 · see citing works
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Bile acid metabolism and signalling in liver disease
Fuchs, C. D., Simbrunner, B., Baumgartner, M., Campbell, C., Reiberger, T., & Trauner, M. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.09.032 · Cited by 246 · see citing works
Diet, genetics, and the gut microbiome drive dynamic changes in plasma metabolites
Fujisaka, S., Avila-Pacheco, J., Soto, M., Kostic, A., Dreyfuss, J. M., Pan, H., Ussar, S., Altindis, E., Li, N., Bry, L., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.02.060 · Cited by 231 · see citing works
“For example, primary bile acids are converted to secondary bile acids by gut microbiotas, and these secondary bile acids not only aid in fat absorption, but they also are reabsorbed into the circulation, where they serve as ligands for the bile acid receptors farnesoid X (FXR) and TGR5 on host cells, leading to effect…”
BackgroundGut–liver axis, cirrhosis and portal hypertension: the chicken and the egg
Arab, J. P., Martín‐Mateos, R., & Shah, V. H. (2017) · Hepatology International · doi:10.1007/s12072-017-9798-x · Cited by 229 · see citing works
“On the other hand, it has been described that FXR activation markedly inhibits inflammation and preserves the intestinal barrier function reducing bacterial translocation in inflammatory bowel disease [80] and in a rat model of cholestatic liver injury [81] (Fig.”
Intestinal Bacteria Interplay With Bile and Cholesterol Metabolism: Implications on Host Physiology
Molinero, N., Ruíz, L., Sánchez, B., Margollés, A., & Delgado, S. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00185 · Cited by 228 · see citing works
“The gut microbiota-mediated biotransformation of the BA pool regulates BAs signaling by affecting the activation of host BA receptors such as the nuclear receptor farnesoid X receptor (FXR), which governs bile, glucose and lipid metabolism (Gadaleta et al., 2011).”
BackgroundThe changing metabolic landscape of bile acids – keys to metabolism and immune regulation
Mohanty, I., Allaband, C., Mannochio-Russo, H., Abiead, Y. E., Hagey, L. R., Knight, R. D., & Dorrestein, P. C. (2024) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-024-00914-3 · Cited by 225 · see citing works
“This begs 90,91,179,241 .”
Verbeke, L., Farre, R., Verbinnen, B., Covens, K., Vanuytsel, T., Verhaegen, J., Komuta, M., Roskams, T., Chatterjee, S., Annaert, P., et al. (2015) · The American Journal of Pathology · doi:10.1016/j.ajpath.2014.10.009 · Cited by 225 · see citing works
“FXR deficiency has therefore been linked to increased intestinal permeability and BTL in noneliver-related gastrointestinal disorders, such as inflammatory bowel disease.(25,26) However, whether FXR dysfunction also relates to BTL in chronic liver disease (and also what are the underlying pathophysiological mechanisms…”
BackgroundResultMcMahan, R. H., Wang, X. X., Cheng, L. L., Krisko, T., Smith, M., El Kasmi, K., Pruzanski, M., Adorini, L., Golden-Mason, L., Levi, M., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.446575 · Cited by 225 · see citing works
“Furthermore, FXR exerts homoeostatic functions at the interface between nutrient and lipid metabolism with innate immunity, antagonizing NF- B in hepatic inflammatory responses (17) and inhibiting intestinal inflammatory responses (16, 18).”
BackgroundInfluentialSelf-citationBile Acid Signaling in Inflammatory Bowel Diseases
Fiorucci, S., Carino, A., Baldoni, M., Santucci, L., Costanzi, E., Graziosi, L., Distrutti, E., & Biagioli, M. (2020) · Digestive Diseases and Sciences · doi:10.1007/s10620-020-06715-3 · Cited by 231 · see citing works
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Self-citationRecent advances in the development of farnesoid X receptor agonists.
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“OCA treatment reduced AST and plasma levels of interferon-ɣ and tumor necrosis factor-α in a mouse model of autoimmune hepatitis (108), reduced the expression of profibrotic and fibrosis markers in a mouse model of nephropathy (109), and attenuated colon injury by increasing colon expression of FXR and SHP and reducin…”
BackgroundBile Acid–Gut Microbiota Axis in Inflammatory Bowel Disease: From Bench to Bedside
Yang, M., Gu, Y., Li, L., Liu, T., Song, X., Sun, Y., Cao, X., Wang, B., Jiang, K., & Cao, H. (2021) · Nutrients · doi:10.3390/nu13093143 · Cited by 216 · see citing works
Intestinal absorption of bile acids in health and disease
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Intestinal Barrier and Permeability in Health, Obesity and NAFLD
Portincasa, P., Bonfrate, L., Khalil, M., Angelis, M. D., Calabrese, F. M., D’Amato, M., Wang, D. Q. ‐., & Ciaula, A. D. (2021) · Biomedicines · doi:10.3390/biomedicines10010083 · Cited by 212 · see citing works
“FXR activation protects from chemically induced colitis and decreases gut permeability and inflammatory markers [265].”
BackgroundBile acids and colon cancer: Solving the puzzle with nuclear receptors
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Review: Mechanisms of How the Intestinal Microbiota Alters the Effects of Drugs and Bile Acids
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The cross talk between microbiota and the immune system: metabolites take center stage
Shapiro, H., Thaiss, C. A., Levy, M., & Elinav, E. (2014) · Current Opinion in Immunology · doi:10.1016/j.coi.2014.07.003 · Cited by 189 · see citing works
“The beneficial effect of bile acid signaling via FXR and TGR5 comprising attenuation of pro-inflammatory innate immune response has been demonstrated in several diseases, such as non-alcoholic fatty liver disease (NAFLD) [43], LPS-induced hepatic damage and inflammation [40], atherosclerosis [41 ] and inflammatory bow…”
BackgroundAgeing of the gut microbiome: Potential influences on immune senescence and inflammageing
Conway, J., & Duggal, N. A. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101323 · Cited by 194 · see citing works
Gadaleta, R. M., Oldenburg, B., Willemsen, E. C. L., Spit, M., Murzilli, S., Salvatore, L., Klomp, L. W. J., Siersema, P. D., van Erpecum, K. J., & van Mil, S. W. C. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.04.005 · Cited by 195 · see citing works
Self-citationBile acid signaling in the regulation of whole body metabolic and immunological homeostasis
Jia, W. P., Li, Y., Cheung, K. C.-P., & Zheng, X. (2023) · Science China Life Sciences · doi:10.1007/s11427-023-2353-0 · Cited by 201 · see citing works
“The attenuation effect is thought to be mediated by TGR5-induced inhibition of DCs activation through inhibition of the NF-κB activation pathway in DCs (Hu et al., 2021).”
InfluentialFXR agonists in NASH treatment
Adorini, L., & Trauner, M. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.07.034 · Cited by 197 · see citing works
Self-citationCrosstalk between bile acid-activated receptors and microbiome in entero-hepatic inflammation
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Update on FXR Biology: Promising Therapeutic Target?
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“In addition, FXR activation by OCA treatment inhibited the chemically induced intestinal inflammation in mice, proposing the role of FXR in the intestinal epithelial barrier in inflammatory bowel disease [95].”
BackgroundBile acids and their receptors
Martinot, E., Sèdes, L., Baptissart, M., Lobaccaro, J.-M., Caira, F., Beaudoin, C., & Volle, D. H. (2017) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2017.01.006 · Cited by 162 · see citing works
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“FXR activation by bile acids or FXR agonists maintains the mucosal integrity by regulating the expression of a variety of genes involved in mucosa protection and defense against inflammation in rodents subjected to BDL [11, 12] or dextran sulfate sodium-induced colitis [10, 18].”
BackgroundSchwabl, P., Hambruch, E., Seeland, B. A., Hayden, H., Wagner, M., Garnys, L., Strobel, B., Schubert, T.-L., Riedl, F., Mitteregger, D., et al. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2016.12.005 · Cited by 178 · see citing works
Duparc, T., Plovier, H., Marrachelli, V. G., Hul, M. V., Essaghir, A., Ståhlman, M., Matamoros, S., Geurts, L., Pardo-Tendero, M., Druart, C., et al. (2016) · Gut · doi:10.1136/gutjnl-2015-310904 · Cited by 177 · see citing works
- Authors
- Gadaleta, R. M., van Erpecum, K. J., Oldenburg, B., Willemsen, E. C. L., Renooij, W., Murzilli, S., Klomp, L. W. J., Siersema, P. D., Schipper, M. E. I., Danese, S., Penna, G., Laverny, G., Adorini, L., Moschetta, A., & Mil, S. W. C. V.
- Affiliations
- University Medical Center Utrecht (NL)
- Mario Negri Sud Foundation (IT)
- Corresponding author
- Mil, Saskia W C van
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2011-01-17
- Volume
- 60
- Issue
- 4
- Pages
- 463-472
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- OpenAlex
- W2134059673
- Cited by
- 870
- References
- 43
- Citations by year
- 2026: 72 · 2025: 87 · 2024: 95 · 2023: 75 · 2022: 96 · 2021: 84 · 2020: 59 · 2019: 46 · 2018: 35 · 2017: 44 · 2016: 40 · 2015: 36 · 2014: 29 · 2013: 35 · 2012: 21
- FWCI
- 19.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion)
- Funders
- Intercept Pharmaceuticals
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- farnesoid X receptor, FXR agonists, inflammatory bowel disease, colitis, intestinal barrier function, epithelial permeability, goblet cell loss, inflammatory cytokines, TNF-α, dendritic cells, monocytes, lamina propria, bile salts, DSS-induced colitis
- MeSH terms
- Receptor, Farnesoid X-Activated, Animals, Chenodeoxycholic Acid, Colon, Disease Models, Animal, Drug Evaluation, Preclinical, Gene Expression Regulation, Humans, Ileum, Intestinal Absorption, Mice, Inbred C57BL, Trinitrobenzenesulfonic Acid, Tumor Necrosis Factor-alpha, Inflammatory Bowel Diseases, Cytokines, Dextran Sulfate, Receptors, Cytoplasmic and Nuclear, Inflammation Mediators, Caco-2 Cells, Reverse Transcriptase Polymerase Chain Reaction, Mice
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