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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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In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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 citing paper
“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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“(80) reported that the FXR agonist, INT-747, alleviates symptoms of dextran sodium sulfate (DSS)-induced colitis (weight loss, rectal bleeding, and change in colon length) and protects against DSS-induced intestinal barrier permeability in mouse.”
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Roda, A., Pellicciari, R., Gioiello, A., Neri, F., Camborata, C., Passeri, D., Franco, F., Spinozzi, S., Colliva, C., Adorini, L., et al. (2014) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.114.214650 · Cited by 59
“, 2012), inflammatory bowel disease (Gadaleta et al., 2011), and cholestasis (Zollner et al.”
BackgroundSelf-citationDing, S., Ma, Y., Liu, G., Yan, W., Jiang, H., & Fang, J. Q. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.01152 · Cited by 58
Soni, J., Sardoiwala, M. N., Choudhury, S., Sharma, S., & Karmakar, S. (2021) · Materials Science and Engineering C: Materials for Biological Applications · doi:10.1016/j.msec.2021.112038 · Cited by 49
Vincenzo, F. D., Puca, P., Lopetuso, L. R., Petito, V., Masi, L., Bartocci, B., Murgiano, M., Felice, M. D., Petronio, L., Gasbarrini, A., et al. (2022) · Nutrients · doi:10.3390/nu14132664 · Cited by 63
“The presence of FXR agonists during the in vitro stimulation of LPMCs with LPS determined a reduced production of pro-inflammatory cytokines, such as INFy, IL17, and TNFa, compared to the absence of FXR agonists [37].”
BackgroundIntegrating the gut microbiome and pharmacology
Verdegaal, A. A., & Goodman, A. L. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.adg8357 · Cited by 67
“Furthermore, host-derived primary and bacteria-derived secondary bile acids vary in their ability to activate or antag-onize host nuclear receptors such as FXR, further linking microbial modulation of the bile acid pool with possible alterations to intestinal permeability ( 35 – 37 ).”
BackgroundBile acid signaling through farnesoid X and TGR5 receptors in hepatobiliary and intestinal diseases
Stanimirov, B., Stankov, K., & Mikov, M. (2015) · Hepatobiliary & pancreatic diseases international · doi:10.1016/s1499-3872(14)60307-6 · Cited by 56
den Bossche, L. V., Borsboom, D., Devriese, S., Welden, S. V., Holvoet, T., Devisscher, L., Hindryckx, P., Vos, M. D., & Laukens, D. (2017) · Laboratory Investigation · doi:10.1038/labinvest.2017.6 · Cited by 58
Cycloastragenol improves hepatic steatosis by activating farnesoid X receptor signalling
Gu, M., Zhang, S., Zhao, Y., Huang, J., Wang, Y., Li, Y., Fan, S., Yang, L., Ji, G., Tong, Q., et al. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.04.021 · Cited by 56
Metabolic regulation in the immune response to cancer
Wu, Q., Yu, X., Li, J., Sun, S., & Tu, Y. (2021) · 癌症：英文版 · doi:10.1002/cac2.12182 · Cited by 57
“Consistently, the inflammatory damage of colitis was alleviated in response to the administration of a BAR synthetic agonist [227, 228], but aggravated in BAR-deficient mice [227].”
BackgroundMicrobiota-Associated Metabolites and Related Immunoregulation in Colorectal Cancer
Chen, Y., & Chen, Y. (2021) · Cancers · doi:10.3390/cancers13164054 · Cited by 54
Hu, J., Zhang, Y., Yi, S., Wang, C., Huang, X., Pan, S., Yang, J., Yuan, G., Tan, S., & Li, H. (2022) · International Journal of Biological Sciences · doi:10.7150/ijbs.71287 · Cited by 54
“INT-747 has been shown to inhibit the activation and differentiation of intestinal DCs, and exacerbated the severity of colitis in FXR-/- mice [33,34].”
BackgroundTorres, J., Bao, X., Iuga, A. C., Chen, A., Harpaz, N., Ullman, T. A., Cohen, B. L., de Chambrun, G. P., Asciutti, S., Odin, J. A., et al. (2013) · Inflammatory Bowel Diseases · doi:10.1097/mib.0b013e318286ff2e · Cited by 54
“counterregulating inflammatory cytokine expression in immune cells.(14,15) FXR mRNA expression seems to be decreased in colon”
BackgroundAttinkara, R., Mwinyi, J., Truninger, K., Reguła, J., Gaj, P., Rogler, G., Kullak-Ublick, G. A., Eloranta, J. J., & The Swiss IBD Cohort Study Group (2012) · BMC Research Notes · doi:10.1186/1756-0500-5-461 · Cited by 56
“Our finding that FXR genetic variants are associated with IBD, together with prior observations on FXR expression being altered in Crohn’s disease [56] and on FXR promoting intestinal barrier integrity [27] and antibacterial defence [26], further emphasizes the potential benefits of FXR ligand administration also in I…”
BackgroundBile acids: Key players in inflammatory bowel diseases?
Kriaa, A., Mariaule, V., Jablaoui, A., Rhimi, S., Mkaouar, H., Hernandez, J., Korkmaz, B., Lesner, A., Maguin, E., Aghdassi, A., et al. (2022) · Cells · doi:10.3390/cells11050901 · Cited by 53
“Murine studies have demonstrated that BA-regulated FXR modulates intestinal immunity [49,50].”
BackgroundKortner, T. M., Penn, M. H., Björkhem, I., Måsøval, K., & Krogdahl, Å. (2016) · BMC Veterinary Research · doi:10.1186/s12917-016-0819-0 · Cited by 53
“Specifically, FXR activation has been shown to decrease epithelial permeability and suppress proinflammatory cytokine levels in murine intestinal mucosa [17].”
BackgroundFan, Y., Xu, C., Xie, L., Wang, Y., Zhu, S., An, J., Li, Y., Tian, Z., Yan, Y., Yu, S., et al. (2022) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2022.956528 · Cited by 52
“Moreover, BA-dependent TGR5 activation significantly inhibited the activation of NF-kB in wildtype mice injected with lipopolysaccharide compared with TGR5-deficient mice (Wang et al., 2011).”
BackgroundYntema, T., Koonen, D. P. Y., & Kuipers, F. (2023) · Nutrients · doi:10.3390/nu15081850 · Cited by 58
Ciaula, A. D., Bonfrate, L., Khalil, M., & Portincasa, P. (2023) · Internal and Emergency Medicine · doi:10.1007/s11739-023-03343-3 · Cited by 53
Farnesoid X Receptor an Emerging Target to Combat Obesity
Filho, C. D. D. M., Downes, M., & Evans, R. M. (2017) · Digestive Diseases · doi:10.1159/000450909 · Cited by 52
Liu, H.-M., Liao, J., & Lee, T.-Y. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.06.129 · Cited by 52
“FXR is a ligand-regulated transcription factor expressed in the liver and gastrointestinal tract that regulates bile acid homeostasis [15,16].”
BackgroundZhu, J., Xu, S., Li, J., Song, J., Luo, B., Song, Y.-P., Zhang, Z.-H., Chen, Y.-H., Xie, D., Yu, D.-X., et al. (2018) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2018.09.009 · Cited by 46
“Recently, several studies indicate that FXR has anti-inflammatory effects (Gadaleta et al., 2011; Hao et al., 2017).”
BackgroundZhang, P., Jiao, H., Wang, C., Lin, Y., & You, S. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00325 · Cited by 52
Bile Acids, Liver Cirrhosis, and Extrahepatic Vascular Dysfunction
Sauerbruch, T., Hennenberg, M., Trebicka, J., & Beuers, U. H. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.718783 · Cited by 55
Gut microbiota and inflammatory bowel disease
Chen, L., & Wang, J. (2021) · WIREs Mechanisms of Disease · doi:10.1002/wsbm.1540 · Cited by 55
Gut Microbiome and Organ Fibrosis
Costa, C. F. F. A., Sampaio‐Maia, B., Araújo, R., Nascimento, D. S., Ferreira‐Gomes, J., Pestana, M., Azevedo, M. J., & Alencastre, I. S. (2022) · Nutrients · doi:10.3390/nu14020352 · Cited by 53
“Farnesoid-X receptor signaling exerts protective effects on intestinal epithelial barrier properties, and therefore its suppression promotes the disruption of the intestinal barrier [55], which can contribute to the perpetuation of the insult on the liver and the persistent activation of stellate cells, which would th…”
BackgroundGut-liver axis: Pathophysiological concepts and medical perspective in chronic liver diseases
Rodrigues, S. G., der Merwe, V., Krag, A. A., & Wiest, R. (2024) · Seminars in Immunology · doi:10.1016/j.smim.2023.101859 · Cited by 51
Gut Microbiota of Nonalcoholic Fatty Liver Disease
Abdou, R., Zhu, L., Baker, R. D., & Baker, S. S. (2016) · Digestive Diseases and Sciences · doi:10.1007/s10620-016-4045-1 · Cited by 52
“They also preserve the integrity of the IB [115].”
Qiu, Y., Liu, S., Hou, L., Li, K., Wang, L., Gao, K., Yang, X., & Jiang, Z. (2020) · Journal of Nutrition · doi:10.1093/jn/nxaa331 · Cited by 57
Ocansey, D. K. W., Zhang, Z., Xu, X., Liu, L., Amoah, S., Chen, X., Wang, B., Zhang, X., & Mao, F. (2022) · Biomaterials Science · doi:10.1039/d2bm00559j · Cited by 51
Regulation of gut microbiota-bile acids axis by probiotics in inflammatory bowel disease
Li, L., Liu, T., Gu, Y., Wang, X., Xie, R., Sun, Y., Wang, B., & Cao, H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.974305 · Cited by 52
Burris, T. P., de Vera, I. M. S., Côté, I., Flaveny, C. A., Wanninayake, U. S., Chatterjee, A., Walker, J. K., Steinauer, N., Zhang, J., Coons, L. A., et al. (2023) · Pharmacological Reviews · doi:10.1124/pharmrev.121.000436 · Cited by 54
Metadata
- 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
- Health Sciences › Medicine › Gastroenterology › 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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